Development of Synthetic Strategies for the Total Synthesis of Ent-Kauranoid and Diterpenoid Alkaloid Natural Products Citation Mak, Victor Wei-Dek (2018) Development of Synthetic Strategies for the Total Synthesis of Ent-Kauranoid and Diterpenoid Alkaloid Natural Products. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Z9ST7N04. https://resolver.caltech.edu/CaltechTHESIS:08042017-162439257 Abstract As part of an ongoing synthetic effort directed towards biologically active ent -kauranoid natural products, the preparation of two structurally unique natural products, (–)-trichorabdal A and (–)-longikaurin E, is presented. The syntheses intercept an early intermediate from the synthetic route towards the rearranged natural product (–)-maoecrystal Z, and thus, represents a unified synthetic strategy to access structurally unique ent -kauranoids. Specifically, the syntheses are enabled by a palladium-mediated oxidative cyclization of a silyl ketene acetal to install a key quaternary center within the bicyclo[3.2.1]octane unit, as well as a reductive cyclization of an aldehyde-lactone to construct the oxabicyclo[2.2.2]octane motif of (–)-longikaurin E. A synthetic strategy to access C19-diterpenoid alkaloids, specifically of the aconitine type, is presented. These highly bridged polycyclic natural products are generally characterized by a substituted piperidyl ring bridging a hydrindane framework that is further attached to a bicyclo[3.2.1]octane. The synthetic strategy relies on the enantioselective synthesis of two bicyclic fragments, which are coupled in a convergent fashion through a 1,2-addition/semipinacol rearrangement sequence to forge a sterically hindered quaternary center. Efficient access to late stage intermediates has enabled the synthesis of the aconitine carbocyclic core, with appropriate functionality for advancement to a selective voltage-gated K + channel blocker, talatisamine. Additionally, the synthetic strategy described herein is well applicable to the synthesis of related denudatine and napelline type C 20 -diterpenoid alkaloids. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: Total Synthesis; Natural Product; Ent-Kauranoid; Trichorabdal; Longikaurin; Diterpenoid Alkaloid; Talatisamine Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Reisman, Sarah E. Thesis Committee: Stoltz, Brian M. (chair) Reisman, Sarah E. Hsieh-Wilson, Linda C. Fu, Gregory C. Defense Date: 17 July 2017 Record Number: CaltechTHESIS:08042017-162439257 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:08042017-162439257 DOI: 10.7907/Z9ST7N04 Related URLs: URL URL Type Description https://doi.org/10.1016/j.tet.2014.03.071 DOI Article adapted for Ch. 2 https://doi.org/10.1021/ja406599a DOI Article adapted for Ch. 2 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 10364 Collection: CaltechTHESIS Deposited By: Victor Mak Deposited On: 14 Sep 2017 17:15 Last Modified: 23 Oct 2020 23:05 Thesis Files Preview PDF (Full Thesis) - Final Version See Usage Policy. 70MB Preview PDF (Intro and TOC) - Final Version See Usage Policy. 185kB Preview PDF (Chapter 1) - Final Version See Usage Policy. 450kB Preview PDF (Chapter 2) - Final Version See Usage Policy. 1MB Preview PDF (Appendix 1) - Final Version See Usage Policy. 9MB Preview PDF (Chapter 3) - Final Version See Usage Policy. 12MB Preview PDF (Appendix 2) - Final Version See Usage Policy. 27MB Preview PDF (Appendix 3) - Final Version See Usage Policy. 330kB Preview PDF (About the Author) - Final Version See Usage Policy. 48kB Repository Staff Only: item control page

Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 1 Chapter 1 An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 1.1 INTRODUCTION Terpenoid natural products are one of the largest classes of biologically active small molecules, and hold importance in areas of flavors, fragrances, poisons, and medicines. 1 The Isodon diterpenes, which encompass the ent-kauranoids, possess important biological properties such as antibacterial and anticancer activity. Further investigations of these natural products and analogues as medical treatments have been hampered by the lack of efficient synthetic routes. The biosynthetically related diterpenoid alkaloids also remain relatively understudied with respect to their syntheses, even though a significant number of the natural products possess biological activity involving modulation of voltage-gated ion channels. In this chapter, the rich history of ent-kauranoid and diterpenoid alkaloids is discussed in terms of biosynthesis, Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 2 distribution, structure, and biological activity with the aim of understanding motivations behind the surge of synthetic studies in recent years. 1.2 TERPENE BIOSYNTHESIS In nature, linear hydrocarbons undergo cyclizations, rearrangements, and oxidations to create terpenoids. The building blocks of these linear hydrocarbons are C5 isoprenyl monomers (3 and 4) derived from acetyl coenzyme A (acetyl-CoA, 1) or deoxyxylulose (2), and are produced by the biosynthetic mevalonate or deoxyxylulose pathways (Figure 1.1).2 The monomers (3 and 4) are stitched together to form linear, pyrophosphorylated polyenes of varying lengths, such as geranyl pyrophosphate (5), farnesyl pyrophosphate (6), squalene (8) and so on, and in turn afford terpenes belonging to general classes such as monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), and triterpenes (C30, e.g. steroids). Cyclizations and rearrangements can form varieties of carbocyclic skeletons, and subsequent oxidations result in an even larger degree of diversity. The biosynthesis of monoterpenes from geranyl pyrophosphate (5) is used as an example to demonstrate the complexity and diversity exhibited by the natural products. 5, which contains only two prenyl units, can undergo cyclization and/or rearrangement to afford seven unique carbocyclic skeletons (Figure 1.2). Polyenes containing more prenyl units would provide an even greater number of unique carbocyclic skeletons. Oxidation of the carbocycles generates another degree of complexity, as exemplified by the many menthane type monoterpene natural products. Additionally, with larger terpenes such as sesquiterpenes and diterpenes, there are more possible sites for oxidation. Thus, the 3 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids complexity and diversity of terpenoid natural products increase exponentially with each additional prenyl unit. mevalonate pathway O Me C5 isoprenyl monomers SCoA Me acetyl-CoA (1) OPP deoxyxylulose pathway OH Me O Me isopentyl diphosphate (IPP, 3) OP Me isomerase OPP dimethyl allyl diphosphate (DMAPP, 4) OH deoxyxylulose (2) Linear polyene precursors Me Me Me Me Me Me Me Me OPP squalene (8) geranyl pyrophosphate (5) Me Me Me Me Me Me Me Me Me Me Me Me OPP OPP geranylgeranyl pyrophosphate (7) farnesyl pyrophosphate (6) Figure 1.1. Biosynthesis of terpene precursors. Me OPP Me Me geranyl pyrophosphate (5) menthane type pinane type Me Me bornane type fenchane type Me isocamphane type carane type Me Me O [O] thujane type OH + more OH menthane type Me limonene Me Me menthol Figure 1.2. Biosynthesis of monoterpenes. O Me Me Me pulegone carvone Me Me carvacrol Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 4 OVERVIEW OF ENT-KAURANOIDS 1.3 The Isodon diterpenoids are a large family of natural products that are principally based on the structure of the diterpene ent-kaurene. The first study of Isodon extracts dates back to 1910,3 and the first isolation of an Isodon diterpenoid was achieved in 1958.4e–g Since then, more than 600 Isodon diterpenoids have been isolated, with the family exhibiting structural diversity in the form of oxygenation patterns and rearranged frameworks.5 The structural homology between many ent-kauranoids suggests the benefit of a unified synthetic strategy to access this biologically active family of natural products. Plants from the genus Isodon have long been used for medical purposes in East Asian countries, and the isolated diterpenoids have exhibited antibacterial and antitumor properties. 1.3.1 Structure and Biological Activity The vast majority of Isodon diterpenoids share the same carbocyclic skeleton as ent-kaurene (9, Figure 1.3). Oxidation of the skeleton returns oxygenated natural products such as adenanthin (10), and others with bridging oxygen heterocycles, as in 7,20-epoxy type longikaurin E (11). The 6,7-seco-ent-kauranoids represent the largest group of products deviating from the ent-kaurene carbocyclic skeleton, and are derived from oxidative scission of the C6–C7 bond of their 7,20-epoxy- precursors. Representative members of this type include trichorabdals A and B (12 and 13), sculponeatin N (14), and enmein (15), which has undergone translactonization at C1/C7. More exotically rearranged products have also been discovered, as exemplified by maoecrystals V and Z (16 and 17). 5 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 3 Me 18 OH 1 2 10 9 11 7 Me 6 Me 8 12 4 5 20 19 14 15 H Me 16 17 O O H Ac O Me O OH Me O O OAc O O OH 1 O 7 O enmein (15) Me O O O H R HO O trichorabdal A (12: R = H) trichorabdal B (13: R = OAc) H H Me 20 sculponeatin N (14) Me longikaurin E (11) OH Me 6 O O Me O H O OH Me adenanthin (10) Me Me HO O OAc Me O Me OAc 13 ent-kaurene (9) H O Me maoecrystal V (16) H HO Me OAc O O O maoecrystal Z (17) Figure 1.3. Ent-kaurene (9) and representative ent-kauranoids. Most of the biologically active ent-kauranoids share a common α,β-unsaturated carbonyl as part of a bridging cyclopentane D-ring. This structural motif is a pharmacaphore that is crucial for biological activity of the natural products, and possibly acts through electrophilicity of the Michael acceptor for covalent modification.6 In early studies on structure-activity relationships (SAR), Fujita and coworkers reported that hydrogenation of the enone moiety significantly weakened antitumor and antibacterial activity of ent-kauranoids and derivatives.4bc,7 Furthermore, adenanthin (10) has been shown to selectively inhibit peroxiredoxin enzymes by covalent modification of a key cysteine residue, while its saturated analog was found to be biologically inactive.8 1.3.2 Ent-Kauranoid Biosynthesis The diterpene ent-kaurene (9) is known to arise from enzyme-mediated cyclizations and rearrangements of geranylgeranyl diphosphate (7, Figure 1.4).9 An initial cyclization mediated by copalyl diphosphate synthase affords the bicyclic product 18, and a second cyclization mediated by kaurene synthase B results in rearrangements to 6 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids eventually provide ent-kaurene (9). Hong and Tantillo have also proposed concerted biosynthetic pathways that avoid secondary carbocations.10 OPP Me H copalyl DPP synthase Me H kaurene synthase B Me Me Me Me OPP Me Me geranylgeranyl diphosphate (7) Me copalyl diphosphate (18) Me Me Me Me Me 19 Me Me 20 H Me Me ent-kaurene (9) Figure 1.4. Biosynthesis of ent-kaurene (9). Enzymatic oxidations of ent-kaurene (99) return natural products that are classified based on oxidation at C20. Notably, 7,20-epoxy-ent-kauranoids of the general structure 21 are prone to undergo oxidative cleavage of the C6–C7 bond to afford 6,7seco-ent-kauranoids (22, Figure 1.5). The rearranged natural product, maoecrystal Z (17, see Figure 1.3), likely arises from a retro-aldol reaction from the 6,7-seco type (22 and intramolecular aldol cyclization of the resulting enolate (23) to tetracycle 24. This hypothesis is further supported by studies from Fujita and coworkers, who demonstrated that trichorabdal B (13) rearranged to tetracycle 25 under basic conditions (Figure 1.5b).4c From the ent-kaurene framework, sequences of oxidation, C6–C7 bond cleavage, and skeletal rearrangements ultimately produce the over 600 known structurally distinct ent-kauranoids. 7 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids (a) [O] ent-kaurene (9) HO OH Me Me 6 20 oxidative cleavage H Me 7 O OH O O 6 Me O 7,20-epoxy type (21) skeletal rearrangement Me O Me Me O H Me NaOH, MeOH H AcO O O O HO retro-Dieckmann/ aldol reaction trichorabdal B (13) O O O O H HO Me O rearranged type (24) 23 (b) 7 6,7-seco type (22) H O HO Me AcO OMe HO OH O O O 25 Figure 1.5. (a) Biosynthesis and rearrangement of ent-kauranoids. (b) Methoxidemediated rearrangement of trichorabdal B (13). 1.4 OVERVIEW OF DITERPENOID ALKALOIDS The ent-atisane and ent-kaurene diterpenes are widely considered as the biogenetic precursors to all diterpenoid alkaloids. This family alkaloids share structural features similar to those of diterpenoids, but differ from “true alkaloids” in that the carbocyclic cores are derived from terpene biosynthesis, rather than α-amino acid precursors. The diterpenoid alkaloids are divided into three general categories based on the number of carbons in the molecular framework: C20-, C19-, and C18-diterpenoid alkaloids; and these are further divided into subclasses based on the connectivity of their skeletons (e.g. hetidines, hetisines, atisanes, etc…).11 As of July 2008, about 400 C20-, 700 C19-, and 80 C18-diterpenoids have been isolated. In past literature, the diterpenoid alkaloids are often referred to as the Aconitum alkaloids, as they were primarily isolated from the Aconitum genus of plants.12 However, 8 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids these widespread alkaloids have now been isolated from Delphinium, Consolida, and Spiraea genera of plants as well. These plants have long been used in traditional Chinese and Japanese medicine for their antiarrhythmic, antipyretic, and analgesic properties. Indeed, diterpenoid alkaloids possess a wide range of biological activities, namely antiinflammatory, anticancer, antiepileptiform, antihypertensive, and antiarrhythmic properties. With many of the natural products possessing important pharmacological activity, strong interest in the synthesis of their complex structures has sustained over the decades since their first structural elucidation. 1.4.1 Isolation, Structure, and Biological Activity The diterpenoid alkaloids are primarily isolated from the Aconitum and Delphinium genera of plants. Isolates from these plants have been known for centuries, and extracts containing aconitine (“aconite”) have been used throughout history as local anesthetic, but more commonly as a poison for hunting or warfare purposes. It has therefore acquired colloquial names such as “queen of all poisons,” and “wolf’s bane,” while its appearance has evoked nicknames such as “monkshood” or “devil’s helmet”. Despite the history of practical use, the chemical structures of diterpenoid alkaloids remained unknown until Wiesner’s seminal report in 1954. 13 Before the advent of NMR, structural elucidation heavily relied on oxidation and dehydrogenation experiments, leading to the proposed structures of C20-diterpenoid alkaloids veatchine (25) and garryine (26, Figure 1.6). The pharmacological and medicinal properties aconitine (33), one the most well known alkaloids, has been known since 1833.14 However, the structure 9 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids was not fully elucidated until 1971, after decades of extensive chemical and X-ray crystallographic studies.15 (a) C20-diterpenoid alkaloids. OH A Me H OH Me Me E N O OH Me 15 6 N O H O OH Ac H N H O N 20 veatchine (25) garryine (26) Me OH OH Me N Me N Et guan-fu base A (28) hetisine types O HO OH OH HO OH Me Me N H H delcarduchol (30) hetidine type H N Et O O napelline (29) napelline type OAc OH kobusine (27) veatchine types 13 14 H atisine (31) atisine type denudatine (32) denudatine type (b) C19 - and C18 -diterpenoid alkaloids. HO MeO OMe 18 MeO N Et OBz OH OMe AcO OH aconitine (33) OMe 1 OH MeO 18 N Et OMe HO talatisamine (34) C19 aconitine types OMe O 4 AcHN O 6 N Et OMe OH OMe HO lappaconitine (35) C18 lappaconitine type Figure 1.6. Representative Diterpenoid Alkaloids. Many of the C20-diterpenoid alkaloids structurally resemble to ent-atisane and entkaurene diterpenes, as one might predict based on their biosynthetic pathways. For example, the hetisine, hetidine, atisine, and denudatine types (i.e. 27, 28, 31–32, Figure 1.6) all bear a bicyclo[2.2.2]octane, while the veatchine and napelline types (i.e. 25, 26, 29) bear a bicyclo[3.2.1]octane. The C19-diterpenoid alkaloids, which are biogenetically derived from their C20 counterparts, typically possess a rearranged hexacyclic framework that lacks resemblance to any diterpene equivalent. Lastly, the C18-diterpenoid alkaloids share the same hexacyclic core as their C19 precursors, but lack the exocyclic C18 moiety. Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 10 A basic tertiary amine is common to all classes of diterpenoid alkaloids, although the nitrogen is also found in the form of lactams, hemiaminals, and cyclic imines. Among all classes, the 3-azabicyclo[3.3.1]nonane that constitutes the AE-ring system is another highly conserved structural feature. The pharmacological properties of the diterpenoid alkaloids span a wide range, which most notably include anti-inflammatory, analgesic, and antiarrhythmic effects. Although they are notorious for their poisonous properties, several diterpenoid alkaloids have been used in East Asian medicines. The C20-diterpenoid alkaloid, guan-fu base A (28), and its derivatives have been used for its anti-inflammatory and antiarrhythmic effects, and the C20–C14–C13 aminoalcohol subunit was determined to be a pharmacaphore. 16 Derivatives of kobusine (27) were also tested for antifibrillatory activity, and it was concluded that free hydroxyl groups, especially the C6 alcohol, and aromatic esters at C15 were important for biological activity.17 A number of C19- and C18-diterpenoid alkaloids have been studied for their antiinflammatory, analgesic, and antiarrhythmic effects. 3-Acetylaconitine, lappaconitine (35), and crassicauline A have all been clinically used in China as non-narcotic analgesic drugs, and lappaconitine (35) has been used in Russia as an antiarrhythmic drug.18 Broad SAR studies revealed that aromatic ester functionalities at C1, C4, C6, and C14 are crucial for biological activity, in addition to the basicity of the tertiary amine.19 Ameri categorized the alkaloids in to three subgroups based on structure and biological activity,20 and summarized the following: (1) diesters such as aconitine (33) suppress inactivation of voltage-gated Na+ channels by binding to the α-subunit of the protein channel, and are the most toxic, (2) monoester alkaloids such as lappaconitine (35) block Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 11 voltage-gated Na+ channels, are competitive antagonists, and are considerably less toxic, (3) natural products lacking ester groups are the least toxic, but are reported to still have antiarrhythmic action, suggesting affinities to various subtypes of the α-subunit of the sodium channel. Talatisamine (34) was found to block voltage-gated K+ channels, and demonstrated an in vitro neuroprotective effect against β-amyloid oligomers induced cytotoxicity in cortical neurons.21 1.4.2 Biosynthesis of Diterpenoid Alkaloids Although relatively few studies on biosynthesis have been performed,22 it is generally accepted that the diterpenoid alkaloids are biogenetically derived from the diterpenes ent-kaurene and ent-atisane.23 As depicted in Figure 1.7, oxidation of both parent diterpenes and incorporation of serine in the form of β-aminoethanol24 directly provides the C20 veatchine and atisine type alkaloids, respectively. The exact order of oxidation and the point of amination still remain unknown. From the veatchine type alkaloid, a Mannich reaction can form the C7–C20 bond of the napelline type, or interconversion via Wagner–Meerwein rearrangement can produce the atisine type as well. From the atisine type alkaloids, a Mannich reaction can form the C7–C20 bond of the denudatine type alkaloids, with a final Wagner–Meerwein rearrangement providing the napelline type alkaloids. 12 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids OH OH Me 12 13 20 + serine 16 Mannich reaction N N 7 Me OH Me Me (O) ent-kaurene (9) veatchine type Me Me napelline type Wagner–Meerwein rearrangement Wagner–Meerwein rearrangement OH (O) Me + serine Mannich reaction OH OH N OH N Me Me Me Me (O) ent-atisane atisine type Me denudatine type Figure 1.7. Postulated Biosynthesis of several C20-Diterpenoid Alkaloids. From the C20 atisine, denudatine, and napelline type alkaloids, three pathways are postulated to provide the C19-, and in turn the C18-diterpenoid alkaloids.12b In the atisine pathway, Wagner–Meerwein rearrangement affords rearranged framework A, after which oxidative scission of the exocyclic olefin provides the C19 proaconine (7,17-seco) type alkaloids. An aza-Prins reaction then forges the C7–C17 bond of the C19 aconitine type alkaloids. Alternatively, the denudatine pathway involves a Wagner–Meerwein rearrangement to provide rearranged type B, which provides the C19 aconitine type alkaloids after oxidative scission of the exocyclic olefin. Currently, there is one known alkaloid of the rearranged type B, actaline, which lends credence to this biosynthetic pathway.25 In 1975, Kodama et al. proposed the napelline pathway to the C19-diterpenoid alkaloids that involves two sequential Wagner–Meerwein rearrangements of the C20 napelline type alkaloids.26 Based on the broad distribution of denudatine and napelline type alkaloids in plants of the Aconitum genus, the denudatine and napelline pathways are 13 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids considered to be the major pathways to C19-diterpenoid alkaloids.27 Functionalizations including hydroxylation, methylation, and esterification of the skeletal frameworks contribute largely to the high number and complexity of the C19 diterpenoid alkaloids. As the C18-diterpenoid alkaloids often occur naturally with their C19 counterparts, it is also logical to conclude they are produced by removal of the C18 methylene unit of the aconitine type alkaloids. OPP N –H2O –CH2 Wagner–Meerwein rearrangement O N Me N OH Me Me Me Me C 20 atisine type Me C 20 rearranged type (A) C19 protoaconine type aza-Prins OPP N Wagner–Meerwein rearrangement O –CH2 N Me N OH Me Me OH Me Me C 20 denudatine type Me C 20 rearranged type (B) C19 aconitine type Wagner–Meerwein rearrangement –CH2 OPP O Wagner–Meerwein rearrangement N OPP Me Me N N OH Me Me C 20 napelline type C 20 rearranged type (C) OH Me H C18 lappaconine type Figure 1.8. Postulated Biosynthesis of C19-Diterpenoid Alkaloids. 1.5 CONCLUDING REMARKS The Isodon diterpenes comprise over 600 structurally diverse natural products possessing numerous frameworks and oxidation patterns. Many of the biologically active Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 14 members share the α,β-unsaturated carbonyl moiety that is hypothesized to covalently modify target proteins. Though historically there have been strikingly few reports of synthetic studies towards ent-kauranoids, renewed interest in their antibacterial and anticancer properties have resulted in numerous total syntheses accomplished in the last decade. These synthetic studies will be discussed, alongside our own syntheses, in the following chapter. The diterpenoid alkaloids possess incredibly complex structures that represent significant challenges to synthetic chemists. As these natural products are found in traditional East Asian medicines, it comes as no surprise that they possess significant and compelling biological activity, and has provided commercialized antiarrhythmic drugs. The identification of talatisamine as a novel voltage-gated K+ channel blocker represents a novel discovery that suggests there is still unknown biological activity within this class of natural products. Efficient access to these natural products remains an elusive goal in the field of total synthesis. Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 1.6 (1) 15 NOTES AND REFERENCES Breitmaier, E. Terpenes: Flavors, Fragrances, Pharmaca, Pheromones; WileyVCH: Weinheim, Germany, 2006. (2) Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach. John Wiley & Sons, Ltd, 2002. (3) Yagi, S. J. Kyoto Med. Soc., 1910, 7, 30. (4) Isolation of select Isodon (also known as Rabdiosa) natural products: Maoecrystal Z: (a) Han, Q.-B.; Cheung, S.; Tai, J.; Qiao, C.-F.; Song, J.-Z.; Tso, T.-F.; Sun, H.-D.; Xu, H.-X. Org. Lett. 2006, 8, 4727. Trichorabdal A: (b) Node, M.; Sai, M.; Fuji, K.; Fujita, E.; Shingu, T.; Watson, W. H.; Grossie, D. Chem. Lett. 1982, 2023. Trichorabdal B: (c) Fujita, E.; Fuji, K.; Sai, M.; Node, M.; Watson, W. H.; Zabel, V. J. Chem. Soc., Chem. Commun. 1981, 899. Longikaurin E: (d) Fujita, T.; Takeda, Y.; Shingu, T. Heterocycles, 1981, 16, 227. Enmein: (e) Takahashi, M.; Fujita, T.; Koyama, Y. Yakugaku Zasshi, 1985, 78, 699. (f) Ikeda, T.; Kanatomo, S. Yakugaku Zasshi 1958, 78, 1128. (g) Naya, K. Nippon Kagaku Zasshi, 1958, 79, 885. Maoecrystal V: (h) Li, S.-H.; Wang, J.; Niu, X.-M.; Shen, Y.-H.; Zhang, H.-J.; Sun, H.-D.; Li, M.-L.; Tian, Q.-E.; Lu, Y.; Cao, P.; Zheng, Q.-T. Org. Lett. 2004, 6, 4327. Adenanthin: (i) Xu, Y.-L.; Sun, H.-D.; Wang, D.Z.; Iwashita, T.; Komura, H.; Kozuka, M.; Naya, K.; Kubo, I. Tetrahedron Lett. 1987, 28, 499. Sculponeatin N: (j) Li, X.; Pu, J.-X.; Weng, Z.-Y.; Zhao, Y.; Zhao, Y.; Xiao, W.-L.; Sun, H.-D. Chem. Biodiversity 2010, 7, 2888. (5) Sun, H.-D.; Huang, S.-X.; Han, Q.-B. Nat. Prod. Rep. 2006, 23, 673. Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids (6) 16 (a) Serafimova, I. M.; Pufall, M. A.; Krishnan, S.; Duda, K.; Cohen, M. S.; Maglathlin, R. L.; McFarland, J. M.; Miller, R. M.; Frödin, M.; Taunton, J. Nat. Chem. Biol. 2012, 8, 471. (b) Gersch, M.; Kreuzer, J.; Sieber, S. A. Nat. Prod. Rep. 2012, 29, 659. (7) (a) Fujita, E.; Nagao, Y.; Kaneko, K.; Nakazawa, S.; Kuroda, H. Chem. Pharm. Bull. 1976, 24, 2118. (b) Fuji, K.; Node, M.; Sai, M.; Fujita, E.; Takeda, S.; Unemi, N. Chem. Pharm. Bull. 1989, 37, 1472. (8) Liu, C.-X.; Yin, Q.-Q.; Zhou, H.-C.; Wu, Y.-L.; Pu, J.-X.; Xia, L.; Liu, W.; Huang, X.; Jiang, T.; Wu, M.-X.; He, L.-C.; Zhao, Y.-X.; Wang, X.-L.; Xiao, W.L.; Chen, H.-Z.; Zhao, Q.; Zhou, A.-W.; Wang, L.-S.; Sun, H.-D.; Chen, G.-Q. Nat. Chem. Biol. 2012, 8, 486. (9) Bohlmann, J.; Meyer-Gauen, G.; Croteau, R. Proc. Natl. Acad. Sci. USA 1998, 95, 4126. (10) (a) Hong, Y. J.; Tantillo, D. J. J. Am. Chem. Soc. 2010, 132, 5375; (b) Tantillo, D. J. Nat. Prod. Rep. 2011, 28, 1035. (11) Wang, F.-P.; Chen, Q.-H.; Liu, X.-Y. Nat. Prod. Rep. 2010, 27, 529. (12) (a) Pelletier, S. W.; Mody, N. V. The Structure and Synthesis of C19-Diterpenoid Alkaloids in The Alkaloids; Manske, R. H. F.; Rodrigo, R. G. A., Ed.; Academic Press, Inc: New York, 1979; Vol. 17, p. 1–103. (b) Wang, F.-P.; Chen, Q.-H. The C19-Diterpenoid Alkaloids. in The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Elsevier Science: New York, 2010; Vol. 69, p. 1–577. Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids (13) 17 Wiesner, K.; Armstrong, R.; Bartlett, M. F.; Edwards, J. A. J. Am. Chem. Soc. 1954, 76, 6068. (14) Geiger, P. L. Ann. 1833, 7, 269. (15) (a) Bachelor, F. W.; Brown, R. F. C.; Buchi, G. Tetrahedron Lett. 1960, 1, 1. (b) Birbaum, K. B.; Wiesner, K.; Jay, E. W. K.; Jay, L. Tetrahedron Lett. 1971, 13, 867. (16) (a) Wang, R. B.; Peng, S. X.; Hua, W. Y. Acta Pharm. Sinica 1993, 23, 583. (b) Ren, Y.; Peng, S. X.; Hua, W. Y.; Zhu, D. Y. J. China. Pharm. Univ. 1996, 27, 261. (17) (a) Wada, K.; Ishzuki, S.; Mori, T.; Fujihara, E.; Kauahara, N. Biol. Pharm. Bull. 1998, 21, 140. (b) Wada, K.; Ishzuki, S.; Mori, T.; Fujihara, E.; Kauahara, N. Biol. Pharm. Bull. 2000, 23, 607. (18) Vakhitova, Y. V.; Farafontova, E. I.; Khisamutdinova, R. Y.; Yunusov, V. M.; Tsypysheva, I. P.; Yunusov, M. S. Russ. J. Bioorg. Chem. 2013, 39, 92. (19) (a) Salimov, B. T.; Kuzibaeva, Z. K.; Dzhakhangirov, F. N. Chem. Nat. Compds. 1996, 32, 366. (b) Dzhakhangirov, F. N.; Sultankhodzhaev, M. N.; Tashkhodzha, B.; Salimov, B. T. Chem. Nat. Compds. 1997, 33, 190. (c) Wang, J.-L.; Shen, X.L.; Chen, Q.-H.; Gong, Q.; Wang, W.; Wang, F.-P. Chem. Pharm. Bull. 2009, 57, 801. (20) Ameri, A. Prog. Neurobiol. 1998, 56, 211. Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids (21) 18 (a) Song, M.-K.; Liu, H.; Jiang H.-L.; Yue, J.-M.; Hu, G.-Y.; Chen, H.-Z. Neuroscience 2008, 155, 469. (b) Wang, Y.; Song, M.; Hou, L.; Yu, Z.; Chen, H. Neurosci. Lett. 2012, 518, 122. (22) (a) Herbert, E. J.; Kirby, G. W. Tetrahedron Lett. 1963, 4, 1505. (b) Benn, M. N.; May, J. Experientia 1964, 20, 252. (c) Frost, J. M.; Hale, R. L.; Waller, G. R.; Zalkov, L. H.; Girota, N. N. Chem. Ind. 1967, 320. (23) Xiao, P. G.; Wang, F. P.; Gao, F.; Yan, L. P.; Chen, D. L.; Liu, Y. Acta Phytotaxon. Sin. 2006, 44, 1. (24) Zhao, P. Z.; Gao, S.; Fan, L. M.; Nie, J. C.; He, H. P.; Zeng, Y.; Shen, Y. M.; Hao, X. J. J. Nat. Prod. 2009, 72, 645. (25) Nishanov, A. A.; Tashkhozhaev, B.; Sultankhodzhaev, M. I.; Ibragimov, B. T.; Yunusov, M. S. Chem. Nat. Compds. 1989, 25, 32. (26) Kodama, M.; Karihara, H.; Ito, S. Tetrahedron Lett. 1975, 16, 1301. (27) Wang, F. P.; Liang, X. T. C20-Diterpenoid Alkaloids in The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Elsevier Science, New York, 2002; Vol. 59, p. 1–280.  Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 19 Chapter 2 Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E† 2.1 INTRODUCTION In 2011, our group reported the total synthesis of the rearranged ent-Kauranoid maoecrystal Z. Key to the synthesis was a spirolactone intermediate that was prepared in good yield and excellent diastereoselectivity via a Ti(III)-mediated reductive coupling reaction. Given that several biologically active ent-kauranoids possess a spirocyclic lactone or lactol moiety, we set out to explore whether the spirolactone intermediate could be used for the synthesis of the more general 6,7-seco framework and its biogenetically related 7,20-epoxy type frameworks. This chapter introduces the state of the art prior to and concurrent with our synthetic efforts. A detailed account of our total †  The research discussed within this chapter was completed in collaboration with Dr. John T. S. Yeoman. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 20 syntheses of (–)-trichorabdal A and (–)-longikaurin E via a common intermediate is described. This work, taken together with our synthesis of (–)-maoecrystal Z, represents a unified synthetic strategy to access structurally distinct ent-kauranoid natural products. 2.2 PREVIOUS AND CONCURRENT SYNTHETIC EFFORTS Synthetic efforts relating to 6,7-seco-ent-kauranoids are discussed in this section with the aim of contextualizing our synthetic efforts with prior state of the art. Several syntheses of ent-kauranoid natural products followed our communication on the total synthesis of (–)-trichorabdal A and (–)-longikaurin E;1 for the sake of brevity, these syntheses will not be reviewed in this section. 2.2.1 Fujita’s Relay Synthesis of Enmein In light of their compelling biological activity and structural complexity, several research groups have reported total syntheses of 6,7-seco-ent-kauranoids. Perhaps the most challenging synthetic aspect of these diterpenoids is the formation of the two quaternary centers, which include the C8 quaternary center and the C10 quaternary center contained within the central spirolactone. As early as 1974, Fujita reported the total synthesis of enmein (15) through an optically active relay compound (Figure 2.1).2 In the synthesis, the C8 quaternary center was introduced via enolate alkylation. Thiol ether 37 was accessed in 12 steps from phenanthrene derivative 36. Deprotection of thiol ether 37 and ozonolysis afforded a ketoaldehyde that underwent a sodium methoxide-mediated aldol reaction to form bicyclo[3.2.1]octane 38 of the ent-kaurene core. After 21 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E advancement to alkene 39, ozonolysis cleaved the C6–C7 bond to form the 6,7-seco framework of 40, which was advanced a further 18 steps to enmein (15). H MeO 2C SBu 1. KOH, EtOH 12 steps 8 OMe O O MeO Me Me 36 O 8 steps O Me OH H Me 6 HO 7 39 H 2. O 3; DMS O (43% yield, 3 steps) CH2N 2 O O Me MeO Me O H 10 H O 3. NaOMe OH Me 37 O 3; Jones reagent; 8 OH Me Me OH O 38 OH Me 6 O O 20 O 6 OH O Me O 7 1 OMe 40 O 7 O enmein (15) Figure 2.1. Key transformations in Fujita’s relay synthesis of enmein (15). Mander’s Synthesis of 15-Desoxyeffusin 2.2.2 More than a decade later after Fujita’s studies, Mander reported the synthesis of 15-desoxy derivatives of effusin and longikaurin C (Figure 2.2).3 Similar to Fujita’s strategy, oxidative cleavage of the C6–C7 bond of a lactol precursor provided access to the seco-ent-karanoid framework. To construct the bicyclo[3.2.1]octane, α-diazoketone 41 was treated with trifluoroacetic acid to afford dienone 42 through an intramolecular aromatic alkylation. A further 12 steps provided lactone 43, which smoothly underwent intramolecular α-alkylation to furnish ent-kauranoid framework 44 after desilylation and oxidation. This intermediate was advanced to 15-desoxylongikaurin C (45), and oxidative cleavage of the C6–C7 bond upon exposure to periodic acid afforded the 6,7seco type desoxyeffusin (46) in a biomimetic fashion. Notably, oxidation of C15 on both 45 and 46 to afford the corresponding natural products was not achieved at the time. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 22 O CF3CO2H N2 MeO (88% yield) OMe 12 steps O 8 O OMe 41 42 H Br H 1. LDA, THF 2. TBAF OMOM O OMOM H 10 steps Me 3. PDC O Me H OTBS O (82% yield, 3 steps) 43 O O 44 H H Me OH 6 AcO 7 O OH H 5IO 6 Me Et 2O AcO 15 O O O (94% yield) 15-desoxylongikaurin C (45) H 15-desoxyeffusin (46) Figure 2.2. Mander’s synthesis of 15-desoxy analogues. 2.2.3 Zhai’s Total Synthesis of Sculponeatin N Zhai and colleagues recently disclosed a concise total synthesis of sculponeatin N (14) that utilizes a radical cyclization to build the bicyclo[3.2.1]octane unit (Figure 2.3).4 Beginning with known diester 47, a silyl diene unit was appended, and a reduction/acylation sequence provided 48 as an intramolecular Diels–Alder cycloaddition precursor. Heating to 190 °C in the presence of a radical scavenger simultaneously constructed the B and C-rings, and after silylation, provided tricycle 49 in 76% yield over two steps. The C8 quaternary center of 51 was introduced via alkylation of the lactone with 2,3-dibromopropene (50). In a crucial step of the synthesis, exposure of 51 to triethylborane and tris(trimethylsilyl)silane rapidly furnished 6,7-seco-ent-kauranoid core 52. Lastly, allylic oxidation and desilylation provided sculponeatin N (14) in just 13 steps from diester 47. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E TMS 6 steps Me Me O CO2Me 47 LDA, HMPA, THF, –78 °C; H O TBSO 50 Br O Br 49 O H O TBSO 3. 1 M HCl, THF O TBSO O Br Et 3B (TMS)3SiH PhH, 25 °C O (68% yield) 51 1. SeO2, TBHP 2. Dess–Martin Me Me (76% yield, 2 steps) Me Me (88% yield) H 2. TBSCl, imidazole O 48 O H Me Me 1. BHT, PhMe, 190 °C; p-TsOH, 120 °C; K 2CO3, MeOH Me Me CO2Me 23 H Me HO (80% yield, 3 steps) 52 O O Me O sculponeatin N (14) Figure 2.3. Zhai’s total synthesis of sculponeatin N (14). 2.3 SYNTHETIC APPROACH 2.3.1 Total Synthesis of (–)-Maoecrystal Z Our interest in the 6,7-seco-ent-kauranoids was piqued by maoecrystal Z (17), which possesses a unique rearranged skeleton.5 In 2011, our group reported the total synthesis of (–)-maoecrystal Z (17) that featured, among other key steps, a dialdehyde cyclization cascade to form the tetracyclic core.6 The synthetic strategy was partially guided by Fujita’s studies that showed treatment of trichorabdal B (13) initiated a retroDieckmann–aldol sequence to form the tetracyclic framework of 17. 7 In the retrosynthetic analysis, 17 was envisioned to arise from a SmII-initiated cascade cyclization of 54 through Sm-enolate 53 (Figure 2.4). Dialdehyde 54 would arise from Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 24 alkylation with alkyl iodide 55 of the key spirolactone 56 that is found within the skeleton of many ent-kauranoids. cascade cyclization H Me H H HO Me OAc O H H Me O O Me H O maoecrystal Z (17) O H Me O SmIII O SmIII O O Me H 53 O H O 54 H I OTBS + Me TBSO Me 55 O O 56 Figure 2.4. Retrosynthetic analysis of (–)-maoecrystal Z (17). In the forward direction, (–)-γ-cyclogeraniol (57) was converted to the silyl ether and treated with m-CPBA to form epoxide 58 as an inconsequential mixture of diastereomers (Figure 2.5). After much optimization, it was found that spirolactone 56 could be accessed diastereoselectively through a titanocene-mediated coupling with trifluoroethyl acrylate. Alkylation and oxidation afforded enoate 59, which was deprotected and treated with Dess–Martin periodinane to form the cyclization precursor, dialdehyde 54. In the key step of the synthesis, exposure of dialdehyde 54 to SmI2 and LiBr with t-BuOH as a proton source furnished a single diastereomer of tetracycle 60. This reaction likely proceeds through ketyl formation at C12, undergoing radical cyclization and further reduction to form Sm-enolate 53 (see Figure 2.4). A subsequent aldol reaction affords the central 5-membered ring, overall providing two new rings and setting four stereocenters in a single step. Lastly, bis-acetylation to diacetate 61 followed 25 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E by ozonolysis and α-methylenation provided enal 62, which was monodeprotected to afford maoecrystal Z (17). 1. TBSCl, imidazole Me Me OH (– )- γ-cyclogeraniol (57) 58 3 : 1 dr 1. O 3, CH2Cl2, –78 °C; Et 3N workup 2. [Me 2NCH 2]I Et 3N, CH2Cl2 (80% yield, 2 steps) s-collidine•HCl THF Me O O 56 single diastereomer H 1. H 2SiF6, 0 °C Me O 2. DMP O OTBS 59 H Me Ac2O TMSOTf OH CH2Cl2, 0 °C O H O O Me H O H O 54 H Me Ac O Me OAc O O (74% yield) 60 2 rings 4 stereogenic centers 61 H Me Ac H 12 Me (86% yield, 2 steps) 12 HO Me O (54% yield) Me TBSO (76% yield) Me TBSO 2. KHMDS, 0 °C PhSeBr, –78 °C; 30% H 2O 2, 0 °C THF, –78 °C H Cp2TiCl2, Zn OTBS (90% yield) 1. LHMDS, 55 THF/HMPA (4:1) 0 to 23 °C SmI2, LiBr t-BuOH Me Me 2. m-CPBA NaHCO 3 CO2CH2CF 3 O H H O Me OAc O O 62 O 1 M NaOH MeOH/H 2O (1:1) (38% yield) Me H HO Me OAc O O O (– )-maoecrystal Z (17) Figure 2.5. Total synthesis of (–)-maoecrystal Z (17). Our group’s total synthesis of (–)-maoecrystal Z (17) proceeded in 12 synthetic steps from (–)-γ-cyclogeraniol (57). The successful utilization of the key spirolactone 56 prompted our investigations to the biogenetically related ent-kauranoids (–)-trichorabdal A (12) and (–)-longikaurin E (11). Ultimately, spirolactone 56 would serve as an important building block for the completion of structurally distinct ent-kauranoid natural products. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 26 Retrosynthesis of (–)-Trichorabdal A and (–)-Longikaurin E 2.3.2 Retrosynthetically, 11 and 12 were both envisioned to arise from exo-olefin 63 (Figure 2.6). To access (–)-longikaurin E (11), we hoped to forge the central oxabicyclo[2.2.2]octane via the reductive cyclization of a C6-aldehyde precursor.8 The bicyclo[3.2.1]octane motif of 63 would arise through a transition metal-mediated oxidative cyclization reaction of silyl ketene acetal 64. Although the oxidative cyclization of silyl enol ethers is well precedented,9,10 there were no examples of transition metalmediated oxidative cyclizations between silyl ketene acetals and simple olefins that generated all-carbon quaternary centers reported prior to our studies.11 Mindful of this challenge, we were nonetheless eager to employ such a strategy for the assembly of this pivotal intermediate, as it was anticipated that the Sm(II)-mediated cyclization chemistry devised en route to (–)-maoecrystal Z (17) would enable the facile synthesis of tricycle 64 from aldehyde 65 and intermediate 59. Thus, the strategy would enable the divergent synthesis of three architecturally unique ent-kauranoids via a common precursor. H Me H O O Me O HO O Me (– )-trichorabdal A (12) H Sm-mediated reductive cyclization O OH Me Pd-mediated oxidative cyclization H H O Me O OR O Me TBSO H Me OSiR'3 O 63 64 7 Me 6 O OH Sm-mediated reductive cyclization OAc (– )-longikaurin E (11) TBSO H Me RO H H HO Me OAc O H H O maoecrystal Z (17) O H Me TBSO Me TBSO O Me Me O 59 O O H O 65 Figure 2.6. Retrosynthesis of (–)-trichorabdal A (12) and (–)-longikaurin E (11). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 2.4 FORWARD SYNTHETIC EFFORTS 2.4.1 Development of a Pd(II)-Mediated Oxidative Cyclization 27 To investigate the proposed oxidative cyclization, we needed to prepare silyl ketene acetal 64 from enoate 59 (Figure 2.7). The more sterically accessible silyl ether of 59 was deprotected and oxidized to afford aldehyde 66. Treatment with a mixture of SmI2 and LiBr in THF in the presence of t-BuOH at low temperature formed the cyclization product 67 as a single diastereomer in 57% yield. MOM-protection of the secondary alcohol of 67 allowed for smooth conversion to silyl ketene acetal 64 upon deprotonation and trapping with TBSCl. It was found that use of silyl protecting groups gave lower yields of silyl ketene acetal 64, presumably due to 1,3-diaxial interactions that made deprotonation at C8 challenging. O 1. n-Bu4NHSO 4 p-TsOH, MeOH 59 2. DMP, CH2Cl2 SmI2, LiBr t-BuOH H Me TBSO THF, –78 °C Me O (77% yield, 2 steps) HO H H Me O MOMCl n-Bu 4NI, DIPEA DMF, 45 °C Me TBSO H Me (91% yield) O 68 O (57% yield) 66 MOMO H H Me TBSO O 67 H KHMDS TBSCl, DMPU 8 THF, –78 °C O MOMO H Me TBSO H Me (85% yield) O OTBS 64 Figure 2.7. Preparation of silyl ketene acetal 64. With oxidative cyclization precursor 64 in hand, a survey of conditions for the key oxidative cyclization step was conducted. Upon exposure of 64 to 10 mol % Pd(OAc)2 in DMSO at 45 °C under an air atmosphere, we were delighted to isolate tetracycle 69, albeit in only 7% yield (Table 1, entry 1). Fortunately, the use of 28 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E stoichiometric Pd(OAc)2 substantially improved both conversion and the yield of 69 (entry 2), and a survey of reaction conditions was conducted. The desired transformation does proceed in MeCN at ambient temperature (entry 3); however, increased side product formation is observed. Other solvents (e.g., PhMe, glyme, dioxane, t-BuOH, DMF) yielded only traces of 69. Other palladium sources also performed poorly (entries 4–6): for example, the major product when using PdCl2 and AgBF4 (entry 6) was methyl ketone 70, via Wacker oxidation. No desaturated products from Saegusa–Ito-type pathways were observed.12 H Me TBSO Me MOMO H H Pd II O O OMOM TBS DMSO, 45 °C air Me TBSO 64 Me TBSO O Me O OMOM Me H O H Me O 69 O 70 Entry Pd source (equiv) Additive (equiv) Yield 69 (%)a 1 Pd(OAc)2 (0.1) -- 7 2 Pd(OAc)2 (1.0) -- 35 3b Pd(OAc)2 (1.0) -- 28c 4 Pd(TFA)2 (1.0) -- 19 5 PdCl2 (1.0) -- 0 6 PdCl2 (1.0) AgBF4 (2.0) 5d 7e Pd(OAc)2 (1.0) H2O (5.0) 38 8 Pd(OAc)2 (1.0) K2CO3 (5.0) 0 9 Pd(OAc)2 (1.0) AcOH (0.5) 56 10 Pd(OAc)2 (0.1) AcOH (0.5) 7 11 Pd(OAc)2 (1.0) AcOH (1.0) 31 12 Pd(OAc)2 (1.0) p-TsOH (0.5) 46 13 Pd(OAc)2 (1.0) BzOH (0.5) 32 14 Pd(OAc)2 (1.0) PivOH (0.5) 40 a Isolated yield. bReaction conducted in MeCN at 23 °C. cProduct isolated as an inseparable 4.3:1 mixture with an olefin isomerization side product. d13% yield of methyl ketone 70 was also isolated. eRun under a N2 atmosphere. Table 2.1. Reaction optimization of the oxidative cyclization of 64. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 29 High variability in both the yield and purity of 69 upon attempts to increase reaction scale beyond a few milligrams prompted an examination of the roles of adventitious water and Brønsted acid. Indeed, similar reaction conditions with water and Brønsted acid have been used to promote Wacker-type oxidation of terminal olefins.13 Control experiments demonstrated that water had little effect on product formation (entry 7), whereas the addition of bases such as K2CO3 inhibits the reaction (entry 8). On the other hand, the use of 0.5 equiv AcOH as an additive afforded 69 in 56% yield (entry 9) with a much cleaner reaction profile, a result reproducible on preparative scales. Neither an increased amount of AcOH nor the use of other acids examined were found to further improve the yield. To the best of our knowledge, this represents the first example of a Pd-mediated oxidative cyclization of a silyl ketene acetal to generate an all-carbon quaternary center. 2.4.2 Total Synthesis of (–)-Trichorabdal A Having now established the carbon framework present in many 6,7-seco-ent- kauranoids, the remaining steps for the synthesis of 12 included installation of the exoenone and C6 aldehyde. Ozonolysis of 69 and subsequent α-methylenation using bis(dimethylamino)methane and acetic anhydride delivered β-ketolactone 72 (Figure 2.8).14 Notably, the analogous two-step procedure using Eschenmoser’s salt provided significantly diminished yields of 72. Exposure to 6 M aqueous HCl in dioxane at 45 °C smoothly effected global deprotection, and selective oxidation of the C6 primary alcohol was accomplished using catalytic TEMPO and PhI(OAc)2,15 delivering (–)-trichorabdal A (12).16 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E H Me TBSO H O 3, CH2Cl2, –94 °C; O Me then PPh 3 OMOM O Me TBSO O DMF, 95 °C Me (69% yield) H Me TBSO Me 2NCH 2NMe 2, Ac2O O OMOM O 69 O Me OMOM O 72 (82% yield) 71 H 1. HCl (aq) dioxane, 45 °C O 30 Me H 2. TEMPO, PhI(OAc) 2 CH2Cl2 O O Me O O HO (– )-trichorabdal A (12) (73% yield, 2 steps) Figure 2.8. Total synthesis of (–)-trichorabdal A (12). Total Synthesis of (–)-Longikaurin E 2.4.3 With the synthesis of 12 complete, we turned our attention to the aldehydelactone reductive coupling required for the synthesis of (–)-longikaurin E (11). Treatment of exo-olefin 69 with 6 M aqueous HCl in dioxane at 45 °C resulted in global deprotection to afford diol 73; subsequent oxidation with catalytic TEMPO and PhI(OAc)2 likewise proceeded smoothly (Figure 2.9). Aldehyde 74 was acetylated using acetic anhydride and DMAP to furnish 75, and a screen of reaction parameters for the proposed reductive cyclization was conducted. H Me TBSO H HCl (aq) O dioxane, 60 °C Me Me HO OMOM O Me 73 H Me H Ac2O, DMAP O O CH2Cl2 OH O (89% yield) 69 TEMPO PhI(OAc) 2 O Me H O OH CH2Cl2 (58% yield, 2 steps) 74 Figure 2.9. Synthesis of aldehyde-lactone 75. Me O O Me H O 75 OAc Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 31 H OH Me H Me O O Me SmI2 additives Me H O H H Me 75 OAc 76 THF OAc O OH Me HO Me O OH OAc O Me 77 O OAc 78 Entry Equivs SmI2 Additives (equivs) Temperature (°C) Yielda (brsm) 1 5.0 LiCl (50), t-BuOH (1.0) –78 no reaction 2 5.0 LiBr (50), t-BuOH (1.0) –78 no reaction 3 5.0 t-BuOH (1.0) –78 no reaction 4 5.0 HMPA (50), t-BuOH (1.0) –78 0%b 5 5.0 LiCl (50), t-BuOH (1.0) 0 54% 78 6 5.0 LiBr (50), t-BuOH (1.0) 0 38% 78 7 5.0 t-BuOH (1.0) 0 25% 76 (100%) 8 2.2 -- 23 55% 76 (75%) 2.4 -- 23 55% 76 (62%) t-BuOH (1.0) 23 72% 77 9 10 a c 5.0 b c Isolated yield. Complex mixture. Run to full consumption of 75. Table 2.2. Optimization of Sm-mediated pinacol-type coupling. Surprisingly, treatment of aldehyde-lactone 75 with LiCl, LiBr, or no lithium salt in the presence of t-BuOH at –78 °C (Table 2.2, entries 1–3) led to recovery of starting material, while use of a bulkier additive, HMPA, resulted in a complex mixture of products (entry 4). The use of lithium salts with t-BuOH at higher temperature induced reduction of the aldehyde to alcohol 78 with no recovered starting material (entries 5–6). Fortunately, omitting the lithium salts at 0 °C gave 20% yield of desired hydroxyl-lactol 76 (entry 7). Further raising the temperature to 23 °C improved conversion, while utilizing less equivalents of SmI2, and excluding the proton source lowered the amount of 32 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E side-products. Overall, this resulted in a 55% isolated yield of the desired product (76), along with 27% yield of recovered starting material (entry 8). The remainder of the mass balance was attributed to C6-deoxy lactol 77 and over-reduction side products. Attempts to push the reaction to completion, for example by raising the equivalents of SmI2, resulted in larger amounts of side-product 77 (entry 9). In fact, running the reaction to full consumption of 75 gave lactol 77 in 72% yield (entry 10). Completion of the total synthesis from hydroxyl-lactol 76 proceeded via ozonolysis and α-methylenation under previously described conditions (Figure 2.10). Notably, a significant amount of an epoxide product was observed in the ozonolysis of 76. Formation of this epoxide was suppressed by using lower temperatures, down to –94 °C. Lastly, α-methylenation of ketone 79 delivered (–)-longikaurin E (11) in 67% yield.17 This represents the first total synthesis of a 7,20-epoxy-ent-kauranoid natural product. H H OH Me Me O 3, DCM, –94 °C O OH 76 OAc then PPh 3 (66% yield) O Me 2NCH 2NMe 2 Ac2O OH Me Me O OH 79 OAc DMF, 95 °C (67% yield) H O OH Me Me O OH OAc (– )-longikaurin E (11) Figure 2.10. Total synthesis of (–)-longikaurin E (11). 2.5 CONCLUDING REMARKS In summary, a unified synthetic strategy to prepare three unique ent-kauranoid frameworks from unsaturated lactone 59 has been established. The first total synthesis of (–)-trichorabdal A (12) and (–)-longikaurin E (11) proceeded in 15 and 17 steps and 3.2% and 1.0% overall yield, respectively, from (–)-γ-cyclogeraniol (57). The pivotal transformations that enabled these syntheses include a new PdII-mediated oxidative Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 33 cyclization of a silyl ketene acetal (64) to form an all-carbon quaternary center, as well as a SmII-mediated pinacol-type coupling to forge the oxabicyclo[2.2.2]octane of 11. Taken with our group’s total synthesis of (–)-maoecrystal Z (17), we have demonstrated the synthetic utility of single-electron chemistry in diastereoselectively forming vicinal stereocenters in complex polycyclic systems and have also established a non-biomimetic synthetic relationship among three architecturally distinct ent-kaurane diterpenoids. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 2.6 EXPERIMENTAL SECTION 2.6.1 Materials and Methods 34 Unless otherwise stated, reactions were performed under an inert atmosphere (dry N2 or Ar) with freshly dried solvents utilizing standard Schlenk techniques. Glaswarewas oven-dried at 120 °C for a minimum of four hours, or flame-dried utilizing a Bunsen burner under high vacuum. Tetrahydrofuran (THF), methylene chloride (CH2Cl2), acetonitrile (MeCN), tert-butyl methyl ether (TBME), benzene (PhH), and toluene (PhMe) were dried by passing through activated alumina columns. Triethylamine (Et3N) and N,N-Diisopropylethylamine (DIPEA) were distilled over calcium hydride, 1,3Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) and hexamethylphosphoramide (HMPA) were distilled over calcium hydride under reduced pressure, and dimethylsulfoxide (DMSO) was dried over 4 Å MS for at least 48 hours prior to use. Unless otherwise stated, chemicals and reagents were used as received. All reactions were monitored by thin-layer chromatography using EMD/Merck silica gel 60 F254 precoated plates (0.25 mm) and were visualized by UV, p-anisaldehyde, KMnO4, or CAM staining staining. Flash column chromatography was performed using silica gel (SiliaFlash® P60, particle size 40-63 microns [230 to 400 mesh]) purchased from Silicycle. Optical rotations were measured on a Jasco P-2000 polarimeter using a 100 mm path-length cell at 589 nm. 1H and 13C NMR spectra were recorded on a Bruker Avance III HD with Prodigy cryoprobe (at 400 MHz and 101 MHz respectively), a Varian 400 MR (at 400 MHz and 101 MHz, respectively), a Varian Inova 500 (at 500 MHz and 126 MHz, respectively), or a Varian Inova 600 (at 600 MHz and 150 MHz, respectively), and are reported relative to internal CHCl3 (1H, δ = 7.26) and CDCl3 (13C, δ = 77.0). Data for 35 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 1 H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, app = apparent. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm–1). HRMS were acquired using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), or mixed (MM) ionization mode. Preparative HPLC was performed with an Agilent 1100 Series HPLC utilizing an Agilent Eclipse XDB-C18 5µm column (9.4 x 250 mm). Preparative Procedures and Spectroscopic Data 2.6.2 Preparation of aldehyde 66: TBSO Me Me MeOH, 0 °C O TBSO 59 O O HO n-Bu4NHSO 4 p-TsOH DMP Me Me DCM O TBSO S1 O Me Me O TBSO (77% yield, 2 steps) O 66 To a solution of enoate 59 (1.94 g, 3.43 mmol) in 35 mL MeOH cooled to 0 °C was added n-Bu4NHSO4 (128 mg, 0.378 mmol, 0.11 equiv) and p-TsOH (26 mg, 0.14 mmol, 0.04 equiv). After stirring at 0 °C for 1.5 h, the reaction mixture was diluted with sat. NaHCO3 (25 mL) and concentrated in vacuo to remove MeOH. The aqueous layer was then extracted with EtOAc (3 x 15 mL). The combined organic extracts were then washed with brine (15 mL), dried over Na2SO4, and concentrated in vacuo to provide crude alcohol S1. Crude S1 was immediately dissolved in DCM (35 mL) and Dess– Martin periodinane (2.91 g, 6.87 mmol, 2.0 equiv) was added. After stirring at ambient Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 36 temperature for 30 min, sat. NaHCO3 (20 mL) and sat. Na2S2O3 (20 mL) were added and the biphasic mixture was stirred vigorously until both layers became clear (20 min). The layers were separated and the aqueous phase was extracted with DCM (3 x 15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (10 to 12% EtOAc/Hex) to provide aldehyde 66 as a clear gum (1.18 g, 77% yield from 59). 1 H NMR (500 MHz, CDCl3): δ 9.71 (t, J = 2.0 Hz, 1H), 6.39 (s, 1H), 5.78 – 5.66 (m, 1H), 5.09 – 4.99 (m, 2H), 4.48 (dd, J = 11.2, 1.9 Hz, 1H), 4.40 (dd, J = 11.2, 1.4 Hz, 1H), 3.81 – 3.71 (m, 2H), 2.48 – 2.26 (m, 4H), 2.20 – 2.10 (m, 2H), 2.01 (dt, J = 13.9, 7.6 Hz, 1H), 1.84 (d, J = 13.6 Hz, 1H), 1.69 – 1.49 (m, 2H), 1.48 – 1.39 (m, 2H), 1.25 (td, J = 13.0, 4.3 Hz, 1H), 1.14 (td, J = 13.0, 4.4 Hz, 1H), 1.01 (s, 3H), 0.89 (s, 3H), 0.86 (s, 9H), 0.02 (s, 6H) 13 C NMR (126 MHz, CDCl3): δ 202.5, 164.8, 155.6, 135.6, 126.2, 117.6, 69.9, 61.3, 55.5, 47.3, 42.0, 39.7, 38.6, 36.0, 33.1, 33.0, 32.8, 32.1, 25.8, 23.2, 18.3, 18.1, -5.5, -5.6. FTIR (thin film/NaCl): 3421, 3076, 2927, 2855, 2716, 1728, 1713, 1471, 1393, 1255, 1164, 1150, 1104, 1068, 995, 913, 838, 776 cm–1. HRMS: (MM: ESI–APCI) calc’d for C26H45O4Si [M + H]+ 449.3082, found 449.3067. [𝜶]𝟐𝟓 𝐃 = –33.4° (c = 1.23, CHCl3). An analytical sample of alcohol S1 was obtained (63% yield) by SiO2 chromatography (30% EtOAc/Hex): Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 1 37 H NMR (500 MHz, CDCl3): δ 6.37 (s, 1H), 5.73 (dddd, J = 16.8, 10.4, 7.7, 6.5 Hz, 1H), 5.07 – 4.98 (m, 2H), 4.51 (dd, J = 11.3, 2.1 Hz, 1H), 4.41 (dd, J = 11.3, 1.5 Hz, 1H), 3.83 – 3.71 (m, 3H), 3.67 (dt, J = 11.0, 6.4 Hz, 1H), 2.36 (ddd, J = 13.9, 5.6, 1.3 Hz, 1H), 2.16 – 2.07 (m, 1H), 2.04 (dd, J = 14.0, 8.2 Hz, 1H), 2.01 – 1.92 (m, 2H), 1.91 – 1.78 (m, 2H), 1.66 – 1.49 (m, 3H), 1.49 – 1.34 (m, 3H), 1.32 – 1.21 (m, 1H), 1.21 – 1.09 (m, 1H), 1.02 (s, 3H), 0.92 (s, 3H), 0.87 (s, 9H), 0.03 (s, 6H); 13 C NMR (126 MHz, CDCl3): δ 165.2, 154.6, 136.3, 127.6, 116.8, 70.0, 61.5, 60.6, 55.6, 42.1, 40.0, 38.2, 35.7, 35.3, 33.3, 33.3, 33.0, 32.8, 25.8, 23.3, 18.4, 18.0, -5.5, -5.6; FTIR (thin film/NaCl): 3447, 3074, 2952, 2928, 2856, 1718, 1472, 1462, 1395, 1363, 1256, 1165, 1150, 1105, 1069, 995, 909, 838, 776; HRMS: (MM: ESI–APCI) calc’d for C26H47O4Si [M + H]+ 451.3238, found 451.3251. [𝜶]𝟐𝟓 𝐃 = –44.6° (c = 1.21, CHCl3); Preparation of tricycle 67: O Me Me THF, –78 °C O TBSO 66 HO SmI2, LiBr t-BuOH H H Me TBSO H Me O (57% yield) O O 67 Fresh SmI2 was prepared according to the following procedure:18 A flame-dried flask was charged with finely ground samarium (Aldrich, 1.30 g, 8.64 mmol, 1.7 equiv) and was briefly flame-dried in vacuo. Once cooled, THF (50 mL) was added under argon followed by diiodoethane (1.40 g, 4.96 mmol, 1.0 equiv) with vigorous stirring for 3 h at ambient temperature. The deep blue solution (~0.1M in SmI2) was allowed to settle for at least 10 min prior to use. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 38 A solution of aldehyde 66 (0.676 g, 1.51 mmol) and t-BuOH (0.145 mL, 1.51 mmol, 1.0 equiv) in 150 mL THF was cooled to –78 °C. Inside a glovebox, a separate flame-dried flask was charged with LiBr (3.27 g, 38 mmol, 25 equiv), removed from the glovebox, and to this flask was added freshly prepared 0.1 M SmI2 in THF (38 mL, 3.8 mmol, 2.5 equiv) and stirred vigorously for 2 min. While stirring continued, the resulting homogenous purple solution was added to the aldehyde solution via cannula. After 45 min at –78 °C, sat. NaHCO3 (60 mL), sat. Na2S2O3 (60 mL) and Rochelle salt (10 g) were added, and the mixture was extracted with EtOAc (3 x 80 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (9 to 12% EtOAc/Hex) to afford tricycle 67 as a white foam (0.385 g, 57% yield). 1 H NMR (500 MHz, CDCl3): δ 5.80 – 5.68 (m, 1H), 5.04 – 4.94 (m, 2H), 4.55 (br s, 1H), 4.47 (d, J = 11.4 Hz, 1H), 4.24 (dd, J = 11.5, 1.4 Hz, 1H), 3.72 (dd, J = 11.4, 4.1 Hz, 1H), 3.67 (dd, J = 11.3, 3.3 Hz, 1H), 2.85 (td, J = 12.3, 3.4 Hz, 1H), 2.45 (dtd, J = 13.2, 3.6, 2.0 Hz, 1H), 2.04 – 1.84 (m, 5H), 1.79 – 1.71 (m, 2H), 1.69 (t, J = 3.8 Hz, 1H), 1.56 – 1.36 (m, 4H), 1.27 (td, J = 12.7, 4.9 Hz, 1H), 1.09 (ddd, J = 14.2, 12.5, 2.2 Hz, 1H), 1.01 (s, 3H), 0.98 (t, J = 12.0 Hz, 1H), 0.88 (s, 3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 174.2, 136.2, 116.3, 73.2, 65.5, 60.0, 51.5, 46.6, 41.9, 40.9, 40.8, 39.5, 35.4, 35.1, 34.1, 33.7, 30.6, 27.8, 25.9, 23.6, 18.4, 18.1, -5.5, -5.6. FTIR (thin film/NaCl): 3461, 3075, 2927, 2856, 1716, 1471, 1463, 1394, 1362, 1256, 1220, 1064, 1046, 994, 911, 837, 776, 734 cm–1. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 39 HRMS: (MM: ESI–APCI) calc’d for C26H47O4Si [M + H]+ 451.3238, found 451.3236. [𝜶]𝟐𝟓 𝐃 = –11.3° (c = 2.26, CHCl3). Preparation of MOM ether 68: MOMCl i-Pr2NEt n-Bu4NI HO H H Me TBSO H Me O DMF, 45 °C O 67 (91% yield) MOMO H Me TBSO H H Me O O 68 A solution of tricycle 67 (0.315 g, 0.699 mmol), n-Bu4NI (26 mg, 70 µmol, 0.1 equiv), DIPEA (0.73 mL, 4.2 mmol, 6.0 equiv), and MOMCl (92% tech., 0.29 mL, 3.5 mmol, 5.0 equiv) in 3.5 mL DMF was heated to 45 °C. After stirring for 6 h at 45 °C, the reaction mixture was cooled to room temperature and diluted with sat. NaHCO3 (5 mL) and extracted with Et2O (3 x 5 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude residue was chromatographed on SiO2 (7 to 9% EtOAc/Hex) to afford methoxymethyl ether 68 as a clear gum (0.315 g, 91% yield). 1 H NMR (500 MHz, CDCl3): δ 5.81 – 5.69 (m, 1H), 5.05 – 4.98 (m, 1H), 4.98 (t, J = 1.2 Hz, 1H), 4.68 (d, J = 6.7 Hz, 1H), 4.62 (d, J = 6.7 Hz, 1H), 4.50 (d, J = 11.4 Hz, 1H), 4.37 (dt, J = 3.7, 1.8 Hz, 1H), 4.24 (dd, J = 11.4, 1.4 Hz, 1H), 3.74 (dd, J = 11.4, 4.1 Hz, 1H), 3.67 (dd, J = 11.4, 3.3 Hz, 1H), 3.40 (s, 3H), 2.87 (td, J = 12.3, 3.5 Hz, 1H), 2.47 (dtd, J = 13.1, 3.7, 2.1 Hz, 1H), 2.09 – 1.86 (m, 5H), 1.86 – 1.72 (m, 2H), 1.69 (t, J = 3.7 Hz, 1H), 1.64 – 1.40 (m, 4H), 1.28 – 1.18 (m, 1H), 1.08 – 0.96 (m, 4H), 0.90 (s, 3H), 0.89 (s, 9H), 0.05 (s, 3H), 0.05 (s, 3H). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 13 40 C NMR (126 MHz, CDCl3): δ 173.9, 136.2, 116.3, 95.1, 73.3, 71.4, 59.8, 56.3, 51.4, 47.0, 42.1, 40.8, 39.6, 36.4, 36.1, 35.3, 34.1, 33.9, 31.2, 27.4, 25.9, 23.5, 18.3, 18.1, -5.5, -5.6. FTIR (thin film/NaCl): 3074, 2951, 2927, 2855, 1731, 1472, 1462, 1389, 1361, 1256, 1202, 1149, 1085, 1063, 1045, 918, 838, 776 cm–1. HRMS: (MM: ESI–APCI) calc’d for C28H51O5Si [M + H]+ 495.3500, found 495.3510. [𝜶]𝟐𝟓 𝐃 = –22° (c = 0.76, CHCl3). Preparation of silyl ketene acetal 64: MOMO H Me TBSO KHMDS THF, 0 °C; H H Me O 68 O then –78 °C, DMPU, TBSCl (85% yield) MOMO H Me TBSO H Me O OTBS 64 *Note: 1-methyl-2-pyrrolidinone (NMP; distilled from CaH2) can be readily substituted for DMPU affording identical product yields. To a solution of KHMDS (0.106 g, 0.534 mmol, 2.0 equiv) in 5 mL THF cooled to 0 °C was added MOM ether 68 (0.132 g, 0.267 mmol) dropwise as a solution in THF (3 mL + 1 mL rinse). After stirring at 0 °C for 30 min, the reaction mixture was cooled to –78 °C and DMPU (1.0 mL) was added dropwise. After stirring 5 min, TBSCl (80 mg in 1 mL THF, 0.53 mmol, 2.0 equiv) was added and cooling was maintained at –78 °C. After 1 h, the reaction mixture was warmed to 0 °C, diluted with ice-cold pentane (10 mL) and ice-cold sat. NaHCO3 (5 mL). The layers were separated and the aqueous was extracted with ice-cold pentane (2 x 5 mL). The combined organic layers were washed Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 41 with brine (3 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on Florisil (3% EtOAc/Hex with 0.5% Et3N) to afford silyl ketene acetal 64 as a clear gum (0.139 g, 85% yield). 1 H NMR (500 MHz, CDCl3): δ 5.77 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), 5.02 – 4.93 (m, 2H), 4.68 (d, J = 6.8 Hz, 1H), 4.63 (d, J = 6.8 Hz, 1H), 4.04 (dd, J = 11.4, 2.9 Hz, 1H), 3.99 (d, J = 10.3 Hz, 1H), 3.92 (dt, J = 3.8, 1.8 Hz, 1H), 3.84 (dd, J = 10.4, 1.5 Hz, 1H), 3.81 (dd, J = 11.4, 2.6 Hz, 1H), 3.36 (s, 3H), 2.69 (ddd, J = 13.2, 4.3, 2.1 Hz, 1H), 2.22 (s, 1H), 2.15 (dq, J = 13.8, 2.7 Hz, 1H), 2.02 – 1.87 (m, 2H), 1.79 – 1.66 (m, 2H), 1.59 – 1.39 (m, 4H), 1.31 – 1.15 (m, 2H), 1.05 (s, 3H), 1.02 (s, 3H), 1.00 – 0.93 (m, 2H), 0.93 (s, 9H), 0.90 (s, 9H), 0.13 (s, 6H), 0.03 (s, 3H), 0.03 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 148.5, 137.2, 115.5, 95.8, 82.8, 74.7, 71.9, 61.7, 56.3, 50.1 (br), 45.8, 41.2, 38.5 (br), 38.2, 37.7, 33.8, 33.6, 32.9, 32.8, 30.4 (br), 28.1, 26.0, 25.8, 19.5, 18.1, 18.0, -4.2, -4.4, -5.7, -5.9. FTIR (thin film/NaCl): 3075, 2952, 2929, 2857, 1713, 1472, 1463, 1361, 1250, 1166, 1150, 1099, 1047, 1035, 989, 910, 870, 839, 783 cm–1. HRMS: (MM: ESI–APCI) calc’d for C34H65O5Si2 [M + H]+ 609.4365, found 609.4354. [𝜶]𝟐𝟓 𝐃 = –82.6° (c = 1.50, CHCl3). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 42 Preparation of tetracycle 69: MOMO H Me TBSO Pd(OAc) 2 AcOH H Me O OTBS 64 DMSO, 45 °C air (56% yield) H Me TBSO O Me O OMOM 69 A solution of silyl ketene acetal 64 (0.139 g, 0.228 mmol), Pd(OAc)2 (52 mg, 0.23 mmol, 1.0 equiv), and AcOH (6.9 mg in 0.10 mL DMSO, 0.11 mmol, 0.5 equiv) in 9 mL DMSO was heated to 45 °C in an open flask. After stirring under air for 6 h at 45 °C, the reaction mixture was cooled to room temperature, diluted with 1M HCl (10 mL) and extracted with Et2O (4 x 6 mL). The combined organic extracts were washed with brine (3 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (7 to 9% EtOAc/Hex) to afford tetracycle 69 as a clear gum (63 mg, 56% yield). 1 H NMR (600 MHz, CDCl3): δ 4.98 (s, 1H), 4.94 (s, 1H), 4.65 (d, J = 6.7 Hz, 1H), 4.62 (d, J = 6.8 Hz, 1H), 4.53 (s, 2H), 4.13 (q, J = 4.4 Hz, 1H), 3.79 (dd, J = 11.4, 5.0 Hz, 1H), 3.71 (dd, J = 11.7, 2.0 Hz, 1H), 3.40 (s, 3H), 2.68 (d, J = 5.0 Hz, 1H), 2.58 (d, J = 16.6 Hz, 1H), 2.47 – 2.42 (m, 2H), 2.30 – 2.22 (m, 2H), 2.19 (d, J = 16.3 Hz, 1H), 1.89 (dd, J = 11.8, 3.9 Hz, 1H), 1.78 (d, J = 14.0 Hz, 1H), 1.73 – 1.68 (m, 1H), 1.49 – 1.41 (m, 3H), 1.37 (dd, J = 14.5, 4.5 Hz, 1H), 1.30 – 1.24 (m, 1H), 1.02 (s, 3H), 0.94 (s, 3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.04 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 175.4, 157.0, 106.1, 96.0, 72.9, 71.5, 60.7, 56.1, 53.4, 52.2, 52.1, 42.9, 42.4, 41.4, 35.9, 35.8, 34.4, 34.4, 30.9, 30.6, 25.9, 23.7, 18.3, 18.2, -5.5, -5.5. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 43 FTIR (thin film/NaCl): 3583, 2926, 2853, 1739, 1464, 1388, 1252, 1232, 1147, 1082, 1046, 837, 776 cm–1. HRMS: (MM: ESI–APCI) calc’d for C28H49O5Si [M + H]+ 493.3344, found 493.3355. [𝜶]𝟐𝟓 𝐃 = +23.0° (c = 0.305, CHCl3). Optimization of reaction parameters: General procedure for oxidative cyclization of 64 to 69 (Table 2.1). A vial was charged with silyl ketene acetal 64 (10 mg, 16 µmol), Pd(II) salt, additive, and solvent (0.65 mL), placed under an atmosphere of O2, N2, or air, and heated to the desired temperature. Following the cessation of reaction progress as indicated by LC-MS or TLC analysis, the mixture was cooled to room temperature and diluted with 1M HCl (1 mL) and Et2O (1 mL). The layers were separated and the aqueous layer was extracted further with Et2O (3 x 0.5 mL). The combined organic extracts were washed with brine (0.5 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (7 to 9% EtOAc/Hex) to afford pure tetracycle 69. Preparation of methyl ketone 70: MOMO H Me TBSO H Pd(MeCN) 4(BF4)2 H Me O 68 O DMSO, 45 °C air MOMO H Me TBSO O H Me H Me (26% yield) O O 70 *Note: Methyl ketone 70 was initially isolated as a side product during optimization experiments for the conversion of 64 to 69 (Table 2.1, entry 6, 13% yield). Independent preparation was accomplished using the following procedure. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 44 A solution of MOM ether 68 (16 mg, 32 µmol) and Pd(MeCN)4(BF4)2 (14 mg, 32 µmol, 1.0 equiv) in DMSO (1.3 mL) was heated at 45 °C in an open vial. After stirring under air for 3 h, the reaction mixture was cooled to room temperature and diluted with 1M HCl (2 mL) and extracted with Et2O (3 x 2 mL). The combined organic extracts were washed with brine (1 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (10 to 20% EtOAc/Hex) to afford methyl ketone 70 as a clear gum (4.3 mg, 26% yield). 1 H NMR (500 MHz, CDCl3): δ 4.76 (d, J = 6.8 Hz, 1H), 4.64 (d, J = 6.8 Hz, 1H), 4.50 (d, J = 11.4 Hz, 1H), 4.37 (dt, J = 3.8, 1.8 Hz, 1H), 4.25 (dd, J = 11.4, 1.4 Hz, 1H), 3.74 (dd, J = 11.4, 4.0 Hz, 1H), 3.67 (dd, J = 11.4, 3.3 Hz, 1H), 3.45 (s, 3H), 2.94 (td, J = 12.3, 3.6 Hz, 1H), 2.46 – 2.37 (m, 2H), 2.38 – 2.23 (m, 2H), 2.13 (s, 3H), 2.09 (dq, J = 14.1, 3.2 Hz, 1H), 1.99 – 1.88 (m, 2H), 1.81 – 1.73 (m, 1H), 1.68 (t, J = 3.7 Hz, 1H), 1.59 – 1.42 (m, 4H), 1.29 – 1.19 (m, 1H), 1.11 – 1.03 (m, 1H), 1.02 (s, 3H), 0.90 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.05 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 207.5, 173.6, 95.0, 73.4, 70.7, 59.9, 56.5, 51.4, 50.1, 46.8, 42.1, 39.6, 36.3, 36.0, 35.3, 34.1, 33.9, 30.5, 27.4, 27.1, 25.9, 23.6, 18.4, 18.1, -5.5, -5.5. FTIR (thin film/NaCl): 2951, 2926, 2855, 1732, 1716, 1471, 1463, 1361, 1251, 1206, 1148, 1084, 1063, 1045, 918, 837, 776 cm–1. HRMS: (MM: ESI–APCI) calc’d for C28H51O6Si [M + H]+ 511.3449, found 511.3465. [𝜶]𝟐𝟓 𝐃 = –15° (c = 0.22, CHCl3). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 45 Preparation of ketolactone 71: H H O 3, DCM, –94 °C Me TBSO O Me O 69 OMOM then PPh 3 /polystyrene –94 to 23 °C Me TBSO (69% yield) O O Me O OMOM 71 A solution of tetracycle 69 (30.0 mg, 60.9 µmol) in 6 mL DCM was cooled to –94 °C (liq. N2/acetone) at which time ozone was gently bubbled through the solution (O2 flow rate = 1/8 L/min, 1 setting on ozone generator) for 10 min. The solution was purged with argon for 5 min, polystyrene-bound PPh3 (3 mmol/g loading, 200 mg, 0.61 mmol, 10 equiv) was then added. The reaction was slowly warmed to room temperature over 30 min. After stirring for 3 h, the suspension was filtered through celite and concentrated in vacuo. The crude residue was chromatographed on SiO2 (15 to 20% EtOAc/Hex) to afford ketolactone 71 as a clear gum (20.9 mg, 69% yield). 1 H NMR (500 MHz, CDCl3): δ 4.69 (d, J = 6.7 Hz, 1H), 4.61 (d, J = 6.7 Hz, 1H), 4.59 (d, J = 11.5 Hz, 1H), 4.39 (d, J = 11.4 Hz, 1H), 4.27 (br s, 1H), 3.69 (d, J = 11.3 Hz, 1H), 3.64 (dd, J = 11.7, 6.1 Hz, 1H), 3.41 (s, 3H), 2.83 (d, J = 10.8 Hz, 1H), 2.73 – 2.62 (m, 2H), 2.48 (ddd, J = 18.4, 6.9, 1.4 Hz, 1H), 2.44 – 2.31 (m, 2H), 2.13 (dd, J = 18.4, 3.7 Hz, 1H), 2.07 (t, J = 13.1 Hz, 1H), 1.75 – 1.65 (m, 2H), 1.53 – 1.37 (m, 3H), 1.32 (dd, J = 15.4, 4.4 Hz, 1H), 1.29 – 1.21 (m, 1H), 1.03 (s, 3H), 0.88 (s, 3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 214.1, 171.3, 96.2, 72.9, 70.0, 60.4, 57.4, 56.4, 51.4, 48.2, 47.1, 43.1, 42.5, 35.2, 34.3, 34.2, 32.5, 29.1, 27.1, 25.9, 23.6, 18.2, 18.0, -5.5, -5.5. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 46 FTIR (thin film/NaCl): 2952, 2928, 2856, 1750, 1726, 1471, 1464, 1390, 1236, 1148, 1094, 1047, 959, 945, 915, 838, 778 cm–1. HRMS: (MM: ESI–APCI) calc’d for C27H47O6Si [M + H]+ 495.3136, found 495.3147. [𝜶]𝟐𝟓 𝐃 = +8.2° (c = 0.99, CHCl3). Preparation of enone 72: H Me TBSO Me 2N O Me O H Ac2O O OMOM 71 NMe 2 DMF, 95 °C Me TBSO O O Me O OMOM 72 A solution of ketolactone 71 (19.2 mg, 38.8 µmol), bis(dimethylamino)methane (0.40 mL, 2.9 mmol, 75 equiv), acetic anhydride (0.40 mL, 4.2 mmol, 109 equiv) and 0.40 mL DMF was heated to 95 °C in a sealed vial. After stirring at 95 °C for 1 h, the reaction mixture was cooled to room temperature, diluted with sat. NaHCO3 (1 mL) and extracted with DCM (3 x 1 mL). The combined organic extracts were washed with sat. NaHCO3 (0.5 mL) and brine (0.5 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (10 to 15% EtOAc/Hex) to afford enone 72 as a clear gum (16.1 mg, 82% yield). 1 H NMR (500 MHz, CDCl3): δ 5.98 (s, 1H), 5.46 (s, 1H), 4.69 (d, J = 6.7 Hz, 1H), 4.61 (d, J = 6.7 Hz, 1H), 4.60 (d, J = 11.5 Hz, 1H), 4.37 (d, J = 11.5 Hz, 1H), 4.24 (br s, 1H), 3.66 (d, J = 11.4 Hz, 1H), 3.58 (dd, J = 11.4, 6.1 Hz, 1H), 3.42 (s, 3H), 3.13 (ddt, J = 9.6, 5.0, 1.0 Hz, 1H), 2.85 (d, J = 12.1 Hz, 1H), 2.68 (s, 1H), 2.45 (dd, J = 15.2, 9.3 Hz, 1H), 2.31 (dd, J = 12.3, 4.7 Hz, 1H), 1.93 (t, J = 13.8 Hz, 1H), 1.75 (d, J = 14.4 Hz, 1H), 1.68 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 47 (d, J = 5.1 Hz, 1H), 1.58 (dd, J = 15.1, 4.7 Hz, 1H), 1.54 – 1.39 (m, 3H), 1.30 – 1.20 (m, 1H), 1.03 (s, 3H), 0.88 (s, 3H), 0.84 (s, 9H), 0.01 (s, 3H), -0.02 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 201.0, 171.3, 150.0, 118.1, 96.4, 73.0, 69.3, 60.4, 56.9, 56.4, 51.9, 48.0, 43.7, 42.5, 36.9, 34.4, 34.3, 34.3, 29.7, 29.6, 26.0, 23.7, 18.3, 18.0, 5.6, -5.6. FTIR (thin film/NaCl): 2952, 2928, 2855, 1744, 1719, 1462, 1389, 1366, 1261, 1235, 1147, 1122, 1092, 1047, 989, 932, 838, 778 cm–1. HRMS: (MM: ESI–APCI) calc’d for C28H47O6Si [M + H]+ 507.3136, found 507.3145. [𝜶]𝟐𝟓 𝐃 = +27.6° (c = 1.02, CHCl3). Preparation of diol S2: H H O 6M aq. HCl Me TBSO O Me O 72 OMOM dioxane 45 °C (99% yield) Me HO O O Me O OH S2 To a solution of enone 72 (16.1 mg, 31.8 µmol) in 0.90 mL dioxane was added 0.70 mL 6M HCl (aq), and the mixture was stirred at 45 °C. After 75 min, the reaction mixture was cooled to room temperature, carefully diluted with sat. NaHCO3 (3 mL) and DCM (3 mL) and stirred until cessation of bubbling (10 min). The layers were separated and the aqueous layer was extracted with DCM (3 x 2 mL). The combined organic extracts were washed with sat. NaHCO3 (1 mL) and brine (1 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (50 to 65% EtOAc/Hex) to afford diol S2 as a white solid (11.0 mg, 99% yield). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 1 48 H NMR (500 MHz, CDCl3): δ 6.01 (s, 1H), 5.48 (s, 1H), 4.63 (d, J = 11.5 Hz, 1H), 4.55 (br s, 1H), 4.32 (dd, J = 11.4, 1.2 Hz, 1H), 3.79 (dd, J = 11.4, 1.8 Hz, 1H), 3.65 (dd, J = 11.4, 6.3 Hz, 1H), 3.16 (ddt, J = 8.8, 4.9, 1.1 Hz, 1H), 3.00 (d, J = 12.2 Hz, 1H), 2.65 (d, J = 3.2 Hz, 1H), 2.31 (ddd, J = 12.2, 4.8, 1.4 Hz, 1H), 2.14 (ddd, J = 15.1, 8.9, 1.9 Hz, 1H), 2.11 – 2.01 (m, 1H), 1.87 – 1.79 (m, 2H), 1.76 (d, J = 6.1 Hz, 1H), 1.56 – 1.43 (m, 4H), 1.37 – 1.27 (m, 2H), 1.07 (s, 3H), 0.88 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 201.3, 171.2, 149.7, 118.2, 69.5, 66.1, 60.1, 56.8, 51.7, 47.3, 43.4, 42.0, 34.6, 34.3, 33.9, 30.2, 30.1, 29.7, 24.0, 18.1. FTIR (thin film/NaCl): 3434, 2921, 2848, 1734, 1700, 1457, 1390, 1357, 1260, 1124, 1039, 1021, 928, 836, 749 cm–1. HRMS: (MM: ESI–APCI) calc’d for C20H29O5 [M + H]+ 349.2010, found 349.2014. [𝜶]𝟐𝟓 𝐃 = +14° (c 0.16, CHCl3). Preparation of (–)-trichorabdal A (12): H Me HO O TEMPO PhI(OAc) 2 O Me O S2 OH DCM H Me H O O Me O O (74% yield) OH (– )-trichorabdal A (12) To a solution of diol S2 (11.0 mg, 31.6 µmol) in 1.6 mL DCM was added 2,2,6,6tetramethylpiperidine 1-oxyl (1.0 mg, 6.3 µmol, 0.1 equiv) and iodobenzene diacetate (14.2 mg, 44.2 µmol, 1.4 equiv). After stirring for 3.5 h at ambient temperature, the reaction mixture was diluted with sat. NaHCO3 (0.5 mL) and sat. Na2S2O3 (0.5 mL). The layers were separated, the aqueous layer was extracted with DCM (3 x 1 mL), the combined organic extracts were washed with brine (1 mL), dried over Na2SO4, filtered Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 49 through a small plug of silica gel, and concentrated in vacuo. The crude residue was purified by preparative reverse phase HPLC (40 to 70% MeCN/H2O, 10 minute gradient, tR=6.8 min) to afford (–)-trichorabdal A (12) as a white solid (8.1 mg, 74% yield). 1 H NMR (600 MHz, pyridine-d5, at 60 °C): δ 10.06 (d, J = 4.3 Hz, 1H), 6.49 (s, 1H), 6.01 (s, 1H), 5.38 (s, 1H), 5.12 (d, J = 11.4 Hz, 1H), 4.88 – 4.64 (m, 1H), 4.65 – 4.60 (m, 1H), 3.46 (d, J = 11.8 Hz, 1H), 3.13 (dd, J = 8.9, 4.6 Hz, 1H), 2.91 (d, J = 4.3 Hz, 1H), 2.64 – 2.57 (m, 1H), 2.48 – 2.38 (m, 3H), 2.04 – 1.95 (m, 1H), 1.78 (dd, J = 14.8, 5.0 Hz, 1H), 1.68 – 1.59 (m, 1H), 1.52 – 1.42 (m, 2H), 1.27 – 1.19 (m, 1H), 1.04 (s, 3H), 0.99 (s, 3H); 13 C NMR (126 MHz, pyridine-d5, at 60 °C): δ 205.3, 201.5, 171.1, 150.9, 117.6, 70.8, 65.0, 60.9 (br), 56.9 (br), 47.9 (br), 42.7 (br), 42.1, 40.3 (br), 35.3, 34.3, 32.4, 31.6, 28.6, 25.9 (br), 18.7. FTIR (thin film/NaCl): 3467, 2922, 2849, 1744, 1711, 1647, 1490, 1459, 1391, 1349, 1271, 1238, 1180, 1124, 1079, 1038, 1024, 928, 850, 730 cm–1. HRMS: (MM: ESI–APCI) calc’d for C20H27O5 [M + H]+ 347.1853, found 347.1837. [𝜶]𝟐𝟓 𝐃 = –61° (c 0.12, EtOH). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 50 1 H NMR comparison table for trichorabdal A (12). Natural*16 Natural Natural Synthetic Synthetic (400 MHz, (600 MHz, C5D5N, 40 °C) C5D5N, 60 °C) δ (ppm) mult J (Hz) δ (ppm) mult 10.03 d, 1H 3 10.06 d, 1H 6.05 s, 1H 6.01 s, 1H 5.35 s, 1H 5.38 s, 1H 5.10 ABq, 1H 12 5.12 d, 1H 4.71 ABq, 1H 12 4.72 m, 1H 4.60 m, 1H 4.62 m, 1H 3.45 d, 1H 12 3.46 d, 1H 3.12 dd, 1H 10,4 3.13 dd, 1H 2.90 d, 1H 3 2.91 d, 1H 1.00 s, 3H 1.04 s, 3H 0.95 s, 3H 0.99 s, 3H * No further 1H signals were reported. Synthetic J (Hz) 4.3 11.4 11.8 8.9, 4.6 4.3 - Δ (ppm) +0.03 –0.04 +0.03 +0.02 +0.01 +0.02 +0.01 +0.01 +0.01 +0.04 +0.04 13 C NMR comparison table for trichorabdal A (12).** Natural16 Synthetic (100 MHz, C5D5N, 60 °C) (126 MHz, C5D5N, 60 °C) δ (ppm) δ (ppm) 204.5 205.3 200.7 169.5 150.6 117.1 70.7 64.9 60.7 56.7 47.8 42.7 42.0 40.3 35.2 34.2 32.3 31.5 28.4 26.0 18.6 201.5 171.1 150.9 117.6 70.8 65.0 60.9 56.9 47.9 42.7 42.1 40.3 35.3 34.3 32.4 31.6 28.6 25.9 18.7 Δ (ppm) +0.8 +0.8 +0.6 +0.3 +0.5 +0.1 +0.1 +0.2 +0.2 +0.1 0.0 +0.1 0.0 +0.1 +0.1 +0.1 +0.1 +0.2 –0.1 +0.1 ** It should be noted that conformational flexibility of the natural product results in significant broadening of some carbon signals, even at elevated temperatures. For discussion of the conformational equilibria of these structures, see Osawa et al.16 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 51 Preparation of diol 73: H H 6M aq. HCl Me TBSO O Me O 69 OMOM dioxane 45 °C Me HO O Me (89% yield) O OH 73 To a solution of tetracycle 69 (59.2 mg, 0.120 mmol, 1.0 equiv) in 3.7 mL dioxane was added 2.8 mL 6M HCl(aq). The resulting solution was heated to 45 °C and stirred for 30 min. The reaction mixture was then cooled to 0 °C and diluted with sat. NaHCO3 (10 mL) and DCM (10 mL) and stirred until bubbling ceased (15 min). The layers were separated, and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (40 to 50% EtOAc/Hex) to provide diol 73 (35.9 mg, 89% yield). 1 H NMR (500 MHz, CDCl3): δ 4.98 – 4.95 (m, 2 H), 4.46 (br s, 2H), 4.40 (dtd, J = 6.6, 5.2, 3.6 Hz, 1H), 3.87 (dt, J = 11.5, 4.5 Hz, 1H), 3.82 (dt, J = 11.5, 2.9 Hz, 1H), 2.64 (d, J = 5.2 Hz, 1H), 2.60 (ddt, J = 16.6, 5.4, 2.6 Hz, 1H), 2.52 – 2.43 (m, 2H), 2.37 (td, J = 13.3, 4.3 Hz, 1H), 2.26 (br s, 1 H), 2.22 (dq, J = 16.2, 2.0 Hz, 1H), 1.97 (dtd, J = 14.2, 6.4, 1.2 Hz, 1H), 1.90 (t, J = 3.6 Hz, 1H), 1.88 – 1.81 (m, 3H), 1.66 (ddt, J = 14.2, 5.2, 1.9 Hz, 1H), 1.52 – 1.41 (m, 3H), 1.31 (ddd, J = 14.1, 13.1, 4.3 Hz, 1H), 1.05 (s, 3H), 0.92 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 175.5, 156.1, 106.3, 71.7, 66.4, 60.6, 54.0, 53.0, 51.4, 42.5, 41.7, 40.4, 39.7, 36.5, 34.4, 34.1, 31.5, 31.4, 23.5, 18.4. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 52 FTIR (NaCl/thin film): 3246, 2929, 2872, 2848, 1734, 1459, 1388, 1353, 1298, 1242, 1087, 1044, 1023, 997, 989 cm–1. HRMS: (ESI+) calc’d for C20H31O4 [M + H]+ 335.2217, found 335.2228. [𝜶]𝟐𝟓 𝐃 = –28° (c = 0.66, CHCl3). Preparation of acetate 75. H Me HO TEMPO PhI(OAc) 2 O Me O 73 OH DCM H Me O Ac2O DMAP O Me H O 74 OH DCM H Me O O Me H O (58% yield, 2 steps) OAc 75 To a solution of diol 73 (35.2 mg, 0.105 mmol, 1.0 equiv) in DCM (5.3 mL) was added PhI(OAc)2 (47.6 mg, 0.148 mmol, 1.4 equiv) and 2,2,6,6-tetramethylpiperidine 1oxyl (3.3 mg, 21 µmol, 0.20 equiv). The resulting solution was stirred for 4.5 h, and then diluted with sat. Na2S2O3 (20 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide crude aldehyde 74. The crude residue was chromatographed on SiO2 (25% EtOAc/Hex) to provide 25.4 mg 74 (~85% purity, contaminated with ketoaldehyde from over-oxidation). Impure 74 was dissolved in DCM (7.6 mL), and Ac2O (36 µL, 0.38 mmol, 5.0 equiv) and DMAP (93 mg, 0.76 mmol, 10 equiv) were added. The solution was stirred at ambient temperature until TLC indicated full consumption of starting material (30 min). The reaction mixture was then diluted with sat. NaHCO3 (20 mL) and DCM (20 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 53 chromatographed on SiO2 (20% EtOAc/Hex) to provide acetate 75 (22.8 mg, 58% yield from 73). 1 H NMR (500 MHz, CDCl3): δ 9.93 (d, J = 4.4 Hz, 1H), 5.27 (q, J = 5.0 Hz, 1H), 4.99 (m, 2H), 4.84 (br d, J = 9.3 Hz, 1H), 4.68 (d, J = 11.8 Hz, 1H), 2.65 – 2.54 (m, 1H), 2.46 (q, J = 6.1 Hz, 1H), 2.39 (d, J = 4.4 Hz, 1H), 2.33 – 2.17 (m, 3H), 2.07 (s, 3H), 2.01 – 1.87 (m, 3H), 1.82 – 1.67 (m, 1H), 1.66 – 1.49 (m, 3H), 1.28 – 1.16 (m, 2H), 1.14 (s, 3H), 1.04 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 205.1, 174.2, 169.7, 155.0, 107.3, 70.4, 67.7, 62.5, 53.2, 51.9, 41.9, 41.7, 40.4, 36.5, 36.1, 34.5, 33.7, 30.6, 29.6, 23.8, 21.8, 18.2. FTIR (NaCl/thin film): 3079, 2953, 2849, 2751, 1735, 1712, 1654, 1462, 1371, 1231, 1085, 1071, 1036, 914 cm–1. HRMS: (ESI+) calc’d for C22H31O5 [M + H]+ 375.2166, found 375.2175.  [𝜶]𝟐𝟓 𝐃 = –6.9° (c = 0.42, CHCl3). An analytical sample of aldehyde 74 was obtained (65% yield) by preparative reverse phase HPLC (45% to 70% MeCN/H2O, 10 minute gradient, tR = 7.0 min). 1 H NMR (600 MHz, CDCl3): δ 9.95 (d, J = 5.4 Hz, 1H), 4.99 (s, 1H), 4.95 (t, J = 2.4 Hz, 1H), 4.88 (br s, 1H), 4.71 (d, J = 11.8 Hz, 1H), 4.25 (dq, J = 5.4, 3.5 Hz, 1H), 2.64 (d, J = 5.4 Hz, 1H), 2.59 – 2.53 (m, 1H), 2.51 – 2.47 (m, 1H), 2.46 – 2.35 (m, 2H), 2.17 (dq, J = 16.3, 2.0 Hz, 1H), 2.00 (d, J = 3.0 Hz, 1H), 1.96 (dt, J = 13.5, 6.6 Hz, 1H), 1.90 – Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 54 1.82 (m, 2H), 1.63 – 1.54 (m, 4H), 1.50 (dt, J = 13.2, 3.5 Hz, 1H), 1.31 (m, 1H), 1.18 (s, 3H), 1.00 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 206.6, 174.9, 155.5, 107.6, 71.3, 66.0, 63.4, 53.5, 53.5, 41.9, 41.2, 40.6, 39.5, 36.2, 34.4, 33.6, 31.4, 29.9, 23.6, 18.4. FTIR (NaCl/thin film): 3467, 2990, 2946, 2844, 2717, 1718, 1653, 1465, 1390, 1280, 1233, 1201, 1117, 1088, 1025, 881 cm–1. HRMS: (ESI+) calc’d for C20H29O4 [M + H]+ 333.2060, found 333.2070. [𝜶]𝟐𝟓 𝐃 = –65.4° (c = 0.37, CHCl3). Preparation of hydroxylactol 76: H Me H SmI2 O O Me H O 75 OAc OH Me THF (55% yield, 75% brsm) Me O OH OAc 76 To a solution of 75 (4.4 mg, 12 µmol, 1.0 equiv) in THF (0.27 mL) was added freshly prepared 0.1 M SmI2 (0.23 mL, 23 µmol, 2.0 equiv). The solution was stirred until the reaction turned from blue to green (ca. 1.5 h). The reaction mixture was then diluted with sat. NaHCO3 (1 mL), sat. Na2S2O3 (1 mL), and DCM (2 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 x 2 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (17% to 25% EtOAc/Hex) to provide recovered 75 (1.2 mg, 27% yield) and hydroxylactol 76 (2.4 mg, 55% yield). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 1 55 H NMR (500 MHz, CDCl3): δ 6.16 – 6.14 (m, 1H), 5.14 (ddd, J = 5.8, 4.1, 1.9 Hz, 1H), 5.11 (dd, J = 2.6, 1.2 Hz, 1H), 4.23 (dd, J = 9.1, 1.9 Hz, 1H), 4.10 (dd, J = 9.1, 1.8 Hz, 1H), 4.03 (dd, J = 7.3, 1.9 Hz, 1H), 2.59 (s, 1H), 2.50 – 2.42 (m, 2H), 2.40 (d, J = 1.9 Hz, 1H), 2.29 (dt, J = 8.9, 4.2 Hz, 1H), 2.17 – 2.09 (m, 2H), 2.06 (s, 3H), 1.75 (dt, J = 5.7, 1.5 Hz, 1H), 1.67 (dd, J = 11.7, 3.6 Hz, 1H), 1.51 – 1.41 (m, 3H), 1.39 – 1.32 (m, 3H), 1.27 – 1.22 (m, 2H), 1.12 (s, 3H), 1.09 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 169.9, 155.2, 113.0, 97.5, 75.4, 69.3, 69.1, 62.0, 57.3, 53.7, 46.7, 41.3, 37.2, 34.4, 34.2, 34.0, 33.6, 29.9, 27.2, 22.6, 22.0, 18.5. FTIR (NaCl/thin film): 3436, 2927, 2851, 1733, 1648, 1443, 1376, 1264, 1237, 1210, 1073, 1029 cm–1. HRMS: (ESI+) calc’d for C20H29O3 [M – OAc]+ 317.2111, found 317.2119. [𝜶]𝟐𝟓 𝐃 = –47.2° (c = 0.30, CHCl3). Preparation of lactol 77: H Me O SmI2 t-BuOH O Me H O 75 OAc THF (72% yield) H Me Me O OH OAc 77 To a solution of aldehyde 75 (5.0 mg, 13 µmol, 1.0 equiv) in THF (1.3 mL) was added t-BuOH (1.3 µL, 13 µmol, 1.0 equiv) and freshly prepared 0.1 M SmI2 (0.67 mL, 67 µmol, 5.0 equiv) dropwise over 1 min. The resulting solution was stirred until the reaction turned from blue to green (ca. 6 h), and then diluted with sat. NaHCO3 (5 mL), sat. Na2S2O3 (5 mL), and DCM (10 mL). The layers were separated and the aqueous layer was extracted with DCM (3 x 10 mL). The organic extracts were dried over Na2SO4, Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 56 filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (25% to 33% EtOAc/Hex) to provide lactol 77 (3.6 mg, 72% yield). 1 H NMR (500 MHz, CDCl3): δ 5.18 (dd, J = 2.7, 1.5 Hz, 1H), 5.14 (td, J = 6.0, 1.6 Hz, 1H), 4.92 – 4.90 (m, 1H), 4.23 (s, 2H), 2.60 (dd, J = 13.9, 11.1 Hz, 1H), 2.56 (ddt, J = 15.6, 5.1, 2.3 Hz, 1H), 2.41 (s, 1H), 2.40 (ddt, J = 11.9, 3.2, 1.0 Hz, 1H), 2.29 (dt, J = 9.6, 4.7 Hz, 1H), 2.15 (ddt, J = 15.7, 9.5, 1.3 Hz, 1H), 2.12 (ddt, J = 15.7, 3.0, 1.5 Hz, 1H), 2.06 (s, 3H), 1.91 (dd, J = 14.0, 8.6 Hz, 1H), 1.64 (ddt, J = 11.6, 4.0, 1.0 Hz, 1H), 1.58 (d, J = 5.3 Hz, 1H), 1.52 – 1.47 (m, 2H), 1.45 – 1.32 (m, 3H), 1.29 (dtd, J = 13.7, 3.3, 1.5 Hz, 1H), 1.19 (td, J = 13.4, 5.1 Hz, 1H), 1.11 (td, J = 12.7, 4.0 Hz, 1H), 1.10 (s, 3H), 0.89 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 170.1, 156.7, 105.5, 97.3, 69.1, 68.8, 61.1, 53.4, 49.2, 45.3, 40.8, 37.3, 36.0, 33.9, 33.7, 32.7, 32.0, 30.4, 27.1, 22.0, 21.1, 18.6. FTIR (NaCl/thin film): 3402, 2929, 1729, 1646, 1444, 1366, 1236, 1210, 1182, 1101, 1044, 915 cm–1. HRMS: (ESI+) calc’d for C20H29O2 [M – OAc]+ 301.2162, found 301.2164. [𝜶]𝟐𝟓 𝐃 = –135° (c = 0.30, CHCl3). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 57 Preparation of primary alcohol 78: H Me O SmI2 LiCl, t-BuOH O Me H O 75 OAc THF, 0 °C H Me HO O Me O (54% yield) OAc 78 Freshly prepared 0.1 M SmI2 (0.17 mL, 17 µmol, 5.0 equiv) was added directly to a vial charged with LiCl (7.2 mg, 170 µmol, 50 equiv) and stirred until the solution had turned emerald green and all solids were dissolved (< 10 min). The resulting solution was added dropwise via cannula into a solution of aldehyde 75 (1.3 mg, 3.5 µmol, 1.0 equiv) and a solution of t-BuOH in THF (0.01 M, 0.35 mL, 3.5 µmol, 1.0 equiv) stirring at 0 °C. Stirring continued until the reaction turned yellow (35 min). The reaction mixture was diluted with sat. NaHCO3 (1 mL), sat. Na2S2O3 (1 mL), and H2O (0.5 mL), then Rochelle salt (100 mg) and EtOAc (2 mL) were added. The layers were separated, and the aqueous layer extracted with EtOAc (3 x 2 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (20 to 25% EtOAc/Hex) to afford alcohol 78 (0.7 mg, 54% yield). 1 H NMR (500 MHz; CDCl3): δ 5.47 (ddd, J = 5.4, 4.5, 3.4 Hz, 1H), 4.96 (t, J = 2.4 Hz, 1H), 4.90 (t, J = 1.9 Hz, 1H), 4.57 (d, J = 11.5 Hz, 1H), 4.46 (d, J = 11.5 Hz, 1H), 3.82 (d, J = 11.8 Hz, 1H), 3.73 (dt, J = 10.9, 4.7 Hz, 1H), 2.81 (d, J = 4.3 Hz, 1H), 2.65 (ddt, J = 16.8, 5.8, 2.7 Hz, 1H), 2.45 (q, J = 6.8 Hz, 1H), 2.36 (dd, J = 11.9, 2.7 Hz, 1H), 2.24 (dq, J = 16.9, 2.2 Hz, 1H), 2.08 – 2.02 (m, 1H), 2.07 (s, 3H), 1.99 (dd, J = 12.2, 4.8 Hz, 1H), 1.86 (d, J = 13.6 Hz, 1H), 1.67 – 1.57 (m, 2H), 1.53 – 1.45 (m, 4H), 1.28 – 1.24 (m, 1H), 1.19 (td, J = 14.3, 5.3 Hz, 1H), 1.05 (s, 3H), 0.90 (s, 3H). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 13 58 C NMR (126 MHz, CDCl3): δ 174.7, 170.1, 156.5, 105.2, 70.4, 68.0, 60.3, 53.3, 52.4, 51.2, 42.8, 42.4, 40.9, 37.4, 35.8, 34.3, 34.2, 30.2, 30.0, 23.7, 21.9, 18.1. IR (NaCl/thin film): 3463, 2951, 2925, 2868, 2848, 1737, 1729, 1651, 1460, 1447, 1388, 1372, 1233, 1181, 1083, 1021 cm–1. HRMS: (ESI+) calc’d for C20H29O3 [M – OAc]+ 317.2117, found 317.2105. [𝜶]𝟐𝟓 𝐃 = –7.5° (c = 0.16, CHCl3). General procedure for reductive cyclization of aldehyde 75 (Table 2.2): To a flask charged with aldehyde 75 (1.3 mg, 3.5 µmol, 1.0 equiv) was added one of the following: 0.35 mL THF; 0.35 mL 10 mM t-BuOH /THF solution (3.5 µmol, 1.0 equiv); 0.35 mL THF and 30 uL HMPA (0.175 mmol, 50 equiv) and maintained at the indicated temperature. Inside a glove box, an oven-dried vial was charged with LiCl or LiBr (170 µmol, 50 equiv) or naught, and removed from the glove box, or not. Freshly prepared 0.1 M SmI2 was added directly to the reaction vessel dropwise, or to the vial containing LiX, which was stirred for 1–10 min until all solids were dissolved, and the resulting solution then added dropwise via cannula to the reaction vessel. Following addition of SmI2 or SmI2/LiX, the reaction was allowed to stir at the indicated temperature until the appearance of a yellow solution (35–55 min). At this point, the reaction was diluted with sat. NaHCO (1 mL), sat. Na2S2O3 (1 mL), and H2O (0.5 mL), and Rochelle salt (100 mg) and EtOAc (2 mL) were added. The layers were separated, and the aqueous extracted with EtOAc (3 x 2 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 59 chromatographed on SiO2 (17% to 33% EtOAc/Hex) to afford hydroxylactol 76, lactol 77, primary alcohol 78, or recovered aldehyde 75. Preparation of ketolactol 79: H H O 3, DCM, –94 °C OH Me Me O OH OAc 76 then PPh 3 /polystyrene –94 to 23 °C (66% yield) O OH Me Me O OH OAc 79 A solution of lactol 76 (4.4 mg, 12 µmol, 1.0 equiv) in DCM (2 mL) was cooled to –94 °C (liq. N2/acetone), and ozone was gently bubbled through the solution (O2 flow rate = 1/8 L/min, 1 setting on ozone generator) for 10 min. The solution was purged with argon for 10 min, and then polystyrene-bound PPh3 (3 mmol/g loading, 39 mg, 0.12 mmol, 10 equiv) was added. After 25 min, the reaction was warmed to 0 °C and stirred for 30 min, and finally warmed to room temperature and stirred for an additional 30 min. The solution was filtered through a pad of celite and concentrated in vacuo. The crude residue was chromatographed on SiO2 (33% EtOAc/Hex) to afford ketolactol 79 (2.9 mg, 66% yield). 1 H NMR (500 MHz, CDCl3): δ 5.63 (d, J = 12.0 Hz, 1H), 5.24 (td, J = 4.9, 1.4 Hz, 1H), 4.16 (dd, J = 9.4, 1.9 Hz, 1H), 4.09 (dd, J = 9.3, 1.7 Hz, 1H), 3.79 (dd, J = 12.0, 7.5 Hz, 1H), 3.53 (s, 1H), 2.71 (ddd, J = 12.4, 4.0, 1.3 Hz, 1H), 2.70 – 2.65 (m, 1H), 2.50 (ddd, J = 18.7, 7.1, 1.6 Hz, 1H), 2.30 – 2.24 (m, 2H), 2.18 (dd, J = 18.6, 4.0 Hz, 1H), 2.10 (s, 3H), 1.59 (dd, J = 4.9, 1.2 Hz, 1H), 1.54 – 1.42 (m, 3H), 1.38 – 1.33 (m, 2H), 1.26 – 1.21 (m, 3H), 1.13 (s, 3H), 1.11 (s, 3H). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 13 60 C NMR (126 MHz, CDCl3): δ 222.7, 169.7, 94.8, 74.7, 68.9, 68.1, 59.6, 58.8, 53.6, 49.3, 41.3, 36.9, 35.9, 33.9, 33.7, 30.6, 29.1, 25.9, 22.5, 21.9, 18.3. FTIR (NaCl/thin film): 3338, 2924, 2870, 1728, 1446, 1373, 1306, 1238, 1212, 1061, 1021, 939 cm–1. HRMS: (ESI+) calc’d for C21H31O6 [M + H]+ 379.2115, found 379.2123.  [𝜶]𝟐𝟓 𝐃 = –86° (c = 0.30, CHCl3). Preparation of (–)-longikaurin E (11): H Me 2N O Me Me NMe 2 Ac2O OH DMF, 95 °C O OH 79 OAc (67% yield) H O OH Me Me O OH OAc (– )-longikaurin E (11) To a solution of 79 (2.6 mg, 6.9 µmol, 1.0 equiv) in DMF (0.23 mL) was added bis(dimethylamino) methane (0.23 mL, 1.7 mmol, 240 equiv) and Ac2O (0.23 mL, 2.1 mmol, 300 equiv), and the resulting mixture was stirred at 95 °C for 45 min in a sealed vial. After cooling to room temperature, the solution was diluted with 1M HCl (2 mL) and extracted with Et2O (3 x 4 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (33% EtOAc/Hex) to afford (–)-longikaurin E (11) (1.8 mg, 67% yield). 1 H NMR (500 MHz, CDCl3): δ 6.00 (t, J = 0.9 Hz, 1H), 5.84 (d, J = 12.0 Hz, 1H), 5.47 (t, J = 0.8 Hz, 1H), 5.27 (ddd, J = 5.5, 4.5, 1.1 Hz, 1H), 4.13 (dd, J = 9.3, 1.4 Hz, 1H), 4.10 (dd, J = 9.3, 1.9 Hz, 1H), 3.87 (dd, J = 12.0, 8.1 Hz, 1H), 3.53 (s, 1H), 3.13 (dd, J = 9.4, 4.7 Hz, 1H), 2.71 (dd, J = 12.3, 0.8 Hz, 1H), 2.31 (ddd, J = 16.2, 9.3, 1.0 Hz, 1H), Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 61 2.21 (ddd, J = 12.2, 4.6, 1.2 Hz, 1H), 2.11 (s, 3H), 1.79 (ddt, J =16.0, 5.5, 1.1 Hz, 1H), 1.62 (d, J = 4.0 Hz, 1H), 1.51 – 1.42 (m, 2H), 1.39 – 1.33 (m, 2H), 1.32 – 1.20 (m, 3H), 1.15 (s, 3H), 1.13 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 208.4, 169.7, 151.7, 118.5, 95.0, 74.8, 69.1, 68.0, 58.5, 58.5, 53.7, 41.4, 38.0, 37.1, 34.1, 33.7, 33.6, 31.3, 26.3, 22.8, 21.9, 18.4. FTIR (NaCl/thin film): 3270, 2953, 2918, 2854, 1727, 1714, 1644, 1504, 1372, 1373, 1264, 1241, 1167, 1057, 940 cm–1. HRMS: (ESI+) calc’d for C22H31O6 [M + H]+ 391.2115, found 391.2125. 𝟐𝟓  [𝜶]𝟐𝟓 𝐃 = –51° (c = 0.30, C5H5N); [𝜶]𝐃 = –39° (c = 0.17, CHCl3). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 62 1 H NMR comparison table for longikaurin E (11). Natural*17 Natural Natural Synthetic (CDCl3) (CDCl3, 500 δ (ppm) mult J (Hz) MHz) δ (ppm) 5.26 dd, 1H 4.5, 4.5 5.27 4.11 br s, 2H 4.13 4.10 3.91 dd, 1H 12, 8 3.87 2.09 s, 3H 2.11 1.71 – 1.88 m** 1.79 1.62 1.25 1.14 1.12 m** m** s, 3H s, 3H - 1.62 1.20 – 1.32 1.15 1.13 13 C NMR comparison table for longikaurin E (11). Natural* 17 Synthetic (CDCl3) (CDCl3, 126 MHz) δ (ppm) δ (ppm) Δ (ppm) 208.4 208.4 0.0 169.6 169.7 +0.1 151.7 151.7 0.0 118.2 118.5 +0.3 95.0 95.0 0.0 74.5 74.8 +0.3 68.9 69.1 +0.2 68.1 68.0 –0.1 * No further 1H or 13C signals were reported. ** Integrations not reported. Synthetic Synthetic mult J (Hz) ddd, 1H dd, 1H dd, 1H dd, 1H s, 3H ddt, 1H 5.5, 4.5, 1.1 9.3, 1.4 9.3, 1.9 12.0, 8.1 16.0, 5.5, 1.1 4.0 - d, 1H m, 3H s, 3H s, 3H Δ (ppm) +0.01 –0.04 +0.02 0.00 +0.01 +0.01 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 2.7 (1) 63 NOTES AND REFERENCES (a) Lu, P.; Gu, Z.; Zakarian, A. J. Am. Chem. Soc. 2013, 135, 14552. (b) Cherney, E. C.; Green, J. C.; Baran, P. S. Angew. Chem., Int. Ed. 2013, 52, 9019. (c) Zhu, L.; Luo, J.; Hong, R. Org. Lett. 2014, 16, 2162. (d) Moritz, B. J.; Mack, D. J.; Tong, L.; Thomson, R. J. Angew. Chem., Int. Ed. 2014, 53, 2988. (e) Lazarski, K. E.; Moritz, B. J.; Thomson, R. J. Angew. Chem., Int. Ed. 2014, 53, 10588. (f) Lu, P.; Mailyan, A.; Gu, Z.; Guptill, D. M.; Wang, H.; Davies, H. M. L.; Zakarian, A. J. Am. Chem. Soc. 2014, 136, 17738. (g) Liu, W.; Li, H.; Cai, P.-J.; Wang, Z.; Yu, Z.-X.; Lei, X. Angew. Chem., Int. Ed. 2016, 55, 3112. (h) Cernijenko, A.; Risgaard, R.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 9425. (i) Zhao, X.; Li, W.; Wang, J.; Ma, D. J. Am. Chem. Soc. 2017, 139, 2932. (j) He, C.; Hu, J.; Wu, Y.; Ding, H. J. Am. Chem. Soc. 2017, 139, 6098. (2) (a) Fujita, E.; Shibuya, M.; Nakamura, S.; Okada, Y.; Fujita, T. J. Chem. Soc., Chem. Commun. 1972, 1107. (b) Fujita, E.; Shibuya, M.; Nakamura, S.; Okada, Y.; Fujita, T. J. Chem. Soc., Perkin Trans. 1 1974, 165. (3) 13-desoxyeffusin: (a) Kenny, M. J.; Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1986, 27, 3923. (b) Kenny, M. J.; Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1986, 27, 3927. Semisynthesis of longirabdolactone: (c) Adamson, G.; Mander, L. N. Aust. J. Chem. 2003, 56, 805. (4) Pan, Z.; Zheng, C.; Wang, H.; Chen, Y.; Li, Y.; Cheng, B.; Zhai, H. Org. Lett. 2014, 16, 216. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E (5) 64 Han, Q.-B.; Cheung, S.; Tai, J.; Qiao, C.-F.; Song, J.-Z.; Tso, T.-F.; Sun, H.-D.; Xu, H.-X. Org. Lett. 2006, 8, 4727. (6) Cha, J. Y.; Yeoman, J. T.; Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 14964. (7) Fujita, E.; Fuji, K.; Sai, M.; Node, M.; Watson, W. H.; Zabel, V. J. Chem. Soc., Chem. Commun. 1981, 899. (8) Seminal reports of SmII-mediated pinacol couplings: (a) Namy, J. L.; Souppe, J.; Kagan, H. B. Tetrahedron Lett. 1983, 24, 765. (b) Molander, G. A.; Kenny, C. J. Org. Chem. 1988, 53, 2132. Selected examples of SmII-mediated ketone-ester reductive couplings: (c) Hasegawa, E.; Okamoto, K.; Tanikawa, N.; Nakamura, M.; Iwaya, K.; Hoshi, T.; Suzuki, T. Tetrahedron Lett. 2006, 47, 7715. (d) Liu, Y.; Zhang, Y. Tetrahedron Lett. 2001, 42, 5745. (e) Iwaya, K.; Nakamura, M.; Hasegawa, E. Tetrahedron Lett. 2002, 43, 5067. (f) Iwaya, K.; Tamura, M.; Nakamura, M.; Hasegawa, E. Tetrahedron Lett. 2003, 44, 9317. (g) Li, H.; Fu, B.; Wang, M. A.; Li, N.; Liu, W. J.; Xie, Z. Q.; Ma, Y. Q.; Qin, Z. Eur. J. Org. Chem. 2008, 1753. Other examples of ketone-ester reductive couplings: (h) Miyazaki, T.; Maekawa, H.; Yonemura, K.; Yamamoto, Y.; Yamanaka, Y.; Nishiguchi, I. Tetrahedron 2011, 67, 1598. (i) Kise, N.; Arimoto, K.; Ueda, N. Tetrahedron Lett. 2003, 44, 6281. (9) Seminal reports of stoichiometric PdII-mediated silyl enol ether oxidative cyclizations: (a) Ito, Y.; Aoyama, H.; Hirao, T.; Mochizuki, A.; Saegusa, T. J. Am. Chem. Soc. 1979, 101, 494. (b) Kende, A. S.; Roth, B.; Sanfilippo, P. J. J. Am. Chem. Soc. 1982, 104, 1784. For the development of PdII-catalyzed Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 65 cyclizations, see: (c) Toyota, M.; Wada, T.; Fukumoto, K.; Ihara, M. J. Am. Chem. Soc. 1998, 120, 4916. (d) Toyota, M.; Rudyanto, M.; Ihara, M. J. Org. Chem. 2002, 67, 3374. For a review, see: (e) Toyota, M.; Ihara, M. Synlett 2002, 1211. Selected synthetic examples: (f) Kende, A. S.; Roth, B.; Sanfilippo, P. J.; Blacklock, T. J. J. Am. Chem. Soc. 1982, 102, 5808. (g) Jeker, O. F.; Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 3474. (h) Nicolaou, K. C.; Tria, G. S.; Edmonds, D. J.; Kar, M. J. Am. Chem. Soc. 2009, 131, 15909. (i) Varseev, G. N.; Maier, M. E. Angew. Chem., Int. Ed. 2009, 48, 3685. (j) Toyota, M.; Sasaki, M.; Ihara, M. Org. Lett. 2003, 5, 1193. (k) Toyota, M.; Odashima, T.; Wada, T.; Ihara, M. J. Am. Chem. Soc. 2000, 122, 9036. (10) For the preparation of similar bridged ring systems by AuI-catalyzed cyclizations of alkynyl silyl enol ethers, see: (a) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.; LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991. (b) Huwyler, N.; Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 13066. (c) Lu, Z.; Li, Y.; Deng, J.; Li, A. Nature Chem. 2013, 5, 679. (11) For the formation of all-carbon quaternary centers from silyl enol ether precursors, see references 19b, d, f, and g. For diester, ketoester, and lactam-ester precursors, see: (a) Takeda, K.; Toyota, M. Tetrahedron 2011, 67, 9909. For ketonitrile precursors, see: (b) Kung, L.-R.; Tu, C.-H.; Shia, K.-S.; Liu, H.-J. Chem. Commun. 2003, 2490. For the formation of a tertiary center via PdIImediated oxidative cyclization of a silyl ketene acetal, see: (c) Hibi, A.; Toyota, M. Tetrahedron Lett. 2009, 50, 4888. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 66 (12) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011. (13) Wang, Y.-F.; Gao, Y.-R.; Mao, S.; Zhang, Y.-L.; Guo, D.-D.; Yan, Z.-L.; Guo, S.H.; Wang, Y.-Q. Org. Lett. 2014, 16, 1610. (14) (a) DeSolms, S. J. J. Org. Chem. 1976, 41, 2650. (b) Taylor, E. C.; Shvo, Y. J. Org. Chem. 1968, 33, 1719. (15) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62, 6974. (16) Spectroscopic data obtained were consistent with isolation data reported by Node and coworkers: (a) Node, M.; Sai, M.; Fuji, K.; Fujita, E.; Shingu, T.; Watson, W. H.; Grossie, D. Chem. Lett. 1982, 2023. For additional spectroscopic data, see also (b) Fuji, K.; Node, M.; Sai, M.; Fujita, E.; Takeda, S.; Unemi, N. Chem. Pharm. Bull. 1989, 37, 1472. (c) Fuji, K.; Node, M.; Sai, M.; Fujita, E.; Shingu, T.; Watson, W. H.; Grossie, D. A.; Zabel, V. Chem. Pharm. Bull. 1989, 37, 1465. (d) Yunlong, X.; Ming, W. Phytochemistry 1989, 28, 1978. (e) Osawa, K.; Yasuda, H.; Maruyama, T.; Morita, H.; Takeya, K.; Itokawa, H. Phytochemistry 1994, 36, 1287. (17) Spectroscopic data obtained were consistent with isolation data reported by Fujita and coworkers: Fujita, T.; Takeda, Y.; Shingu, T. Heterocycles, 1981, 16, 227. (18) Reisman, S. E.; Ready, J. M.; Hasuoka, A.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc. 2006, 128, 1448.  Appendix 1 – Spectra Relevant to Chapter 2 67 Appendix 1 Spectra Relevant to Chapter 2: Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 10 9 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 2.500 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7127407 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 40 sec Sample #13, Operator: yeomanjo 8 7 6 5 TBSO 4 O S1 0.99 1.03 Me Me O 3.09 1.08 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: May 31 2012 2.09 HO 3 2 1.06 1.08 4.13 Sample Name: jtsy-viii-101 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-viii-101 FidFile: PROTON01 1 0.48 3.21 3.24 1.76 1.16 3.22 2.93 9.85 jtsy-viii-101 ppm Appendix 1 – Spectra Relevant to Chapter 2 68 6.08 1.00 1.05 1.03 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 512 repetitions OBSERVE C13, 125.6528709 MHz DECOUPLE H1, 499.7152303 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 1.0 Hz FT size 65536 Total time 17 min 180 Sample #13, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 31 2012 Sample Name: jtsy-viii-101 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-viii-101 FidFile: CARBON01 jtsy-viii-101 160 140 120 TBSO Me Me O 100 S1 HO 80 O 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 69 10 0.94 9 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 2.500 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7127410 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 40 sec Sample #48, Operator: yeomanjo 8 7 6 5 TBSO Me Me 2.03 O 4 66 O O 3 2 2.01 1.04 0.96 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: May 30 2012 1 2.08 2.01 1.05 0.99 2.98 2.91 9.41 Sample Name: jtsy-viii-097 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-viii-097 FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 70 6.03 3.97 2.00 0.94 1.01 0.99 0.96 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 512 repetitions OBSERVE C13, 125.6528718 MHz DECOUPLE H1, 499.7152303 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 17 min 180 Sample #48, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 30 2012 Sample Name: jtsy-viii-097 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-viii-097 FidFile: CARBON01 160 140 120 100 TBSO Me Me O 80 66 O O 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 71 10 9 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 2.500 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7225128 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 40 sec Sample #20, Operator: yeomanjo 8 7 6 5 2.24 Me TBSO 4 Me 67 1.08 1.08 1.03 1.03 1.03 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Mar 15 2012 O H 3 H O 1.00 HO 2 1 2.05 1.16 4.55 4.30 8.84 H ppm 2.98 3.00 Sample Name: jtsy-vii-089char Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-vii-089char FidFile: PROTON01 Appendix 1 – Spectra Relevant to Chapter 2 72 2.17 1.09 4.49 5.45 1.03 1.08 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 512 repetitions OBSERVE C13, 125.6553299 MHz DECOUPLE H1, 499.7250019 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 17 min 180 Sample #20, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Mar 15 2012 Sample Name: jtsy-vii-089char Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-vii-089char FidFile: CARBON01 160 140 120 100 Me TBSO Me 67 HO 80 H O H O 60 H 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 73 10 9 8 7 6 Me 1.05 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 2.500 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7225195 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 40 sec 5 68 2.14 Me TBSO H O H O 1.01 1.01 1.02 1.01 1.02 Sample #14, Operator: yeomanjo 4 3 2 5.32 MOMO H 1 3.87 3.12 9.25 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Feb 14 2012 ppm 3.03 3.09 Sample Name: jtsy-vii-191char Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-vii-191char FidFile: PROTON01 Appendix 1 – Spectra Relevant to Chapter 2 74 1.36 2.13 1.04 3.35 1.01 1.00 3.14 1.03 1.02 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 512 repetitions OBSERVE C13, 125.6553270 MHz DECOUPLE H1, 499.7250019 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 17 min 180 Sample #14, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Feb 14 2012 Sample Name: jtsy-vii-191char Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-vii-191char FidFile: CARBON01 160 140 Me 120 Me TBSO O H H 100 68 MOMO H O 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 75 10 9 8 7 6 Me 1.01 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 2.500 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7225125 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 40 sec 5 64 2.00 Me TBSO H O 4 OTBS 0.91 1.00 0.97 1.95 Sample #20, Operator: yeomanjo 3 2 0.88 0.95 1.93 MOMO H 1 4.37 2.99 3.68 9.37 10.19 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Feb 28 2012 ppm 5.77 2.76 3.40 Sample Name: jtsy-vii-231plug Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-vii-231plug FidFile: PROTON01 Appendix 1 – Spectra Relevant to Chapter 2 76 3.84 1.89 0.92 2.93 0.98 0.98 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 1700 repetitions OBSERVE C13, 125.6553261 MHz DECOUPLE H1, 499.7250019 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 1.0 Hz FT size 65536 Total time 58 min 180 Sample #20, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Feb 28 2012 Sample Name: jtsy-vii-231plug Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-vii-231plug FidFile: CARBON01 160 140 Me TBSO Me 120 64 MOMO H O H 100 OTBS 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 77 10 9 Relax. delay 2.000 sec Pulse 45.0 degrees Acq. time 3.000 sec Width 7995.2 Hz 8 repetitions OBSERVE H1, 499.7049152 MHz DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 0 min 40 sec Sample #46, Operator: yeomanjo 8 7 6 5 69 O 0.99 0.97 Me O 4 OMOM 0.90 Me TBSO 0.99 1.14 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Jan 23 2013 3 2 0.90 1.02 2.02 2.04 1.06 H 1 3.21 3.01 10.43 Sample Name: jtsy-ix-081B-f23-39 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-081B-f23-39 FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 78 6.73 3.07 1.07 2.64 0.94 0.98 1.01 3.01 2.10 2.03 220 200 Relax. delay 0.100 sec Pulse 45.0 degrees Acq. time 1.043 sec Width 31421.8 Hz 48000 repetitions OBSERVE C13, 125.6871022 MHz DECOUPLE H1, 499.8513810 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 2.0 Hz FT size 65536 Total time 15 hr, 14 min Temp. 25.0 C / 298.1 K Operator: yeomanjo 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Jan 12 2012 FidFile: jtsy-vii-125-c13 Sample directory: Sample Name: jtsy-vii-125 Data Collected on: daytona.caltech.edu-inova500 Archive directory: 160 140 Me 120 Me TBSO H O 69 O 100 80 OMOM 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 79 Me TBSO Me H 69 O O OMOM Appendix 1 – Spectra Relevant to Chapter 2 80 Me TBSO Me H 69 O O OMOM Appendix 1 – Spectra Relevant to Chapter 2 81 Me TBSO Me H 69 O O OMOM Appendix 1 – Spectra Relevant to Chapter 2 82 Me TBSO Me H 69 O O OMOM Appendix 1 – Spectra Relevant to Chapter 2 83 10 9 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 3.000 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7049153 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 44 sec 8 7 Me TBSO 6 Me 79 O H 5 O Me 0.93 0.99 1.03 0.95 0.98 Sample #46, Operator: yeomanjo 4 O 3 0.90 H 2 1.90 1.99 3.01 1.10 1.18 0.90 1.07 1.04 6.35 MOMO H 1 2.52 1.08 3.38 3.07 10.32 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Jun 13 2013 ppm 3.41 3.28 Sample Name: jtsy-ix-199f30-35 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-199f30-35 FidFile: PROTON01 Appendix 1 – Spectra Relevant to Chapter 2 84 3.00 1.00 1.00 220 200 Relax. delay 0.100 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 3000 repetitions OBSERVE C13, 125.6509014 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 2.0 Hz FT size 65536 Total time 57 min 180 Sample #46, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Jun 13 2013 Sample Name: jtsy-ix-199f30-35 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-199f30-35 FidFile: CARBON01 160 Me 140 Me TBSO H O 120 79 MOMO H H O 100 Me O 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 85 10 9 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 3.000 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7049151 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 44 sec Sample #32, Operator: yeomanjo 8 7 6 Me TBSO Me O 5 71 O 4 OMOM 0.86 0.92 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Mar 5 2013 3 2 1.08 0.90 O 1 3.37 12.80 H ppm 3.03 3.01 0.96 2.00 Sample Name: jtsy-ix-133Bf15-23 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-133Bf15-23 FidFile: PROTON01 Appendix 1 – Spectra Relevant to Chapter 2 86 1.53 1.33 3.19 1.13 1.79 0.84 1.94 1.06 1.91 3.17 0.91 0.91 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 1000 repetitions OBSERVE C13, 125.6509033 MHz DECOUPLE H1, 499.7074131 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 1.0 Hz FT size 65536 Total time 34 min 180 Sample #32, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Mar 5 2013 Sample Name: jtsy-ix-133Bf15-23 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-133Bf15-23 FidFile: CARBON01 160 140 Me TBSO 120 Me H O 71 O O 100 OMOM 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 87 10 9 8 7 6 0.92 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 3.000 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7049151 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 44 sec Me 72 O 5 OMOM 0.99 1.99 O 0.87 0.94 Sample #39, Operator: yeomanjo Me TBSO 0.96 O 4 3 1.00 H 2 1 3.31 3.67 9.73 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Feb 13 2013 ppm 3.17 2.96 Sample Name: jtsy-ix-107 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-107 FidFile: PROTON01 Appendix 1 – Spectra Relevant to Chapter 2 88 2.42 0.88 1.03 1.02 2.04 3.19 0.92 0.93 0.86 0.91 0.90 0.88 3.20 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 1000 repetitions OBSERVE C13, 125.6509014 MHz DECOUPLE H1, 499.7074131 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 1.0 Hz FT size 65536 Total time 34 min 180 Sample #39, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Feb 13 2013 Sample Name: jtsy-ix-107 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-107 FidFile: CARBON01 160 140 Me TBSO Me O 72 O 120 H O 100 OMOM 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 89 10 9 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 3.000 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7049151 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 44 sec 8 7 6 5 Me HO Me 1.01 1.01 Sample #39, Operator: yeomanjo 1.01 O 4 S2 O O OH 3 1.02 1.00 H 2 1.06 1.07 1.10 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Feb 15 2013 1 3.25 1.01 0.99 1.00 Sample Name: jtsy-ix-115f16-35 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-115f16-35 FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 90 3.64 2.15 1.09 1.83 3.91 2.53 1.01 1.01 220 200 Relax. delay 0.100 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 20000 repetitions OBSERVE C13, 125.6871032 MHz DECOUPLE H1, 499.8513810 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 3.0 Hz FT size 65536 Total time 6 hr, 20 min Temp. 25.0 C / 298.1 K Operator: yeomanjo 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Feb 17 2013 FidFile: jtsy-ix-115f16-35 Sample directory: Sample Name: jtsy-ix-115f16-35 Data Collected on: daytona.caltech.edu-inova500 Archive directory: 160 140 Me HO Me O S2 O 120 H O 100 OH 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 91 9 8 7 6 5 Me O O 4 0.92 O OH 3 (– )-trichorabdal A (12) H 0.91 10 0.95 Me 0.98 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.708 sec Width 9594.6 Hz 8 repetitions OBSERVE H1, 599.6348295 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 0 min 22 sec 0.96 O 0.91 3.15 Temp. 60.0 C / 333.1 K Operator: yeomanjo 1.02 H 2 0.82 Pulse Sequence: PROTON (s2pul) Solvent: pyridine Data collected on: Mar 13 2013 1 0.99 3.06 3.11 Sample Name: jtsy-ix-143prep Data Collected on: fid.caltech.edu-inova600 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-143prep FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 92 1.00 1.00 2.01 0.52 1.18 1.00 0.85 220 200 Relax. delay 0.100 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 13000 repetitions OBSERVE C13, 125.6870252 MHz DECOUPLE H1, 499.8512260 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 5.0 Hz FT size 65536 Total time 4 hr, 7 min Temp. 60.0 C / 333.1 K Operator: yeomanjo 180 Pulse Sequence: CARBON (s2pul) Solvent: pyridine Data collected on: Mar 15 2013 FidFile: jtsy-ix-143prep-c13 Sample directory: Sample Name: jtsy-ix-143prep Data Collected on: daytona.caltech.edu-inova500 Archive directory: 160 140 120 H Me O O O O OH 100 80 60 (– )-trichorabdal A (12) Me H 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 93 (– )-trichorabdal A (12) Me H H Me O O O O OH Appendix 1 – Spectra Relevant to Chapter 2 94 (– )-trichorabdal A (12) Me H H Me O O O O OH Appendix 1 – Spectra Relevant to Chapter 2 95 (– )-trichorabdal A (12) Me H H Me O O O O OH Appendix 1 – Spectra Relevant to Chapter 2 96 (– )-trichorabdal A (12) Me H H Me O O O O OH Appendix 1 – Spectra Relevant to Chapter 2 97 10 9 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 2.621 sec Width 6250.0 Hz 16 repetitions OBSERVE H1, 499.7049153 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 0 min 58 sec 8 7 6 5 Me O 4 73 O 1.00 1.02 Sample #27, Operator: vmak Me HO 2.00 H OH 3 2 1.08 1.01 3.04 1.73 1.94 1.05 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: May 1 2013 1 3.13 2.93 Sample Name: VWM2-007-c2f13-24 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-007-c2f13-24 FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 98 3.16 1.08 2.15 2.02 1.08 1.96 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 1000 repetitions OBSERVE C13, 125.6509033 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 1.0 Hz FT size 65536 Total time 34 min Sample #27, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 1 2013 Sample Name: VWM2-007-c2f13-24 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-007-c2f13-24 FidFile: CARBON01 160 Me 140 Me HO H O 120 73 O OH 100 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 99 0.94 10 9 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.705 sec Width 9611.9 Hz 8 repetitions OBSERVE H1, 599.6357305 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 0 min 22 sec Temp. 25.0 C / 298.1 K Operator: vmak 8 7 6 5 2.07 0.80 1.04 Pulse Sequence: PROTON (s2pul) Solvent: CDCl3 Data collected on: May 9 2013 Me H 1.02 4 Me O H O 74 O 3 OH 2 1.05 1.10 1.13 1.87 1.05 0.90 1.18 2.00 Sample Name: VWM2-019 Data Collected on: fid.caltech.edu-inova600 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-019 FidFile: PROTON01 1 4.17 1.09 1.17 3.00 3.18 VWM2-019 ppm Appendix 1 – Spectra Relevant to Chapter 2 100 220 200 Relax. delay 0.500 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 2250 repetitions OBSERVE C13, 125.6509043 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 4.0 Hz FT size 65536 Total time 58 min Sample #22, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 9 2013 Sample Name: VWM2-019-comb Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-019-comb FidFile: CARBON01 160 140 120 100 80 60 Me H Me O H O 40 74 O 20 OH 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 101 0.93 10 9 Relax. delay 2.000 sec Pulse 45.0 degrees Acq. time 2.048 sec Width 8000.0 Hz 32 repetitions OBSERVE H1, 499.7049153 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 2 min 10 sec 8 7 6 5 Me H 2.07 0.77 1.04 Sample #35, Operator: vmak O 75 O 4 Me O H 3 OAc 2 0.98 1.08 1.00 1.00 2.13 3.12 2.96 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: May 7 2013 1 1.84 3.09 3.13 Sample Name: VWM2-017-f14-19 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-017-f14-19 FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 102 1.08 6.57 1.00 220 200 Relax. delay 0.500 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 2250 repetitions OBSERVE C13, 125.6509033 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 4.0 Hz FT size 65536 Total time 58 min Sample #21, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 9 2013 Sample Name: VWM2-021-comb Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-021-comb FidFile: CARBON01 160 140 Me Me O 120 H H O 75 O 100 OAc 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 103 10 9 8 7 6 Me Me O OH OAc 4 5 76 OH 1.04 0.99 Relax. delay 2.000 sec Pulse 45.0 degrees Acq. time 2.621 sec Width 6250.0 Hz 32 repetitions OBSERVE H1, 499.7049149 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 2 min 28 sec H 1.07 0.97 0.98 Sample #33, Operator: vmak 3 2 0.98 2.08 1.03 1.08 2.20 3.14 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: May 17 2013 1 3.42 3.09 2.13 3.01 3.02 Sample Name: VWM2-033c Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-033c FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 104 1.06 1.10 0.96 220 200 Relax. delay 0.100 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 3000 repetitions OBSERVE C13, 125.6509004 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 57 min Sample #33, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 17 2013 Sample Name: VWM2-033c Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-033c FidFile: CARBON01 160 140 Me 120 Me H OAc 100 O OH 76 OH 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 105 10 9 Relax. delay 2.000 sec Pulse 45.0 degrees Acq. time 2.621 sec Width 6250.0 Hz 128 repetitions OBSERVE H1, 499.7049153 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 9 min 53 sec 8 7 6 5 1.00 1.00 0.99 Sample #36, Operator: vmak Me 4 O OH OAc 77 2.04 Me H 3 2 2.04 1.01 2.26 3.21 1.08 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Jun 5 2013 1 1.07 1.13 2.11 3.19 1.07 1.07 3.00 2.93 Sample Name: VWM2-025-652013 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-025-652013 FidFile: PROTON02 ppm Appendix 1 – Spectra Relevant to Chapter 2 106 2.11 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 8000 repetitions OBSERVE C13, 125.6509021 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 4 hr, 33 min Sample #36, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Jun 5 2013 Sample Name: VWM2-025-652013 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-025-652013 FidFile: CARBON01 160 140 Me 120 Me H 77 OAc 100 O OH 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 107 10 9 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 3.000 sec Width 8000.0 Hz 32 repetitions OBSERVE H1, 499.6951455 MHz DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 2 min 8 sec 8 7 6 Me 5 Me HO O 78 O 1.05 1.00 0.97 Sample #18, Operator: vmak 1.00 1.00 H 4 OAc 1.03 1.02 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Jan 21 2014 3 2 4.22 1.21 1.06 Sample Name: VWM3-063 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM3-063 FidFile: PROTON05 1 1.69 1.66 3.35 3.23 VWM3-063 ppm Appendix 1 – Spectra Relevant to Chapter 2 108 2.32 4.34 1.06 1.05 1.02 0.98 0.99 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 5000 repetitions OBSERVE C13, 125.6484443 MHz DECOUPLE H1, 499.6976415 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 2.0 Hz FT size 65536 Total time 2 hr, 50 min Sample #18, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Jan 21 2014 Sample Name: VWM3-063 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM3-063 FidFile: CARBON01 VWM3-063 160 140 Me HO Me O 78 O 120 H 100 OAc 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 109 10 9 8 7 6 Me 0.97 5 Me 1.00 O 4 O OH OAc 79 OH 0.99 1.00 Relax. delay 2.000 sec Pulse 45.0 degrees Acq. time 2.621 sec Width 6250.0 Hz 64 repetitions OBSERVE H1, 499.7049153 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 4 min 56 sec H 1.01 Sample #22, Operator: vmak 3 2 2.13 1.06 2.99 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Jun 13 2013 1 1.02 1.06 2.28 2.00 3.83 3.01 3.06 Sample Name: VWM2-063-f24-41 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-063-f24-41 FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 110 1.03 2.15 0.94 220 200 Relax. delay 0.100 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 3100 repetitions OBSERVE C13, 125.6509011 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 1.0 Hz FT size 65536 Total time 59 min Sample #34, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 24 2013 Sample Name: VWM2-043-f26-36 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-043-f26-36 FidFile: CARBON01 160 140 Me Me O 100 O OH OAc 79 OH 120 H 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 111 10 9 8 7 6 0.99 O OH OAc 5 4 (– )-longikaurin E (11) Me 1.02 0.97 1.04 Relax. delay 2.000 sec Pulse 45.0 degrees Acq. time 2.621 sec Width 6250.0 Hz 128 repetitions OBSERVE H1, 499.7049153 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 9 min 53 sec Me 1.00 O 0.91 Sample #35, Operator: vmak 0.99 1.00 OH 3 0.99 H 1 2 1.06 1.02 2.99 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Jun 23 2013 1.05 1.01 2.21 2.04 2.84 3.02 3.06 Sample Name: VWM2-067-c2 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-067-c2 FidFile: PROTON06 ppm Appendix 1 – Spectra Relevant to Chapter 2 112 1.02 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 12500 repetitions OBSERVE C13, 125.6509014 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 7 hr, 7 min Sample #20, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Jun 22 2013 Sample Name: VWM2-067-c2 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-067-c2 FidFile: CARBON01 160 Me OH O OH O OAc 140 120 100 (– )-longikaurin E (11) Me H 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 113  Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 114 Chapter 3 Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 3.1 INTRODUCTION The diterpenoid alkaloids have garnered much attention from the synthetic community due to their structural complexity and compelling biological activity.1 Early efforts in the 1960s were directed towards classic targets such as C20 veatchine2 and atisine type alkaloids,3 and later, pioneering work towards C19 aconitine type alkaloids.4 More recently, synthetic studies towards more complex C20 hetidine and hetisine type alkaloids have sparked a new interested in the field,5 specifically towards the C18 and C19 natural products. This chapter reviews completed total syntheses of natural products that bear the aconitine core (e.g. C18- and C19-diterpenoid alkaloids), as well as syntheses of related C20-diterpenoid alkaloids employing divergent strategies. Lastly, a detailed account of our own progress towards talatisamine, a C19 aconitine type alkaloid, is Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 115 presented, as well as a unified strategy to access C20 denudatine and napelline type alkaloids in a non-biomimetic manner. 3.2 STRUCTURAL AND BIOSYNTHETIC CONSIDERATIONS A major challenge in the synthesis of diterpenoid alkaloids is construction of the highly caged polycyclic framework. The C18- and C19-diterpenoid alkaloids possess a complex hexacyclic skeleton that is abundantly decorated with oxygenated functionality (Figure 3.1). Specifically, a piperidyl E-ring bridges the hydrindane AF-ring system, that is adjoined to a bicyclo[3.2.1] CD-rings through the central cyclohexyl B-ring. The AF/B-C rings also constitute a 6/7/5-ring system rearranged from a 6/6/6-phenanthrene core. The natural products possess at least 11 contiguous stereocenters that include two quaternary centers at C4 and C11 at the bridgehead positions of the AE bicycle. Ring labelling and atom numbering 13 12 17 2 Et 1 A NE 3 4 19 C 14 9 D 10 11 F 5 6 2 3 16 18 4 A 1 19 R B 8 15 NEt 5 11 10 17 6 12 7 9 7 8 NEt R E F B 15 C 18 R 14 13 OMe MeO OMe D 16 NEt OH MeO N Et H OMe HO talatisamine (34) HO HO OMe Figure 3.1. Structural depictions of C19-Diterpenoid Alkaloids Although there have only been a handful of completed syntheses of C19- and C18diterpenoid alkaloids, several reports, most of which detail approaches to the AEF or CD 116 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine rings, have been published.6 A majority of the successful syntheses have employed Diels–Alder cycloadditions to form a [2.2.2]-bicycle and Wagner–Meerwein rearrangement to generate the [3.2.1]-bicyclic CD-ring system. These strategies have relied on the biomimetic rearrangement of the C20 denudatine skeleton into the C19 aconitine framework. Chemical evidence for this transformation was first demonstrated by Johnston and Overton, who were able to convert atisine to derivative 80, containing a tosylate leaving group (Figure 3.2). 7 Gas phase pyrolysis at 500 °C successfully converted the [2.2.2]-bicycle into the [3.2.1]-bicycle of 81 in 77% yield. Wiesner also achieved a solution phase Wagner–Meerwein rearrangement several years later, in a tricyclic model system.4b Under solvolytic conditions, tosylate 82 underwent rearrangement to tricycles 83 as a 1:1 mixture of olefins. This biomimetic conversion was key to their strategy to access C19 aconitine and C20 napelline type alkaloids. Johnston and Overton (1971) NAc Me 0.5 mmHg 500 °C Wiesner (1975) Me 2N (77% yield) TsO O 80 NH NAc Me TsO O 81 X OMe 82 X = -OCH2CH2O- NMe 2 DMSO 180 °C O O (85% yield) OMe 83 1:1 olefin isomers Figure 3.2. Chemical support for biomimetic Wagner–Meerwein rearrangements. 3.3 PRIOR TOTAL SYNTHESES 3.3.1 Wiesner’s Synthesis of C19- and C20-Diterpenoid Alkaloids Wiesner’s landmark synthesis of talatisamine (34) in 1974 constitutes the first total synthesis of a C19-diterpenoid alkaloid.4a Implementation of the Wagner–Meerwein Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 117 rearrangement in the more complex context of total synthesis proved challenging, but was eventually accomplished during the late stage of the synthesis. The synthesis begins with an initial Diels–Alder cycloaddition between bicycle 84 and diene 85 afforded two diastereomeric tricycles that were independently advanced to sulfonamide 86 (Figure 3.3).4b Deprotonation by sodium hydride and cyclization afforded the piperidine ring, and after mesylate reduction and methylation, provided aromatic intermediate 87. At this stage, a dissolving metal reduction, amine acylation, and olefin isomerization afforded enone 88, which readily underwent [2 + 2] cycloaddition with allene to furnish cyclobutane 89. Another three steps involving oxidative cleavage of the exocyclic olefin, generated cyclobutanol 90, and upon exposure to Brønsted acid, underwent a retro-aldol reaction to ketoaldehyde 91 and intramolecular aldol cyclization to provide the [2.2.2]bicycle of atisine framework 92. A further seven steps were required to install the tosylate leaving group of 93 in the requisite stereochemical configuration. With tosylated atisine analogue 93, the biomimetic Wagner–Meerwein rearrangement would forge the [3.2.1]-bicyclic CD-rings of talatisamine (34). Under previously described conditions employing a tetramethylguanidine base at elevated temperatures, 93 underwent rearrangement to presumably produce carbocationic intermediate 94, and subsequently, an equimolar mixture of olefinic isomers 95 and 96 (Figure 3.4). Although the rearrangement proceeded in good overall yield, isomer 95 could not be advanced in a productive manner; only isomer 96 was carried forward to pentacycle 97. Upon mercuric acetate-mediated oxidation, a biomimetic aza-Prins cyclization formed the last C7–C17 bond, completing the first total synthesis of a C19diterpenoid alkaloid, talatisamine (34). 118 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine OMs MsO OAc CN H 18 steps OMe NHMs + OMe NMs MeO 1. NaH 2. Red-Al 3. NaH, MeI OAc OMe OMe 84 85 86 OMe NAc MeO 1. Na/NH 3 2. Ac2O 87 OMe 1. HO(CH 2)2OH 2. OsO 4, NaIO 4 hυ 3. HCl, MeOH 88 3. NaBH 4 O 89 OMe NAc MeO X = –OCH2CH2O– O OMe NAc 7 steps X = –OCH2CH2O– O O 92 X OH 90 MeO OMe NAc MeO HCl 91 OMe NAc MeO OMe NAc MeO TsO O OH X OMe 93 Figure 3.3. Synthesis of Wagner–Meerwein rearrangement precursor 93. NH OMe NAc MeO Me 2N TsO OMe NAc MeO OMe NAc MeO NMe 2 + DMSO 180 °C X OMe OMe NAc MeO O X = –OCH2CH2O– O 93 O OMe 94 OMe NEt MeO 3 steps 17 96 7 O O O OMe 95 (40% yield) OMe NEt MeO OMe NEt MeO Hg(OAc) 2 H H 2O (40% yield) HO OMe 97 OMe 96 (40% yield) HO OMe 98 Figure 3.4. Wiesner’s total synthesis of talatisamine (34). HO HO 34 OMe 119 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine In an effort to improve the synthesis, Wiesner and coworkers hypothesized that performing the biomimetic rearrangement with the C7–C17 bond in place would preclude the unproductive, strained olefin isomer 95. Accordingly, they began synthetic efforts towards 13-desoxydelphonine (99), which possesses a C6-methoxy group. Olefin 100 was synthesized in 11 steps from o-cresol, and then engaged in an aziridination and azasemipinacol rearrangement of 101 to form the C7–C17 bond (aconitine numbering) of acetamide 102 (Figure 3.5). A 20-step sequence appended a cyclohexyl ring bearing a methyl ester (103), and another 5 steps involving lactam formation provided aromatic intermediate 104. Most importantly, this intermediate (104) possesses the C7–C17 bond that was absent in their first generation synthesis of talatisamine (34). H NAc NHAc 17 CO2Me 1. TMSN3 CO2Me 2. Ac2O, AcOH 85 °C Me MeO Me 7 101 102 O AcO NHAc 20 steps OMe 17 O MOMO 7 MeO O OMe 103 MeN Me O 5 steps OAc MeO AcOH (75% yield) 100 11 steps from o-cresol Me MeO CO2Me MeO OMe O NMe OMe 17 17 MeO 7 OMe MOMO 7 MeO 104 MOMO OH Figure 3.5. Synthesis of pentacyclic aromatic intermediate 104. From aromatic intermediate 104, the endgame strategy mirrors that of their synthesis of talatisamine (34), however with the C7–C17 bond in place, significant improvements were observed. Rather than a reductive dearomatization, three steps involving oxidative dearomatization of arene 104 provided diene 105 as a mixture of 120 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine diastereomers and brominated/unbrominated products (Figure 3.6). The mixture of products underwent an intermolecular Diels–Alder cycloaddition with benzyl vinyl ether, and after global reduction with zinc metal, afforded a single hexacyclic product 106 that comprises the C20 denudatine framework. Elaboration of 106 to hexacyclic intermediate 107 required 12 steps, thereby installing a bromide leaving group for the crucial rearrangement. Under previously described conditions, the Wagner–Meerwein rearrangement of bromide 107 proceeded smoothly to afford aconitine framework 108 as a single isomer in 89% yield. This rearrangement is a significant improvement from their previous synthesis, which provided a 1:1 mixture of olefinic isomers. A final four steps involving deprotection, reductions, and hydrations provided 13-desoxydelphonine (99). The fourth generation synthetic strategy obviated the low yielding aza-Prins cyclization, since the C7–C17 bond was formed at a relatively early stage in the synthesis. This seminal work leveraged the conversion of denudatine framework 107 into the aconitine framework 108, a finding that would be pivotal for the success of future syntheses. OMe O NMe MeO 3 steps 104 1. MeO R OBn MeO O O O O 106 105 R = H, Br (2:1) OMe O NMe MeO OMe O NMe MeO N O OMe O H Br 107 DMSO/o-xylene 180 °C (89% yield) OMe NMe MeO 4 steps N MeO 12 steps OBn 2. Zn, AcOH O OMe O NMe MeO H MeO O O HO OMe 108 H MeO HO OMe 13-desoxydelphonine (99) Figure 3.6. Wiesner’s total synthesis of 13-desoxydelphonine (99). 121 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine During the course of Wiesner’s work towards C19 aconitine type alkaloids, his group also explored the biomimetic conversion of the denudatine scaffold to the napelline scaffold through a similar Wagner–Meerwein rearrangement (Figure 3.7).8 Denudatine framework 109 was synthesized in a fashion analogous to the previously described synthesis of 13-desoxydelphonine (99). By installing a leaving group at C13 instead of C15, rearrangement of mesylate 109 occurred readily under reflux in acetic acid to furnish triacetate 110. This was advanced three steps to triketone 111, which constituted a formal synthesis of napelline (29) based on their earlier work.8c Me OAc O NEt OMs O Me 15 OAc OAc Me AcOH Me N Et MsO OAc Me O Me reflux 13 O (95% yield) OAc N Et 109 110 O 3 steps Ac OAc O Me Me Me O HO OH O OH N Et N Et 111 napelline (29) Figure 3.7. Wiesner’s total synthesis of napelline (29). Wiesner’s work towards the synthesis of C19- and C20-diterpenoid alkaloids was initially part of a structural elucidation effort, but undoubtedly inspired future syntheses that also feature elegant use of Wagner–Meerwein rearrangements for conversions of denudatine scaffolds to aconitine scaffolds. Although Wiesner’s syntheses cannot be held to the same standards as modern total synthesis, their influence on the field is incredibly significant, as the diterpenoid alkaloids remain formidable targets for total synthesis, even with modern synthetic methods. 122 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Gin’s Synthesis of Neofinaconitine 3.3.2 The next total synthesis of a diterpenoid alkaloid possessing the aconitine core came nearly four decades after Wiesner’s work. In Gin’s posthumous synthesis of the C18-diterpenoid alkaloid neofinaconitine (112), a convergent strategy was employed to assemble the aconitine scaffold and to access to synthetic material for stereochemical/structural confirmation.9 Notably, the synthesis did not utilize the same Wagner–Meerwein rearrangement as the past and future syntheses. In their retrosynthetic analysis, Gin and coworkers envisioned forming the C7–C8 bond of neofinaconitine (112) through a radical cyclization and the C11 quaternary center through an intramolecular Mannich reaction at C17 (Figure 3.8). The deconstructed polycycle 113 could be accessed in a convergent manner by Diels–Alder cycloaddition of dihydroazepinone 114 and siloxydiene 115. The fused cyclopropane of 115 could be prepared by another unusual Diels–Alder cycloaddition between siloxydiene 116 and cyclopropene 117. O NH 2 O OMe NEt O MeO 2C Mannich reaction 11 17 11 7 7 8 MeO O HO 8 radical cyclization OMe 17 Et N O CO2Me NEt Br 17 azepinone Diels–Alder H 7 H Br 11 O 8 MeO neofinaconitine (112) OR MeO OR 113 TBSO Et N cyclopropene Diels–Alder O CO2Me Br TBSO + + OMe 114 MeO 115 OTIPS 116 Figure 3.8. Gin’s retrosynthetic analysis of neofinaconitine (112). OR 117 123 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine O + OTIPS 118 119 [6 steps] 120 N Br 2. HBr/AcOH C6H 5F, 0 °C 122 Br (62% yield, 2 steps) OTIPS Et N (1 : 1.6) OTIPS 121 (desired) OMe O Me 1. TBAF, THF MeO MeO OTIPS MeO OMe N 4 steps + 0 °C MeO O TBSO TBSO Et 3N TBSOTf MeO 123 Et N O CO2Me 114 Br (87% yield) 1. MgBr Br 2. TBSOTf, KHMDS THF, –78 °C MeO (77% yield, 2 steps) 124 Et N CO2Me H O Br MeO TBSO O H SnCl4, 4 Å MS MeCN Me 126 single isomer 1. OsO 4, NMO, THF/H2O then Pb(OAc) 4 O CO2Me Br H H O 2. DBU, toluene (57% yield, 2 steps) MeO 127 O Figure 3.9. Convergent assembly of Mannich cyclization precursor 127. The C/D bicycle was generated at an early stage in the synthesis through a Diels– Alder cycloaddition between cyclopropene 119 and a siloxydiene generated in situ from cyclopentene 118 (Figure 3.9). This produced two isomeric cycloadducts 120 and 121 in a 1:1.6 ratio, in favor of the desired isomer. This mixture was advanced four steps to Weinreb amide 122, which was ultimately isolable as a single isomer. Since the cyclopropylmethyl silyl ether moiety of 122 was detrimental to diastereoselectivity of the ensuing azepinone Diels–Alder, it was converted to homoallyl bromide 123, which served as an α,β-unsaturated ketone precursor. Addition of vinyl-Grignard and silyl ether formation provided siloxydiene 124 as a single olefin isomer. With the homoallylic bromide of 124, it was suspected that the sterically large bromine atom would hinder the 124 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine “back” face of the diene and restrict rotation, thereby improving the diastereofacial selectivity. Remarkably, Diels–Alder cycloaddition with azepinone 114 in the presence of tin tetrachloride provided cycloadduct 126 in 87% yield as a single product. Lastly, homoallyl bromide 126 was converted to enone 127 by oxidative scission of the exocyclic olefin, followed by β-elimination of the bromide. Et N 17 Br CO2Me H 7 O O O H 1 11 8 O Br Tf2NH 7 CO2Me Et 3 N 17 1 CH2Cl2 8 O O MeO 2C 7 H 8 O MeO MeO 2C 1. TMSOTf, Et 3N 2. PhSeCl, 0 °C MeO 1. LiBH 4, THF 133 PhH, 80 °C O O NEt O MeO 2C NEt 1. Pd/C, H 2, EtOAc 2. NaBH 4, MeOH, 0 °C H 3. MeI, KOt-Bu, THF 0 °C H O MeO MeO HO O (30% yield, 3 steps) 132 NH 2 O OMe O NEt HO OMe NEt O 3 steps H H 2. CrO3, H 2SO4 (aq) (40% yield, 2 steps) O 129 131 OMe O (99% yield) MeO 3. NaIO 4, THF/H2O OMe O NEt HO 8 O MeO 2C (51% yield, 3 steps) H Bu 3SnH, AIBN 128 130 4 N 7 (66% yield, 2 steps) O NEt CO2Me Et 2. MsCl, Et 3N CH2Cl2, 50 °C O MeO O 127 1. CAN, CH 3CN H 2O, 60 °C 11 (75% yield) MeO Br MeO HO OMe 134 MeO HO OMe neofinaconitine (112) Figure 3.10. Gin’s total synthesis of neofinaconitine (112). The assembly of the aconitine core required two crucial C–C bond formations. The C11–C17 bond was to be formed by an intramolecular Mannich-type N-acyliminium cyclization, and the C7–C8 bond was to be formed by an intramolecular radical cyclization. Protonation of enamide 127 with triflimide produced an N-acyliminium ion that underwent Mannich reaction with a C1–C11 enol to forge the desired C11–C17 bond Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 125 (Figure 3.10). Unfortunately, the C1 ketone underwent cyclization onto the D-ring enone to forge the unproductive C8–O bond of 128. Cleavage of this undesired C8–O bond required three steps, and was accomplished by allylic oxidation at C3, followed by mesylation and elimination to produce bis-enone 129. Remarkably, the radical cyclization proceeded smoothly to construct the C7–C8 bond of the aconitine core (130) in quantitative yield. To date, this remains the most expedient synthesis of the full aconitine scaffold. The remainder of the synthesis necessitated functional group interconversions to establish alcohol and methyl ether stereocenters, oxidative truncation of the C4 methyl ester, and selective acylation of the resulting C4 alcohol. The tertiary alcohol at C8 was introduced utilizing the D-ring ketone of 130 (Figure 3.10). Silyl enol formation and selenation provided an α-selenide that underwent oxidation/elimination by treatment with sodium meta-periodate. The transiently generated bridgehead olefin (131) readily underwent hydration to provide tertiary alcohol 132. Hydrogenation, borohydride reduction, and methylation provided 133 in 30% yield over three steps. Although this sequence terminated with a low yielding, non-selective bis-methylation, an efficient protocol involving global methylation and formal C8-OMe demethylation was developed in subsequent semisynthetic studies. From C19 acontine scaffold 133, borohydride reduction of the methyl ester was followed by oxidative truncation to provide the C4 alcohol of the C18-diterpenoid alkaloids (134). Finally, amide reduction and acylation provided neofinaconitine (112) in an additional three steps. Structural assignment of the synthetic material was also confirmed through relay synthesis from the C19-diterpenoid alkaloid condelphine. Gin’s synthesis of neofinaconitine (112) showcases the advantages 126 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine of a non-biomimetic, convergent strategy for the synthesis of highly caged, polycyclic frameworks. Sarpong’s Unified Strategy towards C20-, C19-, and C18Diterpenoid Alkaloids 3.3.3 Wiesner’s landmark syntheses of C19 aconitine type and C20 napelline type alkaloids demonstrated the viability of biomimetic conversions of denudatine scaffolds to napelline and aconitine scaffolds in total synthesis. These conversions would be employed once again in the synthesis of weisaconitine D (135) and liljestrandinine (154), which Sarpong reported as the first strategy to access both C18- and C19-diterpenoid alkaloids.10 In contrast to Gin’s synthesis of neofinaconitine (112), which oxidatively truncates the C4–C18 bond of a C19-framework,9 Sarpong’s synthesis excludes C18 for the synthesis of 135, and modularly constructs the C4–C18 bond of C19-diterpenoid alkaloid 154. In their retrosynthetic analysis of 135, the B-ring was identified as the maximally bridged ring, and was disconnected, along with the C/D-rings, to arene-olefin 136 (Figure 3.11). The maximally bridged piperidine E-ring of 136 was disconnected at the C19–N bond to arrive at hydrindane 137. This bicycle would serve as the divergence point for C19- and C20-diterpenoid alkaloids, which require quaternization at C4. Bicycle 137 would arise from a Diels–Alder cycloaddition between diene 138 and enone 139. H OMe NEt 4 OMe NEt H OMe OMe 4 B HO EtO OMe weisaconitine D (135) + CN MeO TBSO O MeO 2C E H HO TBSO 136 137 138 Figure 3.11. Sarpong’s retrosynthetic analysis of weisaconitine D (135). 139 127 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine The synthesis of weisaconitine D (135) proceeded in 30 steps from diene 138, which itself is available in five steps from commercial materials (Figure 3.12). A Diels– Alder cycloaddition between 138 dienophile 139 provided a cycloadduct that was hydrogenated to give bicycle 140. The ketone of 140 was converted to the vinyl triflate, which underwent cross-coupling with sodium cyanide to yield α,β-unsaturated nitrile 131 in 70% yield over the two steps. Next, a Rh-catalyzed conjugate addition with in situ generated lithium boronate 142 simultaneously generated two adjacent stereocenters in 143. The nitrile was stereospecifically converted to the carbamate through a Hoffmann rearrangement, with additional steps providing mesylate 144. Subjection to potassium tert-butoxide then effected intramolecular alkylation to forge the piperidine ring of 145 in 76% yield. Methoxymethyl ether cleavage and oxidative dearomatization afforded the intramolecular Diels–Alder substrate 146. OMe O MeO 2C + OMe 1. toluene, 110 °C 2. Pd/C, H 2, EtOAc TBSO (70% yield, 2 steps) TBSO 138 (70% yield, 2 steps) 140 OMe Li(MeO) 3B OMe OMOM CO2Me CN OMe TBSO H 141 2. CuI, NaCN, Pd(PPh 3)4 H 139 CO2Me CN 1. LiHMDS, PhNTf 2 CO2Me O 142 TBSO [RhCOD(OH)] 2 H 2O, 100 °C H 7 steps OMe OMOM 143 (60% yield) OMe H N MsO OMe H O THF 0 °C to rt MeO (76% yield) 144 MOMO H KOt-Bu OMe NCO 2Me O (98% yield, 2 steps) MOM H 1. HCl, i-PrOH 2. PhI(OAc) 2 NaHCO 3, MeOH MeO OMe NCO 2Me MeO MeO O 145 Figure 3.12. Preparation of intramolecular Diels–Alder precursor 146. 146 128 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Dienone 146 readily underwent cycloaddition in refluxing para-xylene to produce the bicyclo[2.2.2] moiety of 147 (Figure 3.13). Four functional group manipulations provided alcohol 148, and exposure to triflic anhydride generated an intermediate triflate that underwent the key Wagner–Meerwein rearrangement to forge the [3.2.1]-bicycle of 149. The rearrangement produced a single product, even though two isomeric alcohols are possible; presumably, the allylic isomer of 149 is precluded due to ring strain from a bridgehead olefin. Another eight steps were required to install the final C–O bond, the Nethyl group, and the C16 methoxy group of weisaconitine D (135). OMe NCO 2Me H OMe p-xylene MeO 150 °C MeO O (77% yield) NCO 2Me H 4 steps MeO O HO OMOM 147 148 OMe 146 1. Tf2O, Py, CH2Cl2 –78 °C to rt OMe NCO 2Me H OMe NCO 2Me H 8 steps OMe NEt H 2. DBU, DMSO, 120 °C (55% yield, 2 steps) MOMO HO 149 HO EtO 16 OMe weisaconitine D (135) C18 lappaconitine type Figure 3.13. Sarpong’s total synthesis of weisaconitine D (135). Extension of this strategy to the synthesis of C19- and C20-diterpenoid alkaloids necessitated quaternization at C4. To this end, alcohol 150 was oxidized under Swern conditions to the aldehyde (not shown) to facilitate α-functionalization (Figure 3.14). Unfortunately, attempts to alkylate the aldehyde were unfruitful, leading to decomposition or alkylation from the undesired α-face. Ultimately, an aldol-Cannizzaro sequence was developed to access a 1,3-diol that was subsequently mesylated to afford 129 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine bis-mesylate 151 with the C4 stereocenter ablated. At this stage, intramolecular Nalkylation provided the piperidine ring of tetracycle 152, and mesylate displacement with methoxide afforded the C18 methoxy group of 153. This was advanced to C19- diterpenoid alkaloid liljestrandinine (154) in a further 12 steps analogous to the weisaconitine D (135) synthesis. OMe OMe MsO 4 H N OMe H HO O MeO 1. DMSO, (COCl)2 Et 3N MsO 4 H N OMe H O 2. KOH, CH2O 3. MsCl, Py KOt-Bu THF, 50 °C MeO (78% yield, 3 steps) MOMO MsO 18 4 OMe NCO 2Me 1. NaOMe, MeOH MeO 2. K 2CO3, ClCO2Me (26% yield, 3 steps) MOMO 151 4 OMe NCO 2Me 12 steps 18 120 °C MeO MOMO 150 MeO MeO MOMO HO 152 OMe NEt 4 153 HO liljestrandinine (154) C19 aconitine type Figure 3.14. Sarpong’s total synthesis of liljestrandinine (154). By establishing a protocol to functionalize C4, bis-mesylate 151 is well suited for advancement to C20 denudatine type alkaloids.11 Optimal conditions for piperidine ring formation were identified using potassium hydride instead of potassium tert-butoxide, providing 154 in a substantially improved 83% yield (Figure 3.15). Reductive cleavage of the C18 mesylate to the methyl group and oxidative dearomatization/intramolecular Diels–Alder cycloaddition were accomplished in four steps to furnish hexacycle 155, which possesses the bicyclo[2.2.2] moiety of the denudatine type alkaloids. A final seven 130 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine steps of functional group interconversions provided cochlearenine (156), as well as Noxidized and C17-veratroylated natural analogues. OMe MsO MsO MsO H N OMe H O MeO Me NCO 2Me O MeO 155 O Me MeO NCO 2Me 4 steps MOMO 154 H OMe O 7 steps O Me O OH OH OH OMe N OMe DMF 151 OMe MeO 18 (83% yield) MOMO Me KH OMe 4 N Me cochlearenine (156) C 20 denudatine type Figure 3.15. Sarpong’s total synthesis of cochlearenine (156). The installation of stereocenters relies completely on diastereocontrol from stereocenters established in the initial Diels–Alder cycloaddition that forms the hydrindane unit. Thus, an enantioselective variant of the transformation would render the syntheses asymmetric. For this purpose, dienophile 157 was synthesized and utilized in a Cu-catalyzed enantioselective Diels–Alder cycloaddition with diene 138, providing cycloadduct 158 in 92% enantiomeric excess. The carbonylcarbamate functionality could be converted to the methyl ester by subjection to bismuth(III) triflate in methanol, and after re-protection of the silyl ether in the same pot, provides hydrindane 159 thereby intercepting an early intermediate in the syntheses. Sarpong’s synthetic strategy targets C18-, C19-, and C20-diterpenoid alkaloids in a modular fashion through C4 quaternization and biomimetic Wagner–Meerwein rearrangements of denudatine frameworks to aconitine frameworks. Specifically, by 131 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine diverging at an early stage in the synthesis through arene olefin 150 (see Figure 3.14), the strategy demonstrate that C18 variants need not necessarily derive from C19 or C20 variants through C4–C18 bond scission. These syntheses also highlight the potential of de novo syntheses to access biogenetically related diterpenoid alkaloids. OMe O O O TBSO R PhMe/CH 2Cl2, –20 °C 157 (68% yield) >20:1 dr, 92% ee 138 Me Ln = OMe [Cu-Ln ](OTf)2 (20 mol%) OMe N H + O t-Bu H Me O N O TBSO N t-Bu Bi(OTf) 3, MeOH then Et 3N, imid. TBSCl (63% yield) 158 (R = (CO)NHCO2Me) 159 (R = CO2Me) Figure 3.16. Enantioselective [4 + 2] for the synthesis of hydrindane 159. 3.3.4 Fukuyama’s Alkaloids Synthesis of C19- and C20-Diterpenoid In 2014, Fukuyama reported the first total synthesis of a C20 denudatine type alkaloid, lepenine (160).12 In their follow up study, an intermediate in their synthesis was advanced to the C19 aconitine type alkaloid, cardiopetaline (162), by employing a microwave-assisted Wagner–Meerwein rearrangement. 13 Both lepenine (160) and cardiopetaline (162) were accessed from common intermediate 161 (Figure 3.17). Retrosynthetically, lepenine (160) was proposed to arise from arene 163. Ultimately, their sequence for installing the bicyclo[2.2.2] moiety mirrored that of Wiesner’s fourth generation synthesis of 13-desoxydelphonine (99, see Figure 3.6). The C7–C20 bond (denudatine numbering) of 163 could be constructed by an intramolecular Mannich cyclization between the ketone of 164 and an in situ generated iminium ion. 132 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Coincidentally, the analogous C11–C17 bond of neofinaconitine (112) is also constructed by an intramolecular Mannich cyclization in Gin’s synthesis.9 The tricyclic core of 164 could be stereoselectively generated by an intramolecular Diels–Alder cycloaddition of 165, which possesses only a single stereogenic center. OH Me HO OH OH Me OH OMe NEt Me OH NEt Me OMe N N Me O MeO Me lepenine (160) C 20 denudatine type 161 common intermediate O Mannich reaction 7 Me O 20 HO HO cardiopetaline (162) C19 aconitine type OMe H OH OH H H OH Me 163 OMe OMe OMe N Et O H NHEt 164 O Me O O 165 Figure 3.17. Divergent strategy for lepenine (160) and cardiopetaline (162). The first stereogenic center is derived from L-lactic acid methyl ester. In two steps (not shown), allylic alcohol 166 was synthesized, and a tandem Johnson–Claisen rearrangement/Claisen rearrangement occurred upon refluxing in triethylorthoacetate to afford trans-olefin 167 in 85% yield (Figure 3.18). Mesylation, ozonolysis/reduction, and pivaloylation provided pivalate 168, which was determined to have an enantiomeric excess of 91%, indicating successful chirality transfer during the Claisen rearrangement. Friedel–Crafts acylation of an intermediate carboxylic acid afforded tetralone 169, which was advanced four steps to Diels–Alder precursor 170. In the subsequent cycloaddition, heating in the presence of a radical scavenger successfully constructed the phenanthrene 133 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine core of 171. At this stage, crystallization of intermediate 171 provided enantiomerically pure material. OMe O Me EtO 2C (EtO)3CMe, reflux 1. MsCl, Et 3N, 0 °C 2. O 3, then NaBH 4 OH 166 EtO 2C (58% yield, 3 steps) OPiv 167 168 91% ee OMe 1. LiOH, MeOH THF, 0 °C O OMe OMs 4 steps OMs BHT PhCN, 160 °C 2. TFAA, TFA OPiv (82% yield, 2 steps) O 169 O OMs H (84% yield) Me 170 OMe O H NEt O Alloc 171 recrystallized to >99% ee 2. AcCl/MeOH, then PhI(OAc) 2 (84% yield, 2 steps) OH Me N Et Pd(PPh 3)4, AcOH H CH2Cl2, reflux O (75% yield) Me OMe N Et OMs 173 172 OMe O OMe 174 O H OMs O 1. KOH, then NaBH 4 OMe 4 steps Me Me OMs 3. PivCl, Py, DMAP Me (85% yield) OH OMe OMe 4-NO2C6H 4OH (5 mol%) ethylene (70 bar) CH2Cl2, 70 °C (84% yield) OH Me N Et O OMe OMe 175 Figure 3.18. Synthesis of denudatine core 175. In four steps, the olefin of 171 was hydrated, and the bridging lactone is converted to aminoaldehyde 172. Upon Pd-catalyzed removal of the Alloc group, an intramolecular Mannich reaction occurred to provided pentacycle 173 in 75% yield. This single step constructs two bridged ring systems in the piperidine ring and bicyclo[2.2.1] moiety. From 173, cleavage of the mesylate, in situ borohydride reduction, and oxidative dearomatization then afforded ortho-quinone monoketal 174. Heating 174 under an 134 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine ethylene atmosphere smoothly furnished the bicyclo[2.2.2] system of 175, which constitutes the C20 denudatine core. OH NEt Me OH Me MeO O N Et 175 OMe O OMe 8 steps OMe 10 steps lepenine (160) NEt 1. µwave, MeOH 150 °C Me OMOM NEt O 176 (71% yield, 2 steps) OH NEt Me H 2SO4 (aq) 110 °C 2. NaBH(OAc)3 AcOH, 40 °C PhO 2S HO OH N Et OMOM Me OH Me HO OMe 177 (86% yield) HO HO cardiopetaline (162) Figure 3.19. Fukuyama’s total syntheses of lepenine (160) and cardiopetaline (162). With the denudatine core 175 in place, eight steps of standard functional group manipulations including hydration of the olefin and methylenation provided C20 denudatine type alkaloid, lepenine (160, Figure 3.19). In order to access the C19- diterpenoid alkaloid scaffold, 175 was converted to sulfonyloxirane 176 in 10 steps. The epoxide underwent a microwave-assisted Wagner–Meerwein rearrangement, and upon reduction, provided the alcohol of aconitine core 177. Finally, methoxymethyl ether cleavage and formal demethylation at C8 was accomplished by heating in aqueous sulfuric acid, providing cardiopetaline 162 in 86% yield. Although Fukuyama’s studies appear to draw heavily from Wiesner’s fourth generation methods,4f synthesis of the analogous aromatic intermediate was significantly improved, and the strategy successfully transferred asymmetry from the chiral pool. Additionally, a new additive- Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 135 free method for the Wagner–Meerwein rearrangement was identified for sulfonyloxirane 176. Summary of Previous Synthetic Strategies 3.3.5 Wiesner’s pioneering studies heavily influenced future syntheses. The salient transformation of Wiesner’s, Sarpong’s, and Fukuyama’s syntheses is a biomimetic Wagner–Meerwein rearrangement that transforms a denudatine scaffold to an aconitine scaffold. The requisite bicyclo[2.2.2] systems were constructed using inter- and intramolecular Diels–Alder cycloadditions. However, as demonstrated in the three syntheses, stereoselective installation of the necessary leaving groups required long sequences of minimally productive functional group manipulations. Thus, syntheses that construct the CD-[3.2.1]-bicycle in a non-biomimetic fashion may circumvent these issues. Although Gin’s synthesis of neofinaconitine (112) certainly addresses these challenges, the initial cyclopropene [4 + 2] cycloaddition proceeds with poor regioselectively, providing a 1:1.6 mixture of inseperable isomers. Our group’s synthetic strategy, described in the next sections, represents a distinct approach to the aconitine core. 3.4 SYNTHETIC APPROACH TO DITERPENOID ALKALOIDS A majority of the diterpenoid alkaloids possess a common structural motif in the AEF tricycle (Figure 3.20). This motif is comprised of a hydrindane framework (A/F rings) that is bridged by a substituted piperidyl ring (E ring). This tricycle is conjoined to a [3.2.1]-bicycle in the aconitine and napelline type alkaloids (e.g. 34 and 29) and a 136 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine [2.2.2]-bicycle in the denudatine type alkaloids (e.g. 160). We sought to identify a synthetic approach that would access these highly bridged polycyclic structures with a unified strategy. Talatisamine (34) was chosen as an initial target due to its compelling biological activity as a selective voltage-gated K+ channel blocker. In a convergent manner, the central 6-membered B ring can be retrosynthetically disconnected to two polycycles of similar complexity: the AEF-rings (178) and the CD-[3.2.1]-bicycle (179). Analogous disconnections are envisioned for napelline (29), which possesses a [3.2.1]bicycle with different relative connectivity to the AEF tricycle, and lepenine (160), which possesses a [2.2.2]-bicycle. Notably, the C20-diterpenoid alkaloids bear an additional quaternary center at C8 that represents another major synthetic challenge for attachment to the F-ring. Nevertheless, we anticipate that development of a convergent synthesis of talatisamine (34), specifically through conjoining the two polycycles 178 and 179, will be highly informative for the synthesis of C20 napelline and denudatine type alkaloids. OMe A MeO E OH Me F N Et OMe A N Et talatisamine (34) C19 aconitine type A OMe NEt E F B C HO H lepenine (160) C 20 denudatine type OMe MeO NEt D OMe 8 N Et H HO HO OH F E 8 napelline (29) C 20 napelline type convergent fragment coupling OH A OH Me F E HO MeO HO OH + HO 178 HO OMe 179 Figure 3.20. Synthetic strategy to convergently access diterpenoid alkaloids. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 137 In order to achieve a truly convergent fragment coupling, enantioselective syntheses of both fragments must be developed. Furthermore, in addition to the bridged polycyclic structure, another major challenge for the synthesis of talatisamine (34) are the 12 contiguous stereocenters, including two quaternary centers at C4 and C11. In our retrosynthetic analysis, a key disconnection of the piperidine E-ring, through a lactam intermediate, to secondary amine 180 simplifies the construction of the C4 quaternary center to the facile α-functionalization of a diester (Figure 3.21). The secondary amine of 180 could be introduced via reductive amination of ketone 181, which provides a functional handle to bisect the central B-ring at both α-positions of the ketone. Specifically, it was envisioned that an intramolecular aldol of diketone 182 would close the central B-ring, and a semipinacol rearrangement would construct the hindered C10– C11 bond and C11 quaternary center of 182 via epoxy alcohol 183. Epoxy alcohol 183 is the direct product of a convergent fragment coupling between vinyl lithium 184 and epoxyketone 185. This strategy streamlines the synthesis of bridged polycyclic compounds by enabling the coupling of two relatively complex fragments through the robust chemistry of 1,2-additions into ketones. The subsequent semipinacol rearrangement exploits the enthalpically favorable ring-opening of epoxides as a driving force for the formation of a hindered quaternary center,14 and in this case, ultimately enables the crucial retrosynthetic disconnection of the C10–C11 bond, resulting in a highly convergent synthetic plan. 138 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine OMe NEt MeO E lactam formation/ reduction MeO 2C 4 OMe CO2Me NHEt reductive amination OMe CO2Me O MeO 2C B H H HO HO HO OMe MeO 2C 11 10 17 H OMe HO 180 talatisamine (34) C19 aconitine type OH CO2Me O HO semipinacol rearrangement MeO 2C MeO 2C H intramolecular aldol HO OMe 181 O 11 17 O MeO 2C MeO 2C H OH 1,2-addition 10 O Li O 185 + OR' HO O OMe 182 HO OMe 183 RO OMe 184 Figure 3.21. Retrosynthetic analysis of talatisamine (34). 3.5 FORWARD SYNTHETIC EFFORTS In the following sections, our synthetic efforts towards C19-diterpenoid alkaloid talatisamine (34) are described. A racemic route to epoxyketone 185 was developed first, and this was used in a model system to explore the 1,2-addition/semipinacol rearrangement sequence as well as the intramolecular aldol and reductive amination steps. Subsequently, enantioselective routes to epoxyketone 185 and [3.2.1]-bicycles were developed and employed in the 1,2-addition/semipinacol rearrangement sequence to convergently couple both fragments. Lastly, efforts to complete the total synthesis of talatisamine (34) are detailed. 3.5.1 Semipinacol Rearrangement Model Studies towards a Tetracyclic Analogue Our first task was to establish proof of concept for a convergent fragment coupling towards diterpenoid alkaloids beginning with the synthesis of the AEF tricycle. 139 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Thus, a racemic route to epoxyketone 185 was devised (Figure 3.22). Beginning with dimethyl malonate (186), alkylation with commercially available alkyl bromide 187 followed by Michael addition with 2-cyclopenten-1-one (188) forged the first quaternary center of 189 in modest yield. Exposure to aqueous hydrochloric acid at elevated temperature resulted in ketal deprotection and intramolecular aldol condensation to afford enone 190 in 84% yield. This three-step procedure efficiently constructs the hydrindane framework (AF rings) from cheap and readily available starting materials in a scalable manner. O 1. NaH, n-Bu4NI 187, THF, reflux MeO 2C 2 (66% yield, 2 steps) 186 O MeO 2C MeO 2C 2. NaOMe, 188 MeOH, 0 °C MeO 2C HCl (aq) O 189 MeO 2C MeO 2C H acetone 70 °C O 190 (84% yield) O O S N Br OH 191 O MeCN/H 2O (67% yield) MeO 2C MeO 2C H 192 O O O Br 187 188 O Et 3N Br CH2Cl2 MeO 2C MeO 2C H (99% yield) 185 O O Figure 3.22. Racemic synthesis of epoxyketone 185. In order to establish the epoxide stereochemistry with the trans-fused ring junction, enone 190 was converted to bromohydrin 182 by treatment with Nbromosaccharin (191) in the presence of water.15 This transformation presumably occurs by initial formation of a bromonium ion on the β-face, followed by nucleophilic addition of water from the α-face at the less substituted position. Other brominating reagents, such as N-bromosuccinimide, tetrabutylammonium tribromide, pyridinium tribromide, and bromine, were unsuccessful in activating the olefin of 190; N-bromosaccharin 140 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine appears to be electrophilic enough to activate the non-nucleophilic olefin of 190. Although this transformation did not occur with perfect regio- or stereocontrol, the major isomer 192 was separated from other isomers during purification by crystallization. Attempts to improve the selectivity by modifying reaction parameters (temperature, equivalents of water, etc.) were also unfruitful. Nonetheless, the bromohydration of enone 190 was easily scalable and permitted the diastereoselective synthesis of epoxyketone 185. The last transformation was accomplished by simple exposure to triethylamine base to facilitate epoxide ring closure. Nucleophilic epoxidation of enone 190 was also explored, but did not provide isolable products; this method would also hypothetically produce the undesired cis-ring junction. O Br 1. PBr 3, DMF 2. NaBH 4 193 Br + TIPSO 195 (1.0 equiv) CH2Cl2 HO 194 (50% yield, 2 steps) MeO 2C MeO 2C H 185 (1.0 equiv) [Si]–Cl imidazole O RO (76% yield) 195 (R = TIPS) (76% yield) 196 (R = TMS) t-BuLi, then 185 O Br THF, –94 °C (72% yield) O MeO 2C MeO 2C H OH TIPSO 197 Figure 3.23. Synthesis of semipinacol rearrangement precursor 197. Vinyl halides readily undergo lithium-halogen exchange and addition into carbonyls, and vinylic functionality is known to have good migratory aptitude. Therefore, vinyl bromide 195 was chosen as an appropriate model compound, as it possesses a 5membered ring that resembles the aconitine C-ring as well as a pendant silyl ether for the intramolecular aldol step (Figure 3.23). The synthesis of vinyl bromide 195 commenced 141 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine with a known two-step procedure engaging cyclopentanone (193) with Vilsmeier salt and in situ vinyl-bromide formation, followed by borohydride reduction to produce vinyl bromide 194.16 The allylic alcohol was then silyl protected to afford the corresponding silyl ethers 195 and 196 in good yield. Lithium-halogen exchange of vinyl bromide 195 using tert-butyllithium at low temperature provided the alkenyllithium, and addition of one equivalent of epoxyketone 185 afforded tertiary alcohol 197 as a single diastereomer in 72% yield. It was crucial to perform the 1,2-addition by inverse addition at –94 °C, as exposing the in situ generated vinyllithium to higher temperatures resulted in competing Wurtz dimerization. Nevertheless, cyclopentene 195 was successfully coupled to epoxyketone 185 while simultaneously establishing the requisite anti-relationship between the migrating cyclopentene and the epoxide of 197. OR O MeO 2C MeO 2C H OH OR MeO 2C Lewis acid MeO 2C MeO 2C H CH2Cl2 TIPSO CO2Me O O OTIPS OTIPS 197 198 Entry Lewis acid Additive Temperature Result 1 ZnBr2 -- rt no reaction 2 AlMe3 -- –78 °C to rt no reaction 3 AlMe2Cl -- –78 °C to rt chlorohydrin 4 EtAlCl2 -- –78 °C to rt chlorohydrin 5 BF3•OEt2 -- –45 °C fluorohydrin 6 TiCl4 -- –78 °C to rt decomposition 7 Yb(OTf)3 -- rt desilylation 8 Sc(OTf)3 -- –78 °C to rt decomposition 9 TMSOTf -- –78 °C decomposition 10 TMSOTf 2,6-lutidine 0 °C 90% yield (R = TMS) Table 3.1. Screen of Lewis acids for semipinacol rearrangement of 197. 142 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine With an established protocol for the coupling of vinyl halides with epoxyketone 185, we investigated the key semipinacol rearrangement to determine the feasibility of the proposed strategy to construct the challenging C11 quaternary center. For this purpose, a broad screen of common Lewis acids was conducted on epoxy alcohol 197 in dichloromethane (Table 3.1). Several common Lewis acids failed to promote reactivity (entries 1 and 2), while others promoted non-specific decomposition of the substrate (entries 6, 8, and 9) or desilylation (entry 7). Interestingly, alkylaluminum chlorides and boron trifluoride resulted in nucleophilic epoxide ring opening to halohydrins instead of semipinacol rearrangement (entries 3–5). In an attempt to protect the tertiary alcohol of 197, it was discovered that subjection to TMSOTf in the presence of 2,6-lutidine directly afforded the desired rearrangement product 198 in 90% yield (entry 10). Presumably, the amine base acts to buffer the triflic acid formed in the alcohol protection step, and excess TMSOTf facilitates semipinacol rearrangement of the in situ generated silyl ether. The use of a stronger base, such as triethylamine, resulted in further conversion of ketone 198 to the silyl enol ether. Br + TMSO t-BuLi, then 185 O MeO 2C MeO 2C H O THF, –94 °C O MeO 2C MeO 2C H OTMS 196 (1.0 equiv) 185 (1.0 equiv) 199 OTMS MeO 2C CO2Me O then TMSOTf 2,6-lutidine, 0 °C (54% yield) 200 OTMS Figure 3.24. One pot 1,2-addition and semipinacol rearrangement. OLi 143 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Further highlighting the utility of this convergent fragment coupling strategy, the 1,2-addition and semipinacol rearrangement could be performed in a single vessel (Figure 3.24). Thus, lithium-halogen exchange of vinyl bromide 196 with tert-butyllithium followed by addition of epoxyketone 185 produces intermediate lithium alkoxide 199. After warming the reaction temperature to 0 °C, TMSOTf and 2,6-lutidine are added to the reaction mixture, resulting in rapid semipinacol rearrangement to afford 54% yield of 200 in a single step. This remarkable transformation provides rearrangement product 200 as a single diastereomer from one equivalent of each coupling partner. This method enables the efficient construction of the aconitine C11 quaternary center directly from vinyl halides and epoxyketone 185, and demonstrates potential for the synthesis of C20diterpenoid alkaloids as well. MeO 2C OTMS OTMS OTMS CO2Me O CO2Me O CO2Me O MeO 2C AcOH (aq) THF OTMS MeO 2C DMP CH2Cl2 (97% yield) OH 200 H (81% yield) O 201 202 OTMS CO2Me O MeO 2C KOt-Bu THF, –78 °C OTMS MOMCl, n-Bu4NI i-Pr2NEt DMF, 45 °C OH (83% yield >20:1 dr) OMOM H 2SiF6 MeCN, 0 °C (94% yield) 204 OH CO2Me O OMe Me 3OBF 4 Proton sponge CO2Me O MeO 2C CH2Cl2 OMOM (71% yield) 205 OMOM (91% yield) 203 MeO 2C CO2Me O MeO 2C OMe EtNH 2, Ti(Oi-Pr)4 CO2Me NHEt MeO 2C 17 then NaBH 4, EtOH OMOM (90% yield) 206 207 Figure 3.25. Investigations on intramolecular aldol and reductive amination steps. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 144 We next attempted to investigate the intramolecular aldol and reductive amination steps. Because difficulty was encountered in differentiating the primary triisopropyl (TIPS) ether and secondary trimethylsilyl (TMS) ether of 198, bis-TMS ether 200 was used for further model studies (Figure 3.25). Exposure of 200 to aqueous acetic acid in tetrahydrofuran resulted in selective deprotection of the primary silyl ether to alcohol 201 in excellent yield. Oxidation using Dess–Martin periodinane provided ketoaldehyde 202, which was poised to undergo intramolecular aldol reaction. Treatment of ketoaldehyde 202 with hexamethyldisilazide bases produced aldol product 203 in variable diasteomeric ratios, but nevertheless forging the central B-ring in good yield. The yield and diastereomeric ratio was improved when potassium tert-butoxide was employed, providing aldol product 203 in 83% yield and >20:1 diastereoselectivity. However, the relative configuration was not determined at this stage since β-hydroxyketone 203 underwent spontaneous epimerization upon standing (likely through a retro-aldol/aldol process) and desilylation. The alcohol was promptly protected as the methoxymethyl ether (204) and desilylated using hexafluorosilicic acid to reveal the C1 alcohol (205). Reductive amination on ketone 205 proved to be intractable at the time, possibly due to the free alcohol at C1; we therefore sought to methylate the alcohol to the methyl ether present in talatisamine (34). Methylation attempts under basic conditions were met with limited success, resulting in decomposition likely stemming from retro-aldol of the βhydroxyketone. The use of trimethyloxonium tetrafluoroborate and Proton sponge provided methyl ether 206 in 71% yield. With ketone 206 in hand, treatment with ethylamine in the presence of a titanium tetraisopropoxide led to complete conversion to Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 145 an intermediate iminium ion (observed by LCMS). Dilution of the reaction mixture with ethanol and addition of sodium borohydride resulted in reduction to secondary amine 207. Rigorous analysis of 2D NMR data revealed that the newly formed C17 stereocenter possessed the undesired configuration for lactam ring closure to the piperidine E-ring. Although unexpected, this finding can be rationalized by steric encumberance imposed by the pseudoaxial MOM-ether. The model studies discussed thus far validated our synthetic approach and demonstrated that both C4 and C11 quaternary centers could be accessed in a rapid sequence from commercially available starting materials. Specifically, hydrindane 185 was readily available in just five steps from dimethyl malonate (186) using operationally simple chemistry. With the model system (vinyl bromide 196), 1,2-addition and semipinacol rearrangement were accomplished in a single step, thereby establishing an efficient means to couple both fragments in a convergent fashion and directly forge the challenging C11 quaternary center. This short sequence also enabled important investigations of subsequent key steps, including an intramolecular aldol cyclization to create the central B-ring and reductive amination to afford the secondary amine, albeit in the undesired configuration. Ultimately, tetracyclic analogue 207 possesses four of the six rings present in talatisamine (34), and was synthesized in 12 steps from dimethyl malonate (186). Although these studies were compelling, they did not yet address the challenge of [3.2.1]-bicyclic CD-ring system or the enantioselective syntheses of both fragments described in the retrosynthetic analysis. 146 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Enantioselective Syntheses of Two Bicyclic Fragments 3.5.2 The most straightforward manner to render the epoxyketone (185) route asymmetric was to employ an enantioselective Michael addition between α-substituted malonate 208 and cyclopenten-1-one (188) to intercept ketone 189 (Figure 3.26). Only one such method has been reported, by the Shibasaki group, utilizing an elaborate lanthanum-bound linked-BINOL catalyst.17 Attempts to utilize this chemistry were met with initial success, but reproducibility issues hampered future use since the catalyst quality varied depending on the batch of lanthanum from commercial vendors. Another limiting factor was the high catalyst loading (10 mol%) of the non-recoverable linkedBINOL ligand, which was synthesized in seven steps from (S)-BINOL. O O + (S,S)-La-linked-BINOL (10 mol%) DME/HFIP, 4 °C, 84 h MeO 2C CO2Me 208 O O O 188 (61% yield, 98% ee) irreproducible 2 MeO 2C MeO 2C H 189 O O O La O O O H (S,S)-La-linked-BINOL (7 steps from (S)-BINOL) Figure 3.26. Catalytic enantioselective Michael addition of 208 and 188. An alternative route utilized another procedure developed by Shibasaki (Figure 3.27).18 An enantioselective Michael addition between dimethyl malonate (186) and cyclopenten-1-one (188) was catalyzed by GaNa-(S)-BINOL and sodium tert-butoxide to deliver α-functionalized malonate 209 in 92% yield and 91% enantiomeric excess. The reaction is proposed to occur through attack of a sodium enolate onto the bimetallic catalyst, coordination of the α,β-unsaturated ketone to the Ga center, and Michael addition via an organized transition state to generate the new stereogenic center. This 147 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine reaction was reproducible and scalable, and also did not require cryogenic temperatures. The remainder of the sequence resembles the racemic route with minimal adjustments. Protection of ketone 209 under standard conditions provided ketal 210, which was alkylated with alkyl bromide 187 to forge the C4 quaternary center of bis-ketal 211. Heating in aqueous hydrochloric acid and acetone resulted in ketal deprotection and intramolecular deprotection to intercept enone 190. Bromohydration was again achieved with N-bromosaccharin (191) and water. Notably, purification by recrystallization effectively enriched the enantiomeric excess to >99%, thereby providing enantiopure material. Epoxide ring closure proceeded uneventfully to afford epoxyketone 185 in six steps from dimethyl malonate (186). MeO 2C O + GaNa-(S)-BINOL (10 mol%) NaOt-Bu (7 mol%) 186 188 O H O O O NaH, n-Bu4NI O 2 THF, reflux HCl (aq) O MeO 2C MeO 2C H (78% yield, 98% brsm) 210 benzene, reflux (83% yield) 209 O Br MeO 2C O H (92% yield, 91% ee) 187 MeO 2C MeO 2C THF/Et2O, rt MeO 2C ethylene glycol p-TsOH MeO 2C O 211 acetone, 70 °C (67% yield) OH MeO 2C MeO 2C H 190 NBSac (191) O MeCN/H 2O (62% yield) recrystallized to >99% ee MeO 2C MeO 2C H 192 Et 3N Br O CH2Cl2 MeO 2C MeO 2C H (99% yield) O O 185 Figure 3.27. Alternative enantioselective route to epoxyketone 185. We envisioned utilizing a meta-photocycloaddition for the synthesis of the bicyclo[3.2.1]octane fragment, as it is an established method for the construction of 148 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine bicyclic compounds in total 19 synthesis. However, intermolecular meta- photocycloadditions, particularly with anisole (212) and electron rich olefins (e.g. 213) are known to react with poor regioselectivity in the cyclopropane ring-forming step as well as poor endo/exo selectivity, forming up to four isomeric products (Figure 3.28).20 Sugimura et al. have devised a valuable solution to this problem by joining the arene and olefin reactants with a chiral tether as in 216.21 Irradiation of arene olefin 216 at 254 nm resulted in photocycloaddition to initially produce the 6-substituted product 217, which subsequently underwent vinyl-cyclopropane rearrangement to form the 7-substituted product 218. In typical systems, these two isomeric products undergo photoequilibration. However, 6-substituted photoadduct 217 absorbs more strongly at 254 nm, resulting in a complete shift in equilibrium to produce 7-substituted photoadduct 218 in 70% isolated yield. Sugimura advanced cyclopropane 218 to enantiomerically pure bicyclo[3.2.1]octane 220 in a five step sequence involving cyclopropane ring-opening. meta-photocycloaddition OMe OR H OMe H OR + 212 213 non-selective formation of four isomeric products Me Me R S O O H hυ Me hν (254 nm) Me 6 vinylcyclopropane rearrangement H 7 O H Me H OR O OH O 7 6 7-substituted (218) 1. (HOCH2)2, p-TsOH 2. PCC HO 3. K 2CO3, MeOH O (67% yield, 3 steps) O H Me (70% yield) Me 2. Hg(OAc)2, H 2O then NaBH 4 (45–50% yield, 2 steps) H 215 O 6 1. H 2, Pd/C H 214 6-substituted (217) 216 + 7 Me pentane H O H OMe H O 219 Figure 3.28. Sugimura’s diastereoselective meta-photocycloaddition. 220 149 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine We sought to employ Sugimura’s method for construction of enantiopure [3.2.1]bicycles for the synthesis of talatisamine (34). Rather than reducing the olefin of photoadduct 218, we plan to instead engage it in an electrophilic ring opening of the neighboring cyclopropane, which would also be assisted by the ether substituent (Figure 3.29). Photoadduct 218 can therefore undergo Grob fragmentation to produce oxocarbenium ion 221, which would hydrolyze to form ketone 222. Tether cleavage would proceed identically to Sugimura’s sequence, and functional group interconversions of the resulting alcohol would produce vinyl bromide 223. This sequence could potentially provide access to a variety of enantiopure [3.2.1]-bicycles bearing a vinylic anion (e.g. 224–226) for 1,2-addition and semipinacol rearrangement into epoxyketone 185, and functionality on the 3-carbon bridge to facilitate B-ring formation. H E+ E H Me electrophile (E+ ) O Me H 218 O H Me Me H Li–halogen exchange tether cleavage O O 221 Br OH H 2O O Me O Me 222 Li Li E Li H FGI's RO E 223 RO H RO 224 Cl 225 O RO 226 Figure 3.29. Forward plan for elaborating photoadduct 218. The synthesis of photoadduct 218 was performed using procedures modified from Sugimura’s initial report.21a Beginning with commercially available (2R,4R)-pentanediol (227), a Mitsunobu reaction with phenol provided the aryl ether, and Hg(II)-catalyzed vinylation with ethyl vinyl ether provided arene olefin 216 (Figure 3.30). Although 150 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Sugimura’s studies were conducted on small scale, we were able to obtain comparable yields of the meta-photocycloaddition on 1.5 g scale after optimization of the reaction setup. Because the reaction profiles were generally clean, reactions could be run in 1.5 g batches, concentrated to crude mixtures, and combined with future batches for a single purification to provide multigram quantities of photoadduct 218. H Me R R OH 227 Me OH 1. phenol (1.1 equiv) DIAD, PPH 3, THF Me R S O O 2. Hg(OAc) 2 (20 mol%) OEt 45 °C Me 216 (55% yield, 2 steps) hν (254 nm) pentane 25 °C, 27 h (1.5 g batches, 67% avg. yield) O Me H O H Me 218 Figure 3.30. Scalable synthesis of photoadduct 218. Our first attempts to advance photoadduct 218 were through protonation of the olefin with Brønsted acid (Figure 3.31). The 6-substituted product 217 could be isolated at partial conversions of the meta-photocycloaddition, and subjection to aqueous hydrochloric acid at elevated temperatures provided ketone 228 in 37% yield. However, attempts to optimize this reaction were unfruitful, and ultimately this substrate was not pursued because the photocycloaddition could not be easily optimized for selective synthesis of 6-substituted adduct 217. Under similar conditions, the 7-substituted adduct 218 surprisingly afforded diene 229. Although one can surmise this occurs by elimination of the tether to form a C6–C7 olefin, evidence supported the intermediacy of cyclopropylcarbinyl cation 230. For instance, diene 229 was not observed in acidolysis of the 6-substituted adduct 217, as one would expect from elimination at C6/C7. At room temperature, ketalization of the ketone of 229 was observed, indicating that the free alcohol of intermediate 230 can ketalize prior to hydrolysis. Similar results were reported 151 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine by Fenton and Gilbert, who found that treatment of 7-acetate-substituted metaphotoadducts with acidic methanol resulted in formation of ketone 229 as well.22 In an attempt to harness this reactivity, vinyl bromide 230, the product of metaphotocycloaddition of aryl bromide 231, could potentially undergo acidolysis to directly afford bicyclo[3.2.1]octane 232. This would significantly shorten the synthetic route, as it effects tether cleavage and vinyl bromide formation in a single step to provide a functionalized fragment that can be used directly in the 1,2-addition/semipinacol rearrangement sequence. Unfortunately, preliminary experiments with aryl bromide 230 did not deliver photoadduct 231, and instead resulted in significant polymer formation. Future studies are still warranted, particularly with other aryl functionalities that can be rapidly advanced to a vinyl anion equivalent. Me Me H O H OH HCl (aq) O O H O (37% yield) 6-substituted (217) 6 H 6 via: HCl (aq) O H H+ 7 O O 6 H 6 7 HO O (yield nd) Me 229 H O H Me 230 7-substituted (218) H H 7 dioxane, 40 °C Me Me H 228 7 H O H 7 Me 6 Me Me via: 6 THF, 60 °C 7 Me Me Br Br Me hν (254 nm) O O O Br Me 230 H O 231 Figure 3.31. Acidolysis of meta-photoadducts. Me H 3O+ Me O H O Me 232 152 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Subsequent attempts to functionalize photoadduct 218 involved halogenation of the olefin (Figure 3.32). Treatment with N-chlorosaccharin in THF and water resulted in formation of allylic chloride 233 in 84% yield. Protection of the ketone and oxidation of the tether provided ketone 234 in 80% yield over two steps. Cleavage of the tether required low temperatures to prevent further fragmentation of the [3.2.1]-bicycle, and was accomplished with potassium hexamethyldisilazide at –78 °C to afford alcohol 235. DMP oxidation then delivered ketone 236. Unfortunately, ketone 236 could not be advanced to vinyl bromide 237 due to the labile allylic chloride, and therefore this substrate was not further pursued. Me H NCSac O Me H O Me 218 Me OH 1. O TMSOTf (20 mol%) 2. DMP, NaHCO 3, CH2Cl2 THF/H2O H (84% yield) O Cl Me Me O O O O (80% yield, 2 steps) 233 KHMDS Cl 234 Br O HO THF, –78 °C OTMS TMSO DMP, NaHCO 3 O CH2Cl2 O (56% yield) Cl (53% yield) 235 O O O Cl 236 O Cl 237 Figure 3.32. Synthesis of a chlorinated bicyclo[3.2.1]octane. In hopes that an allylic ether would be less labile than the chloride, photoadduct 218 was epoxidized with m-CPBA produced an intermediate epoxide (238) that was immediately activated with Brønsted acid to furnish allylic alcohol 239 in 79% yield (Figure 3.33).23 In order to differentiate both secondary alcohols of 239, the allylic alcohol would be selectively protected as part of a 1,3-diol. Therefore, reduction with sodium borohydride in the presence of cerium trichloride furnished 1,3-diol 240 as a 153 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine single diastereomer in 91% yield. Interestingly, borohydride reduction of 239 in the absence of cerium trichloride provided a 1 : 2.3 mixture of diols 240 and 244, favoring the anti-diastereomer 244. The formation of 244 could proceed by directed delivery of the hydride by the allylic alcohol of 239. The oxophilic cerium salt likely chelates to the hydroxyl groups, thereby preventing the directed hydride delivery and providing triol 240 as a single diastereomer. Attempts to protect the syn-diastereomer 240 as the acetonide were met with complications relating to hydrolysis of the allylic alcohol under acidic conditions, resulting in non-selective formation of allyl ethers 241 and 242, and further fragmentation to arene 243. Efforts to synthesize other acetals were largely unfruitful due to the tendency of the allyl alcohol to undergo hydrolysis and fragmentation. H H H H Me O O CH2Cl2, rt H Me H O Me MeOH, –78°C (79% yield) O 239 Me Me Me 2C(OMe)2 p-TsOH (10 mol%) O (91% yield) OH 238 Me OH NaBH 4, CeCl3•7H2O O H Me 218 Me OH HCl (aq) m-CPBA O Me O Me OH Me O Me OH O + + O CH2Cl2, rt OH 240 O OMe OH OH OH 241 OMe 242 243 Me tentative assignments based on 1 H NMR and LCMS Me Me Me OH O NaBH 4 Me OH Me O OH OH 239 O + MeOH, 0 °C O Me HO OH 240 (29% yield) OH OH 244 (67% yield) Figure 3.33. Epoxidation of photoadduct 218 and elaboration to triol 240. Me 154 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine In order to circumvent the lability of allyl alcohol 240, silylene protection at low temperatures mitigated hydrolysis, providing siliconide 245 in 91% yield (Figure 3.34). Oxidation of the tether with DMP, elimination mediated by KHMDS, and another oxidation afforded bicyclic ketone 248, which was also converted to triflate 249 under standard conditions for subsequent investigations. Me Me Me OH t-Bu2Si(OTf)2 2,6-lutidine O Me OH Me O O OH OH (91% yield) O DMP, NaHCO 3 CH2Cl2, rt CH2Cl2, –78 °C 240 Me O Si O 245 t-Bu t-Bu O Si O t-Bu (99% yield) 246 t-Bu TfO O HO KHMDS THF, –78 °C (89% yield) KHMDS PhNTf 2 DMP, NaHCO 3 O Si O t-Bu t-Bu 247 CH2Cl2, rt (91% yield) THF, –78 °C O Si O t-Bu t-Bu 248 (95% yield) O Si O t-Bu t-Bu 249 Figure 3.34. Silylene protection and advancement to bicyclic triflate 249. With the functionalized bicyclo[3.2.1]octane in place, efforts were directed towards conversion to a vinyl anion precursor for the following 1,2-addition. For ketone 248, Shapiro conditions and triphenyl phosphite-halogen-based conditions failed to provide isolable samples of vinyl bromide 250.24,25 Barton’s method for preparation of vinyl iodides by oxidation of intermediate hydrazones successfully delivered vinyl iodide 251, albeit in a modest 39% yield.26 Vinyl triflate 249 could also be used for the preparation of vinyl bromide 250 and vinyl stannane 252. Under Pd-catalyzed conditions reported by Buchwald, vinyl bromide 250 was formed in low yield, possibly due to competing deprotection of the silylene group at high temperature.27 Coupling of the vinyl 155 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine triflate with stannyl cuprates provided tributylstannane 252 in a moderate 50% yield, but was hampered by scalability issues. 28 Ultimately, the highest yielding procedure employed a Pd-catalyzed Stille cross-coupling with hexamethylditin to produce vinyl stannane 253.29 Although this stannane could be used directly in the 1,2-addition, the crude material was converted to vinyl iodide 251 due to safety concerns regarding volatile tetra-alkylstannane byproducts. Nevertheless, this two-step procedure efficiently and reliably provided multigram quantities of vinyl iodide 251 to enable subsequent investigations on the 1,2-addition and semipinacol rearrangement. O [KF, KOAc, or K 3PO 4 ] KBr (2.0 equiv) Pd 2dba3 (2.5 mol%) t-BuBrettPhos(7.5 mol%) Br • i. TrisNHNH2 ii. n-BuLi, (BrCF2)2 dioxane, 130 °C –or– O Si O t-Bu t-Bu TfO O Si O t-Bu t-Bu • P(OPh) 3, Br 2, Et 3N –60 to 45 °C 248 O Si O t-Bu (26–32% yield) t-Bu 249 250 I Bu 3Sn NH 2NH 2, Et 3N EtOH, 55 °C then t-BuNC(NMe 2)2 I 2, THF, 90 °C (39% yield) LDA, Bu 3SnH, then CuCN O Si O t-Bu t-Bu 251 O Si O t-Bu t-Bu then 249 –25 °C 252 Me 3Sn TfO Me 6Sn2, LiCl Pd(PPh 3)4 THF, 70 °C O Si O t-Bu t-Bu 249 (50% yield) I I2 O Si O t-Bu t-Bu CH2Cl2 (80% yield, 2 steps) 253 subjected crude Figure 3.35. Preparation bicyclic vinyl anion precursors. O Si O t-Bu t-Bu 251 156 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Convergent Fragment Coupling 3.5.3 In consideration of the fragment coupling between bicyclic vinyllithium 254 and epoxyketone 185, 1,2-addition should provide epoxyalcohol 255, and semipinacol rearrangement should generate rearranged product 256 (Figure 3.36). Based on earlier model studies, we anticipated that the allyl ether moiety of 256 might undergo ionization to allyl cation 257, which upon enol ether formation, is poised to undergo cationic cyclization to furnish the carbocyclic core (258) of the aconitine alkaloids. This hypothesis was supported by investigations of epoxy alcohol 259, which underwent rearrangement with concomitant elimination of the allyl ether moiety, presumably through allyl cation 260, to provide diene products such as 261. Li 1,2-addition O MeO 2C MeO 2C H O MeO 2C MeO 2C H OH + O semipinacol rearrangement O X O 185 254 OTMS CO2Me O MeO 2C 255 MeO 2C OTMS CO2Me OR O X O cationic cyclization MeO 2C OTMS CO2Me O H O X O O X O LA 256 257 O MeO 2C MeO 2C H TMSOTf 2,6-lutidine OH HO 258 MeO 2C OTMS OTMS CO2Me O CO2Me O MeO 2C CH2Cl2, 0 °C TMSO OPg OTMS 259 260 OTMS 261 Figure 3.36. Proposed cationic cyclization for carbocyclic core 258. 157 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine I MeO 2C MeO 2C H 185 Conditions O O MeO 2C MeO 2C H O OH + O Si O t-Bu t-Bu O Si O t-Bu t-Bu 251 262 Entry Conditions Yield 262 (%) Notes 1 t-BuLi (2.0 equiv), THF, –78 °C; then 185, –94 °C 55 inverse additiona 2 PhLi (2.0 equiv), THF, –78 °C; then 185, –94 °C 50 inverse additiona 3 t-BuLi (3.0 equiv) added into 185 and 251, THF, –94 °C 50 “one-pot” conditionsb 4 t-BuLi (2.0 equiv), THF, –78 °C; solution added to 185, –94 °C 72 normal additionc 5 t-BuLi (2.0 equiv), THF, –78 °C; then HMPA, 185, –94 °C 0 only protodehalogenation 6 t-BuLi (2.0 equiv), THF, –78 °C; added to CeCl3/THF; then 185 51 -- 7 t-BuLi (2.0 equiv), TMEDA/THF, –78 °C; then 185, –94 °C 47 -- 8 t-BuLi (2.0 equiv), TMEDA/hexane, –78 °C; then 185, toluene, –94 °C 0 only protodehalogenation 9 i-PrMgCl•LiCl (1.1 equiv), THF, rt; then 185, –94 °C 0 only protodehalogenation 10 i-PrMgCl•LiCl (1.1 equiv), toluene, rt; then 185, rt 0 only protodehalogenation a Inverse addition: epoxyketone 185 added to pre-stirred solution of vinyllithium (t-BuLi/251). b “One-pot” conditions: t-BuLi added directly to solution of 185 and 251. c Normal addition: pre-stirred solution of vinyllithium (t-BuLi/251) added to epoxyketone 185. Table 3.2. 1,2-addition optimization for tertiary alcohol 262. 158 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Under previously developed conditions for 1,2-addition into epoxyketone 185, reaction with bicyclic vinyl iodide 251 furnished epoxy alcohol 262 in 55% yield (Entry 1, Table 3.2). Other reagents for lithium-halogen exchange such as phenyllithium failed to increase the yield, as did single pot conditions in which tert-butyllithium was added directly to a mixture of epoxyketone 185 and vinyl iodide 251 (Entries 2 and 3). Although the conditions in Entry 1 were developed to prevent Wurtz coupling of the model system discussed in Section 3.5.1, it was discovered that bicycle 251 did not undergo the same dimerization and thus did not require inverse addition. Normal addition of the intermediate vinyllithium into a pre-cooled solution of epoxyketone 185 at –94 °C delivered epoxy alcohol 262 in 72% yield on a 1.6 g scale (entry 4). A survey of additives including HMPA, CeCl3, and TMEDA provided lower yields or protodehalogenation (Entries 6–8). Iodine/magnesium exchange with “turbo Grignard” also exclusively resulted in protodehalogenation of 251, likely by α-deprotonation of epoxyketone 185 (Entries 9 and 10).30 MeO 2C MeO 2C H O OH TMSOTf amine base MeO 2C MeO 2C H O OTMS CO2Me O MeO 2C OTMS CH2Cl2 262 O Si O t-Bu t-Bu MeO 2C OTMS CO2Me O 263 MeO 2C O Si O t-Bu O Si O t-Bu t-Bu t-Bu 264 (<33% yield) OTMS OTMS CO2Me O CO2Me O MeO 2C MeO 2C OTMS CO2Me O H O Si O LA t-Bu t-Bu 265 OR RO NR 3 266 amine base = Et 3N or 2,6-lutidine RO 267 2,6-tBu2-4-Me-pyridine 258 not observed Figure 3.37. Semipinacol rearrangement of 262 and side product formation. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 159 At this juncture, extensive efforts were directed to achieve the proposed cationic cyclization. Standard conditions for semipinacol rearrangement necessitated TMSOTf as the Lewis acid, and an amine base to buffer the reaction media from triflic acid generated in situ. At low temperatures (below 0 °C), rapid protection of tertiary alcohol 262 to the silyl ether 263 occurred (Figure 3.37). Approaching room temperature, semipinacol rearrangement to 264 was observed; however, this was formed as a mixture with other side-products, and purification returned <33% yield of semipinacol product 264. When the reactions were allowed to reach full conversion, tentatively assigned products 266 and 267 were observed. These products are proposed to arise from the intermediate allyl cation 265. With triethylamine or 2,6-lutidine as bases, ammonium/lutidinium products 266 were observed by 1H NMR; we speculate that these may arise from nonregioselective attack of the base onto allyl cation 265. With the non-nucleophilic base 2,6-ditert-butyl-4-methylpyridine, ortho-substituted styrene 267 was observed by 1H NMR; this may occur by rearrangement of allyl cation 265 through an elaborate mechanism in which the [3.2.1]-bicycle is fragmented (as in Figure 3.33). Unfortunately, no products containing silyl enol ethers or cationic cyclization product 258 were observed during the course of these studies. MeO 2C MeO 2C H O OH TMSOTf, Et 3N MeO 2C MeO 2C H O OTMS CH2Cl2, –10 °C 262 O Si O t-Bu t-Bu (97% yield) 263 Figure 3.38. Trimethylsilyl protection of epoxy alcohol 263. O Si O t-Bu t-Bu Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 160 Although we were initially discouraged by these results, we remained optimistic since the semipinacol rearrangement occurred readily at room temperature. We elected to devise a procedure for efficient preparation of semipinacol product 264. For these studies, epoxy alcohol 262 was protected as silyl ether 263 with TMSOTf at –10 °C (Figure 3.38). Since this reaction was clean and high yielding, we posited that low temperatures mitigated ionization of the allyl ether moiety. To this effect, we optimized the semipinacol rearrangement of silyl ether 263 at low temperatures using a stronger Lewis acid, TMSNTf2, and non-nucleophilic base, 2,6-ditert-butyl-4-methylpyridine, to preclude N-silylation (Table 3.3).31 At –78 °C, low yields of rearrangement product 264 were obtained at extended reaction times, but the reaction profile and yield improved with shorter reaction times (Entries 1 and 2). Lowering the reaction temperature and time even further provided improved yields of up to 90% (Entries 3 and 4). However, with one equivalent of Lewis acid, the reaction scaled poorly, and the yield diminished to as low as 59% on a 280 mg scale (Entries 5–7). We reasoned that use of silyl ether 263 as the rearrangement substrate negated the need for a full equivalent of TMSNTf2, which could in fact be regenerated in situ. Using catalytic amounts of Lewis acid successfully delivered semipinacol product 264 in quantitative yield, and tolerated elevated temperatures and extended reaction times (Entry 8). Additionally, this reaction was highly scalable, providing semipinacol product 264 in 97% yield on a 1.2 g scale (Entry 9). The coupling epoxyketone 185 with bicyclo[3.2.1]octane 251 currently proceeds in three steps. However, the sequence is efficient, occurring in an overall 67% yield. The ability to reliably advance multigram quantities of epoxyketone 185 and bicycle 251 161 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine to semipinacol product 264 proved to be crucial for enabling subsequent studies towards talatisamine (34). MeO 2C MeO 2C H O OTMS TMSNTf2 2,6-t-Bu2-4-MePy OTMS CO2Me O MeO 2C CH2Cl2 263 O Si O t-Bu O Si O t-Bu t-Bu t-Bu 264 Equivs Temperature TMSNTf2 (°C) 10 mg 1.0 –78 45 min <25 2 10 mg 1.0 –78 60 sec 50 3 10 mg 1.0 –94 85 sec 82 4 10 mg 1.0 –94 10 sec 90 5 75 mg 1.0 –94 10 sec 88 6 150 mg 1.0 –94 10 sec 82 7 280 mg 1.0 –94 10 sec 59 8 10 mg 0.10 –70 to 0 2.5 hr 99 9 1.2 g 0.10 –70 15 min 97 Entry Scale 1 Time Isolated yield 264 (%) Table 3.3. Semipinacol rearrangement optimization of silyl ether 263. 3.5.4 Assembly of the Carbocyclic Core of Talatisamine At this juncture, several options were explored to advance semipinacol rearrangement product 264 to the carbocyclic core of talatisamine (34), which required construction of the final C7–C8 bond to complete the central B-ring. We first explored a radical cyclization of α-bromoketone 268 onto the D-ring olefin (Figure 3.39). 162 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Deprotonation of ketone 264 with LiHMDS and addition of NBS provided bromoketone 268 in 82% yield. To our dismay, an extensive survey of reaction conditions to effect the desired 6-exo radical cyclization failed to deliver carbocyclic core 269. Instead, all attempts returned starting material (268) or the hydrodebromination product (264). It was unclear to us at that juncture whether cyclization to radical 271 was unfavorable due to resonance-stabilized radical 270, or if cyclization suffered from poor polarity matching. OTMS CO2Me O MeO 2C OTMS CO2Me O MeO 2C LHMDS, NBS (82% yield) O Si O t-Bu t-Bu 268 OTMS CO2Me O OTMS CO2Me O MeO 2C • O Si O t-Bu t-Bu 270 B radical cyclization t-Bu 264 MeO 2C MeO 2C 6-exo Br THF, –78 °C O Si O t-Bu OTMS CO2Me O • O Si O t-Bu t-Bu 271 X O Si O t-Bu t-Bu 269 Conditions attempted: • Bu 3SnH, AIBN, PhH, 80 °C • Bu 3SnH, AIBN (syringe pump addn), PhH, 80 °C • (TMS)3SiH, AIBN (syringe pump addn), PhH, 80 °C • (TMS)3SiH, ACHN (syringe pump addn), PhMe, 110 °C • DLP, t-dodecanethiol, Et 3SiH, cyclohexane, 85 °C • Bu 6Sn2, h υ (halogen lamp), PhH, 80 °C • Ph3Sn–SC(S)OEt, Bu 3SnH, AIBN, PhH, 80 °C Figure 3.39. Survey of 6-exo radical cyclization conditions for pentacycle 269. Reflecting on the success of the intramolecular aldol reaction in the model system (see Section 3.5.1), we elected to perform an intramolecular Michael addition to complete the aconitine carbocyclic core. To this end, selective deprotection of silylene 264 was accomplished using HF•pyridine to deliver diol 272 in 98% yield (Figure 3.40). Under conditions developed by Steves and Stahl, allylic oxidation occurred to afford α,β- 163 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine unsaturated ketone 273 in good yield, although over-oxidation to the diketone was occasionally observed at prolonged reaction times, resulting in slightly diminished yields.32 Protection of the secondary alcohol provided the corresponding methoxymethyl ether of 274 in 84% yield. Treatment of 274 with tert-butoxide base at low temperature resulted in an intramolecular Michael addition to furnish pentacycle 275, thereby completing the central B-ring of the aconitine carbocycle. OTMS CO2Me O MeO 2C OTMS CO2Me O MeO 2C HF•Py MeCN O Si O t-Bu t-Bu (84–98% yield) OH OH OH 272 264 OTMS CO2Me O MeO 2C O 273 OTMS CO2Me O MeO 2C B KOt-Bu DMF, 55 °C (84% yield) OTMS CO2Me O MeO 2C MeCN (98% yield) MOMCl, n-Bu4NI i-Pr2NEt Cu(MeCN) 4OTf, ABNO, NMI, MeObpy THF, –78 °C O MOMO (quantitative crude) 274 O MOMO 275 Figure 3.40. Intramolecular Michael addition for carbocyclic core 275. Completion of the aconitine carbocycle 275 marks the successful implementation of our convergent fragment coupling strategy. In our retrosynthetic analysis, the principle disconnections were bisection across the central B-ring. We have thus demonstrated that the aconitine core can be assembled in a convergent manner by constructing the C10–C11 bond via semipinacol rearrangement and the C7–C8 bond via intramolecular Michael addition. 164 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Endgame Efforts 3.5.5 From aconitine carbocycle 275, the remaining hurdles for the total synthesis of talatisamine (34) include hydrogenation of the bridgehead olefin, installation of the C8 alcohol, and construction of the piperidine E-ring. Guided by Gin’s synthesis of neofinaconitine (112), we elected to install the C8 alcohol through oxy-Michael addition of an intermediate α,β-unsaturated ketone.9 Deprotonation of diketone 275 occured chemoselectively α to the C16 ketone to afford α-selenide 276 in 80% yield (Figure 3.41). Oxidation of a selenide possessing a free C1 alcohol resulted in rupture of the central B-ring through the C7–C8 bond via a retro-aldol process. However, with the C1 TMS-ether, β-hydroxyketone 277 was furnished in 44% yield. As in Gin’s system, we propose that selenoxide elimination occurs to generate an intermediate enone, which is rapidly hydrated to relieve strain in the bridgehead olefin. MeO 2C OTMS CO2Me O 1 MeO 2C LiHMDS, PhSeCl THF, –78 °C MOMO 16 275 O (80% yield) OTMS CO2Me O 8 7 SePh O MOMO 276 1 MeO 2C n-Bu4NIO 4 CH2Cl2 (44% yield) OTMS CO2Me O 8 MOMO HO 7 O 277 Figure 3.41. Initial investigation of oxy-Michael addition for the C8-alcohol. During these studies, we observed that the C1 silyl ether was labile and occasionally underwent spontaneous deprotection. For this reason, silyl ether 275 was converted to lactone 278 by exposure to trifluoroacetic acid (Figure 3.42). Hydrogenation of the bridgehead olefin proceeded smoothly under standard conditions to provide saturated product 279 in 96% yield over two steps.33 Selenation of the ketone 165 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine afforded α-selenide 280, and oxidation with sodium meta-periodate yielded tertiary alcohol 281 in moderate yield. However, because the substrate lacks alkene functionality, oxidation of the selenide could proceed under ozonolytic conditions without complication. This also allowed the use of methanol as both the solvent and nucleophile for the oxy-Michael addition. As such, ozonolysis of 280 in methanol followed by addition of pyridine, which accelerated selenoxide elimination, furnished C8-methyl ether 282 in 88% yield. The methyl ether would serve as a protecting group for the C8 alcohol of talatisamine (34), since selective formal demethylation at the position is known to occur through a carbocation intermediate.34 MeO 2C OTMS CO2Me O O MeO 2C TFA O CH2Cl2 O MOMO 275 O (96% yield, 2 steps) O O O THF, –78 °C O NaIO 4 SePh O O THF/H2O (51% yield) O MOMO 279 MeO 2C O O O MOMO 278 MeO 2C (88% yield) H EtOH/EtOAc MOMO LiHMDS, PhSeCl O MeO 2C H 2 (1 atm) Pd/C O MOMO 280 HO O 281 O3 MeOH, –78 °C O MeO 2C O O then pyridine –78 °C to rt (89% yield) MOMO MeO O 282 Figure 3.42. Functionalization to C8-methoxylated lactone 282. Alongside several functional group manipulations, the last challenge is to install the piperidine E-ring of talatisamine (34). The original proposal was to implement a 166 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine reductive amination of the C17 ketone. Unfortunately, preliminary experiments showed that chemoselective reduction of the C17 ketone of 282 proceeded stereoselectively from the α-face, providing alcohol 283 in 66% yield (Figure 3.43). The diastereoselectivity of this reduction is conflicting with lactam formation, since hypothetical reduction of C17 imine 284 would provide β-disposed secondary amine 285, which is geometrically unable to undergo cyclization with the lactone carbonyl to form lactam 286. This outcome forced us to devise a new scheme for installing the piperidine E-ring. O MeO 2C O O MeO 2C NaBH 4 O 17 OH O EtOH/THF, 0 °C MOMO MeO O (66% yield) MOMO 282 O MeO 2C NEt O 17 MOMO MeO 284 O NaBH 4 undesired diastereoselectivity MeO O 283 O MeO 2C NHEt OH O NEt H MeO 2C O * MOMO MeO O * MOMO 285 HO O 286 Figure 3.43. Unexpected diastereoselectivity for reduction of the C17 ketone. An important note regarding the lactone functionality is that it differentiates the C18 and C19 carbonyls, which were formerly both methyl esters. As part of the oxabicyclo[2.2.2] system, the lactone also bears an substantial degree of ring strain. We therefore sought to engage the lactone in an aminolysis reaction with ethylamine. When treated with ethylamine in THF at room temperature, lactone 282 underwent aminolysis to afford amide 287 in 69% yield (Figure 3.44). Alternatively, the aminolysis could be performed in the same pot as the selenoxide elimination reaction, affording amide 287 in 167 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 87% yield from α-selenide 280. From amide 287, a final C17–N bond formation through a nucleophilic displacement would complete the full framework of talatisamine (34). The C17 ketone of 287 could again be chemo- and diastereoselectively reduced with sodium borohydride to produce diol 288. However, we were unable to mesylate the C17 alcohol of 288, as mesylation of the C1 alcohol and amide activation often occurred competitively. O MeO 2C OH O NHEt O MeO 2C O EtNH 2 O THF MOMO MeO O (69% yield) MOMO 282 O MeO 2C O3 MeOH, –78 °C O O SePh O 287 O MeO 2C EtNH 2 then pyridine –78 °C to rt THF MOMO 280 MeO (87% yield) O MOMO 282 1 MeO 2C NaBH 4 OH O NHEt OH 17 OH O NHEt O MeO 2C O O O MOMO MeO MsCl –or– Ms 2O MeO O 287 OH O NHEt OMs MeO 2C OH O NEt MeO 2C 17 EtOH/THF 0 °C (65% yield) MOMO MeO 288 O MOMO MeO O 289 MOMO MeO O 290 Figure 3.44. Initial investigations on lactone aminolysis. Due to the difficulties encountered with diol 288, alcohol 283 was mesylated instead, as it lacks the problematic the C1 alcohol and C18 amide (Figure 3.45). Standard mesylation conditions employing triethylamine or pyridine with mesyl chloride or mesyl anhydride in dichloromethane provided no reaction at room temperature, and returned 168 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine intractable reaction profiles at prolonged reaction times or higher temperatures. Interestingly, the use of n-butyllithium or LiHMDS at low temperatures for alkoxide formation prior to mesylation resulted in conversion to cyclic mesyl acetal 291, which was disappointingly inert to aminolysis conditions. Switching to a potassium counterion in KOt-Bu and KHMDS provided moderate conversions to desired mesylate 293. These results are promising, and further optimization of this mesylation step is required. n-BuLi or LiHMDS MsCl O MeO 2C O O OH (>50% conversion) MOMO 283 O O OMs MeO MOMO MeO MOMO 291 O MeO H 2NEt O THF, –78 °C MeO 2C H KHMDS Ms 2O OMs O H 2NEt OH O NHEt OMs MeO 2C neat THF, –78 °C (32% yield, 46% brsm) OMs 292 O MeO 2C OH O NHEt H MeO 2C MOMO MeO 293 O (88% yield) MOMO MeO O 294 Figure 3.45. Preliminary results for mesylation and aminolysis of lactone 283. With mesylate 293 in hand, subjection to neat ethylamine in a sealed vessel produced aminolysis product 294 in 88% yield. Amide 294 is poised to undergo intramolecular cyclization and mesylate displacement to produce aconitine core. A preliminary screen of conditions has thus far proved unsuccessful. If accomplished, the resulting lactam possesses all the functionality required for advancement to talatisamine (34), and remaining steps include global reduction of the carbonyl functional groups, global methylation, and deprotection of the MOM ether and C8-methoxy group; all of these transformations are well precedented based on previous syntheses. Preliminary Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 169 investigations to forge aconitine core 290 have revealed a surprising reluctance of amide 293 to undergo intramolecular cyclization. Basic conditions have led to side products arising from enolization and elimination of the C8-methoxy group, while acidic conditions have failed to induce reactivity in 293. Preliminary experiments have also suggested that solvolytic conditions, such as those employed by Wiesner and Sarpong, may result in ionization of the mesylate and lactam formation.4,10 Further efforts to this end are required for the total synthesis of talatisamine (34). OH O NHEt OMs MeO 2C OH O NEt MeO 2C • NaH, DMF, 0 °C • NaH, THF, rt to 50 °C • K 2CO3, MeOH, 40 °C • KOt-Bu, THF, 0 °C to rt MOMO MeO O MOMO 294 MeO 290 O • AcOH, MeCN, 40 °C * DBU, DMSO/o-xylene, 180 °C Figure 4.46. Preliminary investigations on lactam ring closure. 3.6 FUTURE DIRECTIONS Immediate objectives will focus on the final challenge of amide cyclization of mesylate 294 to form lactam 290, as well as optimization of the mesylation step (Figure 3.47). Should these efforts be successful, the remaining steps to access talatisamine (34) are straightforward. Global reduction with lithium aluminum hydride in refluxing dioxane should provide triol 295, and subsequent methylation should afford protected intermediate 296. Lastly, as demonstrated by Pelletier, Gin, and Fukuyama, subjection to aqueous sulfuric acid at high temperature should result in cleavage of the methoxymethyl ether and formal demethylation at C8 to produce talatisamine (34).34 170 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine OH O NHEt OMs MeO 2C MOMO MeO OH O NEt MeO 2C DBU LiAlH 4 DMSO, 140 °C dioxane reflux O MOMO 294 MeO O MOMO 290 H 2SO4 (aq) THF reflux 110 °C MeO OH OMe NEt MeO NaH, MeI MOMO MeO 295 OMe NEt MeO OH NEt HO OMe 296 HO HO OMe talatisamine (34) Figure 3.47. Proposed completion of talatisamine (34). As a long-term objective, we propose to implement the convergent fragment coupling strategy in the synthesis of denudatine and napelline type C20-diterpenoid alkaloids. The piperidine rings of napelline (29) and lepenine (160) can be retrosynthetically deconstructed to amides 297 and 299, respectively. Scission across the central ring through the bonds shown in red lead to [3.2.1]- and [2.2.2]-bicyclic vinyllithiums 298 and 300. Enantioselective syntheses of both bicyclic fragments also require development, but epoxyketone 185 can serve as the precursor to the AF rings of napelline (29) and lepenine (160). Successful syntheses of these alkaloids would validate the approach as a unified strategy to access C19- and C20-diterpenoid alkaloids, and access to C18-diterpenoid alkaloids may also be possible by oxidative scission of the C4–C18 bond as demonstrated in Gin’s synthesis of neofinaconitine (112).9 171 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Me HO OH A HO OH OH F Li MeO 2C HO OH OH E N Et EtHN O napelline (29) C 20 napelline type Me OH A E N Et 297 HO OH OH MeO 2C F R O H HO OH O 298 O O 185 H EtHN lepenine (160) C 20 denudatine type MeO 2C MeO 2C H OH Li R H O 299 300 Figure 3.47. Retrosynthetic analysis of C20-diterpenoid alkaloids. 3.7 CONCLUDING REMARKS The C19-diterpenoid alkaloids represent highly challenging targets for total synthesis and test the limits of current state-of-the-art methods and strategies. Syntheses by Wiesner, Sarpong, and Fukuyama have thoroughly established the [4 + 2] cycloaddition and biomimetic Wagner–Meerwein rearrangement as a viable method to construct the aconitine skeleton.4,10,13 These syntheses have also shown that biogenetically related C20-diterpenoid alkaloids can be accessed via common intermediates. On the other hand, Gin’s synthesis of the C18 neofinaconitine (112) has demonstrated that a non-biomimetic approach can lead to a relatively expedient synthesis of the aconitine core.9 Our approach to talatisamine (34) showcases the advantages of a convergent strategy to couple two relatively complex, chiral fragments. Scalable and enantioselective syntheses of epoxyketone 185 and bicyclo[3.2.1]octane 251 have been developed, and novel application of a 1,2-addition/semipinacol rearrangement sequence has successfully constructed the hindered C11 quaternary center of the diterpenoid alkaloids. This Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 172 approach has enabled efficient access to the carbocyclic core of the C19 aconitine type alkaloids, with requisite functionalities in place for advancement to talatisamine (34). Additionally, the coupling of additional bicyclic fragments with epoxyketone 185 via the 1,2-addition/semipinacol rearrangement method can possibly provide access to a range of C20-diterpenoid alkaloids possessing a common AEF tricycle, as in napelline (29) and lepenine (160). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 3.8 EXPERIMENTAL SECTION 3.8.1 Materials and Methods 173 Unless otherwise stated, reactions were performed under an inert atmosphere (dry N2 or Ar) with freshly dried solvents utilizing standard Schlenk techniques. Glaswarewas oven-dried at 120 °C for a minimum of four hours, or flame-dried utilizing a Bunsen burner under high vacuum. Tetrahydrofuran (THF), methylene chloride (CH2Cl2), acetonitrile (MeCN), tert-butyl methyl ether (TBME), benzene (PhH), and toluene (PhMe) were dried by passing through activated alumina columns. Triethylamine (Et3N) and N,N-diisopropylethylamine (DIPEA) were distilled over calcium hydride prior to use. Unless otherwise stated, chemicals and reagents were used as received. All reactions were monitored by thin-layer chromatography using EMD/Merck silica gel 60 F254 precoated plates (0.25 mm) and were visualized by UV, p-anisaldehyde, KMnO4, or CAM staining. Flash column chromatography was performed using silica gel (SiliaFlash® P60, particle size 40-63 microns [230 to 400 mesh]) purchased from Silicycle. Optical rotations were measured on a Jasco P-2000 polarimeter using a 100 mm path-length cell at 589 nm. 1H and 13C NMR spectra were recorded on a Bruker Avance III HD with Prodigy cryoprobe (at 400 MHz and 101 MHz respectively), a Varian 400 MR (at 400 MHz and 101 MHz, respectively), a Varian Inova 500 (at 500 MHz and 126 MHz, respectively), or a Varian Inova 600 (at 600 MHz and 150 MHz, respectively), and are reported relative to internal CHCl3 (1H, δ = 7.26) and CDCl3 (13C, δ = 77.0). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, app = apparent. IR 174 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm–1). HRMS were acquired using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI), or mixed (MM) ionization mode, or obtained from the Caltech Mass Spectral Facility in fast-atom bombardment mode (FAB). 3.8.2 Preparative Procedures and Spectroscopic Data Preparation of diester 208: MeO 2C O O + MeO 2C O O THF, reflux MeO 2C 186 NaH, n-Bu4NI Br MeO 2C 187 (78% yield) 208 In a 250-mL, round-bottomed flask equipped with a reflux condenser, NaH (60% dispersion in mineral oil, 1.05 g, 43.7 mmol, 1.17 equiv) was suspended in THF (44 mL) and cooled to 0 °C. To this suspension was added dimethyl malonate (186, 5.0 mL, 43.7 mmol, 1.17 equiv) dropwise with a vent needle to allow pressure release caused by H2 evolution. The reaction was then warmed to room temperature with stirring for 30 minutes, after which n-Bu4NI (1.38 g, 3.74 mmol, 0.10 equiv) and 2-(2-bromoethyl)-1,3dioxolane (187, 4.4 mL, 37.4 mmol, 1.0 equiv) was added. The solution was heated to reflux and stirred for 4 h, and then quenched by addition of sat. NH4Cl (100 mL). The aqueous phase was extracted with Et2O (3 x 200 mL), and the combined organic extracts were washed with 1 N HCl (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (20 to 23% EtOAc in hexanes) provided diester 208 (6.76 g, 29.1 mmol, 78% yield) as a colorless oil. 175 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 H NMR (400 MHz, CDCl3): δ 4.88 (t, J = 4.5 Hz, 1H), 4.00 – 3.91 (m, 2H), 3.90 – 3.80 (m, 2H), 3.74 (s, 6H), 3.47 (t, J = 7.5 Hz, 1H), 2.08 – 2.01 (m, 2H), 1.74 – 1.68 (m, 2H). Preparation of racemic ketal 189: O MeO 2C O O O + NaOMe MeOH, 0 °C MeO 2C 208 188 O (85% yield) MeO 2C MeO 2C O (±)-189 In a 500-mL, round-bottomed flask, Na (2.18 g, 94.9 mmol, 1.1 equiv) was added to MeOH (110 mL). After consumption of the solid Na, the solution was cooled to 0 °C, and a solution of diester 208 (20.0 g, 86.3 mmol, 1.0 equiv) in MeOH (30 mL) was added via cannula, followed by dropwise addition of a solution of 2-cyclopenten-1-one (188, 7.95 mL, 94.9 mmol, 1.1 equiv) in MeOH (30 mL) over 20 minutes. The reaction was stirred for an additional 2 h, and then quenched with sat. NH4Cl (300 mL). The mixture was concentrated in vacuo to remove MeOH, and the resulting solution was extracted with EtOAc (3 x 150 mL). The combined organic extracts were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (20% acetone in hexanes) afforded ketal 189 (23.1 g, 73.5 mmol, 85% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 4.85 (td, J = 4.4, 0.9 Hz, 1H), 4.01 – 3.91 (m, 2H), 3.89 – 3.80 (m, 2H), 3.74 – 3.73 (m, 6H), 2.85 – 2.74 (m, 1H), 2.48 (dd, J = 18.5, 7.6 Hz, 1H), 2.31 (dd, J = 17.2, 8.4 Hz, 1H), 2.25 – 2.11 (m, 3H), 2.08 – 2.03 (m, 2H), 1.73 – 1.58 (m, 3H). 176 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 C NMR (101 MHz, CDCl3): δ 217.4, 170.9, 170.8, 103.7, 59.4, 52.4, 52.4, 41.1, 40.2, 38.5, 28.9, 27.7, 24.9. FTIR (NaCl, thin film): 2956, 2890, 1743, 1730, 1451, 1435, 1407, 1222, 1147, 1036 cm-1. HRMS: (FAB) calc’d for C15H23O7 [M + H]+ 315.1444, found 315.1438. Preparation of allylic alcohol 194: O Br PBr 3 DMF 0 °C to rt 193 Br NaBH 4 EtOH O S3 (50% yield, 2 steps) HO 194 In a 1-L, round-bottomed flask, PBr3 (14.3 mL, 153 mmol, 2.7 equiv) was added via syringe to a solution of DMF (14.0 mL, 181 mmol, 3.2 equiv) in CH2Cl2 (80 mL) at 0 °C. After stirring for 1 h, a solution of cyclopentanone (193, 5.0 mL, 56.5 mmol, 1.0 equiv) in CH2Cl2 (30 mL, 10 mL rinse) was added via cannula. The reaction was allowed to warm to ambient temperature, and stirred for an additional 21 h. The reaction was cooled again to 0 °C, and quenched carefully with sat. NaHCO3 (500 mL). Solid NaHCO3 was added periodically as needed until bubbling ceased. The resulting mixture was extracted with Et2O (3 x 250 mL), and the combined organic extracts were washed with H2O (2 x 500 mL) and brine (500 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (15% EtOAc in hexanes) to afford bromoenal S3 (ca. 5.8 g), which was used in the next step without rigorous removal of solvent. In a 500-mL, round-bottomed flask, bromoenal S3 (ca. 5.8 g) was dissolved in EtOH (33 mL) and cooled to 0 °C. NaBH4 (1.5 g, 39.8 mmol, 1.2 equiv) was added, and Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 177 the reaction was stirred for 1 h. The reaction was quenched with H2O (200 mL), and the mixture was concentrated in vacuo to remove ethanol. The resulting aqueous solution was extracted with Et2O (3 x 200 mL), and the combined organic extracts were washed with brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (15% EtOAc in hexanes) afforded allylic alcohol 194 (5.05 g, 28.5 mmol, 50% yield over two steps) as a colorless oil. Spectroscopic data for bromoenal S3 and allylic alcohol 194 matched that reported in the literature.16 Caution: Bromoenal S3 was found to decompose exothermically upon standing for several hours. It could be safely stored as a solution in Et2O in a –20 °C freezer, but in most cases was immediately used in subsequent reactions. Bromoenal S3: 1 H NMR (300 MHz, CDCl3): δ 9.90 (s, 1H), 2.94 – 2.86 (m, 4H), 2.57 – 2.49 (m, 4H), 2.02 (pd, J = 7.9, 1.1 Hz, 4H). Allylic alcohol 194: 1 H NMR (300 MHz, CDCl3): δ 4.29 – 4.21 (m, 2H), 2.73 – 2.59 (m, 2H), 2.54 – 2.40 (m, 2H), 1.97 (tt, J = 8.3, 6.6 Hz, 2H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 178 Preparation of silyl ethers 195 and 196: Br TIPSCl or TMSCl imidazole CH2Cl2 HO 194 Br RO (76% yield) 195 (R = TIPS) (76% yield) 196 (R = TMS) In a 200-mL, round-bottomed flask, allylic alcohol 194 (5.05 g, 28.5 mmol, 1.0 equiv) and imidazole (4.66 g, 68.5 mmol, 2.4 equiv) were dissolved in DMF (57 mL). To this solution was added TMSCl (4.34 mL, 34.2 mmol, 1.2 equiv), and the reaction was stirred for 12 h. The reaction was quenched with sat. NaHCO3 (100 mL) and H2O (100 mL), and extracted with Et2O (3 x 200 mL). The combined organic extracts were washed with H2O (200 mL) and brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude oil was purified by silica gel chromatography (0.5% Et3N/5% EtOAc in hexanes) to afford TMS ether 196 (5.44 g, 21.8 mmol, 76% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 4.24 (tt, J = 1.6, 1.0 Hz, 2H), 2.67 – 2.61 (m, 2H), 2.46 – 2.38 (m, 2H), 1.99 – 1.90 (m, 2H), 0.13 (s, 9H). 13 C NMR (126 MHz,CDCl3): δ 139.8, 116.8, 60.4, 40.3, 32.4, 21.5, -0.4. FTIR (NaCl, thin film): 2953, 2922, 2852, 1655, 1443, 1319, 1246, 1091, 1023 cm-1. HRMS: (FAB) calc’d for C9H17BrOSiNa [M + Na]+ 271.0130, found 217.0144. The same procedure was used to prepare TIPS ether 195: 1 H NMR (500 MHz, CDCl3): δ 4.35 (tq, J = 1.7, 0.9 Hz, 2H), 2.68 – 2.62 (m, 2H), 2.52 – 2.45 (m, 2H), 1.99 – 1.91 (m, 2H), 1.18 – 1.10 (m, 3H), 1.10 – 1.04 (m, 18H). 13 C NMR (126 MHz, CDCl3): δ 140.7, 115.2, 61.4, 40.2, 32.3, 21.5, 18.0, 12.0. 179 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine FTIR (NaCl, thin film): 2960, 2941, 2892, 2866, 1657, 1463, 1383, 1369, 1104, 1066 cm-1. HRMS: (FAB) calc’d for C15H28BrOSi [M + H – H2]+ 331.1093, found 331.1089. Preparation of epoxy alcohol 197: Br + TIPSO 195 MeO 2C MeO 2C H 185 t-BuLi, then 185 O O O MeO 2C MeO 2C H OH THF, –94 °C TIPSO (72% yield) 197 In a 10-mL, round-bottomed flask, a solution of vinyl bromide 195 (54.3 mg, 0.186 mmol, 1.0 equiv) in THF (0.93 mL) was added to a solution of t-BuLi (220 µL, 0.373 mmol, 2.0 equiv) in THF (0.93 mL) at –94 °C. After stirring for 15 min, a solution of epoxyketone 185 (50.0 mg, 0.186 mmol, 1.0 equiv) in THF (0.93 mL) was added. The reaction was stirred for an additional hour, and then quenched with H2O (5 mL). The mixture was extracted with Et2O (3 x 5 mL), and the combined organic extracts were washed with brine (15 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (11% EtOAc in hexanes) afforded epoxy alcohol 197 (64.5 mg, 0.134 mmol, 72% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3): δ 4.58 (dt, J = 2.8, 1.5 Hz, 2H), 3.75 (s, 3H), 3.71 (s, 3H), 3.29 (d, J = 3.6 Hz, 1H), 2.99 (s, 1H), 2.65 (dd, J = 12.3, 5.7 Hz, 1H), 2.57 – 2.49 (m, 2H), 2.49 – 2.24 (m, 6H), 2.06 – 1.91 (m, 4H), 1.86 – 1.70 (m, 2H), 1.63 – 1.54 (m, 1H), 1.14 – 1.07 (m, 3H), 1.07 – 1.03 (m, 18H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 180 C NMR (126 MHz, CDCl3): δ 171.9, 170.2, 139.4, 136.5, 77.1, 72.1, 60.6, 57.5, 55.0, 52.9, 52.1, 46.3, 39.5, 35.4, 35.0, 29.0, 24.6, 22.0, 21.5, 18.0, 12.0. FTIR (NaCl, thin film): 3493, 2946, 2888, 2865, 1740, 1730, 1463, 1434, 1368, 1305, 1245, 1092, 1062 cm-1. HRMS: (ESI) calc’d for C28H46NaO7Si [M + Na]+ 545.2905, found 545.2906. Preparation of ketone 198: O MeO 2C MeO 2C H OH CH2Cl2, 0 °C TIPSO OTMS OTMS TMSOTf 2,6-lutidine MeO 2C MeO 2C MeO 2C H O OTIPS (90% yield) 197 CO2Me O OTIPS 198 In a 10-mL, round-bottomed flask, epoxy alcohol 197 (94.2 mg, 0.180 mmol, 1.0 equiv) was dissolved in CH2Cl2 (2 mL) and cooled to 0 °C. 2,6-lutidine (63 µL, 0.541 mmol, 3.0 equiv) was added, followed by TMSOTf (65 µL, 0.360 mmol, 2.0 equiv). The reaction was stirred for 15 min, and then quenched with sat. NaHCO3 (5 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (7% EtOAc in hexanes) afforded ketone 198 (95.8 mg, 0.161 mmol, 90% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3): δ 4.21 (s, 1H), 4.12 (d, J = 12.2 Hz, 1H), 3.98 (d, J = 12.2 Hz, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 3.44 (dd, J = 12.7, 7.5 Hz, 1H), 2.62 – 2.54 (m, 1H), 2.45 (dt, J = 15.7, 7.5 Hz, 2H), 2.39 – 2.08 (m, 6H), 1.94 – 1.76 (m, 3H), 1.77 – 1.64 (m, 2H), 1.14 – 1.08 (m, 3H), 1.08 – 1.04 (m, 18H), 0.05 (s, 9H). 181 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 C NMR (126 MHz, CDCl3): δ 220.1, 170.9, 170.8, 139.2, 135.4, 70.3, 61.4, 57.3, 56.1, 52.6, 52.5, 45.7, 38.7, 36.5, 35.0, 28.3, 23.5, 21.5, 19.0, 17.9, 11.9, -0.1. FTIR (NaCl, thin film): 2950, 2892, 2866, 1743, 1462, 1405, 1278, 1278, 1252, 1208, 1169, 1094, 1070, 1020 cm-1. HRMS: (ESI) calc’d for C22H33O6Si [M – OTIPS]+ 421.2041, found 421.2031. Preparation of ketone 200 directly from epoxyketone 185: OTMS Br + TMSO 196 (1.0 equiv) MeO 2C MeO 2C H 185 (1.0 equiv) t-BuLi, then 185 THF, –94 °C O O CO2Me O MeO 2C then TMSOTf 2,6-lutidine, 0 °C OTMS (54% yield) 200 In a 50-mL, round-bottomed flask, vinyl bromide 196 (130 mg, 0.522 mmol, 1.0 equiv) was dissolved in THF (5.2 mL) and cooled to –94 °C (acetone/liquid N2). t-BuLi (0.61 mL, 1.7 M in pentane, 1.04 mmol, 2.0 equiv) was added, and the reaction was stirred for 10 min. In a separate flask, a solution of epoxyketone 185 (140 mg, 0.522 mmol, 1.0 equiv) in THF (5.2 mL) was prepared and added slowly, down the side of the flask, to the first reaction flask. The reaction was stirred for 30 min while allowing the acetone/liquid N2 bath to expire (not exceeding 0 °C). The cooling bath was replaced with an ice bath (0 °C), and then 2,6-lutidine (0.18 mL, 1.57 mmol, 3.0 equiv) was added, followed by TMSOTf (0.19 mL, 1.04 mmol, 2.0 equiv). The reaction was stirred for 20 min, and then another portion of 2,6-lutidine (0.18 mL, 1.57 mmol, 3.0 equiv) was added, followed by another portion of TMSOTf (0.19 mL, 1.04 mmol, 2.0 equiv). The reaction was stirred an additional 20 min, then quenched with sat. NaHCO3 (20 mL). The mixture was extracted with CH2Cl2 (3 x 20 mL), and the combined organic extracts were dried 182 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (5 to 7% EtOAc in hexanes) to provide ketone 200 (142.7 mg, 0.279 mmol, 54% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3): δ 4.21 (s, 1H), 3.98 (d, J = 12.6 Hz, 1H), 3.88 (d, J = 12.8 Hz, 1H), 3.72 (s, 3H), 3.64 (s, 3H), 3.38 (dd, J = 12.8, 7.5 Hz, 1H), 2.48 – 2.25 (m, 6H), 2.25 – 2.08 (m, 3H), 1.93 – 1.64 (m, 5H), 0.11 (s, 9H), 0.05 (s, 9H). 13 C NMR (126 MHz, CDCl3): δ 220.0, 170.8, 170.8, 138.6, 136.0, 70.4, 60.4, 57.3, 56.1, 52.6, 52.6, 45.8, 38.8, 36.7, 35.2, 28.3, 23.5, 21.6, 19.0, -0.1, -0.6. FTIR (NaCl, thin film): 2954, 2904, 2848, 1743, 1460, 1434, 1405, 1252, 1209, 1169, 1072, 1021 cm-1. HRMS: (ESI) calc’d for C22H33O6Si [M – OTMS]+ 421.2041, found 421.2045. Preparation of allylic alcohol 201: MeO 2C OTMS OTMS CO2Me O CO2Me O AcOH (aq) MeO 2C OTMS MeO 2C E OH O THF OTMS 200 (97% yield) OH 201 S4 (E = CO2Me) In a 10-mL, round-bottomed flask, bis-silyl ether 200 (120 mg, 0.235 mmol, 1.0 equiv) was dissolved in THF (2.4 mL). Aqueous AcOH (0.7 mL, 1.0 M, 0.700 mmol, 3.0 equiv) was added, and the reaction was stirred for 45 min. The reaction was then quenched by addition of sat. NaHCO3 (10 mL), and the aqueous phase was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine concentrated in vacuo. 183 Purification by silica gel chromatography (33% EtOAc in hexanes) afforded an equilibrium mixture of allylic alcohol 201 and cyclic hemiketal S4 (100 mg, 0.228 mmol, 97% yield) as a white foam. FTIR (NaCl, thin film): 3479, 2953, 2847, 1739, 1734, 1643, 1445, 1434, 1402, 1251, 1172, 1099, 1075 cm-1. HRMS: (ESI) calc’d for C22H33O6Si [M – OH]+ 421.2041, found 421.2043. Key NMR signals for allylic alcohol 201: 1 H NMR (500 MHz, CDCl3): δ 4.31 (d, J = 16.5 Hz, 1H), 4.17 (dt, J = 16.1, 2.7 Hz, 1H), 3.87 (t, J = 5.5 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.09 (t, J = 9.1 Hz, 1H), 0.15 (s, 9H). 13 C NMR (126 MHz, CDCl3): δ 221.8, 171.9, 170.9, 134.1, 134.1, 0.4. Key NMR signals for cyclic hemiketal S4: 1 H NMR (500 MHz, CDCl3): δ 4.25 (s, 1H), 3.99 (dd, J = 12.4 6.1 Hz, 1H), 3.89 (dd, J = 14.0, 4.8 Hz), 3.76 (s, 3H), 3.71 (s, 3H), 3.36 (dd, J = 12.8, 7.5 Hz, 1H), 0.09 (s, 9H). 13 C NMR (126 MHz, CDCl3): δ 171.0, 170.5, 139.3, 138.1, 106.9, 0.1. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 184 Preparation of ketoaldehyde 202: MeO 2C OTMS OTMS CO2Me O CO2Me O DMP MeO 2C CH2Cl2 OH 201 H (81% yield) O 202 In a 25-mL, round-bottomed flask, allylic alcohol 201 (203.4 mg, 0.464 mmol, 1.0 equiv) was dissolved in CH2Cl2 (4.6 mL). Dess–Martin periodinane (393.4 mg, 0.927 mmol, 2.0 equiv) was added, and the reaction was stirred for 1 h. The reaction was then quenched by addition of sat. NaHCO3 (5 mL) and sat. Na2S2O3 (5 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (25% EtOAc in hexanes) afforded ketoaldehyde 202 (163.7 mg, 0.375 mmol, 81% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 9.77 (s, 1H), 4.39 (s, 1H), 3.73 (s, 3H), 3.64 (s, 3H), 3.45 (dd, J = 12.6, 7.7 Hz, 1H), 2.78 – 2.63 (m, 3H), 2.60 – 2.34 (m, 4H), 2.25 – 2.07 (m, 2H), 1.95 – 1.72 (m, 4H), 1.67 (tdd, J = 14.4, 3.5, 2.0 Hz, 1H), 0.07 (s, 9H). 13 C NMR (126 MHz, CDCl3): δ 218.6, 188.4, 171.0, 170.4, 162.1, 138.6, 70.1, 58.9, 56.5, 52.8, 52.7, 47.6, 38.9, 38.8, 31.8, 28.2, 23.8, 21.7, 19.2, -0.1. FTIR (NaCl, thin film): 2954, 2851, 2756, 1740, 1660, 1594, 1579, 1460, 1434, 1252, 1171, 1099, 1060, 1023 cm-1. HRMS: (ESI) calc’d for C22H33O7Si [M + H]+ 437.1990, found 437.1982. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 185 Preparation of tetracycle 203: MeO 2C OTMS OTMS CO2Me O CO2Me O KOt-Bu THF, –78 °C H O MeO 2C OH (83% yield, >20:1 dr) 202 203 In a 10-mL, round-bottomed flask, ketoaldehyde 202 (40.0 mg, 91.6 µmol, 1.0 equiv) was dissolved in THF (1.8 mL) and cooled to –78 °C. To this solution was added KOt-Bu (101 µL, 1 M in THF, 0.101 mmol, 1.1 equiv), and the reaction was stirred for 5 min at –78 °C. The reaction was quenched by addition of sat. NaHCO3 (2 mL), and the mixture was extracted with CH2Cl2 (3 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (40% EtOAc in hexanes) to afford alcohol 203 (33.1 mg, 75.8 µmol, 83% yield) as a white solid. Note: The aldol product 203 is unstable to long term storage, as it slowly undergoes epimerization at the allylic alcohol (likely through retro-aldol/aldol) and cleavage of the silyl ether. It is also unstable to un-neutralized CDCl3, and thus NMR’s are often contaminated with epimeric/diol side products. The direct aldol product 203 was most often carried onto the next step crude without purification. 1 H NMR (400 MHz, CDCl3): δ 4.26 (s, 1H), 3.99 (dd, J = 9.1, 6.6 Hz, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 2.62 – 2.50 (m, 3H), 2.52 – 2.42 (m, 1H), 2.42 (dd, J = 9.9, 2.3 Hz, 1H), 2.28 – 2.12 (m, 3H), 2.01 – 1.89 (m, 4H), 1.81 – 1.73 (m, 2H), 1.63 (ddd, J = 14.3, 10.0, 1.9 Hz, 1H), 0.12 (s, 9H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 186 C NMR (101 MHz, CDCl3): δ 211.7, 172.2, 170.5, 147.1, 138.1, 78.1, 70.7, 57.3, 55.1, 52.9, 52.3, 51.7, 44.4, 32.6, 31.6, 29.5, 27.4, 26.7, 23.1, 0.9. FTIR (NaCl, thin film): 3445, 2954, 2851, 1738, 1732, 1652, 1435, 1252, 1059, 841 cm-1. HRMS: (ESI) calc’d for C22H33O7Si [M + H]+ 437.1990, found 437.1994. Preparation methoxymethyl ether 204: OTMS CO2Me O MeO 2C OH 203 OTMS MOMCl, n-Bu4NI i-Pr2NEt CO2Me O MeO 2C DMF, 45 °C (91% yield) OMOM 204 In a 1-dram vial, allylic alcohol 203 (8.4 mg, 19.2 µmol, 1.0 equiv) was dissolved in DMF (0.20 mL). To this solution was sequentially added n-Bu4NI (1.4 mg, 3.9 µmol, 0.20 equiv), i-Pr2NEt (20 µL, 0.115 mmol, 6.0 equiv), and MOMCl (7.3 µL, 96.2 µmol, 5.0 equiv). The reaction was heated to 45 °C and stirred for 13 h, and then quenched with sat. NaHCO3 (2 mL). The mixture was extracted with CH2Cl2 (3 x 1 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (40% EtOAc in hexanes) to afford methoxymethyl ether 204 (8.4 mg, 17.5 µmol, 91% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 4.79 (d, J = 7.1 Hz, 1H), 4.69 (d, J = 7.1 Hz, 1H), 4.25 (t, J = 2.5 Hz, 1H), 4.00 (dd, J = 10.2, 5.4 Hz, 1H), 3.73 (s, 3H), 3.67 (s, 3H), 3.43 (s, 3H), 2.63 (ddd, J = 8.6, 3.2, 1.9 Hz, 1H), 2.60 – 2.41 (m, 4H), 2.25 – 2.10 (m, 3H), 2.00 – 1.90 (m, 3H), 1.88 – 1.71 (m, 2H), 1.63 – 1.56 (m, 1H), 0.10 (s, 9). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 187 C NMR (101 MHz, CDCl3): δ 209.5, 172.3, 170.4, 147.4, 135.7, 95.5, 82.5, 70.2, 57.3, 55.4, 54.6, 52.9, 52.3, 47.7, 44.5, 32.9, 31.6, 29.1, 27.3, 26.3, 23.0, 0.9. FTIR (NaCl, thin film): 2953, 2847, 1755, 1732, 1462, 1453, 1434, 1251, 1150, 1099, 1024 cm-1. HRMS: (ESI) calc’d for C24H36KO8Si [M + K]+ 519.1811, found 519.1813. Preparation of alcohol 205: OTMS CO2Me O MeO 2C OMOM OH H 2SiF6 CO2Me O MeO 2C MeCN, 0 °C OMOM (94% yield) 204 205 In a 1-dram vial, silyl ether 204 (8.4 mg, 17.5 µmol, 1.0 equiv) was dissolved in MeCN (0.35 mL) and cooled to 0 °C. H2SiF6 (20–25 wt%, 11.2 µL, 17.5 µmol, 1.0 equiv) was added, and the reaction was stirred for 10 minutes before quenching with sat. NaHCO3 (1 mL). The mixture was extracted with CH2Cl2 (3 x 1 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford pure alcohol 205 (6.7 mg, 16.4 µmol, 94% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 4.79 (d, J = 7.2 Hz, 1H), 4.69 (d, J = 7.0 Hz, 1H), 4.33 – 4.26 (m, 1H), 4.28 (d, J = 11.2 Hz, 1H), 3.82 (td, J = 11.6, 5.1 Hz, 1H), 3.73 (s, 3H), 3.68 (s, 3H), 3.44 (s, 3H), 2.82 – 2.69 (m, 2H), 2.65 – 2.51 (m, 1H), 2.51 – 2.41 (m, 1H), 2.37 (ddd, J = 14.5, 8.6, 1.8 Hz, 1H), 2.27 – 2.13 (m, 3H), 2.10 – 1.91 (m, 3H), 1.86 (td, J = 14.0, 2.7 Hz, 1H), 1.64 (ddd, J = 14.4, 9.9, 2.0 Hz, 1H), 1.46 (qd, J = 13.7, 2.3 Hz, 1H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 188 C NMR (101 MHz, CDCl3): δ 217.5, 171.7, 170.8, 147.4, 136.8, 95.6, 82.8, 71.4, 57.7, 55.5, 53.8, 52.8, 52.5, 47.9, 45.0, 32.9, 31.9, 30.2, 28.1, 27.6, 22.7. FTIR (NaCl, thin film): 3491, 2953, 2892, 2849, 1741, 1732, 1453, 1435, 1298, 1286, 1260, 1215, 1151, 1098, 1080, 1056, 1035, 1024 cm-1. HRMS: (ESI) calc’d for C19H23O6 [M – OCH2OCH3]+ 347.1489, found 347.1484. Preparation of methyl ether 206: OH CO2Me O MeO 2C OMOM OMe Me 3OBF 4 Proton sponge CO2Me O MeO 2C CH2Cl2 OMOM (71% yield) 205 206 In an N2-filled glovebox, alcohol 205 (30.0 mg, 73.4 µmol, 1.0 equiv), Me3OBF4 (32.6 mg, 0.220 mmol, 3.0 equiv), and Proton sponge (63.0 mg, 0.294 mmol, 4.0 equiv) were dissolved in CH2Cl2 (0.5 mL) in a 1-dram vial. The vial was sealed with a Teflon cap, brought out of the glovebox, and stirred for 36 h. The reaction mixture was then filtered directly through a short plug of silica, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (60% EtOAc in hexanes) to afford methyl ether 206 (22.1 mg, 52.3 µmol, 71% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 4.77 (d, J = 7.1 Hz, 1H), 4.65 (d, J = 7.1 Hz, 1H), 4.26 (s, 1H), 3.74 (s, 3H), 3.66 (s, 3H), 3.44 – 3.39 (m, 4H), 3.35 (s, 3H), 2.71 (ddd, J = 8.6, 3.5, 2.0 Hz, 1H), 2.65 – 2.54 (m, 1H), 2.53 – 2.45 (m, 1H), 2.38 (dd, J = 9.9, 2.1 Hz, 1H), 2.34 – 2.15 (m, 3H), 2.09 – 1.90 (m, 3H), 1.85 (ddd, J = 14.3, 12.5, 3.3 Hz, 1H), 1.66 – 1.51 (m, 3H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 189 C NMR (101 MHz, CDCl3): δ 209.6, 172.1, 170.3, 146.9, 136.3, 95.4, 82.1, 79.2, 57.7, 57.1, 55.5, 54.5, 52.9, 52.3, 47.6, 44.8, 33.1, 31.7, 30.0, 26.7, 22.7, 22.0. FTIR (NaCl, thin film): 2952, 2849, 1752, 1732, 1452, 1437, 1258, 1238, 1214, 1149, 1105, 1024 cm-1. HRMS: (ESI) calc’d for C22H30NaO8 [M + Na]+ 445.1833, found 445.1844. Preparation of amine 207: OMe CO2Me O MeO 2C OMOM OMe EtNH 2, Ti(Oi-Pr)4 CO2Me NHEt MeO 2C then NaBH 4, EtOH OMOM (90% yield) 206 207 In a ½-dram vial, EtNH2 (36 µL, 2.0 M in THF, 72 µmol, 3.0 equiv) and Ti(OiPr)4 (37 µL, 0.125 mmol, 6.0 equiv) were added to ketone 206 (10.0 mg, 23.7 µmol, 1.0 equiv). After stirring for 2 h, the mixture was diluted with EtOH (0.47 mL), and NaBH4 (9.0 mg, 0.238 mmol, 10 equiv) was added. The reaction mixture was stirred for an additional 2 h, and then concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 and quenched by addition of sat. NaHCO3 (1 mL) and Rochelle’s salt (ca. 30 mg), and then stirred for 1 h. The layers were separated, and the aqueous phase was extracted CH2Cl2 (3 x 1 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford amine 207 (9.6 mg, 21.3 µmol, 90% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 4.74 (d, J = 6.8 Hz, 1H), 4.60 (d, J = 6.8 Hz, 1H), 3.74 (s, 3H), 3.73 – 3.68 (m, 1H), 3.70 – 3.56 (m, 4H), 3.38 (s, 3H), 3.23 (s, 3H), 3.20 – 3.11 190 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine (m, 1H), 2.79 – 2.56 (m, 4H), 2.56 – 2.45 (m, 3H), 2.33 – 2.03 (m, 4H), 1.89 (p, J = 7.4 Hz, 2H), 1.72 – 1.59 (m, 2H), 1.37 (dd, J = 13.7, 9.7 Hz, 1H), 1.04 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 172.9, 170.8, 145.6, 133.5, 95.2, 77.4, 76.0, 61.5, 56.6, 56.4, 55.3, 52.9, 52.4, 49.0, 47.6, 42.8, 38.7, 33.4, 31.1, 28.9, 24.0, 21.7, 21.5, 15.3. FTIR (NaCl, thin film): 3346, 2951, 2888, 2847, 2824, 1738, 1732, 1463, 1457, 1436, 1372, 1262, 1236, 1198, 1148, 1096, 1029, 988, 917 cm-1. HRMS: (ESI) calc’d for C24H38NO7 [M + H]+ 452.2643, found 452.2634. Preparation of diester 209: MeO 2C O + THF/Et2O, rt MeO 2C 186 GaNa-(S)-BINOL (10 mol%) NaOt-Bu (7 mol%) 188 48 mmol scale: 92% yield, 91% ee 160 mmol scale: 76% yield, 77% ee MeO 2C MeO 2C O H 209 Preparation of GaNa-(S)-BINOL solution (0.05 M in 9:1 THF:Et2O):18 In a 500-mL, round-bottomed flask, a solution of NaOt-Bu (3.29 g, 34.2 mmol, 4.0 equiv) in THF (60 mL) was added to a solution of (S)-BINOL (4.90 g, 17.1 mmol, 2.0 equiv) in THF (52 mL), and the resulting mixture was stirred for 30 minutes. This was then cannulated into a solution of GaCl3 (1.51 g, 8.55 mmol, 1.0 equiv) in THF (43 mL) and Et2O (17 mL). This mixture was stirred for 2 h, and then allowed to stand un-agitated for at least 22 h. Enantioselective Michael addition: A solution of GaNa-(S)-BINOL (96 mL, 0.05 M in 9:1 THF:Et2O, 4.80 mmol, 0.10 equiv) was transferred via syringe to a 500mL, round-bottomed flask. To this was added a solution of NaOt-Bu (323 mg, 3.36 mmol. 0.07 equiv) in THF (7.5 mL), followed by dimethyl malonate (186, 5.5 mL, 48 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 191 mmol, 1.0 equiv) and 2-cyclopenten-1-one (188, 4.0 mL, 48 mmol, 1.0 equiv). The reaction was stirred for 37 h, then quenched with 1 N HCl (300 mL). The mixture was extracted with EtOAc (3 x 200 mL), and the combined organic extracts were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacou. Vacuum distillation of the crude residue afforded diester 209 (9.44 g, 44.1 mmol, 92% yield) as a colorless oil. Spectroscopic data matched that reported in the literature.35 1 H NMR (300 MHz, CDCl3): δ 3.77 (s, 3H), 3.75 (s, 3H), 3.38 (d, J = 9.4 Hz, 1H), 2.95 – 2.78 (m, 1H), 2.51 (dd, J = 18.4, 7.7 Hz, 2H), 2.43 – 2.13 (m, 3H), 2.01 (ddd, J = 18.4, 11.1, 1.3 Hz, 1H), 1.74 – 1.59 (m, 1H). Diester 209 was carried forward to enone 190, where enantiomeric excess was determined to be 91%: SFC data for racemic enone 190: Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 192 SFC data for enantioenriched enone 190 (three steps from diester 209): Large-scale preparation of diester 209: The above protocol was reproduced using 160 mmols of dimethyl malonate (186) and 160 mmols of 2-cyclopenten-1-one (188), affording a 76% yield of diester 209 in 77% ee. [𝜶]𝟐𝟓 𝐃 = –46° (c = 0.84, CHCl3). SFC data for racemic diester 209: Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 193 SFC data for enantioenriched diester 209 prepared on 160 mmol scale: Preparation of ketal 210: MeO 2C MeO 2C ethylene glycol p-TsOH O H 209 benzene, reflux (83% yield) MeO 2C MeO 2C O H O 210 In a 50-mL, round-bottomed flask equipped with a reflux condenser and Dean– Stark trap, ketone 209 (1.33 g, 6.19 mmol, 1.0 equiv) was dissolved in toluene (21 mL). To this solution was added ethylene glycol (0.70 mL, 12.4 mmol, 2.0 equiv) and pTsOH•H2O (120 mg, 0.619 mmol, 0.10 equiv), and the reaction was heated to reflux for 48 h. The reaction was then cooled to room temperature and washed with sat. NaHCO3 (2 x 50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (25% EtOAc in hexanes) provided ketal 210 (1.33 g, 5.15 mmol, 83% yield) as a colorless oil. 194 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 H NMR (400 MHz, CDCl3): δ 3.93 – 3.84 (m, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.31 (d, J = 10.2 Hz, 1H), 2.75 – 2.62 (m, 1H), 2.08 (ddd, J = 13.7, 8.0, 1.2 Hz, 1H), 1.99 – 1.86 (m, 2H), 1.85 – 1.75 (m, 1H), 1.56 (dd, J = 13.6, 9.5 Hz, 1H), 1.48 – 1.36 (m, 1H). 13 C NMR (101 MHz, CDCl3): δ 169.0, 168.9, 117.0, 64.3, 64.2, 56.7, 52.4, 52.4, 40.6, 36.8, 35.5, 28.2. FTIR (NaCl, thin film): 2956, 2885, 1754, 1734, 1435, 1316, 1216, 1151, 1079, 1017, 947 cm-1. HRMS: (PMM) calc’d for C12H19O6 [M + H]+ 259.1176, found 259.1169. [𝜶]𝟐𝟓 𝐃 = +2.2° (c = 1.4, CHCl3). Preparation of bis-ketal 211: 187 Br MeO 2C MeO 2C O O O THF, reflux H O (78% yield, 98% brsm) 210 O O NaH, n-Bu4NI MeO 2C MeO 2C H O O 211 In a 250-mL, round-bottomed flask equipped with a reflux condenser, NaH (60% dispersion in mineral oil, 1.42 g, 35.6 mmol, 1.2 equiv) was washed with hexanes (3 x 10 mL), then cooled to 0 °C. A solution of diester 210 (7.66 g, 29.6 mmol, 1.0 equiv) in THF (70 mL, followed by 3 x 10 mL rinse) was added, and the reaction was heated to 70 °C with stirring for 25 min. n-Bu4NI (1.09 g, 2.96 mmol, 0.10 equiv) and 2-(2bromoethyl)-1,3-dioxolane (187, 5.22 mL, 44.5 mmol, 1.5 equiv) were added sequentially, and the reaction was heated to reflux for 15 h. The reaction was then quenched by addition of sat. NH4Cl (50 mL) and H2O (50 mL). The mixture was 195 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine extracted with CH2Cl2 (3 x 250 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (35 to 40% EtOAc in hexanes) afforded recovered starting material 210 (1.56 g, 20% recovery) and bis-ketal 211 (7.26 g, 23.1 mmol, 78% yield, 98% based on recovered starting material) as a colorless oil. 1 H NMR (500 MHz, CDCl3): δ 4.83 (td, J = 4.5, 1.9 Hz, 1H), 3.97 – 3.81 (m, 8H), 3.71 (s, 3H), 3.71 (s, 3H), 2.70 – 2.60 (m, 1H), 2.05 – 1.95 (m, 3H), 1.91 – 1.80 (m, 2H), 1.80 – 1.66 (m, 2H), 1.64 – 1.50 (m, 3H). 13 C NMR (126 MHz, CDCl3): δ 171.2, 171.1, 116.6, 103.9, 64.9, 64.9, 64.2, 64.1, 59.8, 52.2, 52.1, 40.4, 38.0, 35.3, 29.0, 27.9, 25.4. FTIR (NaCl, thin film): 2954, 2915, 2877, 1728, 1434, 1227, 1141, 1024 cm-1. HRMS: (FAB) calc’d for C17H27O8 [M + H]+ 359.1706, found 359.1716. [𝜶]𝟐𝟓 𝐃 = –0.69° (c = 0.60, CHCl3). Preparation of enone 190: O O HCl (aq) MeO 2C MeO 2C H 211 O O acetone, 70 °C MeO 2C MeO 2C H O (67% yield) 190 In a 200-mL, round-bottomed flask equipped with a reflux condenser, bis-ketal 211 (7.26 g, 23.1 mmol, 1.0 equiv) was dissolved in acetone (92 mL). Aqueous HCl (23.1 mL, 2 N, 46.2 mmol, 2.0 equiv) was added, and the reaction was heated to 70 °C with stirring for 7 h. The reaction was then quenched with sat. NaHCO3 (100 mL) and 196 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine partially concentrated in vacuo to remove acetone. The resulting mixture was extracted with CH2Cl2 (3 x 150 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (25% EtOAc in hexanes) to afford enone 190 (3.91 g, 15.5 mmol, 67% yield) as a white solid. 1 H NMR (500 MHz, CDCl3): δ 6.70 (q, J = 3.8 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 3H), 3.11 (qdd, J = 7.4, 3.5, 2.1 Hz, 1H), 2.53 – 2.37 (m, 4H), 2.32 – 2.22 (m, 2H), 2.11 – 2.00 (m, 1H), 1.99 – 1.90 (m, 1H). 13 C NMR (126 MHz, CDCl3): δ 204.6, 171.9, 169.5, 137.1, 131.3, 55.1, 52.7, 52.2, 42.8, 37.8, 29.4, 23.9, 23.3. FTIR (NaCl, thin film): 3022, 2956, 2898, 2848, 1732, 1659, 1451, 1434, 1283, 1256, 1214, 1174, 1143, 1064 cm–1. HRMS: (FAB) calc’d for C13H17O5 [M + H]+ 253.1076, found 253.1076. [𝜶]𝟐𝟓 𝐃 = –34° (c = 1.7, CHCl3). Preparation bromohydrin 192: O O S N Br OH MeO 2C MeO 2C H 190 191 O O MeCN/H 2O (62% yield) MeO 2C MeO 2C H Br O 192 A 250-mL, round-bottomed flask was charged with enone 190 (3.91 g, 15.5 mmol, 1.0 equiv), MeCN (64 mL), and H2O (12 mL), followed lastly by N- Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 197 bromosaccharin (191, 5.28 g, 20.1 mmol, 1.3 equiv). The reaction was stirred for 6.5 h, then quenched by addition of sat. Na2S2O3 (150 mL). The mixture was extracted with Et2O (3 x 250 mL), and the combined organic extracts were washed with sat. NaHCO3 (2 x 150 mL), brine (150 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford a crude white solid. This was dissolved in Et2O (600 mL) at 35 °C. Ca. 300 mL was concentrated off, and then hexanes (300 mL) was added. The solution was concentrated until ca. 300 mL of solvent remained, with white solids suspended within. The solvent was decanted into a Büchner funnel, washing the flask carefully with hexanes. The residual solids in the flask were collected, affording bromohydrin 192 (3.37 g, 9.65 mmol, 62% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 4.39 – 4.32 (m, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.10 (ddd, J = 12.2, 5.8, 1.5 Hz, 1H), 2.80 – 2.68 (m, 2H), 2.58 – 2.45 (m, 1H), 2.43 – 2.32 (m, 2H), 2.32 – 2.16 (m, 2H), 2.11 – 1.96 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 211.6, 171.3, 171.1, 76.5, 55.5, 53.0, 52.5, 47.9, 42.2, 36.2, 28.2, 27.6, 21.3. FTIR (NaCl, thin film): 3436, 2998, 2955, 2847, 1748, 1732, 1435, 1403, 1252, 1213, 1152, 1091, 1073, 1056, 980 cm-1. HRMS: (FAB) calc’d for C13H18BrO6 [M + H]+ 349.0287, found 349.0275. [𝜶]𝟐𝟓 𝐃 = –49° (c = 0.17, CHCl3). 198 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Preparation of epoxyketone 185: OH MeO 2C MeO 2C H Et 3N Br O 192 CH2Cl2 (99% yield) MeO 2C MeO 2C H O O 185 In a 250-mL, round-bottomed flask, bromohydrin 192 (3.35 g, 9.59 mmol, 1.0 equiv) was dissolved in CH2Cl2 (96 mL). Et3N (1.60 mL, 11.5 mmol, 1.2 equiv) was added, and the reaction was stirred for 9 h. The mixture was loaded directly onto a column of silica gel (slurried in hexanes), and purification by chromatography (100% hexanes, then 40% EtOAc in hexanes) afforded epoxyketone 185 (2.54 g, 9.47 mmol, 99% yield) as a white solid. 1 H NMR (500 MHz, CDCl3): δ 3.76 (s, 1H), 3.76 – 3.73 (m, 4H), 2.93 (dd, J = 12.5, 5.8 Hz, 1H), 2.67 (qd, J = 11.7, 7.4 Hz, 1H), 2.58 (ddd, J = 18.7, 7.6, 1.6 Hz, 1H), 2.48 – 2.28 (m, 4H), 2.12 – 2.01 (m, 1H), 1.72 – 1.61 (m, 1H). 13 C NMR (126 MHz, CDCl3): δ 212.0, 171.4, 169.8, 63.0, 56.1, 55.2, 53.1, 52.4, 43.8, 38.4, 29.3, 23.0, 21.7. FTIR (NaCl/thin film): 3006, 2956, 2903, 2848, 1755, 1732, 1453, 1434, 1408, 1372, 1306, 1251, 1214, 1176, 1139, 1058, 890 cm-1. HRMS: (FAB) calc’d for C13H17O6 [M + H]+ 269.1025, found 269.1050. [𝜶]𝟐𝟓 𝐃 = –171° (c = 0.60, CHCl3). 199 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine SFC data for racemic epoxyketone 185: SFC data for enantiopure epoxyketone 185: Preparation of aryl ether S5: Me Me HO Me + OH OH 227 DIAD, PPh 3 Me OH O THF (58% yield) S5 In a 1-L, round-bottomed flask equipped with an addition funnel, (2R, 4R)pentanediol (227, 7.39 g, 71.0 mmol, 1.0 equiv), phenol (7.35 g, 78.1 mmol, 1.1 equiv), and PPh3 (22.3 g, 85.1 mmol, 1.2 equiv) were dissolved in THF (375 mL). A solution of Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 200 DIAD (16.8 mL, 85.1 mmol, 1.2 equiv) in THF (100 mL) was prepared in another flask, and transferred to the addition funnel. The DIAD solution was added dropwise to the vigorously stirring reaction over 25 min, and the resulting solution was stirred for an additional 24 h and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (15% EtOAc in hexanes) afforded arene S5 (7.4 g, 41 mmol, 52% yield). Spectroscopic data matched that reported by Sugimura et al.21 1 H NMR (500 MHz, CDCl3): δ 7.31 – 7.26 (m, 2H), 6.99 – 6.91 (m, 3H), 4.61 (dqd, J = 8.6, 6.0, 4.4 Hz, 1H), 4.06 (dqt, J = 8.9, 6.1, 2.7 Hz, 1H), 2.56 (s, 1H), 1.95 (dt, J = 14.4, 8.8 Hz, 1H), 1.70 (ddd, J = 14.4, 4.5, 3.1 Hz, 1H), 1.31 (d, J = 6.0 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H). Preparation of arene olefin 216: Me Me Me OH O Hg(OAc) 2 (20 mol%) Me O O OEt 45 °C S5 (>95% yield) 216 In a 250-mL, round-bottomed flask equipped with a reflux condenser, arene S5 (3.90 g, 21.6 mmol, 1.0 equiv) was dissolved in ethyl vinyl ether (108 mL), and Hg(OAc)2 (689 mg, 2.16 mmol, 0.10 equiv) was added. The mixture was heated to reflux and stirred for 18 h, at which point another portion of Hg(OAc)2 (689 mg, 2.16 mmol, 0.10 equiv) was added. After stirring for another 15 h at reflux, the reaction was quenched by addition of sat. NaHCO3 (100 mL). The layers were separated, and the aqueous phase was extracted with Et2O (3 x 200 mL). The combined organic extracts Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 201 were washed with brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by filtering over a short plug of silica (eluting with 10% EtOAc/1% Et3N in hexanes) to provide arene olefin 216 (4.5 g, 21.8 mmol, 100% yield) as a colorless oil. Spectroscopic data matched that reported by Sugimura et al.21 1 H NMR (400 MHz, CDCl3): δ 7.31 – 7.24 (m, 2H), 6.97 – 6.86 (m, 3H), 6.34 (dd, J = 14.2, 6.6 Hz, 1H), 4.52 (h, J = 6.2 Hz, 1H), 4.33 (dd, J = 14.2, 1.6 Hz, 1H), 4.12 (h, J = 6.3 Hz, 1H), 4.03 (dd, J = 6.7, 1.6 Hz, 1H), 2.20 (dt, J = 13.9, 6.9 Hz, 1H), 1.65 (dt, J = 14.0, 6.0 Hz, 1H), 1.33 (d, J = 6.1 Hz, 3H), 1.25 (d, J = 6.2 Hz, 3H). Preparation of 7-substituted meta-photoadduct 218: H Me Me O O 216 hν (254 nm) pentane 25 °C (1.5 g batches, 67% avg. yield) O Me H O H Me 218 In a 1-L, round-bottomed quartz flask, arene olefin 216 (1.5 g, 7.3 mmol, 1.0 equiv) was dissolved in pentane (700 mL). This solution was sparged with Ar for 75 min, then irradiated with stirring using a Honeywell 254 nm lamp for 27 h. The temperature was deliberately maintained at 25 °C using ventilation fans. Upon completion, the reaction was concentrated in vacuo to afford a crude residue. This procedure was repeated for a total of 5 batches. All 5 crude batches were combined and purified by silica gel chromatography (9% EtOAc in hexanes) to afford 7-substituted 202 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine photoadduct 218 (5.0 g, 24.2 mmol, 67% average yield over 5 batches) as a white solid. Spectroscopic data matched that reported by Sugimura et al.21 1 H NMR (300 MHz, CDCl3): δ 5.63 (ddt, J = 5.5, 2.7, 1.0 Hz, 1H), 5.44 (dd, J = 5.5, 1.7 Hz, 1H), 4.49 (dd, J = 7.0, 2.5 Hz, 1H), 4.31 (p, J = 6.5 Hz, 1H), 4.06 (p, J = 6.5 Hz, 1H), 3.26 (dd, J = 8.4, 2.8 Hz, 1H), 2.52 – 2.42 (m, 3H), 2.34 (dt, J = 17.4, 7.4 Hz, 1H), 2.10 (ddd, J = 14.6, 7.0, 0.9 Hz, 1H), 1.60 (d, J = 17.5 Hz, 1H), 1.23 (d, J = 6.3 Hz, 6H). Preparation of 6-substituted meta-photoadduct 217: H Me Me Me O O 216 H hν (254 nm) pentane Me H O + O O Me H O H Me 217 (42% yield) 218 (24% yield) H A 500-mL, round-bottomed quartz flask was charged with arene olefin 216 (244 mg, 1.18 mmol, 1.0 equiv) and pentane (250 mL). The solution was degassed by sparging with argon for 30 minutes. The reaction was then irradiated with stirring using a Honeywell 254 nm lamp for 21.5 h. The reaction was then concentrated in vacuo, and purified by silica gel chromatography (7 to 9% EtOAc in hexanes) to provide 6substituted photoadduct 217 (101.3 mg, 0.491 mmol, 42% yield) and 7-substituted photoadduct 218 (59.1 mg, 0.287 mmol, 24% yield). Spectroscopic data matched that reported by Sugimura et al.21 Note: No extra precautions were taken to prevent heating of this reaction by the irradiation lamp. This caused polymeric material to form on the inner wall of the flask, Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 203 which interfered with light penetration, and thereby effectively diminished conversion of 217 to 218 via vinyl cyclopropane rearrangement to allow isolation of 6-substituted photoadduct 217. 1 H NMR (300 MHz, CDCl3): δ 5.59 (ddd, J = 5.6, 2.4, 0.7 Hz, 1H), 5.42 (ddd, J = 5.7, 2.8, 1.6 Hz, 1H), 4.25 (dtd, J = 9.9, 7.3, 6.8, 5.7 Hz, 1H), 4.16 – 4.07 (m, 1H), 4.02 (tt, J = 7.4, 5.6 Hz, 1H), 3.85 (t, J = 2.6 Hz, 2H), 2.34 (ddt, J = 8.2, 2.2, 1.2 Hz, 1H), 2.09 (ddt, J = 8.4, 6.3, 1.1 Hz, 1H), 1.95 – 1.80 (m, 2H), 1.59 (d, J = 15.3 Hz, 1H), 1.50 (ddd, J = 13.9, 3.0, 1.4 Hz, 1H), 1.22 (d, J = 6.3 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H). Preparation of [3.2.1]-bicycle 228: Me H Me Me H O HCl (aq) Me OH O THF, 60 °C O H (37% yield) 217 O 228 To a 1-dram vial containing 6-substituted photoadduct 217 (18.0 mg, 87.3 µmol, 1.0 equiv) was added THF (0.87 mL) and aqueous HCl (3 M, 0.15 mL, 0.436 mmol, 5.0 equiv). The vial was sealed and heated to 60 °C for 16 h, then quenched by addition of sat. NaHCO3 (3 mL). The mixture was extracted with CH2Cl2 (3 x 3 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (40% EtOAc in hexanes) provided [3.2.1]bicycle 228 (7.3 mg, 32.5 µmol, 37% yield) as a colorless oil. Spectroscopic data matched that reported by Sugimura et al.21 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 204 H NMR (400 MHz, CDCl3): δ 5.88 (dddd, J = 9.4, 7.0, 2.5, 1.0 Hz, 1H), 5.48 (dddd, J = 9.2, 3.7, 2.8, 0.8 Hz, 1H), 4.10 (dd, J = 8.5, 4.4 Hz, 1H), 3.98 – 3.88 (m, 1H), 3.73 – 3.62 (m, 1H), 2.97 (ddt, J = 17.9, 5.2, 2.6 Hz, 1H), 2.86 (s, 1H), 2.68 (dd, J = 13.3, 8.4 Hz, 1H), 2.65 – 2.57 (m, 2H), 2.39 (dt, J = 4.6, 2.0 Hz, 1H), 1.92 (dt, J = 13.1, 5.5 Hz, 1H), 1.67 – 1.58 (m, 1H), 1.50 (ddd, J = 14.5, 4.1, 2.7 Hz, 1H), 1.17 (d, J = 6.1 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H). Preparation of [3.2.1]-bicycle 229: H HCl (aq) O Me H 218 O Me H dioxane, 40 °C O (yield nd) 229 To a 1-dram vial containing 7-substituted photoadduct 218 (4.2 mg, 20.4 µmol, 1.0 equiv) was added dioxane (0.20 mL) and aqueous HCl (3 M, 70 µL, 0.204 mmol, 10.0 equiv). The vial was sealed and heated to 40 °C for 3 h, then quenched by addition of sat. NaHCO3 (1 mL). The mixture was extracted with CH2Cl2 (3 x 1 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. 1 H NMR of the crude residue showed signals for a major product that were consistent with those reported for known [3.2.1]-bicycle 229.36 Diagnostic signals in crude 1H NMR (500 MHz, CDCl3): δ 6.68 (dd, J = 6.8, 3.0 Hz, 1H), 6.21 (dd, J = 6.9, 3.0 Hz, 1H), 6.07 – 6.01 (m, 2H), 5.51 – 5.46 (m, 1H) 2.82 – 2.74 (m, 3H), 2.52 – 2.46 (m, 1H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 205 Preparation of allylic chloride 233: Me H NCSac O Me H O H Me 218 Me OH O THF/H2O (84% yield) O Cl 233 In a 50-mL, round-bottomed flask, photoadduct 218 (250 mg, 1.21. mmol, 1.0 equiv) was dissolved in THF (10 mL) and H2O (2 mL). N-chlorosaccharin (317 mg, 1.45 mmol, 1.2 equiv) was added, and the reaction was stirred for 1.5 h. The reaction was then quenched by addition of sat. NaHCO3 (5 mL) and sat. Na2S2O3 (5 mL) and extracted with CH2Cl2 (3 x 30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (45 to 50% EtOAc in hexanes) to afford allylic chloride 233 (267 mg, 1.03 mmol, 84% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 5.94 (dd, J = 9.1, 7.2 Hz, 1H), 5.79 (ddd, J = 9.0, 3.9, 1.3 Hz, 1H), 4.88 (dd, J = 3.8, 3.2 Hz, 1H), 4.04 (dd, J = 7.3, 1.2 Hz, 1H), 3.90 (dqt, J = 9.2, 6.2, 3.0 Hz, 1H), 3.70 (dqd, J = 8.6, 6.0, 4.6 Hz, 1H), 2.80 (dt, J = 7.4, 1.2 Hz, 1H), 2.73 (ddq, J = 8.0, 3.1, 1.5 Hz, 1H), 2.30 (d, J = 2.8 Hz, 1H), 2.25 (ddd, J = 15.0, 7.4, 1.7 Hz, 1H), 2.15 (ddt, J = 14.9, 8.2, 1.3 Hz, 1H), 1.64 (dt, J = 14.4, 8.7 Hz, 1H), 1.48 (ddd, J = 14.4, 4.6, 3.3 Hz, 1H), 1.17 (d, J = 3.1 Hz, 3H), 1.15 (d, J = 3.0 Hz, 3H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 206 Preparation of ketal S6: Me Me TMSO OH O OTMS TMSOTf (20 mol%) CH2Cl2 O Cl 233 (90% yield) Me Me OH O O O Cl S6 In a 25-mL, round-bottomed flask, ketone 233 (267 mg, 1.03 mmol, 1.0 equiv) and 1,2-bis(trimethylsiloxy)ethane (0.50 mL, 2.06 mmol, 2.0 equiv) were dissolved in CH2Cl2 (10 mL). To this solution was added TMSOTf (37 µL, 0.206 mmol, 0.20 equiv). The reaction was stirred for 15 h, and then quenched with sat. NaHCO3 (10 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide pure ketal S6 (282 mg, 0.931 mmol, 90% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 6.03 (ddd, J = 9.5, 7.1, 0.8 Hz, 1H), 5.75 (ddd, J = 9.3, 3.6, 1.4 Hz, 1H), 4.48 – 4.42 (m, 1H), 4.44 (s, 1H), 4.09 – 3.99 (m, 4H), 4.00 – 3.88 (m, 1H), 3.72 (dd, J = 8.3, 3.0 Hz, 1H), 3.65 (dqd, J = 11.9, 5.9, 2.7 Hz, 1H), 2.48 (td, J = 7.5, 1.8 Hz, 2H), 2.11 (ddd, J = 14.7, 8.6, 3.2 Hz, 1H), 1.95 (dd, J = 14.7, 8.3 Hz, 1H), 1.66 – 1.52 (m, 1H), 1.49 (dt, J = 14.8, 2.1 Hz, 1H), 1.15 (dd, J = 6.3, 1.0 Hz, 3H), 1.11 (d, J = 5.9 Hz, 3H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 207 Preparation of ketone 234: Me Me OH Me O DMP, NaHCO 3 CH2Cl2 O O S6 Cl (89% yield) Me O O O O Cl 234 A 25-mL, round-bottomed flask was charged with alcohol S6 (282 mg, 0.931 mmol, 1.0 equiv), NaHCO3 (313 mg, 3.73 mmol, 4.0 equiv), and CH2Cl2 (9.3 mL). To this solution was added Dess–Martin periodinane (790 mg, 1.86 mmol, 2.0 equiv). The reaction was stirred for 12 h, and then quenched with sat. NaHCO3 (10 mL) and sat. Na2S2O3 (10 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (40% EtOAc in hexanes) afforded ketone 234 (249 mg, 0.828 mmol, 89% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 6.04 (ddd, J = 9.4, 7.4, 0.9 Hz, 1H), 5.71 (ddd, J = 9.4, 3.5, 1.4 Hz, 1H), 4.45 (ddd, J = 3.5, 2.0, 0.9 Hz, 1H), 4.03 – 3.94 (m, 4H), 3.89 (dqd, J = 8.2, 6.1, 4.6 Hz, 1H), 3.65 (dd, J = 8.2, 3.5 Hz, 1H), 2.78 (dd, J = 15.8, 8.2 Hz, 1H), 2.50 (dd, J = 7.4, 1.9 Hz, 1H), 2.44 (ddt, J = 7.8, 3.0, 1.7 Hz, 1H), 2.35 (dd, J = 15.8, 4.6 Hz, 1H), 2.20 (s, 3H), 2.03 (dddd, J = 14.3, 7.8, 3.5, 0.8 Hz, 1H), 1.94 (dd, J = 14.4, 8.2 Hz, 1H), 1.13 (d, J = 6.1 Hz, 3H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 208 Preparation of alcohol 235: Me Me O HO O KHMDS THF, –78 °C O O O O Cl Cl (56% yield) 234 235 In a 25-mL, round-bottomed flask, ketone 234 (249 mg, 0.828 mmol, 1.0 equiv) was dissolved in THF (8.3 mL) and cooled to –78 °C. KHMDS (2.5 mL, 0.5 M in toluene, 1.24 mmol, 1.5 equiv) was added, and then reaction was warmed to 0 °C. After stirring for 30 min, the reaction was quenched with sat. NH4Cl (5 mL) and H2O (5 mL) and extracted with CH2Cl2 (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (40% EtOAc in hexanes) afforded alcohol 235 (100 mg, 0.462 mmol, 56% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 6.02 (ddd, J = 9.5, 7.2, 0.8 Hz, 1H), 5.72 (ddd, J = 9.4, 3.7, 1.5 Hz, 1H), 4.44 (ddd, J = 3.8, 2.2, 0.8 Hz, 1H), 4.12 – 3.99 (m, 4H), 3.91 (ddd, J = 12.3, 5.7, 4.1 Hz, 1H), 3.22 (d, J = 12.3 Hz, 1H), 2.53 – 2.48 (m, 1H), 2.41 (dd, J = 7.2, 1.9 Hz, 1H), 2.02 (dd, J = 5.5, 4.0 Hz, 2H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 209 Preparation of ketone 236: O HO DMP, NaHCO 3 O CH2Cl2 O O Cl (53% yield) 235 O Cl 236 A 25-mL, round-bottomed flask was charged with alcohol 235 (98.0 mg, 0.452 mmol, 1.0 equiv), NaHCO3 (152 mg, 1.81 mmol, 4.0 equiv), and CH2Cl2 (5 mL). To this solution was added Dess–Martin periodinane (384 mg, 0.905 mmol, 2.0 equiv). The reaction was stirred for 15 h, and then quenched with sat. NaHCO3 (5 mL) and sat. Na2S2O3 (5 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (25% EtOAc in hexanes) afforded ketone 236 (51.7 mg, 0.241 mmol, 53% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 5.97 (ddd, J = 9.2, 3.6, 0.8 Hz, 1H), 5.89 (dd, J = 9.3, 7.5 Hz, 1H), 4.64 (dd, J = 3.6, 1.3 Hz, 1H), 4.17 – 3.96 (m, 4H), 2.94 (dtt, J = 7.5, 1.4, 0.7 Hz, 1H), 2.82 – 2.72 (m, 2H), 2.20 (dt, J = 19.0, 4.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 204.4, 128.7, 125.9, 110.3, 65.4, 64.3, 60.1, 53.8, 44.9, 41.9. FTIR (NaCl, thin film): 3043, 2965, 2895, 1753, 1628, 1478, 1407, 1380, 1346, 1312, 1213, 1146, 1097, 1055, 1003, 948, 918 cm-1. HRMS: (FAB) calc’d for C10H12ClO3 [M + H]+ 215.0475, found 215.0454. [𝜶]𝟐𝟓 𝐃 = +544° (c = 1.0, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 210 Preparation of allylic alcohol 239: H Me m-CPBA, CH2Cl2 O Me H O H Me Me OH O then HCl (aq) (79% yield) 218 O OH 239 A 1-L, round-bottomed flask was charged with photoadduct 218 (7.26 g, 35.2 mmol, 1.0 equiv) and CH2Cl2 (350 mL), and cooled to 0 °C. m-CPBA (7.89 g, 35.2 mmol, 1.0 equiv) was added, and the reaction was stirred for 30 min at 0 °C, then warmed to room temperature. After stirring for an additional 90 min at room temperature, 2 N HCl (70 mL, 140 mmol, 4.0 equiv) was added, and the biphasic mixture was stirred vigorously. After 30 min, the reaction was quenched by careful addition of sat. NaHCO3 (200 mL), and stirred until bubbling ceased (ca. 30 min). The layers were separated, and the aqueous phase was extracted with EtOAc (8 x 300 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (45 to 50% acetone in hexanes) afforded allylic alcohol 239 (6.7 g, 28 mmol, 79% yield) as a colorless oil. Note: The product is highly water soluble, and thus requires rigorous extraction with a polar solvent such as EtOAc. 1 H NMR (400 MHz, CDCl3): δ 5.97 (dd, J = 9.0, 7.2 Hz, 1H), 5.77 (ddd, J = 9.0, 3.8, 1.2 Hz, 1H), 4.59 (s, 1H), 4.02 (dd, J = 6.1, 2.2 Hz, 1H), 3.90 (dqd, J = 9.2, 6.2, 3.0 Hz, 1H), 3.70 (dqd, J = 8.8, 6.0, 4.3 Hz, 1H), 2.79 (dd, J = 7.2, 1.5 Hz, 1H), 2.67 – 2.53 (m, 211 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 2H), 2.31 (br s, 1H), 2.18 – 2.05 (m, 2H), 1.62 (dt, J = 14.4, 8.9 Hz, 1H), 1.48 (ddd, J = 14.5, 4.4, 3.1 Hz, 1H), 1.16 (d, J = 3.8 Hz, 3H), 1.14 (d, J = 4.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 213.9, 131.4, 129.6, 81.1, 75.2, 73.9, 67.0, 51.6, 49.5, 45.9, 32.2, 23.6, 20.0. FTIR (NaCl, thin film): 3400, 2969, 2933, 1753, 1458, 1447, 1376, 1329, 1120, 1080, 1048, 926 cm-1. HRMS: (FAB) calc’d for C13H21O4 [M + H]+ 241.1440, found 241.1421. [𝜶]𝟐𝟓 𝐃 = –6.2° (c = 1.0, CHCl3). Preparation of triol 240: Me Me OH Me NaBH 4, CeCl3•7H2O O Me OH O MeOH, –78°C O 239 OH (89% yield) 240 OH OH In a 1-L, round-bottomed flask, ketone 239 (6.7 g, 28 mmol, 1.0 equiv) and CeCl3•7H2O (15.6 g, 41.8 mmol, 1.5 equiv) were dissolved in MeOH (280 mL). The solution was then cooled to –78 °C, and NaBH4 (1.27 g, 33.5 mmol, 1.2 equiv) was added. After stirring for 2 h at –78 °C, the reaction was quenched with 1 M NaOH (200 mL), and concentrated in vacuo to remove MeOH. The aqueous phase was extracted with EtOAc (8 x 250 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Filtration of the crude residue over a short plug of silica (eluting with 50% acetone in hexanes) afforded triol 240 (6.1 g, 25 mmol, 89% yield) as a white solid. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 212 Note: The product is highly water soluble, and thus requires rigorous extraction with a polar solvent such as EtOAc. 1 H NMR (400 MHz, CDCl3): δ 5.88 (ddt, J = 9.9, 3.7, 1.7 Hz, 1H), 5.74 (dd, J = 9.4, 7.0 Hz, 1H), 4.46 (s, 1H), 3.97 (dqd, J = 8.9, 6.3, 2.7 Hz, 1H), 3.85 (br s, 1H), 3.77 – 3.67 (m, 3H), 3.62 (br s, 2H), 2.63 – 2.58 (m, 1H), 2.46 (appar s, 1H), 1.77 (td, J = 4.7, 4.1, 1.7 Hz, 2H), 1.63 – 1.47 (m, 2H), 1.15 (d, J = 6.1 Hz, 3H), 1.12 (d, J = 6.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 129.7, 126.5, 78.3, 75.4, 72.0, 71.7, 68.1, 45.5, 45.4, 40.8, 33.8, 23.4, 20.1. FTIR (NaCl, thin film): 3369, 3032, 2967, 2934, 1757, 1642, 1447, 1420, 1376, 1318, 1180, 1084, 1033, 970, 934 cm-1. HRMS: (FAB) calc’d for C13H23O4 [M + H]+ 243.1596, found 243.1616. [𝜶]𝟐𝟓 𝐃 = –6.2° (c = 1.0, CHCl3). Preparation of triol 244: Me Me Me OH O NaBH 4 Me OH Me O OH OH 239 H O + MeOH, 0 °C O Me HO OH 240 (29% yield) OH H 244 (67% yield) W-coupling observed in OH COSY (4.20 ppm, 3.91 ppm) In a 1-dram vial, ketone 239 (9.2 mg, 38 µmol, 1.0 equiv) was dissolved in MeOH (0.38 mL) and cooled to 0 °C. NaBH4 (2.9 mg, 77 µmol, 2.0 equiv) was added, and the reaction was stirred for 15 minutes, then diluted with acetone (1 mL) and concentrated in vacuo. The resulting residue was dissolved in EtOAc (2 mL) and washed with 1 N Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 213 NaOH (2 mL). The aqueous phase was extracted with EtOAc (3 x 2 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (50 to 55% acetone in hexanes) to provide 1,3-syn-diol 240 (2.7 mg, 11 µmol, 29% yield) and anti-1,3-diol 244 (6.2 mg, 26 µmol, 67% yield). Spectroscopic data for 1,3-anti-diol 244: 1 H NMR (400 MHz, CDCl3): δ 5.89 (dd, J = 9.3, 7.4 Hz, 1H), 5.53 (ddd, J = 9.3, 3.8, 1.5 Hz, 1H), 4.20 (s, 1H), 4.00 (t, J = 3.3 Hz, 1H), 3.94 (ddd, J = 9.5, 6.4, 2.9 Hz, 1H), 3.91 (d, J = 7.1 Hz, 1H), 3.75 – 3.66 (m, 1H), 2.69 (d, J = 7.3 Hz, 1H), 2.58 (br s, 3H), 2.50 (d, J = 7.7 Hz, 1H), 2.04 (ddd, J = 14.6, 8.2, 1.7 Hz, 1H), 1.80 (dd, J = 14.7, 7.2 Hz, 1H), 1.64 (dt, J = 14.5, 9.0 Hz, 1H), 1.47 (ddd, J = 14.5, 4.3, 2.6 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H), 1.15 (d, J = 6.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 132.1, 127.7, 81.0, 74.5, 74.3, 74.1, 67.2, 49.1, 47.3, 45.8, 33.5, 24.0, 19.9. Preparation of siliconide 245: Me Me Me OH t-Bu2Si(OTf)2 2,6-lutidine O Me OH O CH2Cl2, –78 °C OH 240 OH (91% yield) O Si O 245 t-Bu t-Bu A 500-mL, round-bottomed flask was charged with triol 240 (6.1 g, 25 mmol, 1.0 equiv), 2,6-lutidine (7.0 mL, 60 mmol, 2.4 equiv), and CH2Cl2 (250 mL), and then cooled to –78 °C. To this solution was added t-Bu2Si(OTf)2 (9.8 mL, 30 mmol, 1.2 equiv), and Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 214 the reaction was stirred for 1 h. The reaction was quenched with sat. NaHCO3 (100 mL) and H2O (100 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 250 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (25% EtOAc in hexanes) to afford siliconide 245 (8.75 g, 22.9 mmol, 91% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 5.83 (ddd, J = 9.5, 4.4, 1.6 Hz, 1H), 5.74 (ddd, J = 9.6, 6.3, 1.2 Hz, 1H), 4.59 (t, J = 4.8 Hz, 1H), 4.04 – 3.91 (m, 2H), 3.80 – 3.70 (m, 2H), 3.39 (s, 1H), 2.78 (dd, J = 6.3, 4.1 Hz, 1H), 2.77 – 2.67 (m, 1H), 1.82 (ddd, J = 15.2, 7.5, 1.3 Hz, 1H), 1.71 (dd, J = 15.0, 7.9 Hz, 1H), 1.60 (dt, J = 14.5, 9.2 Hz, 1H), 1.52 (ddd, J = 14.5, 4.0, 2.6 Hz, 1H), 1.16 (d, J = 6.2 Hz, 3H), 1.12 (d, J = 6.0 Hz, 3H), 1.05 (s, 9H), 0.96 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 129.8, 129.1, 76.4, 74.7, 73.7, 71.0, 67.6, 46.4, 45.9, 38.6, 33.0, 28.7, 28.2, 23.6, 21.2, 20.7, 20.0. FTIR (NaCl, thin film): 3436, 3032, 2968, 2934, 2900, 2859, 1476, 1388, 1364, 1326, 1196, 1174, 1058, 1036, 1019, 998, 826 cm-1. HRMS: (FAB) calc’d for C21H39O4Si [M + H]+ 383.2618, found 383.2630. [𝜶]𝟐𝟓 𝐃 = +59° (c = 0.90, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 215 Preparation of ketone 246: Me Me OH Me O Me O O DMP, NaHCO 3 CH2Cl2, rt 245 O Si O t-Bu (99% yield) t-Bu 246 O Si O t-Bu t-Bu A 500-mL, round-bottomed flask was charged with alcohol 245 (8.5 g, 22 mmol, 1.0 equiv), NaHCO3 (5.60 g, 66.6 mmol, 3.0 equiv), and CH2Cl2 (225 mL). Dess–Martin periodinane (12.2 g, 28.9 mmol, 1.3 equiv) was added, and the reaction was stirred for 17 h, after which the reaction was filtered through a plug of silica (eluting with 50% EtOAc in hexanes). The filtrate was concentrated in vacuo, and then diluted in CH2Cl2 (100 mL), washed with sat. NaHCO3 (2 x 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide ketone 246 (8.5 g, 22 mmol, 99% yield) as a light yellow oil. 1 H NMR (400 MHz, CDCl3): δ 5.81 (ddd, J = 9.5, 4.4, 1.6 Hz, 1H), 5.73 (ddd, J = 9.5, 6.2, 1.2 Hz, 1H), 4.55 (t, J = 4.8 Hz, 1H), 3.99 (td, J = 4.0, 0.8 Hz, 1H), 3.92 (h, J = 6.1 Hz, 1H), 3.65 (d, J = 7.1 Hz, 1H), 2.74 – 2.64 (m, 3H), 2.42 (dd, J = 16.0, 5.9 Hz, 1H), 2.16 (s, 3H), 1.76 (ddd, J = 14.9, 7.0, 1.4 Hz, 1H), 1.67 (ddt, J = 14.8, 7.7, 1.3 Hz, 1H), 1.11 (d, J = 6.1 Hz, 3H), 1.05 (s, 9H), 0.96 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 207.2, 129.5, 129.4, 76.9, 73.8, 71.1, 70.2, 51.0, 46.7, 38.5, 32.7, 31.2, 28.7, 28.2, 21.2, 20.7, 20.0. FTIR (NaCl, thin film): 3012, 2970, 2934, 2888, 2859, 1719, 1476, 1388, 1364, 1327, 1176, 1087, 1046, 1018, 999, 826 cm-1. HRMS: (FAB) calc’d for C21H37O4Si [M + H]+ 381.2461, found 381.2465. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 216 [𝜶]𝟐𝟓 𝐃 = +67° (c = 1.6, CHCl3). Preparation of alcohol 247: Me Me HO O O KHMDS THF, –78 °C 246 O Si O t-Bu t-Bu (89% yield) O Si O t-Bu t-Bu 247 A 500-mL, round-bottomed flask was charged with ketone 246 (8.5 g, 22 mmol, 1.0 equiv) and THF (225 mL), and cooled to –78 °C. KHMDS (58 mL, 0.5 M in toluene, 29 mmol, 1.3 equiv) was added, and the resulting solution was warmed to 0 °C and stirred for 2.5 h. The reaction was then quenched with sat. NH4Cl (100 mL) and H2O (100 mL) and extracted with CH2Cl2 (3 x 300 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (20% EtOAc in hexanes) to provide alcohol 247 (5.9 g, 20 mmol, 90% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 5.82 (ddd, J = 9.4, 4.3, 1.6 Hz, 1H), 5.77 (ddd, J = 9.5, 6.1, 1.2 Hz, 1H), 4.78 (dd, J = 5.5, 4.1 Hz, 1H), 4.06 (dd, J = 6.6, 1.6 Hz, 1H), 4.01 (t, J = 3.9 Hz, 1H), 2.81 – 2.72 (m, 1H), 2.63 (ddd, J = 6.0, 4.3, 1.2 Hz, 1H), 1.81 (dd, J = 14.8, 6.8 Hz, 1H), 1.71 (ddt, J = 15.0, 7.9, 1.2 Hz, 1H), 1.07 (s, 9H), 0.98 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 129.6, 129.0, 73.6, 71.8, 71.0, 50.4, 38.7, 34.1, 28.7, 28.2, 21.2, 20.7. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 217 FTIR (NaCl, thin film): 3401, 3033, 2968, 2935, 2896, 2860, 1476, 1442, 1388, 1364, 1321, 1280, 1224, 1175, 1032, 998, 920, 825 cm-1. HRMS: (FAB) calc’d for C16H27O3Si [M + H – H2]+ 295.1747, found 295.1730. [𝜶]𝟐𝟓 𝐃 = +89° (c = 1.3, CHCl3). Preparation of ketone 248: O HO DMP, NaHCO 3 O Si O t-Bu t-Bu 247 CH2Cl2, rt (91% yield) O Si O t-Bu t-Bu 248 A 500-mL, round-bottomed flask was charged with alcohol 247 (6.0 g, 20 mmol, 1.0 equiv), NaHCO3 (5.1 g, 60 mmol, 3.0 equiv), and CH2Cl2 (200 mL). Dess–Martin periodinane (10.3 g, 24.3 mmol, 1.2 equiv) was added, and the reaction was stirred for 4 h, after which the reaction was filtered through a plug of silica (eluting with 67% EtOAc in hexanes). The filtrate was concentrated in vacuo, and then diluted in CH2Cl2 (100 mL), washed with sat. NaHCO3 (2 x 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide ketone 248 (5.40 g, 18.3 mmol, 91% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 6.08 (ddd, J = 9.3, 4.6, 1.6 Hz, 1H), 5.76 (ddd, J = 9.2, 6.9, 1.4 Hz, 1H), 4.59 (ddt, J = 5.6, 4.1, 1.1 Hz, 1H), 4.27 (ddd, J = 4.5, 3.4, 0.9 Hz, 1H), 3.14 (dddd, J = 6.8, 4.2, 1.4, 0.7 Hz, 1H), 3.02 (dddq, J = 6.8, 5.0, 3.3, 1.6 Hz, 1H), 2.37 – 2.31 (m, 1H), 2.28 (dd, J = 19.4, 6.4 Hz, 1H), 1.09 (s, 9H), 0.99 (s, 9H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 218 C NMR (101 MHz, CDCl3): δ 206.7, 131.3, 124.8, 71.7, 69.8, 55.1, 38.5, 37.6, 28.6, 28.2, 21.1, 20.8. FTIR (NaCl, thin film): 3036, 2968, 2935, 2859, 1743, 1629, 1476, 1404, 1387, 1365, 1298, 1221, 1187, 1145, 1115, 997, 790 cm-1. HRMS: (FAB) calc’d for C16H27O3Si [M + H]+ 295.1730, found 295.1731. [𝜶]𝟐𝟓 𝐃 = +510° (c = 1.1, CHCl3). Preparation of vinyl triflate 249: TfO O KHMDS PhNTf 2 THF, –78 °C O Si O t-Bu t-Bu 248 (95% yield) O Si O t-Bu t-Bu 249 A 250-mL, round-bottomed flask was charged with ketone 248 (3.00 g, 10.2 mmol, 1.0 equiv), which was subsequently dissolved in THF (60 mL) and cooled to –78 °C. KHMDS (22.4 mL, 0.5 M in toluene, 11.2 mmol, 1.1 equiv) was added, and the reaction was stirred for 15 minutes. In a separate flask, a solution of PhNTf2 (4.00 g, 11.2 mmol, 1.1 equiv) in THF (40 mL) was prepared and cannulated into the first reaction flask. The resulting mixture was stirred for an additional hour, and then quenched with sat. NH4Cl (50 mL) and H2O (50 mL). This mixture was extracted with CH2Cl2 (3 x 100 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (9% EtOAc in hexanes) afforded vinyl triflate 249 (4.13 g, 9.68 mmol, 95% yield) as a white solid. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 219 H NMR (400 MHz, CDCl3): δ 6.21 (ddd, J = 9.6, 6.0, 1.1 Hz, 1H), 5.84 (dddd, J = 9.6, 4.5, 2.0, 0.8 Hz, 1H), 5.49 (dd, J = 4.1, 0.8 Hz, 1H), 4.69 (tt, J = 4.8, 1.0 Hz, 1H), 4.28 (ddd, J = 4.0, 2.9, 0.8 Hz, 1H), 3.13 (ddddd, J = 4.8, 3.9, 2.8, 1.9, 0.9 Hz, 1H), 2.91 (ddq, J = 5.6, 4.7, 0.9 Hz, 1H), 1.08 (s, 9H), 1.01 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 163.3, 131.7, 130.8, 113.2, 75.7, 65.0, 45.2, 44.2, 28.8, 28.2, 21.1, 20.7. FTIR (NaCl, thin film): 3042, 2976, 2938, 2906, 2852, 1640, 1478, 1429, 1380, 1365, 1258, 1249, 1214, 1141, 1123, 1074, 1001, 926, 901 cm-1. HRMS: (FAB) calc’d for C17H26F3SSiO5 [M + H]+ 427.1222, found 427.1205. [𝜶]𝟐𝟓 𝐃 = +20° (c = 1.2, CHCl3). Preparation of vinyl iodide 251 from ketone 248: I O NH 2NH 2, Et 3N EtOH, 55 °C O Si O t-Bu t-Bu then t-BuNC(NMe2)2 I 2, THF, then 90 °C (39% yield) 248 O Si O t-Bu t-Bu 251 To a 1-dram vial containing ketone 248 (10.0 mg, 34.0 µmol, 1.0 equiv) was added hydrazine hydrate (16 µL, 0.340 mmol, 10 equiv), Et3N (47 µL, 0.340 mmol, 10 equiv), and absolute ethanol (0.34 mL). The reaction was heated to 55 °C for 90 minutes, then concentrated in vacuo, azeotroping with benzene (3 x 1 mL). The crude hydrazone was dissolved in THF (0.4 mL) and used in the next step In separate vial, 2-tert-butyl-1,1,3,3-tetramethylguanidine (47 µL, 0.238 mmol, 7.0 equiv) was added to a solution of I2 (18.1 mg, 71.3 µmol, 2.1 equiv) in THF (0.4 mL). To this solution was added the prepared hydrazone solution in a dropwise fashion, and 220 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine the reaction turns from brown to colorless. After stirring for 20 minutes, the solution was concentrated in vacuo, and the resulting crude residue was heated to 90 °C for 5 h. After cooling to room temperature, purification by silica gel chromatography (25 to 30% CH2Cl2 in hexanes) afforded vinyl iodide 251 (5.3 mg, 13 µmol, 39% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 6.23 (ddd, J = 9.6, 6.0, 1.1 Hz, 1H), 6.21 (d, J = 3.9 Hz, 1H), 4.63 (tt, J = 4.7, 1.0 Hz, 1H), 4.21 (ddd, J = 4.4, 3.0, 0.8 Hz, 1H), 2.98 (ddddd, J = 4.8, 3.7, 2.8, 1.9, 0.7 Hz, 1H), 2.87 (ddq, J = 5.9, 4.5, 0.7 Hz, 1H), 1.07 (s, 9H), 1.00 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 137.3, 133.0, 130.2, 106.7, 76.8, 65.2, 54.5, 48.5, 28.8, 28.2, 21.2, 20.7. FTIR (NaCl, thin film): 3043, 2971, 2931, 2888, 2856, 1578, 1476, 1382, 1364, 1314, 1286, 1248, 1200, 1119, 1082, 1001, 809 cm-1. HRMS: (FAB) calc’d for C16H26IO2Si [M + H]+ 405.0747, found 405.0747. [𝜶]𝟐𝟓 𝐃 = +21° (c = 0.96, CHCl3). Preparation of vinyl iodide 251 from vinyl triflate 249: Me 3Sn TfO Me 6Sn2, LiCl Pd(PPh 3)4 THF, 70 °C O Si O t-Bu t-Bu 249 I I2 O Si O t-Bu t-Bu 253 CH2Cl2 (80% yield, 2 steps) O Si O t-Bu t-Bu 251 In an N2-filled glovebox, LiCl (635 mg, 15.0 mmol, 3.0 equiv) and Pd(PPh3)4 (230 mg, 0.200 mmol, 0.04 equiv) were a 250-mL Schlenk tube containing vinyl triflate Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 221 249 (2.13 g, 4.99 mmol, 1.0 equiv). The contents were dissolved in THF (25 mL), and then Me6Sn2 (1.04 mL, 4.99 mmol, 1.0 equiv) was added. The walls of the tube were rinsed with THF (25 mL), and then the tube was sealed and brought out of the glovebox. The reaction was heated to 70 °C with vigorous stirring for 15 h, then cooled to room temperature, diluted with hexanes (ca. 100 mL), and quenched with H2O (50 mL). The solution was extracted with hexanes (3 x 100 mL), and then the combined organic extracts were washed with H2O (50 mL), 10% NH4OH (50 mL), and H2O (50 mL) again. After drying over Na2SO4 and filtration, the filtrate was concentrated in vacuo to afford crude vinyl stannane 253. A small sample was purified by silica gel chromatography (1% EtOAc in hexanes) to afford an analytically pure sample: 1 H NMR (300 MHz, CDCl3): δ 6.07 (ddd, J = 9.5, 6.1, 1.1 Hz, 1H), 5.97 (d, J = 3.5 Hz, 1H), 5.59 (ddd, J = 9.5, 4.5, 1.9 Hz, 1H), 4.47 (t, J = 4.7 Hz, 1H), 4.23 (ddd, J = 4.3, 3.0, 0.6 Hz, 1H), 3.04 – 2.93 (m, 1H), 2.89 (dd, J = 6.2, 4.3 Hz, 1H), 1.08 (s, 9H), 1.01 (s, 9H), 0.14 (s, 9H). The crude vinyl stannane 253 was dissolved in CH2Cl2 (20 mL) and cooled to –20 °C. To this solution was cannulated a solution of I2 (1.25 g, 4.92 mmol, 1.05 equiv) in CH2Cl2 (30 mL). After stirring for 1 h, the reaction was quenched with sat. Na2S2O3 (50 mL), and diluted with H2O (25 mL) and CH2Cl2 (25 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 222 crude residue by silica gel chromatography (25 to 30% CH2Cl2 in hexanes) provided vinyl iodide 251 (1.522 g, 3.76 mmol, 80% yield) as a white solid. Preparation of epoxy alcohol 262: I MeO 2C MeO 2C H 185 O O t-BuLi THF, –78 °C + O Si O t-Bu t-Bu 251 MeO 2C MeO 2C H O OH then 185 THF, –94 °C (72% yield) 262 O Si O t-Bu t-Bu In a 250-mL, round-bottomed flask, vinyl iodide 251 (1.62 g, 4.01 mmol, 1.0 equiv) was dissolved in THF (40 mL) and cooled to –78 °C. To this solution was added t-BuLi (4.7 mL, 1.7 M in pentane, 8.01 mmol, 2.0 equiv) slowly down the side of the flask over 5 minutes, and the resulting mixture was stirred for an additional 15 minutes at –78 °C. This solution was then cannulated over 10 minutes into a pre-cooled solution of epoxyketone 185 (1.40 g, 5.21 mmol, 1.3 equiv) in THF (40 mL) at –94 °C (acetone/liquid N2 bath). The reaction was stirred for an additional 2 h while allowing the acetone/liquid N2 bath to expire, and then quenched with sat. NaHCO3 (100 mL). This was extracted with CH2Cl2 (3 x 100 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (10 to 12% acetone in hexanes) to afford epoxy alcohol 262 (1.58 g, 2.89 mmol, 72% yield) as a white solid. A small sample was recrystallized in hexanes/diethyl ether to obtain crystals suitable for X-ray crystallography. 223 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 H NMR (400 MHz, CDCl3): δ 6.10 (ddd, J = 9.6, 6.1, 1.1 Hz, 1H), 5.70 (ddd, J = 9.4, 4.3, 1.6 Hz, 1H), 5.65 (d, J = 3.8 Hz, 1H), 4.48 (t, J = 4.7 Hz, 1H), 4.25 (ddd, J = 4.0, 3.0, 0.8 Hz, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.32 (d, J = 3.6 Hz, 1H), 3.05 – 3.01 (m, 1H), 2.83 (ddd, J = 6.1, 4.4, 0.8 Hz, 1H), 2.71 (dd, J = 10.7, 7.5 Hz, 1H), 2.53 – 2.42 (m, 1H), 2.47 (s, 1H), 2.42 – 2.29 (m, 2H), 2.10 – 1.98 (m, 2H), 1.97 – 1.86 (m, 2H), 1.61 – 1.47 (m, 1H), 1.08 (s, 9H), 1.02 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 171.7, 170.2, 161.6, 134.5, 129.2, 123.4, 77.7, 75.3, 71.2, 66.1, 56.5, 55.0, 52.9, 52.2, 45.6, 45.2, 44.4, 37.3, 29.3, 28.9, 28.3, 23.3, 21.6, 21.2, 20.7. FTIR (NaCl, thin film): 3496, 3032, 2950, 2860, 1732, 1476, 1458, 1434, 1383, 1364, 1306, 1244, 1176, 1108, 991 cm-1. HRMS: (PPM) calc’d for C29H43O8Si [M + H]+ 547.2722, found 547.2713. [𝜶]𝟐𝟓 𝐃 = –5.1° (c = 0.30, CHCl3). Preparation of silyl ether 263: MeO 2C MeO 2C H O OH TMSOTf, Et 3N MeO 2C MeO 2C H O OTMS CH2Cl2, –10 °C 262 O Si O t-Bu t-Bu (97% yield) 263 O Si O t-Bu t-Bu In a 100-mL, round-bottomed flask, epoxy alcohol 262 (1.06 g, 1.94 mmol, 1.0 equiv) was dissolved in CH2Cl2 (20 mL) and cooled to –10 °C. Et3N (0.81 mL, 5.82 mmol, 3.0 equiv) was added, followed by TMSOTf (0.42 mL, 2.33 mmol, 1.2 equiv). The reaction was stirred for 15 minutes, then quenched by addition of sat. NaHCO3 (20 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 224 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (10 to 12% EtOAc in hexanes) to afford silyl ether 263 (1.17 g, 1.89 mmol, 97% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 6.03 (ddd, J = 9.6, 6.1, 1.1 Hz, 1H), 5.68 (dddd, J = 9.7, 4.5, 1.9, 0.7 Hz, 1H), 5.57 (d, J = 3.7 Hz, 1H), 4.48 (t, J = 4.7 Hz, 1H), 4.26 (ddd, J = 4.1, 3.0, 0.7 Hz, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.30 (d, J = 3.5 Hz, 1H), 3.08 – 3.03 (m, 1H), 2.90 (ddd, J = 6.3, 4.3, 0.9 Hz, 1H), 2.74 (dd, J = 9.8, 8.8 Hz, 1H), 2.61 (dddd, J = 12.9, 11.0, 8.9, 3.9 Hz, 1H), 2.43 – 2.25 (m, 2H), 2.12 (ddd, J = 12.7, 8.7, 3.9 Hz, 1H), 2.08 – 2.01 (m, 1H), 1.96 (ddd, J = 15.1, 8.2, 3.7 Hz, 1H), 1.89 – 1.77 (m, 1H), 1.45 (ddd, J = 13.3, 10.1, 8.4 Hz, 1H), 1.09 (s, 9H), 1.02 (s, 9H), 0.05 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 172.0, 170.4, 163.2, 135.1, 129.0, 122.5, 77.7, 77.6, 70.1, 66.1, 55.0, 54.0, 52.8, 52.1, 45.8, 44.9, 41.4, 34.5, 29.7, 28.9, 28.3, 22.2, 21.6, 21.2, 20.7, 2.2. FTIR (NaCl, thin film): 3028, 2952, 2904, 2860, 1732, 1477, 1462, 1434, 1364, 1250, 1175, 1110, 1058, 992, 881, 842 cm-1. HRMS: (PPM) calc’d for C32H51O8Si2 [M + H]+ 619.3117, found 619.3106. [𝜶]𝟐𝟓 𝐃 = +36° (c = 0.35, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 225 Preparation of ketone 264: MeO 2C MeO 2C H O OTMS TMSNTf2 2,6-t-Bu2-4-MePy OTMS CO2Me O MeO 2C CH2Cl2, –70 °C 263 O Si O t-Bu t-Bu (97% yield) O Si O t-Bu t-Bu 264 A 100-mL, round-bottomed flask was charged with silyl ether 263 (1.168 g, 1.89 mmol, 1.0 equiv) and CH2Cl2 (40 mL), and the solution was cooled to –70 °C in a dry ice/acetone bath. In an N2-filled glovebox, a 100-mL microsyringe was filled with TMSNTf2 (67 mg, 0.189 mmol, 0.10 equiv), plugged with a rubber stopper, and removed from the glovebox. The TMSNTf2 was immediately added in one portion to the reaction mixture. After stirring for an additional 15 minutes at –70 °C, the reaction was quenched with sat. NaHCO3 (30 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 30 mL), and the organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (10% EtOAc in hexanes) to afford ketone 264 (1.13 g, 1.83 mmol, 97% yield) as a white solid. Note: If the starting material is not rigorously dry, the reaction may not reach full conversion. It is possible that trace amounts of water can quench TMSNTf2 and result in early termination. In this case, the crude product can simply be resubjected to the reaction conditions. In order to ensure the starting material is sufficiently free of water, it can be azeotroped with toluene or benzene (1–3x) prior to the reaction. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 226 H NMR (500 MHz, CDCl3): δ 5.88 (ddd, J = 9.5, 6.1, 1.1 Hz, 1H), 5.65 (ddd, J = 9.5, 4.3, 1.9 Hz, 1H), 5.40 (d, J = 3.8 Hz, 1H), 4.66 (t, J = 4.7 Hz, 1H), 4.31 (br s, 1H), 4.23 (appar t, J = 3.0 Hz, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.40 (dd, J = 11.7, 7.3 Hz, 1H), 3.03 – 2.94 (m, 2H), 2.48 (td, J = 14.1, 3.4 Hz, 1H), 2.38 – 2.26 (m, 1H), 2.17 – 2.05 (m, 3H), 1.80 – 1.71 (m, 1H), 1.65 – 1.60 (m, 1H), 1.52 (tdd, J = 14.3, 2.9, 1.9 Hz, 1H), 1.08 (s, 9H), 1.00 (s, 9H), 0.05 (s, 9H). 13 C NMR (126 MHz, CDCl3): δ 215.9, 170.7, 170.6, 158.9, 134.8, 128.2, 124.4, 76.7, 69.9, 66.2, 58.0, 56.2, 52.8, 52.6, 46.2, 46.1, 41.8, 38.8, 28.9, 28.3, 27.4, 23.7, 21.2, 20.7, 19.3, 0.0. FTIR (NaCl, thin film): 3032, 2952, 2896, 2859, 1741, 1477, 1462, 1443, 1384, 1363, 1252, 1170, 1097, 991, 840 cm-1. HRMS: (PMM) calc’d for C32H51O8Si2 [M + H]+ 619.3117, found 619.3105. [𝜶]𝟐𝟓 𝐃 = +92° (c = 0.73, CHCl3). Preparation of α-bromoketone 268: OTMS CO2Me O MeO 2C OTMS CO2Me O MeO 2C LHMDS, NBS Br THF, –78 °C O Si O t-Bu t-Bu 264 (82% yield) O Si O t-Bu t-Bu 268 A 5-mL, round-bottomed flask was charged with ketone 264 (31.6 mg, 51.1 µmol, 1.0 equiv) and THF (0.8 mL), and cooled to –78 °C. LiHMDS (61.0 µL, 61.0 µmol, 1.2 equiv) was added, and the reaction was stirred for 25 minutes, after which a solution of NBS (11.8 mg, 66.4 µmol, 1.3 equiv) in THF (0.5 mL) was prepared and added. The Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 227 reaction was stirred at –78 °C for an additional 40 minutes, and then quenched by addition of sat. Na2S2O3 (2 mL) and H2O (2 mL). The resulting mixture was extracted with CH2Cl2 (3 x 1 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (9% EtOAc in hexanes) to afford a-bromoketone 268 (29.3 mg, 42.0 µmol, 82% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 6.09 (ddd, J = 9.6, 6.1, 1.1 Hz, 1H), 5.68 (ddd, J = 9.5, 4.3, 1.8 Hz, 1H), 5.41 (d, J = 3.8 Hz, 1H), 4.71 (ddt, J = 5.3, 4.4, 1.0 Hz, 1H), 4.34 (br s, 1H), 4.25 – 4.21 (m, 2H), 3.80 (dd, J = 13.5, 6.3 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.13 (dd, J = 6.1, 4.4 Hz, 1H), 3.05 – 2.96 (m, 1H), 2.77 (ddd, J = 14.1, 13.0, 6.6 Hz, 1H), 2.41 (td, J = 14.0, 3.6 Hz, 1H), 2.15 (d, J = 14.8 Hz, 1H), 1.93 (dd, J = 14.1, 6.7 Hz, 1H), 1.69 – 1.48 (m, 2H), 1.08 (s, 9H), 1.00 (s, 9H), 0.03 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 208.1, 170.3, 170.2, 158.2, 135.5, 128.0, 125.5, 76.6, 70.1, 65.8, 58.0, 55.6, 53.0, 52.9, 47.0, 46.4, 46.2, 39.1, 35.0, 28.9, 28.3, 27.0, 21.3, 20.7, 19.4, -0.0. FTIR (NaCl, thin film): 2952, 2941, 2896, 2859, 1755, 1741, 1476, 1460, 1434, 1254, 1230, 1175, 1104, 1054, 994, 894 cm-1. HRMS: (ESI) calc’d for C29H41BrO7Si [M – OSiMe3]+ 607.1721, found 607.1731. [𝜶]𝟐𝟓 𝐃 = +127° (c = 0.45, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 228 Preparation of diol 272: OTMS CO2Me O MeO 2C OTMS CO2Me O MeO 2C HF•Py MeCN O Si O t-Bu (98% yield) t-Bu 264 OH OH 272 A 125-mL Teflon Erlenmeyer flask was charged with silylene 264 (714 mg, 1.15 mmol, 1.0 equiv) and MeCN (55 mL) and cooled to 0 °C with an ice bath. A solution of HF•Py (pyridine ~30%, HF ~70%, 570 mg) in MeCN (3 mL) was added, and the ice bath was removed to allow the reaction to reach ambient temperature. After stirring for 1.5 h, the solution was filtered through a plug of silica (eluting with EtOAc) and concentrated in vacuo to provide pure diol 272 (540 mg, 1.13 mmol, 98% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 5.83 – 5.75 (m, 2H), 5.47 (d, J = 3.6 Hz, 1H), 4.61 (q, J = 5.2 Hz, 1H), 4.28 (br s, 1H), 3.94 (appar d, J = 8.0 Hz, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.38 (dd, J = 12.1, 7.3 Hz, 1H), 2.91 (t, J = 4.5 Hz, 1H), 2.88 – 2.70 (m, 2H), 2.69 – 2.65 (m, 1H), 2.48 (td, J = 14.3, 3.6 Hz, 1H), 2.36 – 2.24 (m, 1H), 2.19 – 2.02 (m, 3H), 1.80 – 1.56 (m, 2H), 1.48 (tdd, J = 14.1, 2.8, 2.0 Hz, 1H), 0.03 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 215.9, 170.7, 170.6, 157.0, 130.9, 129.5, 124.8, 74.3, 69.7, 65.7, 57.8, 56.3, 52.9, 52.7, 47.5, 44.3, 41.8, 38.9, 27.4, 23.6, 19.3, -0.0. FTIR (NaCl, thin film): 3401, 3025, 2954, 1738, 1434, 1404, 1336, 1313, 1252, 1194, 1171, 1074, 1058, 1020, 980, 892, 862, 842 cm-1. HRMS: (PMM) calc’d for C24H33O7Si [M – OH]+ 461.1990, found 461.1980. [𝜶]𝟐𝟓 𝐃 = +92° (c = 1.3, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 229 Preparation of enone 273: OTMS CO2Me O MeO 2C OTMS Cu(MeCN) 4OTf, ABNO, NMI, MeObpy CO2Me O MeO 2C MeCN (84–98% yield) OH OH O HO 272 273 To a 100 mL, round-bottomed flask was added diol 272 (540.0 mg, 1.13 mmol, 1.0 equiv), Cu(MeCN)4OTf (21.0 mg, 56.4 µmol, 0.05 equiv), 4,4’-dimethoxy-2,2’bipyridine (MeObpy, 12.2 mg, 56.4 µmol, 0.05 equiv), N-methylimidazole (9.0 µL, 0.113 mmol, 0.10 equiv), and MeCN (25 mL). Lastly, ABNO (7.9 mg, 56.4 µmol, 0.05 equiv) was added, and the clear brownish reaction mixture was stirred until slightly yellowgreen (ca. 80 min), at which point the solution was filtered through a short plug of silica and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (60 to 70% EtOAc in hexanes) afforded enone 273 (454.0 mg, 0.953 mmol, 84% yield) as a white solid. Note: On a 62 mg scale of diol 272, this same procedure provided enone 273 (60.9 mg) in 98% yield. On larger scale, over-oxidation to the 1,3-diketone occurs to a larger extent and provides diminished yields (lowest of 84% on 540 mg scale). 1 H NMR (400 MHz, CDCl3): δ 6.87 (ddd, J = 9.7, 6.4, 1.6 Hz, 1H), 5.89 (ddd, J = 9.7, 2.0, 1.2 Hz, 1H), 5.62 (d, J = 3.9 Hz, 1H), 5.06 – 4.96 (m, 1H), 4.23 (br s, 1H), 3.75 (s, 3H), 3.66 (s, 3H), 3.41 (dd, J = 12.2, 7.3 Hz, 1H), 3.27 (t, J = 5.5 Hz, 1H), 3.26 – 3.18 (br Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 230 m, 1H), 2.62 – 2.41 (m, 2H), 2.38 – 2.25 (m, 1H), 2.23 – 2.07 (m, 3H), 1.82 – 1.59 (m, 2H), 1.48 (tdd, J = 14.3, 3.5, 1.9 Hz, 1H), 0.02 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 215.7, 195.3, 170.8, 170.4, 156.0, 148.7, 127.5, 124.5, 84.3, 69.6, 61.4, 57.9, 56.2, 53.0, 52.8, 47.1, 41.7, 38.8, 27.5, 23.5, 19.3, -0.1. FTIR (NaCl, thin film): 3467, 3009, 3955, 1738, 1674, 1435, 1376, 1314, 1253, 1230, 1172, 1076, 1060, 1021, 981, 843 cm-1. HRMS: (PMM) calc’d for C24H33O8Si [M + H]+ 477.1939, found 477.1952. [𝜶]𝟐𝟓 𝐃 = +281° (c = 1.1, CHCl3). Preparation of MOM-ether 274: OTMS CO2Me O MeO 2C MOMCl, n-Bu4NI i-Pr2NEt OTMS CO2Me O MeO 2C DMF, 55 °C O HO 273 (84% yield) O MOMO 274 A 50-mL, round-bottomed flask was charged with alcohol 273 (454 mg, 0.953 mmol, 1.0 equiv), n-Bu4NI (70.0 mg, 0.191 mmol, 0.20 equiv), i-Pr2NEt (1.0 mL, 5.72 mmol, 6.0 equiv), and DMF (10 mL), followed lastly by MOMCl (0.36 mL, 4.76 mmol, 5.0 equiv). The reaction mixture was heated to 55 °C with stirring for 15 h, then cooled to room temperature and diluted with H2O (10 mL) and Et2O (10 mL). The layers thoroughly mixed, separated, and then the aqueous phase was extracted with Et2O (2 x 10 mL). The combined organic extracts were washed with water (3 x 10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (30 to 33% EtOAc in hexanes) afforded methoxymethyl ether 274 (417.5 mg, 0.802 mmol, 84% yield) as a white solid. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 231 H NMR (400 MHz, CDCl3): δ 6.82 (ddd, J = 9.8, 6.3, 1.6 Hz, 1H), 5.82 (d, J = 10.1 Hz, 1H), 5.64 (d, J = 3.8 Hz, 1H), 4.75 (td, J = 4.6, 1.6 Hz, 1H), 4.71 (s, 2H), 4.25 (br s, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 3.43 (dd, J = 12.3, 7.3 Hz, 1H), 3.38 – 3.27 (m, 2H), 3.32 (s, 3H), 2.52 (td, J = 14.2, 3.3 Hz, 1H), 2.39 – 2.26 (m, 1H), 2.23 – 2.08 (m, 3H), 1.81 – 1.59 (m, 2H), 1.48 (tdd, J = 14.3, 3.3, 1.9 Hz, 1H), 0.03 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 215.5, 195.7, 170.7, 170.4, 155.9, 148.5, 126.7, 124.4, 96.6, 90.5, 69.7, 60.2, 57.8, 56.2, 56.1, 52.9, 52.8, 45.7, 41.7, 38.8, 27.5, 23.5, 19.3, -0.1. FTIR (NaCl, thin film): 3009, 2954, 1738, 1681, 1462, 1435, 1253, 1230, 1172, 1059, 1040, 981 cm-1. HRMS: (PMM) calc’d for C26H37O9Si [M + H]+ 521.2201, found 521.2207. [𝜶]𝟐𝟓 𝐃 = +258° (c = 1.3, CHCl3). Preparation of pentacycle 275: OTMS CO2Me O MeO 2C OTMS CO2Me O MeO 2C KOt-Bu THF, –78 °C O MOMO 274 (quantitative) O MOMO 275 A 50-mL, round-bottomed flask was charged with enone 274 (417.5 mg, 0.802 mmol, 1.0 equiv), followed by THF (8 mL), and this solution was cooled to –78 °C. KOt-Bu (1.04 mL, 1.0 M in THF, 1.04 mmol, 1.3 equiv) was added to the reaction, which was allowed to stir for 70 minutes. The reaction was quenched by addition of sat. NaHCO3 (20 mL) and extracted with CH2Cl2 (3 x 20 mL). The combined organic Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 232 extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide pentacycle 275 (417.3 mg, 0.801 mmol, quantitative yield) as a white solid. This was used in following reactions without further purification. Note: Purification of Michael addition product 275 led to slightly diminished yields. Crude material was deemed pure by NMR and used in following reactions without further purification for practical purposes. 1 H NMR (400 MHz, CDCl3): δ 5.54 (d, J = 2.6 Hz, 1H), 4.68 (s, 2H), 4.59 (t, J = 5.5 Hz, 1H), 4.31 (dd, J = 6.5, 3.8 Hz, 1H), 3.76 (s, 3H), 3.65 (s, 3H), 3.36 (s, 3H), 3.32 (dd, J = 5.0, 2.6 Hz, 1H), 3.06 (t, J = 5.5 Hz, 1H), 2.91 (dd, J = 10.2, 5.5 Hz, 1H), 2.61 (dd, J = 19.4, 8.7 Hz, 1H), 2.51 – 2.44 (m, 1H), 2.36 – 2.23 (m, 4H), 2.20 (ddd, J = 13.3, 7.5, 5.6 Hz, 1H), 1.88 – 1.79 (m, 1H), 1.72 – 1.54 (m, 2H), 0.10 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 203.7, 202.7, 173.0, 170.5, 146.8, 122.6, 96.3, 78.6, 66.4, 60.5, 59.0, 56.6, 56.1, 53.1, 51.9, 51.2, 42.4, 41.4, 37.9, 36.0, 27.1, 26.1, 25.1, 0.3. FTIR (NaCl, thin film): 3017, 2954, 2904, 2828, 1747, 1732, 1714, 1589, 1461, 1434, 1406, 1361, 1251, 1215, 1152, 1111, 1043, 866 cm-1. HRMS: (PMM) calc’d for C26H37O9Si [M + H]+ 521.2201, found 521.2186. [𝜶]𝟐𝟓 𝐃 = +168° (c = 1.2, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 233 Preparation of lactone 278: MeO 2C OTMS CO2Me O O MeO 2C TFA O O CH2Cl2 O MOMO 275 MOMO O 278 In a 50-mL, round-bottomed flask, diester 275 (417.3 mg, 0.802 mmol, 1.0 equiv) was dissolved in wet CH2Cl2 (8.0 mL). To this solution was added TFA (0.31 mL, 4.05 mmol, 5.0 equiv). The reaction was stirred for 21 h, and then quenched with sat. NaHCO3 (20 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford crude lactone 278 (<350 mg) as a white foam. This crude material was deemed pure by NMR and used in the next step without further purification. 1 H NMR (400 MHz, CDCl3): δ 5.35 (d, J = 2.6 Hz, 1H), 5.20 (dd, J = 4.7, 0.8 Hz, 1H), 4.71 (d, J = 6.9 Hz, 1H), 4.69 (d, J = 6.9 Hz, 1H), 4.63 (t, J = 5.5 Hz, 1H), 3.82 (s, 3H), 3.38 (dd, J = 4.9, 2.6 Hz, 1H), 3.36 (s, 3H), 3.11 (t, J = 5.7 Hz, 1H), 2.99 (dd, J = 9.6, 7.2 Hz, 1H), 2.73 (dd, J = 19.3, 9.1 Hz, 1H), 2.64 (dtd, J = 9.0, 4.5, 1.8 Hz, 1H), 2.47 – 2.22 (m, 5H), 2.10 – 1.99 (m, 2H), 1.82 (dddd, J = 13.8, 11.3, 5.0, 1.0 Hz, 1H), 4.66 – 4.59 (m, 1H). 13 C NMR (101 MHz, CDCl3): δ 203.8, 200.6, 169.2, 169.1, 143.3, 121.9, 96.6, 78.3, 72.0, 62.2, 60.8, 56.2, 52.8, 52.8, 51.3, 43.7, 43.0, 38.8, 36.0, 28.5, 28.0, 21.2. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 234 FTIR (NaCl, thin film): 3009, 2954, 1749, 1711, 1444, 1367, 1298, 1264, 1220, 1153, 1108, 1068, 1047, 997 cm-1. HRMS: (ESI) calc’d for C22H24KO8 [M + K]+ 455.1103, found 455.1096. [𝜶]𝟐𝟓 𝐃 = +183° (c = 0.67, CHCl3). Preparation of carbocycle 279: O MeO 2C O O H 2 (1 atm) Pd/C O MeO 2C H O O EtOH/EtOAc MOMO 278 O (96% yield, 3 steps) MOMO O 279 To a 50-mL, round-bottomed flask containing crude lactone 278 (<350 mg) under N2 was added Pd/C (10 wt%, 333 mg), followed by absolute EtOH (6 mL) and EtOAc (6 mL). The reaction vessel was purged with H2 for 5 minutes via a double-walled balloon, and stirred for another 22 h under H2 (1 atm). The H2 balloon was then removed, and the flask was purged with N2 for 15 minutes. The suspension was filtered through a plug of silica (eluting with EtOAc), and the resulting solution was concentrated in vacuo to provide carbocycle 279 (322.6 mg, 0.771 mmol, 96% yield over 3 steps from enone 274) as a white foam. 1 H NMR (400 MHz, CDCl3): δ 4.77 (dd, J = 4.5, 1.2 Hz, 1H), 4.63 (d, J = 6.9 Hz, 1H), 4.61 (d, J = 6.9 Hz, 1H), 4.19 (t, J = 4.6 Hz, 1H), 3.82 (s, 3H), 3.34 (s, 3H), 2.88 – 2.73 (m, 5H), 2.65 – 2.53 (m, 1H), 2.47 (dd, J = 14.9, 9.7 Hz, 1H), 2.39 (ddd, J = 13.5, 11.8, Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 235 4.8 Hz, 1H), 2.34 (d, J = 18.1 Hz, 1H), 2.23 – 2.09 (m, 2H), 2.05 – 1.86 (m, 3H), 1.80 (dddd, J = 14.1, 11.1, 4.2, 1.2 Hz, 1H), 1.46 (ddd, J = 14.8, 6.6, 0.9 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 213.9, 210.2, 169.3, 169.1, 96.3, 79.2, 74.1, 56.1, 55.9, 53.1, 52.8, 52.8, 51.5, 49.6, 45.3, 39.9, 39.0, 37.6, 28.2, 27.9, 24.2, 19.8. FTIR (NaCl, thin film): 2953, 2915, 2854, 1740, 1711, 1458, 1449, 1377, 1298, 1262, 1151, 1103, 1048, 992, 753 cm-1. HRMS: (ESI) calc’d for C22H28NO8 [M + NH4]+ 436.1966, found 436.1963. [𝜶]𝟐𝟓 𝐃 = +32° (c = 1.0, CHCl3). Preparation of α-selenide 276: MeO 2C OTMS CO2Me O MeO 2C LiHMDS, PhSeCl OTMS CO2Me O THF, –78 °C O MOMO 275 (80% yield) SePh O MOMO 276 In a 1-dram vial, pentacycle 275 (15.0 mg, 28.8 µmol, 1.0 equiv) was dissolved in THF (0.3 mL) and cooled to – 78°C. LiHMDS (35 µL, 1.0 M in THF, 34.6 µmol, 1.2 equiv) was added, and the resulting solution was stirred for 15 minutes. In a separate 1dram vial, a solution of PhSeCl (7.2 mg, 37.5 µmol, 1.3 equiv) in THF (0.3 mL) was prepared, and added to the reaction mixture at –78 °C. After stirring for an additional 2 h, the reaction was quenched with sat. NaHCO3 (1 mL), extracted with CH2Cl2 (3 x 1 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 236 (30% EtOAc in hexanes) to afford α-selenide 276 (15.6 mg, 23.1 µmol, 80% yield) as a yellow foam. 1 H NMR (400 MHz, CDCl3): δ 7.74 – 7.67 (m, 2H), 7.30 – 7.25 (m, 3H), 5.59 (d, J = 2.6 Hz, 1H), 4.58 (s, 2H), 4.53 (t, J = 5.5 Hz, 1H), 4.29 (dd, J = 6.7, 4.1 Hz, 1H), 3.76 (s, 3H), 3.68 (d, J = 4.1 Hz, 1H), 3.64 (s, 3H), 3.50 (dd, J = 5.1, 2.6 Hz, 1H), 3.36 (s, 3H), 3.05 (t, J = 5.5 Hz, 1H), 2.92 (dd, J = 10.2, 5.5 Hz, 1H), 2.69 (q, J = 4.7 Hz, 1H), 2.43 (dd, J = 7.3, 4.7 Hz, 1H), 2.31 – 2.09 (m, 3H), 1.90 – 1.77 (m, 1H), 1.68 – 1.53 (m, 2H), 0.09 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 203.7, 201.6, 172.9, 170.4, 145.9, 135.2, 129.7, 129.0, 127.9, 122.9, 96.0, 78.5, 66.6, 60.8, 59.1, 56.6, 56.3, 53.1, 52.0, 50.1, 48.1, 46.7, 43.4, 41.4, 27.1, 26.0, 25.0, 0.3. FTIR (NaCl, thin film): 3051, 2953, 2896, 1740, 1730, 1579, 1436, 1360, 1250, 1216, 1108, 1039, 931, 869, 841, 753 cm-1. HRMS: (PMM) calc’d for C32H41O9SeSi [M + H]+ 677.1680, found 677.1696. [𝜶]𝟐𝟓 𝐃 = +89° (c = 1.1, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 237 Preparation of β-hydroxyketone 277: MeO 2C OTMS CO2Me O SePh O MOMO MeO 2C n-Bu4NIO 4 OTMS CO2Me O CH2Cl2 (44% yield) 276 MOMO HO O 277 To a 1-dram vial containing α-selenide 276 (15.0 mg, 22.2 µmol, 1.0 equiv) was added n-Bu4NIO4 (38.0 mg, 0.0888 µmol, 4.0 equiv) and wet CH2Cl2 (0.44 mL). The reaction was sealed and stirred for 25 h, then diluted with CH2Cl2 (1 mL) and quenched with sat. NaHCO3 (0.5 mL) and sat. Na2S2O3 (1 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 1 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative thin-layer chromatography (50% acetone in hexanes) to afford 3°alcohol 277 (5.2 mg, 9.69 µmol, 44% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 5.62 (d, J = 2.7 Hz, 1H), 4.76 – 4.69 (m, 3H), 4.34 (dd, J = 7.0, 4.6 Hz, 1H), 3.77 (s, 3H), 3.67 (s, 3H), 3.52 (dd, J = 4.9, 2.7 Hz, 1H), 3.50 (br s, 1H), 3.38 (s, 3H), 3.07 – 2.95 (m, 3H), 2.67 (d, J = 20.0 Hz, 1H), 2.36 (d, J = 7.1 Hz, 1H), 2.32 – 2.13 (m, 3H), 2.03 (dt, J = 14.5, 6.4 Hz, 1H), 1.87 (dddd, J = 13.7, 8.6, 6.9, 1.8 Hz, 1H), 1.71 – 1.59 (m, 1H), 0.10 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 201.6, 200.9, 172.9, 170.4, 144.1, 125.4, 96.6, 79.8, 73.5, 66.5, 60.5, 58.0, 57.6, 56.7, 56.3, 53.2, 52.1, 49.0, 49.0, 41.4, 27.2, 24.9, 23.2, 0.3. FTIR (NaCl, thin film): 3524, 2954, 2919, 2854, 1734, 1458, 1434, 1362, 1251, 1211, 1110, 1040, 841, 754 cm-1. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 238 HRMS: (ESI) calc’d for C26H37O10Si [M + H]+ 537.2151, found 537.2167. [𝜶]𝟐𝟓 𝐃 = +166° (c = 0.37, CHCl3). Preparation of α-selenide 280: O MeO 2C H O O O MeO 2C LiHMDS, PhSeCl O O THF, –78 °C MOMO 279 O (88% yield) SePh O MOMO 280 A 50-mL, round-bottomed flask was charged with diketone 279 (168 mg, 0.401 mmol, 1.0 equiv), which was dissolved in THF (4 mL) and cooled to –78 °C. In a separate flask, a solution of PhSeCl (123 mg, 0.642 mmol, 1.6 equiv) in THF (4 mL) was prepared. LiHMDS (0.60 mL, 1.0 M in THF, 0.60 mmol, 1.5 equiv) was added to the solution of diketone 279, and the resulting mixture was stirred for 30 minutes at –78 °C. The THF solution of PhSeCl was then added, and the mixture was stirred for another 2 hours. The reaction was quenched with sat NaHCO3 (10 mL), and extracted with CH2Cl2 (3 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (90% ethyl acetate in hexanes) to afford α-selenide 280 as a yellow foam (201.5 mg, 0.351 mmol, 88% yield). 1 H NMR (500 MHz, CDCl3): δ 7.72 – 7.68 (m, 2H), 7.31 – 7.27 (m, 3H), 4.75 (dd, J = 4.4, 1.0 Hz, 1H), 4.58 (d, J = 6.9 Hz, 1H), 4.56 (d, J = 6.9 Hz, 1H), 4.22 (t, J = 5.0 Hz, 1H), 3.81 (s, 1H), 3.76 (d, J = 4.5 Hz, 1H), 3.38 (s, 3H), 3.11 (dtd, J = 6.8, 4.4, 2.2 Hz, Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 239 1H), 3.05 (dd, J = 8.4, 5.4 Hz, 1H), 2.85 (q, J = 5.3 Hz, 1H), 2.72 (dd, J = 9.8, 7.3 Hz, 1H), 2.59 – 2.53 (m, 1H), 2.41 (dd, J = 15.1, 9.8 Hz, 1H), 2.40 – 2.33 (m, 1H), 2.21 (dd, J = 6.7, 4.1 Hz, 1H), 2.16 (ddt, J = 14.3, 11.8, 4.5 Hz, 1H), 2.02 – 1.91 (m, 3H), 1.78 (ddd, J = 14.7, 11.4, 4.1 Hz, 1H), 1.50 (dd, J = 15.2, 7.2 Hz, 1H). 13 C NMR (126 MHz, CDCl3): δ 214.0, 207.8, 169.2, 168.9, 134.9, 130.1, 129.1, 128.2, 96.0, 78.7, 73.9, 56.3, 56.2, 53.2, 53.0, 52.8, 51.6, 50.3, 49.2, 47.8, 45.4, 39.5, 28.3, 27.5, 24.4, 19.7. FTIR (NaCl, thin film): 3017, 2952, 2896, 2854, 1755, 1739, 1713, 1477, 1464, 1438, 1377, 1298, 1262, 1103, 1052, 989 cm-1. HRMS: (ESI) calc’d for C28H34NO8Se [M + NH4]+ 592.1444, found 592.1424. [𝜶]𝟐𝟓 𝐃 = +13° (c = 0.60, CHCl3). Preparation of β-hydroxyketone 281: O MeO 2C NaIO 4 O SePh O MOMO 280 O MeO 2C O O O THF/H2O (51% yield) MOMO HO O 281 To a 1-dram vial was added α-selenide 280 (10.4 mg, 18.1 µmol, 1.0 equiv), NaIO4 (19.4 mg, 90.7 µmol, 5.0 equiv), THF (0.3 mL), and H2O (60 µL). The reaction was allowed to stir for 10 h, and then quenched by addition of sat. NaHCO3 (1 mL). The aqueous phase was extracted with EtOAc (3 x 1 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 240 chromatography (40% acetone in hexanes) afforded β-hydroxyketone 281 (4.0 mg, 9.2 µmol, 51% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 4.78 (dd, J = 4.3, 0.9 Hz, 1H), 4.70 (d, J = 6.6 Hz, 1H), 4.65 (d, J = 6.6 Hz, 1H), 4.37 (t, J = 4.9 Hz, 1H), 3.83 (s, 3H), 3.39 – 3.35 (m, 1 H), 3.36 (s, 3H), 2.99 (d, J = 20.1 Hz, 1H), 2.92 (dd, J = 8.2, 5.0 Hz, 1H), 2.85 (dd, J = 15.1, 9.9 Hz, 1H), 2.75 (d, J = 5.6 Hz, 1H), 2.74 (d, J = 19.9 Hz, 1H), 2.66 (dd, J = 9.9, 7.4 Hz, 1H), 2.48 – 2.37 (m, 2H), 2.35 (d, J = 6.5 Hz, 1H), 2.24 – 2.15 (m, 1H), 2.02 – 1.84 (m, 3H), 1.79 (dddd, J = 14.3, 11.2, 4.3, 1.2 Hz, 1H), 1.41 (dd, J = 15.0, 6.8 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 210.7, 207.7, 169.1, 168.9, 96.6, 79.7, 76.7, 73.8, 57.8, 56.5, 56.2, 53.0, 52.8, 52.2, 50.8, 47.6, 45.5, 43.9, 28.3, 24.3, 23.8, 20.1. FTIR (NaCl, thin film): 3468, 2960, 2915, 2851, 1745, 1717, 1464, 1445, 1379, 1298, 1272, 1104, 1051 cm-1. HRMS: (FAB) calc’d for C22H27O9 [M + H]+ 435.1655, found 435.1639. [𝜶]𝟐𝟓 𝐃 = +16° (c = 0.21, CHCl3). Preparation of β-methoxyketone 282: O MeO 2C O3 MeOH, –78 °C O O SePh O MOMO 280 O MeO 2C O O then pyridine –78 °C to rt (88% yield) MOMO MeO O 282 A 25-mL, round-bottomed flask was charged with α-selenide 280 (90.6 mg, 0.158 mmol, 1.0 equiv), CH2Cl2 (4 mL), and methanol (4 mL). The flask was cooled to –78 °C, Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 241 at which time ozone (as a mixture with O2) was gently bubbled through the solution (O2 flow rate = 1/4 L/min, 2 setting on ozone generator) for 20 min. The solution was then sparged with Ar for 15 minutes, and pyridine (64 µL, 0.790 mmol, 5 equiv) was added. The reaction was allowed to warm to ambient temperature, and stirred for a further 48 h. The methanol solvent and pyridine were then removed by concentration in vacuo, and the crude residue was purified by silica gel chromatography (44% acetone in hexane) to afford β-methoxyketone 282 as a white solid (62.3 mg, 0.139 mmol, 88% yield) with a small amount of inseperable arene impurity (<10%). 1 H NMR (400 MHz, CDCl3): δ 4.78 (d, J = 6.9 Hz, 1H), 4.75 (d, J = 4.0 Hz, 1H), 4.56 (d, J = 6.9 Hz, 1H), 4.23 (t, J = 4.6 Hz, 1H), 3.81 (s, 3H), 3.32 (s, 3H), 3.11 (s, 3H), 2.98 (d, J = 17.9 Hz, 1H), 2.79 (dd, J = 7.4, 4.5 Hz, 1H), 2.72 (q, J = 6.0 Hz, 1H), 2.69 – 2.58 (m, 3H), 2.55 (d, J = 6.7 Hz, 1H), 2.45 (dt, J = 11.2, 6.5 Hz, 1H), 2.42 – 2.34 (m, 1H), 2.23 – 2.09 (m, 1H), 2.03 – 1.70 (m, 4H), 1.39 (ddd, J = 14.9, 6.1, 2.8 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 211.5, 208.3, 169.1, 169.1, 95.7, 81.0, 76.9, 74.1, 56.6, 55.8, 53.8, 53.0, 52.8, 52.6, 48.9, 45.8, 45.0, 44.6, 44.5, 28.0, 24.2, 24.2, 20.1. FTIR (NaCl, thin film): 2954, 2915, 2832, 1746, 1711, 1462, 1443, 1375, 1298, 1262, 1221, 1152, 1103, 1049, 916, 753 cm-1. HRMS: (FAB) calc’d for C23H29O9 [M + H]+ 449.1811, found 449.1801. [𝜶]𝟐𝟓 𝐃 = –14° (c = 0.24, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 242 Preparation of alcohol 283: O MeO 2C O O NaBH 4 O MeO 2C OH O EtOH/THF, 0 °C MOMO MeO O (66% yield) MOMO 282 MeO O 283 A solution of 282 (17.0 mg, 37.9 µmol, 1.0 equiv) in absolute EtOH (0.28 mL) and THF (0.28 mL) was cooled to 0 °C in a 5-mL round-bottomed flask. NaBH4 (3.6 mg, 94.8 µmol, 2.5 equiv) was added, and three more equal portions of NaBH4 were added each successive hour. An hour after the fourth portion was added, the reaction was quenched with sat. NaHCO3 (2 mL) and extracted with CH2Cl2 (3 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (3% MeOH in CH2Cl2) to afford alcohol 283 as a clear oil (11.2 mg, 24.9 µmol, 66% yield). Note: Extended reaction time leads to over-reduction of the methyl ester. Remarkably, the methyl ester undergoes facile reduction, while the C16 ketone remains inert. 1 H NMR (400 MHz, CDCl3): δ 4.82 (d, J = 6.8 Hz, 1H), 4.73 (d, J = 4.2 Hz, 1H), 4.61 (d, J = 6.8 Hz, 1H), 4.20 (td, J = 4.9, 1.6 Hz, 1H), 4.16 (dd, J = 4.8, 3.9 Hz, 1H), 3.78 (s, 3H), 3.35 (s, 3H), 3.15 (s, 3H), 2.93 (d, J = 16.9 Hz, 1H), 2.77 (ddd, J = 7.3, 4.0, 1.3 Hz, 1H), 2.71 (d, J = 16.9 Hz, 1H), 2.64 – 2.60 (m, 1H), 2.45 (ddd, J = 6.4, 4.9, 1.3 Hz, 1H), 2.39 (t, J = 5.5 Hz, 1H), 2.35 – 2.23 (m, 3H), 2.22 – 2.10 (m, 2H), 2.06 (dd, J = 9.7, 7.5 Hz, 1H), 1.97 – 1.86 (m, 2H), 1.71 – 1.63 (m, 1H), 1.56 (ddd, J = 14.5, 7.5, 5.9 Hz, 1H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 243 C NMR (101 MHz, CDCl3): δ 212.6, 171.2, 169.4, 95.8, 78.1, 76.0, 74.4, 72.0, 55.7, 53.5, 53.0, 52.6, 48.5, 48.4, 47.7, 47.5, 43.9, 43.3, 40.6, 28.6, 26.6, 25.4, 20.5. FTIR (NaCl, thin film): 3436, 2951, 2854, 2832, 1738, 1730, 1713, 1468, 1449, 1375, 1330, 1287, 1251, 1115, 1050 cm-1. HRMS: (ESI) calc’d for C22H25O8 [M – OMe]+ 419.1700, found 419.1709. [𝜶]𝟐𝟓 𝐃 = –10° (c = 0.53, CHCl3). Preparation of amide 287: O MeO 2C O O OH O NHEt O MeO 2C EtNH 2 THF MOMO MeO O (69% yield) 282 MOMO MeO O 287 To a 1-dram vial containing lactone 282 (4.6 mg, 10.3 µmol, 1.0 equiv) was added ethylamine (0.30 mL, 2.0 M in THF, 0.60 mmol). The resulting solution was stirred for 72 h at room temperature, then concentrated in vacuo. The crude residue was purified by silica gel chromatography (50% acetone in hexanes) to afford amide 287 as a colorless oil (3.5 mg, 7.1 µmol, 69% yield). 1 H NMR (400 MHz, CDCl3): δ 6.66 (t, J = 5.5 Hz, 1H), 4.82 (d, J = 6.9 Hz, 1H), 4.56 (d, J = 6.9 Hz, 1H), 4.29 (t, J = 4.8 Hz, 1H), 4.12 (d, J = 9.6 Hz, 1H), 3.82 (s, 3H), 3.61 (td, J = 9.9, 6.0 Hz, 1H), 3.34 (s, 3H), 3.32 – 3.16 (m, 2H), 3.06 (s, 3H), 2.88 – 2.61 (m, 6H), 2.44 – 2.30 (m, 2H), 2.19 (ddd, J = 15.8, 11.3, 8.0 Hz, 1H), 2.03 (ddd, J = 13.8, 6.1, 4.6 Hz, 1H), 1.98 – 1.87 (m, 2H), 1.84 – 1.63 (m, 3H), 1.10 (t, J = 7.3 Hz, 3H). 244 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 C NMR (101 MHz, CDCl3): δ 216.1, 209.1, 174.6, 169.0, 95.5, 81.9, 77.3, 73.6, 58.3, 55.8, 53.6, 53.3, 52.7, 52.6, 51.3, 48.9, 44.1, 43.2, 42.2, 34.7, 30.3, 29.0, 26.3, 24.8, 14.7. FTIR (NaCl, thin film): 3370, 2952, 2900, 2824, 1720, 1657, 1529, 1452, 1236, 1152, 1046, 753 cm-1. HRMS: (ESI) calc’d for C25H36NO9 [M + H]+ 494.2385, found 494.2381. [𝜶]𝟐𝟓 𝐃 = –30° (c = 0.47, CHCl3). One-pot preparation amide 287: O MeO 2C O3 MeOH, –78 °C O O SePh O O then pyridine –78 °C to rt O MOMO O MeO 2C 280 OH O NHEt O MeO 2C EtNH 2 THF MOMO MeO 282 O (87% yield) MOMO MeO O 287 A 25-mL, round-bottomed flask was charged with α-selenide 280 (30.0 mg, 52.3 µmol, 1.0 equiv) and methanol (3 mL). The flask was cooled to –78 °C, at which time ozone (as a mixture with O2) was gently bubbled through the solution (O2 flow rate = 1/4 L/min, 2 setting on ozone generator) for 10 min. The solution was sparged with Ar for 10 minutes, and then pyridine (85 µL, 1.05 mmol, 20 equiv) was added. The reaction was allowed to warm to ambient temperature, and stirred for a further 17 h. The methanol solvent and pyridine were then removed by concentration in vacuo, and ethylamine (3 mL, 2.0 M in THF) was added. After stirring for 72 h, the reaction mixture was concentrated in vacuo, and the resulting crude residue was purified by silica gel chromatography (50% acetone in hexanes) to provide amide 287 as a white solid (22.4 mg, 45.4 µmol, 87% yield). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 245 Preparation of diol amide 288: OH O NHEt O MeO 2C OH O NHEt OH MeO 2C NaBH 4 EtOH/THF 0 °C MOMO MeO O 287 (65% yield) MOMO MeO O 288 A 25-mL, round-bottomed flask was charged with ketone 287 (20.0 mg, 40.5 µmol, 1.0 equiv), absolute EtOH (1 mL), and THF (1 mL). The resulting solution was cooled to 0 °C, and three portions of NaBH4 (8 mg, 0.211 mmol, 5 equiv) were added over one hour (one portion every 20 minutes, total of 24 mg added). The reaction was then quenched with sat. NaHCO3 (5 mL) and stirred for an additional 15 minutes. The biphasic mixture was concentrated in vacuo to remove ethanol and THF. The aqueous layer was extracted with CH2Cl2 (3 x 5 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (4% MeOH in CH2Cl2) to afford diol amide 288 as a white solid (13.1 mg, 26.4 µmol, 65% yield). Note: Extended reaction time leads to over-reduction of the methyl ester. Remarkably, the methyl ester undergoes facile reduction, while the C16 ketone remains inert. 1 H NMR (400 MHz, CDCl3): δ 6.62 (t, J = 5.4 Hz, 1H), 4.86 (d, J = 6.8 Hz, 1H), 4.62 (d, J = 6.8 Hz, 1H), 4.43 (d, J = 5.2 Hz, 1H), 4.16 (t, J = 4.4 Hz, 1H), 3.84 (q, J = 6.3 Hz, 1H), 3.77 (s, 3H), 3.48 (br s, 1H), 3.36 (s, 3H), 3.26 (qdd, J = 7.3, 5.4, 2.9 Hz, 2H), 3.12 (s, 3H), 2.86 (d, J = 17.0 Hz, 1H), 2.80 – 2.73 (m, 1H), 2.73 (d, J = 17.1 Hz, 1H), 2.60 – Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 246 2.52 (m, 2H), 2.53 – 2.42 (m, 3H), 2.26 – 1.84 (m, 6H), 1.83 – 1.71 (m, 1H), 1.32 (ddd, J = 14.2, 8.2, 6.4 Hz, 1H), 1.12 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 213.0, 175.8, 169.6, 95.7, 78.1, 74.8, 74.5, 70.7, 55.8, 55.7, 53.5, 53.3, 48.3, 47.7, 46.1, 45.9, 45.3, 43.4, 43.0, 34.9, 29.4, 27.1, 23.2, 22.1, 14.5. FTIR (NaCl, thin film): 3369, 2934, 2896, 2847, 2824, 1726, 1708, 1660, 1640, 1545, 1530, 1464, 1449, 1221, 1166, 1115, 1044 cm-1. HRMS: (ESI) calc’d for C25H38NO9 [M + H]+ 496.2541, found 496.2540. [𝜶]𝟐𝟓 𝐃 = –96° (c = 0.23, CHCl3). Preparation of mesyl acetal 291: O MeO 2C OH O n-BuLi, MsCl O MeO 2C O THF, –78 °C to rt MOMO MeO O (15% yield) 283 MeO MOMO H O OMs 291 In a 1-dram vial, n-BuLi (3.2 µL, 2.5 M solution in hexane, 8.06 µmol, 1.1 equiv) was added to a solution of alcohol 283 (3.3 mg, 7.33 µmol, 1.0 equiv) in THF (0.30 mL) at –78 °C. After stirring for 20 minutes, MsCl (3.0 µL, 38.7 µmol, 5.3 equiv) was added. The reaction was allowed to warm to room temperature overnight, and then quenched with sat. NaHCO3 (1 mL) and extracted with CH2Cl2 (3 x 1 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative thin-layer chromatography (5% MeOH in CH2Cl2) to afford mesyl acetal 291 (0.6 mg, 1 µmol, 15% yield). 247 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 H NMR (400 MHz, CDCl3): δ 4.87 (d, J = 4.2 Hz, 1H), 4.74 (d, J = 6.5 Hz, 1H), 4.71 (d, J = 6.8 Hz, 1H), 4.66 (d, J = 6.8 Hz, 1H), 3.86 (dd, J = 4.0, 2.3 Hz, 1H), 3.79 (s, 3H), 3.40 (s, 3H), 3.27 (d, J = 11.2 Hz, 1H), 3.22 (s, 3H), 3.12 (s, 3H), 2.88 (br s, 1H), 2.50 (t, J = 5.9 Hz, 1H), 2.44 – 2.24 (m, 4H), 2.22 – 2.05 (m, 3H), 1.95 (d, J = 12.6 Hz, 1H), 1.91 – 1.84 (m, 2H), 1.43 – 1.30 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 170.5, 169.3, 113.3, 96.2, 81.1, 81.0, 77.4, 75.8, 55.8, 53.1, 52.7, 52.0, 49.5, 49.2, 47.7, 44.9, 42.8, 42.3, 42.2, 38.6, 27.3, 24.7, 24.6, 20.6. Preparation of mesylate 293: O MeO 2C OH O KHMDS Ms 2O O MeO 2C MeO O 283 (32% yield, 46% brsm) MOMO MeO 293 O OH O + THF, –78 °C MOMO O MeO 2C OMs O MOMO MeO OMs S7 In a flame-dried 5-mL, round-bottomed flask, alcohol 283 (24.2 mg, 53.6 µmol, 1.0 equiv) was dissolved in THF (0.8 mL) and cooled to –78 °C. KHMDS (130 µL, 0.5 M in PhMe, 65.0 mmol, 1.2 equiv) was added, and the resulting solution was stirred for 10 minutes. In a separate 1-dram vial, Ms2O (20.5 mg, 0.118 mmol, 2.2 equiv) was dissolved in THF (0.2 mL) and added to the alkoxide solution. After stirring for an additional 40 minutes, the reaction was quenched with sat. NaHCO3 (2 mL) and extracted with CH2Cl2 (3 x 2 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative thin-layer chromatography (5% MeOH in CH2Cl2) to afford mesylate 293 (9.0 mg, 17 µmol, 32% Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 248 yield) as a colorless oil, mesyl enol ether S7 (5.3 mg, 10 µmol, 19% yield) as a colorless oil, and starting material 283 (7.4 mg, 16 µmol, 30% recovery). Data for mesylate 293: 1 H NMR (400 MHz, CDCl3): δ 4.97 (dd, J = 5.2, 1.6 Hz, 1H), 4.84 (d, J = 6.9 Hz, 1H), 4.71 (d, J = 4.3 Hz, 1H), 4.61 (d, J = 6.8 Hz, 1H), 4.20 (t, J = 4.4 Hz, 1H), 3.80 (s, 3H), 3.36 (s, 3H), 3.16 (s, 3H), 3.08 (s, 3H), 3.02 (d, J = 17.2 Hz, 1H), 2.84 (ddd, J = 7.0, 4.0, 1.3 Hz, 1H), 2.71 (d, J = 17.3 Hz, 1H), 2.66 (t, J = 5.6 Hz, 1H), 2.51 (ddd, J = 6.5, 5.0, 1.3 Hz, 1H), 2.41 (dd, J = 14.7, 9.9 Hz, 1H), 2.38 – 2.32 (m, 1H), 2.28 – 2.12 (m, 3H), 1.99 – 1.88 (m, 3H), 1.78 (ddd, J = 14.3, 12.1, 7.5 Hz, 1H), 1.70 (ddd, J = 14.6, 7.8, 5.9 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 211.0, 169.5, 169.0, 95.7, 75.6, 74.9, 73.9, 55.8, 53.4, 52.8, 52.8, 48.7, 47.8, 47.3, 46.7, 43.7, 41.9, 40.5, 38.2, 28.3, 25.9, 25.1, 20.4. FTIR (NaCl, thin film): 3017, 2952, 2839 1756, 1736, 1709, 1466, 1450, 1335, 1287, 1256, 1218, 1177, 1112, 1085, 959, 839 cm-1. HRMS: (PMM) calc’d for C24H36NO11S [M + NH4]+ 546.2004, found 546.2011. [𝜶]𝟐𝟓 𝐃 = +61° (c = 0.70, CHCl3). Data for mesyl enol ether S7: 1 H NMR (400 MHz, CDCl3): δ 5.95 (t, J = 1.4 Hz, 1H), 4.77 (d, J = 6.9 Hz, 1H), 4.72 (d, J = 4.1 Hz, 1H), 4.62 (d, J = 6.9 Hz, 1H), 4.04 (t, J = 3.6 Hz, 1H), 3.96 (t, J = 4.4 Hz, 1H), 3.78 (s, 3H), 3.38 (s, 3H), 3.22 (s, 3H), 3.17 (s, 3H), 2.78 (dd, J = 6.2, 4.6 Hz, 1H), Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 249 2.64 (dd, J = 13.3, 5.5 Hz, 1H), 2.47 (t, J = 5.4 Hz, 1H), 2.35 – 2.17 (m, 4H), 2.12 – 2.00 (m, 3H), 2.00 – 1.88 (m, 2H), 1.74 (ddd, J = 13.3, 11.4, 6.4 Hz, 1H), 1.69 – 1.60 (m, 1H). 13 C NMR (101 MHz, CDCl3): δ 171.0, 169.4, 150.5, 115.1, 95.6, 77.4, 76.0, 74.0, 72.2, 55.7, 53.0, 52.6, 49.2, 47.4, 47.1, 44.0, 43.8, 42.9, 39.9, 38.1, 28.9, 28.9, 25.0, 20.4. FTIR (NaCl, thin film): 2952, 2930, 2851, 2828, 1738, 1730, 1668, 1466, 1451, 1360, 1301, 1180, 1151, 1054, 971 cm-1. HRMS: (ESI) calc’d for C23H29O10S [M – OMe]+ 497.1476, found 497.1462. [𝜶]𝟐𝟓 𝐃 = –2.6° (c = 0.40, CHCl3). Preparation of mesylate amide 294: O MeO 2C OMs O H 2NEt OH O NHEt OMs MeO 2C neat MOMO MeO 293 O (88% yield) MOMO MeO O 294 To a 1-dram vial containing lactone 293 (7.0 mg, 13.2 µmol, 1.0 equiv) was added neat ethylamine (~0.3 mL, distilled from a 70% solution in water and stored over KOH). The vial was sealed with a Teflon cap and allowed to stir for 72 h at room temperature. The reaction was then opened to the atmosphere to allow evaporation of ethylamine. The resulting residue was dissolved in dichloromethane, and further concentrated in vacuo. The crude residue was purified by silica gel chromatography (45% acetone in hexanes) to afford amide 294 as a white solid (6.7 mg, 11.7 µmol, 88% yield). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 250 H NMR (400 MHz, CDCl3): δ 6.73 (t, J = 5.3 Hz, 1H), 5.20 (dd, J = 5.4, 1.1 Hz, 1H), 4.87 (d, J = 6.8 Hz, 1H), 4.62 (d, J = 6.8 Hz, 1H), 4.18 (t, J = 4.4 Hz, 1H), 3.78 (s, 3H), 3.72 (td, J = 8.8, 5.7 Hz, 1H), 3.36 (s, 3H), 3.26 (qd, J = 7.3, 5.5 Hz, 2H), 3.12 (s, 3H), 3.09 (s, 3H), 2.99 (d, J = 17.2 Hz, 1H), 2.89 (d, J = 8.9 Hz, 1H), 2.80 (ddd, J = 7.7, 4.2, 1.2 Hz, 1H), 2.74 – 2.59 (m, 4H), 2.31 – 2.20 (m, 3H), 2.19 – 2.06 (m, 2H), 2.06 – 1.90 (m, 2H), 1.85 (dtd, J = 14.1, 9.0, 1.7 Hz, 1H), 1.43 (ddd, J = 14.3, 7.9, 6.3 Hz, 1H), 1.13 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 211.9, 175.3, 169.0, 95.7, 77.4, 77.4, 74.0, 69.8, 56.2, 55.7, 53.4, 53.3, 48.5, 47.8, 45.6, 44.9, 44.7, 43.0, 42.6, 38.4, 34.9, 28.5, 26.1, 22.4, 21.9, 14.5. FTIR (NaCl, thin film): 3387, 2940, 2900, 2851, 2832, 1710, 1660, 1647, 1529, 1464, 1331, 1220, 1172, 1044, 948, 852 cm-1. HRMS: (ESI) calc’d for C26H40NO11S [M + H]+ 574.2317, found 574.2302. [𝜶]𝟐𝟓 𝐃 = –14° (c = 0.45, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 3.9 251 NOTES AND REFERENCES (1) Cherney, E. C.; Baran, P. S. Isr. J. Chem. 2011, 51, 391. (2) (a) Masamune, S. J. Am. Chem. Soc. 1964, 86, 290. (b) Nagata, W.; Narisada, M.; Wakabayashi, T.; Sugasawa, T. J. Am. Chem. Soc. 1967, 89, 1499. (c) Valenta, Z.; Wiesner, K.; Wong, C. M. Tetrahedron Lett. 1964, 5, 2437. (d) Wiesner, K.; Uyeo, S.; Phillip, A.; Valenta, Z. Tetrahedron Lett. 1968, 9, 6279. (3) (a) Masamune, S. J. Am. Chem. Soc. 1964, 86, 291. (b) Guthrie, R. W.; Valenta, Z.; Wiesner, K. Tetrahedron Lett. 1966, 7, 4645. (c) Nagata, W.; Sugasawa, T.; Narisada, M.; Wakabayashi, T.; Hayase, Y. J. Am. Chem. Soc. 1967, 89, 1483. (d) Ihara, M.; Suzuki, M.; Fukumoto, K.; Kabuto, C. J. Am. Chem. Soc. 1990, 112, 1164. (e) Cherney, E. C.; Lopchuk, J. M.; Green, J. C.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 12592. (f) Cheng, H.; Zeng, F.-H.; Yang, X.; Meng, Y.-J.; Xu, L.; Wang, F.-P. Angew. Chem. Int. Ed. 2016, 55, 392. (4) (a) Wiesner, K.; Tsai, T. Y. R.; Huber, K.; Bolton, S. E.; Vlahov, R. J. Am. Chem. Soc. 1974, 96, 4990. (b) Wiesner, K. Pure Appl. Chem. 1975, 41, 93. (c) Lee, S.F.; Sathe, G. M.; Sy, W. W.; Ho, P.-T.; Wiesner, K. Can. J. Chem. 1976, 54, 1039. (d) Tsai, T. Y. R.; Tsai, C. S. J.; Sy, W. W.; Shanbhag, M. N.; Liu, W. C.; Lee, S. F.; Wisner, K. Heterocycles 1977, 7, 217. (e) Wiesner, K.; Tsai, T. Y. R.; Nambiar, K. P. Can. J. Chem. 1978, 56, 1451. (f) Wiesner, K. Pure Appl. Chem. 1979, 51, 689. (g) Wiesner, K. Tetrahedron, 1985, 41, 485. (5) (a) Peese, K. M.; Gin, D. Y. Org. Lett. 2005, 7, 3323. (b) Gin, D. Y.; Peese, K. M. J. Am. Chem. Soc. 2006, 128, 8734. (c) Peese, K. M.; Gin, D. Y. Chem. Eur. J. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 252 2008, 14, 1654. (d) Hamlin, A. M.; Cortez, J. J.; Lapointe, D.; Sarpong, R. Angew. Chem. Int. Ed. 2013, 52, 4854. (e) Hamlin, A. M.; Lapointe, D.; Owens, K.; Sarpong, R. J. Org. Chem. 2014, 79, 6783. (f) Hamlin, A. M.; Kisunzu, J. K.; Sarpong, R. Org. Biomol. Chem. 2014, 12, 1846. (6) (a) Shishido, K.; Hiroya, K.; Fukumoto, K.; Kametani, T. Tetrahedron Lett. 1986, 27, 1167. (b) Kraus, G. A.; Andersh, B.; Su, Q.; Shim J. Tetrahedron Lett. 1993, 34, 1741. (c) Baillie, L. C.; Batsanov, A.; Bearder. J. R.; Whiting. D. A. J. Chem. Soc. Perkin Trans. 1, 1998, 3471. (d) Baillie, L. C.; Bearder, J. R.; Li, W.-S.; Sherringham, J. A.; Whiting, D. A. J. Chem. Soc. Perkin Trans. 1, 1998, 4047. (e) Taber, D. F.; Liang, J.-L.; Chen, B.; Cai, L. J. Org. Chem. 2005, 70, 8739. (f) Kraus, G. A.; Kesavan, S. Tetrahedron Lett. 2005, 46, 1111. (g) Conrad, R. M.; Du Bois, J. Org. Lett. 2007, 9, 5465. (h) Yang, Z.-K.; Chen, Q.-H.; Wang, F.-P. Tetrahedron 2011, 67, 4192. (i) Liu, Z.-G.; Xu, L.; Chen, Q.-H.; Wang, F.-P. Tetrahedron 2012, 68, 159. (j) Goodall, K. J.; Brimble, M. A.; Barker, D. Tetrahedron 2012, 68, 5759. (k) Liu, Z.-G.; Cheng, H.; Ge, M.-J.; Xu, L.; Wang, F.-P. Tetrahedron 2013, 69, 5431. (l) Cheng, H.; Zeng, F.-H.; Ma, D.; Jiang, M.L.; Xu, L.; Wang, F.-P. Org. Lett. 2014, 16, 2299. (m) Tabuchi, T.; Urabe, D.; Inoue, M. J. Org. Chem. 2016, 81, 10204. (n) Minagawa, K.; Urabe, D.; Inoue, M. J. Antibiotics 2017, In Press. DOI: 10.1038/ja.2017.69. (7) Johnston, J. P.; Overton, K. H. J. C. S. Perkin 1 1971, 1490. (8) (a) Wiesner, K.; Ho, P.-T.; Chang, D.; Lam, Y. K.; Pan, C. S. J.; Ren, W. Y. Can. J. Chem. 1973, 51, 3978. (b) Wiesner, K.; Ho, P.-T.; Tsai, C. S. J. Can. J. Chem. 1974, 52, 2353. (c) Wiesner, K.; Ho, P.-T.; Tsai, C. S. J.; Lam, Y.-K. Can. J. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 253 Chem. 1974, 52, 2355. (d) Atwal, K. S.; Marini-Bettolo, R.; Sanchez, I. H.; Tsai, T. Y. R.; Wiesner, K. Can. J. Chem. 1978, 56, 1102. (e) Sethi, S. P.; Atwal, K. S.; Marini-Bettolo, R. M.; Tsai, T. Y. R.; Wiesner, K. Can. J. Chem. 1980, 58, 1889. (9) Shi, Y.; Wilmot, J. T.; Nordstrøm, L. U.; Tan, D. S.; Gin, D. Y. J. Am. Chem. Soc. 2013, 135, 14313. (10) Marth, C. J.; Gallego, G. M.; Lee, J. C.; Lebold, T. P.; Kulyk, S.; Kou, K. G. M.; Qin, J.; Lilien, R.; Sarpong R. Nature 2015, 528, 493. (11) Kou, K. G. M.; Li, B. X.; Lee, J. C.; Gallego, G. M.; Lebold, T. P.; DiPasquale, A. G.; Sarpong, R. J. Am. Chem. Soc. 2016, 138, 10830. (12) Nishiyama, Y.; Han-ya, Y.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2014, 136, 6598. (13) Nishiyama, Y.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2016, 18, 2359. (14) (a) Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523. (b) Snape, T. J. Chem. Soc. Rev. 2007, 36, 1823. (15) Urankar, D.; Rutar, I.; Modec, B.; Dolenc, D. Eur. J. Org. Chem. 2005, 2349. (16) Rajamannar, T.; Balasubramanian, K. K. Tetrahedron Lett. 1988, 29, 5789. (17) (a) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506. (b) Takita, R.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 4661. (18) Arai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasaki, M. Chem. Eur. J. 1996, 11, 1368. (19) Chappell, D.; Russell, A. T. Org. Biomol. Chem. 2006, 4, 4409. (20) Cornelisse, J. Chem. Rev. 1993, 93, 615. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 254 (21) (a) Hagiya, K.; Yamasaki, A.; Okuyama, T.; Sugimura, T. Tetrahedron: Asymmetry 2004, 15, 1409. (b) Sugimura, T.; Yamasaki, A.; Okuyama, T. Tetrahedron: Asymmetry 2005, 16, 675. (22) Fenton, G. A.; Gilbert, A. Tetrahedron 1989, 45, 2979. (23) (a) Avent, A. G.; Byrne, P. W.; Penkett, C. S. Org. Lett. 1999, 1, 2073. (b) Penkett, C. S;, Byrne, P. W.; Theobald, B. J.; Rola, B.; Ozanne, A.; Hitchcock, P. B. Tetrahedron, 2004, 60, 2771. (24) (a) Habata, Y.; Akabori, S.; Sato, M. Bull. Chem. Soc. Jpn. 1985, 58, 3540. (b) Paquette, L. A.; Pierre, F.; Cottrell, C. E. J. Am. Chem. Soc. 1987, 109, 5731. (25) Spaggiari, A.; Vaccari, D.; Davoli, P.; Torre, G.; Prati, F. J. Org. Chem. 2007, 72, 2216. (26) Barton, D. H. R.; Bashiardes, G.; Fourrey, J.-L. Tetrahedron Lett. 1983, 24, 1605. (27) (a) Shen, X.; Hyde, A. M.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14076. (b) Pan, J.; Wang, X.; Zhang, Y.; Buchwald, S. L. Org. Lett. 2011, 13, 4974. (28) Gilbertson, S. R.; Challener, C. A.; Bos, M. E.; Wulff, W. D. Tetrahedron Lett. 1988, 29, 4795. (29) (a) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033. (b) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron, K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J. Org. Chem. 1986, 51, 277. (30) Ren, H.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2005, 543. (31) Mathieu, B.; Ghosez, L. Tetrahedron 2002, 58, 8219. (32) (a) Steves, J. E.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 15742. (b) Steves, J. E.; Stahl, S. S. J. Org. Chem. 2015, 80, 11184. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine (33) 255 Tang, P.; Wang, L.; Chen, Q.-F.; Chen, Q.-H.; Jian, X.-X.; Wang, F.-P. Tetrahedron 2012, 68, 6249. (34) (a) Joshi, B. S.; Glinski, J. A.; Chokshi, H. P.; Chen, S.-Y.; Srivastava, S. K.; Pelletier, S. W. Heterocycles 1984, 22, 2037. (b) Pelletier, S. W.; Srivastava, S. K.; Joshi, B. S.; Olsen, J. D. Heterocycles, 1985, 23, 331. (c) See also References 9 and 13. (35) Watanabe, M.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2003, 125, 7508. (36) Piers, E.; Lung, G. L.; Ruediger, E. H. Can. J. Chem. 1987, 65, 670.  435 ABOUT THE AUTHOR Victor Wei-Dek Mak was born on March 21, 1991 in Oakland, CA, to parents Michael Mak and Cathy Mak. He grew up around the San Francisco Bay Area, and developed an early interest in science through school and television. He later moved to Irvine, CA to pursue undergraduate studies at University of California, Irvine. He developed an interest in organic chemistry, and in the summer of 2010, began working in the laboratory of Professor Kenneth J. Shea, under the supervision of Dr. Leah Cleary. As an undergraduate, Victor conducted research towards the total synthesis of a biologically active alkaloid, stenine, and found his passion for total synthesis. In 2012, he moved to Pasadena, CA to pursue doctoral studies under Professor Sarah Reisman at Caltech. In her laboratory, Victor has focused on the total synthesis of architecturally complex small molecules such as longikaurin E and talatisamine. Upon completion of his Ph.D., Victor will move back to the Bay Area to join a new medicinal chemistry team at Merck in South San Francisco.  Appendix 2 – Spectra Relevant to Chapter 3 256 Appendix 2 Spectra Relevant to Chapter 3: Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 208 MeO 2C MeO 2C O O Appendix 2 – Spectra Relevant to Chapter 3 257 MeO 2C MeO 2C O 189 O O Appendix 2 – Spectra Relevant to Chapter 3 258 MeO 2C MeO 2C O 189 O O Appendix 2 – Spectra Relevant to Chapter 3 259 O Br S3 Appendix 2 – Spectra Relevant to Chapter 3 260 HO Br 194 Appendix 2 – Spectra Relevant to Chapter 3 261 262 TMSO Br 196 Appendix 2 – Spectra Relevant to Chapter 3 263 TMSO Br 196 Appendix 2 – Spectra Relevant to Chapter 3 TIPSO Br 195 Appendix 2 – Spectra Relevant to Chapter 3 264 TIPSO Br 195 Appendix 2 – Spectra Relevant to Chapter 3 265 266 MeO 2C MeO 2C H 197 TIPSO O OH Appendix 2 – Spectra Relevant to Chapter 3 267 MeO 2C MeO 2C H 197 TIPSO O OH Appendix 2 – Spectra Relevant to Chapter 3 268 OTIPS 198 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 269 OTIPS 198 CO2Me O MeO 2C OTMS Appendix 2 – Spectra Relevant to Chapter 3 270 OTMS 200 CO2Me O MeO 2C OTMS Appendix 2 – Spectra Relevant to Chapter 3 271 OTMS 200 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 MeO 2C 201 OTMS OH CO2Me O S4 (E = CO2Me) MeO 2C OTMS E OH O Appendix 2 – Spectra Relevant to Chapter 3 272 MeO 2C 201 OTMS OH CO2Me O S4 (E = CO2Me) MeO 2C OTMS E OH O Appendix 2 – Spectra Relevant to Chapter 3 273 274 202 O H CO2Me O MeO 2C OTMS Appendix 2 – Spectra Relevant to Chapter 3 O H 202 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 275 276 OH 203 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 277 OH 203 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 278 OH 203 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 OMOM 204 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 279 OMOM 204 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 280 OMOM 205 MeO 2C OH CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 281 282 OMOM 205 MeO 2C OH CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 206 OMOM CO2Me O MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 283 206 OMOM CO2Me O MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 284 207 OMOM CO2Me NHEt MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 285 207 OMOM CO2Me NHEt MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 286 287 207 OMOM CO2Me NHEt MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 288 207 OMOM CO2Me NHEt MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 289 OMOM 207 MeO 2C OMe CO2Me NHEt Appendix 2 – Spectra Relevant to Chapter 3 290 207 OMOM CO2Me NHEt MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 291 H MeO 2C MeO 2C 209 O Appendix 2 – Spectra Relevant to Chapter 3 H MeO 2C MeO 2C 210 O O Appendix 2 – Spectra Relevant to Chapter 3 292 H MeO 2C MeO 2C 210 O O Appendix 2 – Spectra Relevant to Chapter 3 293 294 O 211 MeO 2C MeO 2C H O O O Appendix 2 – Spectra Relevant to Chapter 3 295 O 211 MeO 2C MeO 2C H O O O Appendix 2 – Spectra Relevant to Chapter 3 296 190 MeO 2C MeO 2C H O Appendix 2 – Spectra Relevant to Chapter 3 297 190 MeO 2C MeO 2C H O Appendix 2 – Spectra Relevant to Chapter 3 O 192 Br MeO 2C MeO 2C H OH Appendix 2 – Spectra Relevant to Chapter 3 298 O 192 Br MeO 2C MeO 2C H OH Appendix 2 – Spectra Relevant to Chapter 3 299 300 185 MeO 2C MeO 2C H O O Appendix 2 – Spectra Relevant to Chapter 3 185 MeO 2C MeO 2C H O O Appendix 2 – Spectra Relevant to Chapter 3 301 Me OH S5 O Me Appendix 2 – Spectra Relevant to Chapter 3 302 Me O 216 O Me Appendix 2 – Spectra Relevant to Chapter 3 303 Me 218 O H Me O H H Appendix 2 – Spectra Relevant to Chapter 3 304 305 217 O Me H Me O H H Appendix 2 – Spectra Relevant to Chapter 3 306 Me OH 228 O O Me Appendix 2 – Spectra Relevant to Chapter 3 Me OH O O 233 Me Cl Appendix 2 – Spectra Relevant to Chapter 3 307 308 Me OH O O S6 O Me Cl Appendix 2 – Spectra Relevant to Chapter 3 309 Me O O O 234 O Me Cl Appendix 2 – Spectra Relevant to Chapter 3 310 O HO 235 O Cl Appendix 2 – Spectra Relevant to Chapter 3 311 236 O O O Cl Appendix 2 – Spectra Relevant to Chapter 3 236 O O O Cl Appendix 2 – Spectra Relevant to Chapter 3 312 313 Me OH O O Me 239 OH Appendix 2 – Spectra Relevant to Chapter 3 Me OH O O Me 239 OH Appendix 2 – Spectra Relevant to Chapter 3 314 315 Me OH 240 OH O Me OH Appendix 2 – Spectra Relevant to Chapter 3 316 Me OH 240 OH O Me OH Appendix 2 – Spectra Relevant to Chapter 3 317 Me 244 HO OH O Me OH Appendix 2 – Spectra Relevant to Chapter 3 Me 244 HO OH O Me OH Appendix 2 – Spectra Relevant to Chapter 3 318 319 Me 244 HO OH O Me OH Appendix 2 – Spectra Relevant to Chapter 3 320 Me 244 HO OH O Me OH Appendix 2 – Spectra Relevant to Chapter 3 321 Me O Si O 245 t-Bu t-Bu OH O Me Appendix 2 – Spectra Relevant to Chapter 3 322 Me O Si O 245 t-Bu t-Bu OH O Me Appendix 2 – Spectra Relevant to Chapter 3 323 Me O Si O t-Bu t-Bu 246 O O Me Appendix 2 – Spectra Relevant to Chapter 3 324 Me O Si O t-Bu t-Bu 246 O O Me Appendix 2 – Spectra Relevant to Chapter 3 325 247 O Si O t-Bu t-Bu HO Appendix 2 – Spectra Relevant to Chapter 3 326 247 O Si O t-Bu t-Bu HO Appendix 2 – Spectra Relevant to Chapter 3 327 248 O Si O t-Bu t-Bu O Appendix 2 – Spectra Relevant to Chapter 3 328 248 O Si O t-Bu t-Bu O Appendix 2 – Spectra Relevant to Chapter 3 329 249 O Si O t-Bu t-Bu TfO Appendix 2 – Spectra Relevant to Chapter 3 249 O Si O t-Bu t-Bu TfO Appendix 2 – Spectra Relevant to Chapter 3 330 331 251 O Si O t-Bu t-Bu I Appendix 2 – Spectra Relevant to Chapter 3 332 251 O Si O t-Bu t-Bu I Appendix 2 – Spectra Relevant to Chapter 3 253 O Si O t-Bu t-Bu Me 3Sn Appendix 2 – Spectra Relevant to Chapter 3 333 334 O Si O t-Bu t-Bu 262 MeO 2C MeO 2C H O OH Appendix 2 – Spectra Relevant to Chapter 3 O Si O t-Bu t-Bu 262 MeO 2C MeO 2C H O OH Appendix 2 – Spectra Relevant to Chapter 3 335 336 O Si O t-Bu t-Bu 263 MeO 2C MeO 2C H O OTMS Appendix 2 – Spectra Relevant to Chapter 3 337 O Si O t-Bu t-Bu 263 MeO 2C MeO 2C H O OTMS Appendix 2 – Spectra Relevant to Chapter 3 338 264 O Si O t-Bu t-Bu MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 339 264 O Si O t-Bu t-Bu CO2Me O MeO 2C OTMS Appendix 2 – Spectra Relevant to Chapter 3 340 268 Br O Si O t-Bu t-Bu MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 341 268 Br O Si O t-Bu t-Bu MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 342 MeO 2C 272 OH OH OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 343 MeO 2C 272 OH OH OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 344 HO MeO 2C 273 O OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 345 HO MeO 2C 273 O OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 MOMO MeO 2C 274 O OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 346 347 MOMO MeO 2C 274 O OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 348 275 O MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 349 275 O MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 350 278 MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 351 278 MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 352 278 MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 353 278 MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 354 279 MOMO H MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 355 279 MOMO H MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 356 279 MOMO H MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 357 276 O SePh MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 276 O SePh MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 358 359 277 O HO MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 360 277 O HO MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 361 277 O HO MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 362 277 O HO MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 363 280 MOMO MeO 2C O O O O SePh Appendix 2 – Spectra Relevant to Chapter 3 364 280 MOMO MeO 2C O O O O SePh Appendix 2 – Spectra Relevant to Chapter 3 365 281 HO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 366 281 HO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 367 281 HO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 368 281 HO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 369 282 MeO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 282 MeO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 370 371 282 MeO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 372 282 MeO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 373 283 MeO MOMO MeO 2C O O O OH Appendix 2 – Spectra Relevant to Chapter 3 283 MeO MOMO MeO 2C O O O OH Appendix 2 – Spectra Relevant to Chapter 3 374 375 283 MeO MOMO MeO 2C O O O OH Appendix 2 – Spectra Relevant to Chapter 3 376 283 MeO MOMO MeO 2C O O O OH Appendix 2 – Spectra Relevant to Chapter 3 377 283 MeO MOMO MeO 2C O O O OH Appendix 2 – Spectra Relevant to Chapter 3 378 287 O MeO MOMO MeO 2C OH O NHEt O Appendix 2 – Spectra Relevant to Chapter 3 379 287 O MeO MOMO MeO 2C OH O NHEt O Appendix 2 – Spectra Relevant to Chapter 3 380 287 O MeO MOMO MeO 2C OH O NHEt O Appendix 2 – Spectra Relevant to Chapter 3 381 288 O MeO MOMO MeO 2C OH O NHEt OH Appendix 2 – Spectra Relevant to Chapter 3 382 288 O MeO MOMO MeO 2C OH O NHEt OH Appendix 2 – Spectra Relevant to Chapter 3 383 288 O MeO MOMO MeO 2C OH O NHEt OH Appendix 2 – Spectra Relevant to Chapter 3 384 288 O MeO MOMO MeO 2C OH O NHEt OH Appendix 2 – Spectra Relevant to Chapter 3 385 288 O MeO MOMO MeO 2C OH O NHEt OH Appendix 2 – Spectra Relevant to Chapter 3 386 291 O OMs MeO MOMO MeO 2C O O H Appendix 2 – Spectra Relevant to Chapter 3 387 291 O OMs MeO MOMO MeO 2C O O H Appendix 2 – Spectra Relevant to Chapter 3 388 291 O OMs MeO MOMO MeO 2C O O H Appendix 2 – Spectra Relevant to Chapter 3 389 291 O OMs MeO MOMO MeO 2C O O H Appendix 2 – Spectra Relevant to Chapter 3 390 293 MeO MOMO MeO 2C O O O OMs Appendix 2 – Spectra Relevant to Chapter 3 391 293 MeO MOMO MeO 2C O O O OMs Appendix 2 – Spectra Relevant to Chapter 3 392 293 MeO MOMO MeO 2C O O O OMs Appendix 2 – Spectra Relevant to Chapter 3 393 293 MeO MOMO MeO 2C O O O OMs Appendix 2 – Spectra Relevant to Chapter 3 394 S7 MeO MOMO MeO 2C O O OMs OH Appendix 2 – Spectra Relevant to Chapter 3 S7 MeO MOMO MeO 2C O O OMs OH Appendix 2 – Spectra Relevant to Chapter 3 395 396 294 O MOMO MeO 2C MeO OH O NHEt OMs Appendix 2 – Spectra Relevant to Chapter 3 294 O MOMO MeO 2C MeO OH O NHEt OMs Appendix 2 – Spectra Relevant to Chapter 3 397 398 294 O MOMO MeO 2C MeO OH O NHEt OMs Appendix 2 – Spectra Relevant to Chapter 3 399 294 O MOMO MeO 2C MeO OH O NHEt OMs Appendix 2 – Spectra Relevant to Chapter 3  Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 400 Appendix 3 X-Ray Crystallography Reports Relevant to Chapter 3: Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine† † X-ray crystallographic analysis of 262 was completed by Dr. Michael Takase at the Caltech X-ray crystallography lab and Julie Hofstra, a graduate student in the Reisman lab. Crystals of 262 were obtained by Alice Wong, a graduate student in the Reisman lab. 401 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 A3.1 CRYSTAL STRUCTURE ANALYSIS: EPOXY ALCOHOL 262 Figure A3.1. Epoxy alcohol 262. Table A3.1. Crystal data and structure refinement for epoxy alcohol 262. Identification code ARWIII-253 Empirical formula C29 H42 O8 Si Formula weight 546.71 Temperature 100 K Wavelength 0.71073 Å Crystal system Monoclinic Space group P 1 21 1 Unit cell dimensions a = 8.8034(13) Å α= 90°. b = 24.957(4) Å β= 101.552(5)°. c = 13.429(2) Å γ = 90°. Volume 2890.6(7) Å3 Z 4 Density (calculated) 1.256 Mg/m3 Absorption coefficient 0.129 mm-1 F(000) 1176 Crystal size 0.28 x 0.17 x 0.08 mm3 Theta range for data collection 2.361 to 30.544°. Index ranges -12<=h<=12, -35<=k<=35, -19<=l<=19 Reflections collected 130883 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Independent reflections 17688 [R(int) = 0.0665] Completeness to theta = 26.000° 99.9 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7461 and 0.7071 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 17688 / 1 / 707 Goodness-of-fit on F2 1.036 Final R indices [I>2sigma(I)] R1 = 0.0394, wR2 = 0.0851 R indices (all data) R1 = 0.0512, wR2 = 0.0896 Absolute structure parameter 0.02(2) Extinction coefficient n/a Largest diff. peak and hole 0.295 and -0.229 e.Å-3 402 X-Ray Structure Determination Low-temperature diffraction data (φ- and ω-scans) were collected on a Bruker AXS D8 VENTURE KAPPA diffractometer coupled to a PHOTON 100 CMOS detector with MoKα radiation (λ = 0.71073 Å) from a IµS HB micro-focus sealed X-ray tube. All diffractometer manipulations, including data collection, integration, and scaling were carried out using the Bruker APEXII software.1 Absorption corrections were applied using SADABS.2 The structure was solved by intrinsic phasing using SHELXT3 and refined against F2 on all data by full-matrix least squares with SHELXL-20143 using established refinement techniques.4 All non-hydrogen atoms were refined anisotropically. The coordinates for the hydrogen atoms bound to O1A and O1B were located in the difference Fourier synthesis and refined using a riding model. All other hydrogen atoms were included into the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). Compound 262 crystallizes in the monoclinic space group P21 with two molecules in the 403 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 asymmetric unit. Absolute configuration was determined by anomalous dispersion (Flack = 0.03(2)). 5 Graphical representation of the structure with 50% probability thermal ellipsoids was generated using Mercury visualization software.6 Table A3.2. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2 x 103) for epoxy alcohol 262 U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ Si(1A) -417(1) 3653(1) 6121(1) 14(1) Si(1B) 3569(1) 3793(1) 10636(1) 15(1) O(6A) 5658(2) 6948(1) 5081(1) 19(1) O(7A) 3572(2) 6865(1) 2890(1) 18(1) O(1B) 3404(2) 5702(1) 7078(1) 17(1) O(5A) 3783(2) 6613(1) 5803(1) 18(1) O(8A) 5721(2) 6371(1) 2976(1) 20(1) O(4A) 390(2) 4186(1) 6751(1) 15(1) O(2B) 6490(2) 5967(1) 7042(1) 15(1) O(3B) 3262(2) 4027(1) 9464(1) 17(1) O(6B) 10631(2) 6672(1) 9865(1) 23(1) O(7B) 8245(2) 6976(1) 7998(1) 18(1) O(1A) -110(2) 5232(1) 2172(1) 20(1) O(3A) -674(2) 3811(1) 4908(1) 16(1) O(8B) 10005(2) 6412(1) 7583(1) 22(1) O(2A) 2891(2) 5682(1) 2430(1) 16(1) O(4B) 4357(2) 4295(1) 11372(1) 18(1) O(5B) 9349(2) 6112(1) 10692(1) 36(1) C(18A) 4510(2) 6609(1) 5133(2) 14(1) C(2A) 5081(3) 5280(1) 3699(2) 19(1) C(18B) 9573(2) 6303(1) 9913(2) 17(1) C(14B) 3066(2) 4580(1) 9215(2) 15(1) C(19A) 4436(2) 6520(1) 3293(2) 15(1) 404 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(4A) 4221(2) 6214(1) 4244(2) 13(1) C(15A) 2132(2) 4509(1) 5681(2) 15(1) C(19B) 8910(2) 6554(1) 8099(2) 15(1) C(12B) 3469(2) 5490(1) 9611(2) 14(1) C(13A) -677(2) 4785(1) 5368(2) 13(1) C(12A) -486(2) 5272(1) 4736(2) 14(1) C(7B) 4352(2) 6396(1) 8394(2) 14(1) C(3B) 9366(2) 5568(1) 8668(2) 18(1) C(4B) 8693(2) 6125(1) 8871(2) 14(1) C(17B) 4403(2) 5810(1) 8028(2) 12(1) C(10B) 4023(2) 5406(1) 8768(2) 13(1) C(2B) 8570(3) 5307(1) 7666(2) 20(1) C(15B) 6076(2) 4701(1) 10377(2) 17(1) C(3A) 5338(2) 5728(1) 4506(2) 17(1) C(8A) 1977(2) 4442(1) 4682(2) 16(1) C(26A) 919(2) 3048(1) 6314(2) 19(1) C(5B) 6994(2) 6027(1) 8938(2) 12(1) C(20A) 5995(3) 7333(1) 5903(2) 23(1) C(1B) 6854(2) 5414(1) 7364(2) 15(1) C(11B) 6113(2) 5773(1) 7980(2) 12(1) C(1A) 3447(2) 5226(1) 3093(2) 16(1) C(13B) 3256(2) 4967(1) 10130(2) 15(1) C(17A) 471(2) 5488(1) 3110(2) 15(1) C(9B) 4345(2) 4804(1) 8693(2) 15(1) C(16B) 4716(2) 4789(1) 10890(2) 16(1) C(24B) 939(3) 3115(1) 10428(2) 28(1) C(6A) 1151(2) 6367(1) 3956(2) 17(1) C(11A) 2227(2) 5577(1) 3314(2) 14(1) C(5A) 2573(2) 5989(1) 4149(2) 13(1) C(8B) 5905(2) 4691(1) 9374(2) 16(1) C(22B) 1653(3) 3618(1) 11001(2) 22(1) C(10A) 83(2) 5132(1) 3927(2) 14(1) C(14A) -860(2) 4347(1) 4536(2) 14(1) C(29B) 5046(3) 2887(1) 11684(2) 26(1) C(6B) 5915(2) 6492(1) 9139(2) 15(1) 405 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(24A) -3098(3) 3016(1) 5953(2) 27(1) C(22A) -2378(2) 3531(1) 6467(2) 20(1) C(27A) 2614(3) 3231(1) 6415(2) 29(1) C(26B) 4954(3) 3207(1) 10695(2) 20(1) C(29A) 811(3) 2734(1) 7286(2) 30(1) C(9A) 421(2) 4529(1) 3979(2) 15(1) C(16A) 768(2) 4642(1) 6167(2) 13(1) C(7A) -104(2) 6070(1) 3179(2) 16(1) C(28A) 530(3) 2675(1) 5398(2) 27(1) C(25B) 1813(3) 3532(1) 12148(2) 35(1) C(23A) -3478(3) 3990(1) 6060(3) 32(1) C(28B) 4473(3) 2837(1) 9771(2) 26(1) C(21A) 5882(3) 6600(1) 2016(2) 30(1) C(21B) 10332(3) 6806(1) 6866(2) 37(1) C(23B) 520(3) 4089(1) 10688(3) 35(1) C(27B) 6602(3) 3410(1) 10686(3) 34(1) C(20B) 11536(3) 6842(1) 10841(2) 32(1) C(25A) -2292(3) 3501(1) 7619(2) 34(1) ________________________________________________________________________________ Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.3. Bond lengths [Å] and angles [°] for epoxy alcohol 262. _____________________________________________________ Si(1A)-O(4A) 1.6588(16) Si(1A)-O(3A) 1.6473(16) Si(1A)-C(26A) 1.899(2) Si(1A)-C(22A) 1.900(2) Si(1B)-O(3B) 1.6483(17) Si(1B)-O(4B) 1.6592(17) Si(1B)-C(22B) 1.900(2) Si(1B)-C(26B) 1.896(2) O(6A)-C(18A) 1.331(3) O(6A)-C(20A) 1.450(3) O(7A)-C(19A) 1.203(3) O(1B)-C(17B) 1.423(3) O(1B)-H(1B) 0.78(4) O(5A)-C(18A) 1.204(3) O(8A)-C(19A) 1.339(3) O(8A)-C(21A) 1.444(3) O(4A)-C(16A) 1.458(2) O(2B)-C(1B) 1.461(3) O(2B)-C(11B) 1.448(2) O(3B)-C(14B) 1.422(2) O(6B)-C(18B) 1.321(3) O(6B)-C(20B) 1.454(3) O(7B)-C(19B) 1.201(3) O(1A)-C(17A) 1.415(3) O(1A)-H(1A) 0.75(4) O(3A)-C(14A) 1.427(3) O(8B)-C(19B) 1.343(2) O(8B)-C(21B) 1.446(3) O(2A)-C(1A) 1.467(3) O(2A)-C(11A) 1.447(2) O(4B)-C(16B) 1.456(3) O(5B)-C(18B) 1.200(3) C(18A)-C(4A) 1.529(3) 406 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(2A)-H(2AA) 0.9900 C(2A)-H(2AB) 0.9900 C(2A)-C(3A) 1.542(3) C(2A)-C(1A) 1.510(3) C(18B)-C(4B) 1.524(3) C(14B)-H(14B) 1.0000 C(14B)-C(13B) 1.546(3) C(14B)-C(9B) 1.545(3) C(19A)-C(4A) 1.531(3) C(4A)-C(3A) 1.556(3) C(4A)-C(5A) 1.537(3) C(15A)-H(15A) 0.9500 C(15A)-C(8A) 1.332(3) C(15A)-C(16A) 1.514(3) C(19B)-C(4B) 1.528(3) C(12B)-H(12B) 0.9500 C(12B)-C(10B) 1.334(3) C(12B)-C(13B) 1.510(3) C(13A)-H(13A) 1.0000 C(13A)-C(12A) 1.511(3) C(13A)-C(14A) 1.547(3) C(13A)-C(16A) 1.532(3) C(12A)-H(12A) 0.9500 C(12A)-C(10A) 1.330(3) C(7B)-H(7BA) 0.9900 C(7B)-H(7BB) 0.9900 C(7B)-C(17B) 1.545(3) C(7B)-C(6B) 1.549(3) C(3B)-H(3BA) 0.9900 C(3B)-H(3BB) 0.9900 C(3B)-C(4B) 1.556(3) C(3B)-C(2B) 1.532(3) C(4B)-C(5B) 1.536(3) C(17B)-C(10B) 1.500(3) C(17B)-C(11B) 1.523(3) 407 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(10B)-C(9B) 1.536(3) C(2B)-H(2BA) 0.9900 C(2B)-H(2BB) 0.9900 C(2B)-C(1B) 1.507(3) C(15B)-H(15B) 0.9500 C(15B)-C(16B) 1.513(3) C(15B)-C(8B) 1.324(3) C(3A)-H(3AA) 0.9900 C(3A)-H(3AB) 0.9900 C(8A)-H(8A) 0.9500 C(8A)-C(9A) 1.516(3) C(26A)-C(27A) 1.541(3) C(26A)-C(29A) 1.542(3) C(26A)-C(28A) 1.528(3) C(5B)-H(5B) 1.0000 C(5B)-C(11B) 1.503(3) C(5B)-C(6B) 1.557(3) C(20A)-H(20A) 0.9800 C(20A)-H(20B) 0.9800 C(20A)-H(20C) 0.9800 C(1B)-H(1BA) 1.0000 C(1B)-C(11B) 1.459(3) C(1A)-H(1AA) 1.0000 C(1A)-C(11A) 1.462(3) C(13B)-H(13B) 1.0000 C(13B)-C(16B) 1.538(3) C(17A)-C(11A) 1.531(3) C(17A)-C(10A) 1.503(3) C(17A)-C(7A) 1.546(3) C(9B)-H(9B) 1.0000 C(9B)-C(8B) 1.517(3) C(16B)-H(16B) 1.0000 C(24B)-H(24D) 0.9800 C(24B)-H(24E) 0.9800 C(24B)-H(24F) 0.9800 408 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(24B)-C(22B) 1.539(3) C(6A)-H(6AA) 0.9900 C(6A)-H(6AB) 0.9900 C(6A)-C(5A) 1.547(3) C(6A)-C(7A) 1.548(3) C(11A)-C(5A) 1.508(3) C(5A)-H(5A) 1.0000 C(8B)-H(8B) 0.9500 C(22B)-C(25B) 1.532(4) C(22B)-C(23B) 1.545(3) C(10A)-C(9A) 1.534(3) C(14A)-H(14A) 1.0000 C(14A)-C(9A) 1.541(3) C(29B)-H(29D) 0.9800 C(29B)-H(29E) 0.9800 C(29B)-H(29F) 0.9800 C(29B)-C(26B) 1.537(3) C(6B)-H(6BA) 0.9900 C(6B)-H(6BB) 0.9900 C(24A)-H(24A) 0.9800 C(24A)-H(24B) 0.9800 C(24A)-H(24C) 0.9800 C(24A)-C(22A) 1.534(3) C(22A)-C(23A) 1.530(3) C(22A)-C(25A) 1.535(4) C(27A)-H(27A) 0.9800 C(27A)-H(27B) 0.9800 C(27A)-H(27C) 0.9800 C(26B)-C(28B) 1.536(4) C(26B)-C(27B) 1.540(3) C(29A)-H(29A) 0.9800 C(29A)-H(29B) 0.9800 C(29A)-H(29C) 0.9800 C(9A)-H(9A) 1.0000 C(16A)-H(16A) 1.0000 409 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(7A)-H(7AA) 0.9900 C(7A)-H(7AB) 0.9900 C(28A)-H(28A) 0.9800 C(28A)-H(28B) 0.9800 C(28A)-H(28C) 0.9800 C(25B)-H(25D) 0.9800 C(25B)-H(25E) 0.9800 C(25B)-H(25F) 0.9800 C(23A)-H(23A) 0.9800 C(23A)-H(23B) 0.9800 C(23A)-H(23C) 0.9800 C(28B)-H(28D) 0.9800 C(28B)-H(28E) 0.9800 C(28B)-H(28F) 0.9800 C(21A)-H(21A) 0.9800 C(21A)-H(21B) 0.9800 C(21A)-H(21C) 0.9800 C(21B)-H(21D) 0.9800 C(21B)-H(21E) 0.9800 C(21B)-H(21F) 0.9800 C(23B)-H(23D) 0.9800 C(23B)-H(23E) 0.9800 C(23B)-H(23F) 0.9800 C(27B)-H(27D) 0.9800 C(27B)-H(27E) 0.9800 C(27B)-H(27F) 0.9800 C(20B)-H(20D) 0.9800 C(20B)-H(20E) 0.9800 C(20B)-H(20F) 0.9800 C(25A)-H(25A) 0.9800 C(25A)-H(25B) 0.9800 C(25A)-H(25C) 0.9800 O(4A)-Si(1A)-C(26A) 112.20(9) O(4A)-Si(1A)-C(22A) 108.76(9) 410 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 O(3A)-Si(1A)-O(4A) 105.86(8) O(3A)-Si(1A)-C(26A) 106.49(9) O(3A)-Si(1A)-C(22A) 109.19(10) C(26A)-Si(1A)-C(22A) 113.97(10) O(3B)-Si(1B)-O(4B) 105.73(8) O(3B)-Si(1B)-C(22B) 110.10(10) O(3B)-Si(1B)-C(26B) 107.11(9) O(4B)-Si(1B)-C(22B) 107.86(9) O(4B)-Si(1B)-C(26B) 111.64(10) C(26B)-Si(1B)-C(22B) 114.08(10) C(18A)-O(6A)-C(20A) 115.06(17) C(17B)-O(1B)-H(1B) 106(3) C(19A)-O(8A)-C(21A) 114.45(18) C(16A)-O(4A)-Si(1A) 118.14(13) C(11B)-O(2B)-C(1B) 60.20(13) C(14B)-O(3B)-Si(1B) 123.88(13) C(18B)-O(6B)-C(20B) 115.11(18) C(17A)-O(1A)-H(1A) 105(3) C(14A)-O(3A)-Si(1A) 123.61(13) C(19B)-O(8B)-C(21B) 115.03(19) C(11A)-O(2A)-C(1A) 60.20(13) C(16B)-O(4B)-Si(1B) 118.41(13) O(6A)-C(18A)-C(4A) 112.17(17) O(5A)-C(18A)-O(6A) 123.8(2) O(5A)-C(18A)-C(4A) 123.99(19) H(2AA)-C(2A)-H(2AB) 107.4 C(3A)-C(2A)-H(2AA) 108.4 C(3A)-C(2A)-H(2AB) 108.4 C(1A)-C(2A)-H(2AA) 108.4 C(1A)-C(2A)-H(2AB) 108.4 C(1A)-C(2A)-C(3A) 115.70(17) O(6B)-C(18B)-C(4B) 113.06(18) O(5B)-C(18B)-O(6B) 124.0(2) O(5B)-C(18B)-C(4B) 122.9(2) O(3B)-C(14B)-H(14B) 109.5 411 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 O(3B)-C(14B)-C(13B) 115.46(17) O(3B)-C(14B)-C(9B) 113.19(16) C(13B)-C(14B)-H(14B) 109.5 C(9B)-C(14B)-H(14B) 109.5 C(9B)-C(14B)-C(13B) 99.29(16) O(7A)-C(19A)-O(8A) 123.59(19) O(7A)-C(19A)-C(4A) 124.09(19) O(8A)-C(19A)-C(4A) 112.29(18) C(18A)-C(4A)-C(19A) 107.48(17) C(18A)-C(4A)-C(3A) 109.07(16) C(18A)-C(4A)-C(5A) 107.81(16) C(19A)-C(4A)-C(3A) 113.54(17) C(19A)-C(4A)-C(5A) 112.63(17) C(5A)-C(4A)-C(3A) 106.15(17) C(8A)-C(15A)-H(15A) 118.9 C(8A)-C(15A)-C(16A) 122.13(19) C(16A)-C(15A)-H(15A) 118.9 O(7B)-C(19B)-O(8B) 123.9(2) O(7B)-C(19B)-C(4B) 124.64(19) O(8B)-C(19B)-C(4B) 111.40(18) C(10B)-C(12B)-H(12B) 124.6 C(10B)-C(12B)-C(13B) 110.84(18) C(13B)-C(12B)-H(12B) 124.6 C(12A)-C(13A)-H(13A) 111.7 C(12A)-C(13A)-C(14A) 99.69(16) C(12A)-C(13A)-C(16A) 114.18(16) C(14A)-C(13A)-H(13A) 111.7 C(16A)-C(13A)-H(13A) 111.7 C(16A)-C(13A)-C(14A) 107.09(16) C(13A)-C(12A)-H(12A) 124.7 C(10A)-C(12A)-C(13A) 110.53(18) C(10A)-C(12A)-H(12A) 124.7 H(7BA)-C(7B)-H(7BB) 108.7 C(17B)-C(7B)-H(7BA) 110.5 C(17B)-C(7B)-H(7BB) 110.5 412 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(17B)-C(7B)-C(6B) 105.93(16) C(6B)-C(7B)-H(7BA) 110.5 C(6B)-C(7B)-H(7BB) 110.5 H(3BA)-C(3B)-H(3BB) 107.6 C(4B)-C(3B)-H(3BA) 108.7 C(4B)-C(3B)-H(3BB) 108.7 C(2B)-C(3B)-H(3BA) 108.7 C(2B)-C(3B)-H(3BB) 108.7 C(2B)-C(3B)-C(4B) 114.22(17) C(18B)-C(4B)-C(19B) 108.01(17) C(18B)-C(4B)-C(3B) 106.28(17) C(18B)-C(4B)-C(5B) 108.28(16) C(19B)-C(4B)-C(3B) 113.80(17) C(19B)-C(4B)-C(5B) 113.97(16) C(5B)-C(4B)-C(3B) 106.13(16) O(1B)-C(17B)-C(7B) 114.45(16) O(1B)-C(17B)-C(10B) 106.65(16) O(1B)-C(17B)-C(11B) 112.85(16) C(10B)-C(17B)-C(7B) 113.59(17) C(10B)-C(17B)-C(11B) 109.95(16) C(11B)-C(17B)-C(7B) 99.36(15) C(12B)-C(10B)-C(17B) 128.58(19) C(12B)-C(10B)-C(9B) 108.26(18) C(17B)-C(10B)-C(9B) 123.03(17) C(3B)-C(2B)-H(2BA) 108.6 C(3B)-C(2B)-H(2BB) 108.6 H(2BA)-C(2B)-H(2BB) 107.6 C(1B)-C(2B)-C(3B) 114.73(17) C(1B)-C(2B)-H(2BA) 108.6 C(1B)-C(2B)-H(2BB) 108.6 C(16B)-C(15B)-H(15B) 119.1 C(8B)-C(15B)-H(15B) 119.1 C(8B)-C(15B)-C(16B) 121.8(2) C(2A)-C(3A)-C(4A) 114.13(17) C(2A)-C(3A)-H(3AA) 108.7 413 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(2A)-C(3A)-H(3AB) 108.7 C(4A)-C(3A)-H(3AA) 108.7 C(4A)-C(3A)-H(3AB) 108.7 H(3AA)-C(3A)-H(3AB) 107.6 C(15A)-C(8A)-H(8A) 119.8 C(15A)-C(8A)-C(9A) 120.46(19) C(9A)-C(8A)-H(8A) 119.8 C(27A)-C(26A)-Si(1A) 109.86(16) C(27A)-C(26A)-C(29A) 107.4(2) C(29A)-C(26A)-Si(1A) 112.31(16) C(28A)-C(26A)-Si(1A) 110.04(16) C(28A)-C(26A)-C(27A) 107.91(19) C(28A)-C(26A)-C(29A) 109.2(2) C(4B)-C(5B)-H(5B) 106.5 C(4B)-C(5B)-C(6B) 121.77(17) C(11B)-C(5B)-C(4B) 110.98(16) C(11B)-C(5B)-H(5B) 106.5 C(11B)-C(5B)-C(6B) 103.55(16) C(6B)-C(5B)-H(5B) 106.5 O(6A)-C(20A)-H(20A) 109.5 O(6A)-C(20A)-H(20B) 109.5 O(6A)-C(20A)-H(20C) 109.5 H(20A)-C(20A)-H(20B) 109.5 H(20A)-C(20A)-H(20C) 109.5 H(20B)-C(20A)-H(20C) 109.5 O(2B)-C(1B)-C(2B) 113.35(18) O(2B)-C(1B)-H(1BA) 117.1 C(2B)-C(1B)-H(1BA) 117.1 C(11B)-C(1B)-O(2B) 59.47(13) C(11B)-C(1B)-C(2B) 119.65(18) C(11B)-C(1B)-H(1BA) 117.1 O(2B)-C(11B)-C(17B) 114.71(16) O(2B)-C(11B)-C(5B) 115.82(16) O(2B)-C(11B)-C(1B) 60.33(13) C(5B)-C(11B)-C(17B) 106.44(16) 414 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(1B)-C(11B)-C(17B) 128.31(18) C(1B)-C(11B)-C(5B) 122.08(17) O(2A)-C(1A)-C(2A) 115.00(18) O(2A)-C(1A)-H(1AA) 116.7 C(2A)-C(1A)-H(1AA) 116.7 C(11A)-C(1A)-O(2A) 59.21(13) C(11A)-C(1A)-C(2A) 119.75(19) C(11A)-C(1A)-H(1AA) 116.7 C(14B)-C(13B)-H(13B) 112.0 C(12B)-C(13B)-C(14B) 100.18(17) C(12B)-C(13B)-H(13B) 112.0 C(12B)-C(13B)-C(16B) 113.05(17) C(16B)-C(13B)-C(14B) 106.88(17) C(16B)-C(13B)-H(13B) 112.0 O(1A)-C(17A)-C(11A) 113.37(17) O(1A)-C(17A)-C(10A) 106.75(17) O(1A)-C(17A)-C(7A) 114.45(17) C(11A)-C(17A)-C(7A) 100.62(16) C(10A)-C(17A)-C(11A) 108.91(17) C(10A)-C(17A)-C(7A) 112.71(17) C(14B)-C(9B)-H(9B) 113.6 C(10B)-C(9B)-C(14B) 99.43(16) C(10B)-C(9B)-H(9B) 113.6 C(8B)-C(9B)-C(14B) 108.23(17) C(8B)-C(9B)-C(10B) 107.41(17) C(8B)-C(9B)-H(9B) 113.6 O(4B)-C(16B)-C(15B) 109.99(17) O(4B)-C(16B)-C(13B) 108.24(16) O(4B)-C(16B)-H(16B) 108.9 C(15B)-C(16B)-C(13B) 111.82(18) C(15B)-C(16B)-H(16B) 108.9 C(13B)-C(16B)-H(16B) 108.9 H(24D)-C(24B)-H(24E) 109.5 H(24D)-C(24B)-H(24F) 109.5 H(24E)-C(24B)-H(24F) 109.5 415 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(22B)-C(24B)-H(24D) 109.5 C(22B)-C(24B)-H(24E) 109.5 C(22B)-C(24B)-H(24F) 109.5 H(6AA)-C(6A)-H(6AB) 108.8 C(5A)-C(6A)-H(6AA) 110.7 C(5A)-C(6A)-H(6AB) 110.7 C(5A)-C(6A)-C(7A) 105.37(16) C(7A)-C(6A)-H(6AA) 110.7 C(7A)-C(6A)-H(6AB) 110.7 O(2A)-C(11A)-C(1A) 60.59(13) O(2A)-C(11A)-C(17A) 116.03(17) O(2A)-C(11A)-C(5A) 115.59(17) C(1A)-C(11A)-C(17A) 129.30(19) C(1A)-C(11A)-C(5A) 120.87(18) C(5A)-C(11A)-C(17A) 106.12(16) C(4A)-C(5A)-C(6A) 120.71(17) C(4A)-C(5A)-H(5A) 106.5 C(6A)-C(5A)-H(5A) 106.5 C(11A)-C(5A)-C(4A) 110.91(16) C(11A)-C(5A)-C(6A) 104.79(16) C(11A)-C(5A)-H(5A) 106.5 C(15B)-C(8B)-C(9B) 120.95(18) C(15B)-C(8B)-H(8B) 119.5 C(9B)-C(8B)-H(8B) 119.5 C(24B)-C(22B)-Si(1B) 110.71(15) C(24B)-C(22B)-C(23B) 107.9(2) C(25B)-C(22B)-Si(1B) 112.58(18) C(25B)-C(22B)-C(24B) 109.5(2) C(25B)-C(22B)-C(23B) 107.7(2) C(23B)-C(22B)-Si(1B) 108.20(16) C(12A)-C(10A)-C(17A) 128.24(19) C(12A)-C(10A)-C(9A) 108.72(18) C(17A)-C(10A)-C(9A) 122.89(18) O(3A)-C(14A)-C(13A) 114.88(17) O(3A)-C(14A)-H(14A) 109.5 416 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 O(3A)-C(14A)-C(9A) 113.71(16) C(13A)-C(14A)-H(14A) 109.5 C(9A)-C(14A)-C(13A) 99.37(16) C(9A)-C(14A)-H(14A) 109.5 H(29D)-C(29B)-H(29E) 109.5 H(29D)-C(29B)-H(29F) 109.5 H(29E)-C(29B)-H(29F) 109.5 C(26B)-C(29B)-H(29D) 109.5 C(26B)-C(29B)-H(29E) 109.5 C(26B)-C(29B)-H(29F) 109.5 C(7B)-C(6B)-C(5B) 105.40(16) C(7B)-C(6B)-H(6BA) 110.7 C(7B)-C(6B)-H(6BB) 110.7 C(5B)-C(6B)-H(6BA) 110.7 C(5B)-C(6B)-H(6BB) 110.7 H(6BA)-C(6B)-H(6BB) 108.8 H(24A)-C(24A)-H(24B) 109.5 H(24A)-C(24A)-H(24C) 109.5 H(24B)-C(24A)-H(24C) 109.5 C(22A)-C(24A)-H(24A) 109.5 C(22A)-C(24A)-H(24B) 109.5 C(22A)-C(24A)-H(24C) 109.5 C(24A)-C(22A)-Si(1A) 109.78(15) C(24A)-C(22A)-C(25A) 110.2(2) C(23A)-C(22A)-Si(1A) 109.42(15) C(23A)-C(22A)-C(24A) 107.0(2) C(23A)-C(22A)-C(25A) 107.3(2) C(25A)-C(22A)-Si(1A) 112.99(17) C(26A)-C(27A)-H(27A) 109.5 C(26A)-C(27A)-H(27B) 109.5 C(26A)-C(27A)-H(27C) 109.5 H(27A)-C(27A)-H(27B) 109.5 H(27A)-C(27A)-H(27C) 109.5 H(27B)-C(27A)-H(27C) 109.5 C(29B)-C(26B)-Si(1B) 111.03(16) 417 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(29B)-C(26B)-C(27B) 106.9(2) C(28B)-C(26B)-Si(1B) 111.06(16) C(28B)-C(26B)-C(29B) 110.13(19) C(28B)-C(26B)-C(27B) 107.4(2) C(27B)-C(26B)-Si(1B) 110.16(16) C(26A)-C(29A)-H(29A) 109.5 C(26A)-C(29A)-H(29B) 109.5 C(26A)-C(29A)-H(29C) 109.5 H(29A)-C(29A)-H(29B) 109.5 H(29A)-C(29A)-H(29C) 109.5 H(29B)-C(29A)-H(29C) 109.5 C(8A)-C(9A)-C(10A) 108.19(17) C(8A)-C(9A)-C(14A) 108.27(17) C(8A)-C(9A)-H(9A) 113.4 C(10A)-C(9A)-C(14A) 99.01(16) C(10A)-C(9A)-H(9A) 113.4 C(14A)-C(9A)-H(9A) 113.4 O(4A)-C(16A)-C(15A) 110.26(16) O(4A)-C(16A)-C(13A) 108.11(16) O(4A)-C(16A)-H(16A) 108.9 C(15A)-C(16A)-C(13A) 111.62(17) C(15A)-C(16A)-H(16A) 108.9 C(13A)-C(16A)-H(16A) 108.9 C(17A)-C(7A)-C(6A) 107.01(17) C(17A)-C(7A)-H(7AA) 110.3 C(17A)-C(7A)-H(7AB) 110.3 C(6A)-C(7A)-H(7AA) 110.3 C(6A)-C(7A)-H(7AB) 110.3 H(7AA)-C(7A)-H(7AB) 108.6 C(26A)-C(28A)-H(28A) 109.5 C(26A)-C(28A)-H(28B) 109.5 C(26A)-C(28A)-H(28C) 109.5 H(28A)-C(28A)-H(28B) 109.5 H(28A)-C(28A)-H(28C) 109.5 H(28B)-C(28A)-H(28C) 109.5 418 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(22B)-C(25B)-H(25D) 109.5 C(22B)-C(25B)-H(25E) 109.5 C(22B)-C(25B)-H(25F) 109.5 H(25D)-C(25B)-H(25E) 109.5 H(25D)-C(25B)-H(25F) 109.5 H(25E)-C(25B)-H(25F) 109.5 C(22A)-C(23A)-H(23A) 109.5 C(22A)-C(23A)-H(23B) 109.5 C(22A)-C(23A)-H(23C) 109.5 H(23A)-C(23A)-H(23B) 109.5 H(23A)-C(23A)-H(23C) 109.5 H(23B)-C(23A)-H(23C) 109.5 C(26B)-C(28B)-H(28D) 109.5 C(26B)-C(28B)-H(28E) 109.5 C(26B)-C(28B)-H(28F) 109.5 H(28D)-C(28B)-H(28E) 109.5 H(28D)-C(28B)-H(28F) 109.5 H(28E)-C(28B)-H(28F) 109.5 O(8A)-C(21A)-H(21A) 109.5 O(8A)-C(21A)-H(21B) 109.5 O(8A)-C(21A)-H(21C) 109.5 H(21A)-C(21A)-H(21B) 109.5 H(21A)-C(21A)-H(21C) 109.5 H(21B)-C(21A)-H(21C) 109.5 O(8B)-C(21B)-H(21D) 109.5 O(8B)-C(21B)-H(21E) 109.5 O(8B)-C(21B)-H(21F) 109.5 H(21D)-C(21B)-H(21E) 109.5 H(21D)-C(21B)-H(21F) 109.5 H(21E)-C(21B)-H(21F) 109.5 C(22B)-C(23B)-H(23D) 109.5 C(22B)-C(23B)-H(23E) 109.5 C(22B)-C(23B)-H(23F) 109.5 H(23D)-C(23B)-H(23E) 109.5 H(23D)-C(23B)-H(23F) 109.5 419 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 H(23E)-C(23B)-H(23F) 109.5 C(26B)-C(27B)-H(27D) 109.5 C(26B)-C(27B)-H(27E) 109.5 C(26B)-C(27B)-H(27F) 109.5 H(27D)-C(27B)-H(27E) 109.5 H(27D)-C(27B)-H(27F) 109.5 H(27E)-C(27B)-H(27F) 109.5 O(6B)-C(20B)-H(20D) 109.5 O(6B)-C(20B)-H(20E) 109.5 O(6B)-C(20B)-H(20F) 109.5 H(20D)-C(20B)-H(20E) 109.5 H(20D)-C(20B)-H(20F) 109.5 H(20E)-C(20B)-H(20F) 109.5 C(22A)-C(25A)-H(25A) 109.5 C(22A)-C(25A)-H(25B) 109.5 C(22A)-C(25A)-H(25C) 109.5 H(25A)-C(25A)-H(25B) 109.5 H(25A)-C(25A)-H(25C) 109.5 H(25B)-C(25A)-H(25C) 109.5 _____________________________________________________________ 420 421 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.4. Anisotropic displacement parameters (Å2 x 103) for epoxy alcohol 262. The anisotropic displacement factor exponent takes the form: -2π2[h2 a*2U11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ Si(1A) 12(1) 12(1) 19(1) -1(1) 5(1) 0(1) Si(1B) 14(1) 12(1) 19(1) 1(1) 6(1) -1(1) O(6A) 19(1) 24(1) 14(1) -3(1) 3(1) -6(1) O(7A) 21(1) 19(1) 15(1) 2(1) 1(1) -1(1) O(1B) 16(1) 18(1) 15(1) 2(1) -2(1) -2(1) O(5A) 21(1) 21(1) 14(1) 0(1) 5(1) 0(1) O(8A) 15(1) 33(1) 13(1) 4(1) 4(1) -1(1) O(4A) 16(1) 14(1) 15(1) 1(1) 4(1) -2(1) O(2B) 18(1) 18(1) 11(1) -1(1) 4(1) 3(1) O(3B) 20(1) 10(1) 20(1) -1(1) 3(1) -1(1) O(6B) 22(1) 31(1) 14(1) 0(1) -2(1) -11(1) O(7B) 19(1) 19(1) 16(1) 5(1) 4(1) 1(1) O(1A) 23(1) 22(1) 13(1) -1(1) 0(1) -3(1) O(3A) 18(1) 11(1) 18(1) -2(1) 3(1) -2(1) O(8B) 19(1) 31(1) 19(1) 6(1) 9(1) 5(1) O(2A) 18(1) 19(1) 13(1) 1(1) 5(1) 2(1) O(4B) 22(1) 14(1) 17(1) 2(1) 5(1) -4(1) O(5B) 43(1) 47(1) 12(1) 7(1) -6(1) -21(1) C(18A) 14(1) 16(1) 12(1) 2(1) -1(1) 3(1) C(2A) 18(1) 20(1) 19(1) 0(1) 5(1) 6(1) C(18B) 15(1) 19(1) 14(1) 1(1) -2(1) 0(1) C(14B) 15(1) 12(1) 17(1) 0(1) 2(1) -1(1) C(19A) 16(1) 19(1) 11(1) -2(1) 1(1) -5(1) C(4A) 12(1) 16(1) 11(1) 0(1) 2(1) 1(1) C(15A) 10(1) 15(1) 21(1) 1(1) 4(1) -1(1) C(19B) 12(1) 22(1) 11(1) 2(1) 0(1) -1(1) C(12B) 12(1) 12(1) 20(1) 0(1) 4(1) 2(1) C(13A) 12(1) 12(1) 16(1) -1(1) 4(1) -1(1) C(12A) 14(1) 12(1) 18(1) 1(1) 3(1) 0(1) 422 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(7B) 14(1) 13(1) 16(1) 1(1) 4(1) 2(1) C(3B) 14(1) 20(1) 18(1) 1(1) 1(1) 5(1) C(4B) 14(1) 16(1) 10(1) 1(1) 0(1) 1(1) C(17B) 12(1) 13(1) 12(1) 1(1) 1(1) 1(1) C(10B) 10(1) 11(1) 16(1) 1(1) 0(1) 1(1) C(2B) 19(1) 20(1) 21(1) -5(1) 6(1) 5(1) C(15B) 13(1) 14(1) 24(1) 4(1) 3(1) -1(1) C(3A) 16(1) 21(1) 13(1) 1(1) 2(1) 4(1) C(8A) 17(1) 13(1) 20(1) 3(1) 6(1) 3(1) C(26A) 16(1) 16(1) 27(1) 3(1) 9(1) 3(1) C(5B) 14(1) 12(1) 9(1) 0(1) 3(1) 0(1) C(20A) 25(1) 26(1) 17(1) -6(1) 1(1) -6(1) C(1B) 17(1) 15(1) 13(1) -3(1) 2(1) 2(1) C(11B) 13(1) 13(1) 9(1) 0(1) 1(1) 1(1) C(1A) 18(1) 16(1) 14(1) 1(1) 5(1) 3(1) C(13B) 16(1) 12(1) 17(1) 0(1) 6(1) 0(1) C(17A) 16(1) 16(1) 12(1) 1(1) 2(1) 2(1) C(9B) 19(1) 12(1) 14(1) -1(1) 5(1) 0(1) C(16B) 18(1) 14(1) 15(1) 0(1) 3(1) -4(1) C(24B) 21(1) 22(1) 44(2) -5(1) 12(1) -5(1) C(6A) 15(1) 14(1) 22(1) -1(1) 4(1) 2(1) C(11A) 14(1) 15(1) 12(1) 1(1) 4(1) 1(1) C(5A) 13(1) 14(1) 13(1) 0(1) 4(1) 2(1) C(8B) 15(1) 12(1) 23(1) 3(1) 7(1) 3(1) C(22B) 18(1) 17(1) 34(1) -2(1) 14(1) -2(1) C(10A) 13(1) 14(1) 16(1) 1(1) 1(1) 1(1) C(14A) 14(1) 12(1) 17(1) -1(1) 1(1) 0(1) C(29B) 29(1) 18(1) 31(1) 6(1) 3(1) -1(1) C(6B) 17(1) 14(1) 14(1) -4(1) 5(1) 1(1) C(24A) 18(1) 18(1) 47(2) -4(1) 11(1) -4(1) C(22A) 16(1) 16(1) 30(1) -1(1) 9(1) -1(1) C(27A) 16(1) 24(1) 48(2) 6(1) 9(1) 4(1) C(26B) 16(1) 16(1) 29(1) 6(1) 9(1) 1(1) C(29A) 28(1) 30(1) 35(2) 14(1) 10(1) 10(1) C(9A) 19(1) 14(1) 14(1) -2(1) 4(1) 1(1) 423 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(16A) 14(1) 12(1) 14(1) -1(1) 5(1) -2(1) C(7A) 16(1) 16(1) 16(1) 2(1) 2(1) 4(1) C(28A) 32(1) 16(1) 37(2) -2(1) 16(1) 3(1) C(25B) 45(2) 27(1) 40(2) -4(1) 30(1) -5(1) C(23A) 17(1) 19(1) 63(2) 6(1) 18(1) 2(1) C(28B) 32(1) 17(1) 34(1) 2(1) 16(1) 6(1) C(21A) 19(1) 55(2) 16(1) 10(1) 5(1) -3(1) C(21B) 37(2) 49(2) 30(2) 17(1) 20(1) 7(1) C(23B) 19(1) 24(1) 67(2) 2(1) 22(1) 3(1) C(27B) 17(1) 22(1) 65(2) 12(1) 16(1) 4(1) C(20B) 27(1) 44(2) 20(1) -5(1) -5(1) -14(1) C(25A) 31(1) 40(2) 36(2) -3(1) 20(1) -2(1) ______________________________________________________________________________ 424 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.5. Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2 x 103) for epoxy alcohol 262. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ H(2AA) 5782 5345 3220 23 H(2AB) 5389 4935 4044 23 H(14B) 2029 4636 8763 18 H(15A) 3130 4471 6103 18 H(12B) 3241 5833 9851 17 H(13A) -1621 4812 5674 16 H(12A) -738 5628 4894 17 H(7BA) 3474 6448 8743 17 H(7BB) 4233 6646 7812 17 H(3BA) 10483 5609 8664 22 H(3BB) 9273 5324 9234 22 H(2BA) 9077 5437 7117 23 H(2BB) 8733 4915 7723 23 H(15B) 7081 4652 10784 21 H(3AA) 6420 5858 4591 20 H(3AB) 5208 5575 5164 20 H(8A) 2848 4339 4408 19 H(5B) 7006 5759 9494 14 H(20A) 6811 7578 5783 35 H(20B) 6345 7144 6547 35 H(20C) 5056 7538 5933 35 H(1BA) 6197 5126 6979 18 H(1AA) 3121 4861 2824 19 H(13B) 2317 4971 10444 18 H(9B) 4264 4675 7979 18 H(16B) 4995 5072 11423 19 H(24D) 908 3160 9700 42 H(24E) -116 3064 10543 42 H(24F) 1571 2801 10678 42 425 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 H(6AA) 1414 6714 3675 20 H(6AB) 783 6435 4594 20 H(5A) 2552 5797 4799 16 H(8B) 6772 4611 9078 19 H(14A) -1895 4385 4072 17 H(29D) 5339 3128 12267 39 H(29E) 5824 2604 11720 39 H(29F) 4033 2727 11694 39 H(6BA) 5773 6485 9851 18 H(6BB) 6359 6843 9006 18 H(24A) -3156 3041 5218 40 H(24B) -4143 2970 6089 40 H(24C) -2454 2708 6223 40 H(27A) 2738 3412 5789 43 H(27B) 3300 2918 6531 43 H(27C) 2884 3479 6989 43 H(29A) 1051 2973 7875 46 H(29B) 1554 2437 7372 46 H(29C) -241 2591 7227 46 H(9A) 343 4359 3296 18 H(16A) 1049 4955 6634 15 H(7AA) -1105 6072 3408 20 H(7AB) -252 6246 2506 20 H(28A) -538 2546 5327 41 H(28B) 1243 2369 5496 41 H(28C) 637 2870 4782 41 H(25D) 2402 3203 12350 52 H(25E) 781 3500 12311 52 H(25F) 2360 3837 12515 52 H(23A) -3070 4327 6385 47 H(23B) -4503 3919 6210 47 H(23C) -3565 4020 5323 47 H(28D) 3444 2687 9772 39 H(28E) 5227 2545 9807 39 H(28F) 4442 3042 9146 39 426 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 H(21A) 5044 6470 1477 44 H(21B) 6884 6496 1864 44 H(21C) 5826 6992 2055 44 H(21D) 9439 6837 6301 55 H(21E) 11246 6695 6605 55 H(21F) 10533 7154 7207 55 H(23D) 893 4405 11099 52 H(23E) -510 3990 10799 52 H(23F) 459 4172 9967 52 H(27D) 6599 3608 10055 51 H(27E) 7311 3104 10728 51 H(27F) 6946 3647 11269 51 H(20D) 12329 7099 10730 47 H(20E) 12038 6530 11210 47 H(20F) 10851 7013 11239 47 H(25A) -1696 3184 7894 51 H(25B) -3343 3476 7755 51 H(25C) -1783 3823 7943 51 H(1B) 3550(40) 5932(15) 6710(30) 51 H(1A) 10(40) 5430(15) 1780(30) 51 ________________________________________________________________________________ Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.6. Torsion angles [°] for epoxy alcohol 262. ________________________________________________________________ Si(1A)-O(4A)-C(16A)-C(15A) -71.36(19) Si(1A)-O(4A)-C(16A)-C(13A) 50.91(18) Si(1A)-O(3A)-C(14A)-C(13A) 4.5(2) Si(1A)-O(3A)-C(14A)-C(9A) 118.06(17) Si(1B)-O(3B)-C(14B)-C(13B) 3.5(2) Si(1B)-O(3B)-C(14B)-C(9B) 116.99(17) Si(1B)-O(4B)-C(16B)-C(15B) -71.0(2) Si(1B)-O(4B)-C(16B)-C(13B) 51.4(2) O(6A)-C(18A)-C(4A)-C(19A) -38.0(2) O(6A)-C(18A)-C(4A)-C(3A) 85.5(2) O(6A)-C(18A)-C(4A)-C(5A) -159.66(17) O(7A)-C(19A)-C(4A)-C(18A) -68.7(3) O(7A)-C(19A)-C(4A)-C(3A) 170.5(2) O(7A)-C(19A)-C(4A)-C(5A) 49.9(3) O(1B)-C(17B)-C(10B)-C(12B) -117.6(2) O(1B)-C(17B)-C(10B)-C(9B) 67.1(2) O(1B)-C(17B)-C(11B)-O(2B) 36.7(2) O(1B)-C(17B)-C(11B)-C(5B) 166.21(16) O(1B)-C(17B)-C(11B)-C(1B) -33.9(3) O(5A)-C(18A)-C(4A)-C(19A) 142.1(2) O(5A)-C(18A)-C(4A)-C(3A) -94.5(2) O(5A)-C(18A)-C(4A)-C(5A) 20.4(3) O(8A)-C(19A)-C(4A)-C(18A) 109.53(19) O(8A)-C(19A)-C(4A)-C(3A) -11.2(2) O(8A)-C(19A)-C(4A)-C(5A) -131.87(18) O(4A)-Si(1A)-O(3A)-C(14A) -26.29(16) O(4A)-Si(1A)-C(26A)-C(27A) -34.4(2) O(4A)-Si(1A)-C(26A)-C(29A) 85.08(18) O(4A)-Si(1A)-C(26A)-C(28A) -153.06(14) O(2B)-C(1B)-C(11B)-C(17B) 99.4(2) O(2B)-C(1B)-C(11B)-C(5B) -103.6(2) O(3B)-Si(1B)-O(4B)-C(16B) -4.46(16) O(3B)-Si(1B)-C(22B)-C(24B) 71.23(19) 427 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 O(3B)-Si(1B)-C(22B)-C(25B) -165.81(16) O(3B)-Si(1B)-C(22B)-C(23B) -46.8(2) O(3B)-Si(1B)-C(26B)-C(29B) -167.99(15) O(3B)-Si(1B)-C(26B)-C(28B) -45.10(17) O(3B)-Si(1B)-C(26B)-C(27B) 73.8(2) O(3B)-C(14B)-C(13B)-C(12B) 163.40(16) O(3B)-C(14B)-C(13B)-C(16B) 45.3(2) O(3B)-C(14B)-C(9B)-C(10B) -167.12(17) O(3B)-C(14B)-C(9B)-C(8B) -55.2(2) O(6B)-C(18B)-C(4B)-C(19B) -18.9(2) O(6B)-C(18B)-C(4B)-C(3B) 103.6(2) O(6B)-C(18B)-C(4B)-C(5B) -142.76(18) O(7B)-C(19B)-C(4B)-C(18B) -76.6(3) O(7B)-C(19B)-C(4B)-C(3B) 165.7(2) O(7B)-C(19B)-C(4B)-C(5B) 43.8(3) O(1A)-C(17A)-C(11A)-O(2A) 33.4(2) O(1A)-C(17A)-C(11A)-C(1A) -38.8(3) O(1A)-C(17A)-C(11A)-C(5A) 163.26(17) O(1A)-C(17A)-C(10A)-C(12A) -135.8(2) O(1A)-C(17A)-C(10A)-C(9A) 49.0(2) O(1A)-C(17A)-C(7A)-C(6A) -153.31(18) O(3A)-Si(1A)-O(4A)-C(16A) -3.15(15) O(3A)-Si(1A)-C(26A)-C(27A) 80.99(19) O(3A)-Si(1A)-C(26A)-C(29A) -159.54(17) O(3A)-Si(1A)-C(26A)-C(28A) -37.68(17) O(3A)-C(14A)-C(9A)-C(8A) -54.5(2) O(3A)-C(14A)-C(9A)-C(10A) -167.18(17) O(8B)-C(19B)-C(4B)-C(18B) 99.9(2) O(8B)-C(19B)-C(4B)-C(3B) -17.8(2) O(8B)-C(19B)-C(4B)-C(5B) -139.69(18) O(2A)-C(1A)-C(11A)-C(17A) 100.9(2) O(2A)-C(1A)-C(11A)-C(5A) -103.9(2) O(2A)-C(11A)-C(5A)-C(4A) -36.0(2) O(2A)-C(11A)-C(5A)-C(6A) 95.80(19) O(4B)-Si(1B)-O(3B)-C(14B) -24.72(17) 428 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 O(4B)-Si(1B)-C(22B)-C(24B) -173.86(17) O(4B)-Si(1B)-C(22B)-C(25B) -50.90(19) O(4B)-Si(1B)-C(22B)-C(23B) 68.1(2) O(4B)-Si(1B)-C(26B)-C(29B) 76.71(17) O(4B)-Si(1B)-C(26B)-C(28B) -160.39(14) O(4B)-Si(1B)-C(26B)-C(27B) -41.5(2) O(5B)-C(18B)-C(4B)-C(19B) 163.3(2) O(5B)-C(18B)-C(4B)-C(3B) -74.2(3) O(5B)-C(18B)-C(4B)-C(5B) 39.4(3) C(18A)-C(4A)-C(3A)-C(2A) 175.82(17) C(18A)-C(4A)-C(5A)-C(6A) 59.5(2) C(18A)-C(4A)-C(5A)-C(11A) -177.49(17) C(2A)-C(1A)-C(11A)-O(2A) 103.1(2) C(2A)-C(1A)-C(11A)-C(17A) -156.0(2) C(2A)-C(1A)-C(11A)-C(5A) -0.9(3) C(18B)-C(4B)-C(5B)-C(11B) -171.67(17) C(18B)-C(4B)-C(5B)-C(6B) 66.1(2) C(14B)-C(13B)-C(16B)-O(4B) -73.0(2) C(14B)-C(13B)-C(16B)-C(15B) 48.3(2) C(14B)-C(9B)-C(8B)-C(15B) -34.7(3) C(19A)-C(4A)-C(3A)-C(2A) -64.4(2) C(19A)-C(4A)-C(5A)-C(6A) -58.9(2) C(19A)-C(4A)-C(5A)-C(11A) 64.1(2) C(15A)-C(8A)-C(9A)-C(10A) 71.8(2) C(15A)-C(8A)-C(9A)-C(14A) -34.6(3) C(19B)-C(4B)-C(5B)-C(11B) 68.1(2) C(19B)-C(4B)-C(5B)-C(6B) -54.1(3) C(12B)-C(10B)-C(9B)-C(14B) 31.2(2) C(12B)-C(10B)-C(9B)-C(8B) -81.4(2) C(12B)-C(13B)-C(16B)-O(4B) 177.69(16) C(12B)-C(13B)-C(16B)-C(15B) -61.0(2) C(13A)-C(12A)-C(10A)-C(17A) -179.08(19) C(13A)-C(12A)-C(10A)-C(9A) -3.3(2) C(13A)-C(14A)-C(9A)-C(8A) 68.04(19) C(13A)-C(14A)-C(9A)-C(10A) -44.62(18) 429 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(12A)-C(13A)-C(14A)-O(3A) 164.74(16) C(12A)-C(13A)-C(14A)-C(9A) 43.02(18) C(12A)-C(13A)-C(16A)-O(4A) 176.92(16) C(12A)-C(13A)-C(16A)-C(15A) -61.6(2) C(12A)-C(10A)-C(9A)-C(8A) -81.7(2) C(12A)-C(10A)-C(9A)-C(14A) 31.0(2) C(7B)-C(17B)-C(10B)-C(12B) 9.4(3) C(7B)-C(17B)-C(10B)-C(9B) -165.92(18) C(7B)-C(17B)-C(11B)-O(2B) -84.90(19) C(7B)-C(17B)-C(11B)-C(5B) 44.57(19) C(7B)-C(17B)-C(11B)-C(1B) -155.6(2) C(3B)-C(4B)-C(5B)-C(11B) -57.9(2) C(3B)-C(4B)-C(5B)-C(6B) 179.91(18) C(3B)-C(2B)-C(1B)-O(2B) 71.0(2) C(3B)-C(2B)-C(1B)-C(11B) 4.0(3) C(4B)-C(3B)-C(2B)-C(1B) -34.9(3) C(4B)-C(5B)-C(11B)-O(2B) -38.7(2) C(4B)-C(5B)-C(11B)-C(17B) -167.54(16) C(4B)-C(5B)-C(11B)-C(1B) 31.1(3) C(4B)-C(5B)-C(6B)-C(7B) 136.71(18) C(17B)-C(7B)-C(6B)-C(5B) 16.1(2) C(17B)-C(10B)-C(9B)-C(14B) -152.61(18) C(17B)-C(10B)-C(9B)-C(8B) 94.8(2) C(10B)-C(12B)-C(13B)-C(14B) -24.7(2) C(10B)-C(12B)-C(13B)-C(16B) 88.6(2) C(10B)-C(17B)-C(11B)-O(2B) 155.68(16) C(10B)-C(17B)-C(11B)-C(5B) -74.9(2) C(10B)-C(17B)-C(11B)-C(1B) 85.0(3) C(10B)-C(9B)-C(8B)-C(15B) 71.8(2) C(2B)-C(3B)-C(4B)-C(18B) 177.26(18) C(2B)-C(3B)-C(4B)-C(19B) -64.0(2) C(2B)-C(3B)-C(4B)-C(5B) 62.1(2) C(2B)-C(1B)-C(11B)-O(2B) 101.2(2) C(2B)-C(1B)-C(11B)-C(17B) -159.4(2) C(2B)-C(1B)-C(11B)-C(5B) -2.4(3) 430 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(3A)-C(2A)-C(1A)-O(2A) 65.8(2) C(3A)-C(2A)-C(1A)-C(11A) -1.7(3) C(3A)-C(4A)-C(5A)-C(6A) 176.26(18) C(3A)-C(4A)-C(5A)-C(11A) -60.7(2) C(8A)-C(15A)-C(16A)-O(4A) 110.1(2) C(8A)-C(15A)-C(16A)-C(13A) -10.1(3) C(26A)-Si(1A)-O(4A)-C(16A) 112.62(14) C(26A)-Si(1A)-O(3A)-C(14A) -145.88(15) C(20A)-O(6A)-C(18A)-O(5A) 0.0(3) C(20A)-O(6A)-C(18A)-C(4A) -179.93(18) C(1B)-O(2B)-C(11B)-C(17B) -121.5(2) C(1B)-O(2B)-C(11B)-C(5B) 113.8(2) C(11B)-O(2B)-C(1B)-C(2B) -111.8(2) C(11B)-C(17B)-C(10B)-C(12B) 119.8(2) C(11B)-C(17B)-C(10B)-C(9B) -55.6(2) C(11B)-C(5B)-C(6B)-C(7B) 11.1(2) C(1A)-O(2A)-C(11A)-C(17A) -122.3(2) C(1A)-O(2A)-C(11A)-C(5A) 112.5(2) C(1A)-C(2A)-C(3A)-C(4A) -29.0(3) C(1A)-C(11A)-C(5A)-C(4A) 33.7(3) C(1A)-C(11A)-C(5A)-C(6A) 165.43(18) C(13B)-C(14B)-C(9B)-C(10B) -44.17(18) C(13B)-C(14B)-C(9B)-C(8B) 67.79(19) C(13B)-C(12B)-C(10B)-C(17B) 180.00(19) C(13B)-C(12B)-C(10B)-C(9B) -4.1(2) C(17A)-C(11A)-C(5A)-C(4A) -166.14(17) C(17A)-C(11A)-C(5A)-C(6A) -34.4(2) C(17A)-C(10A)-C(9A)-C(8A) 94.4(2) C(17A)-C(10A)-C(9A)-C(14A) -152.92(19) C(9B)-C(14B)-C(13B)-C(12B) 42.08(18) C(9B)-C(14B)-C(13B)-C(16B) -75.97(19) C(16B)-C(15B)-C(8B)-C(9B) 4.2(3) C(11A)-O(2A)-C(1A)-C(2A) -111.1(2) C(11A)-C(17A)-C(10A)-C(12A) 101.4(2) C(11A)-C(17A)-C(10A)-C(9A) -73.8(2) 431 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(11A)-C(17A)-C(7A)-C(6A) -31.4(2) C(5A)-C(4A)-C(3A)-C(2A) 59.9(2) C(5A)-C(6A)-C(7A)-C(17A) 11.6(2) C(8B)-C(15B)-C(16B)-O(4B) 109.3(2) C(8B)-C(15B)-C(16B)-C(13B) -11.0(3) C(22B)-Si(1B)-O(3B)-C(14B) 91.53(17) C(22B)-Si(1B)-O(4B)-C(16B) -122.23(15) C(22B)-Si(1B)-C(26B)-C(29B) -45.9(2) C(22B)-Si(1B)-C(26B)-C(28B) 77.01(18) C(22B)-Si(1B)-C(26B)-C(27B) -164.13(19) C(10A)-C(17A)-C(11A)-O(2A) 152.03(17) C(10A)-C(17A)-C(11A)-C(1A) 79.9(3) C(10A)-C(17A)-C(11A)-C(5A) -78.1(2) C(10A)-C(17A)-C(7A)-C(6A) 84.5(2) C(14A)-C(13A)-C(12A)-C(10A) -25.7(2) C(14A)-C(13A)-C(16A)-O(4A) -73.74(19) C(14A)-C(13A)-C(16A)-C(15A) 47.7(2) C(6B)-C(7B)-C(17B)-O(1B) -156.67(16) C(6B)-C(7B)-C(17B)-C(10B) 80.5(2) C(6B)-C(7B)-C(17B)-C(11B) -36.19(19) C(6B)-C(5B)-C(11B)-O(2B) 93.54(19) C(6B)-C(5B)-C(11B)-C(17B) -35.28(19) C(6B)-C(5B)-C(11B)-C(1B) 163.32(18) C(22A)-Si(1A)-O(4A)-C(16A) -120.36(15) C(22A)-Si(1A)-O(3A)-C(14A) 90.64(16) C(22A)-Si(1A)-C(26A)-C(27A) -158.56(17) C(22A)-Si(1A)-C(26A)-C(29A) -39.1(2) C(22A)-Si(1A)-C(26A)-C(28A) 82.77(18) C(26B)-Si(1B)-O(3B)-C(14B) -143.91(16) C(26B)-Si(1B)-O(4B)-C(16B) 111.68(15) C(26B)-Si(1B)-C(22B)-C(24B) -49.2(2) C(26B)-Si(1B)-C(22B)-C(25B) 73.7(2) C(26B)-Si(1B)-C(22B)-C(23B) -167.30(18) C(16A)-C(15A)-C(8A)-C(9A) 3.5(3) C(16A)-C(13A)-C(12A)-C(10A) 88.1(2) 432 433 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(16A)-C(13A)-C(14A)-O(3A) 45.6(2) C(16A)-C(13A)-C(14A)-C(9A) -76.15(18) C(7A)-C(17A)-C(11A)-O(2A) -89.3(2) C(7A)-C(17A)-C(11A)-C(1A) -161.5(2) C(7A)-C(17A)-C(11A)-C(5A) 40.6(2) C(7A)-C(17A)-C(10A)-C(12A) -9.3(3) C(7A)-C(17A)-C(10A)-C(9A) 175.45(18) C(7A)-C(6A)-C(5A)-C(4A) 139.42(19) C(7A)-C(6A)-C(5A)-C(11A) 13.5(2) C(21A)-O(8A)-C(19A)-O(7A) -8.7(3) C(21A)-O(8A)-C(19A)-C(4A) 173.00(19) C(21B)-O(8B)-C(19B)-O(7B) -0.9(3) C(21B)-O(8B)-C(19B)-C(4B) -177.4(2) C(20B)-O(6B)-C(18B)-O(5B) -0.3(3) C(20B)-O(6B)-C(18B)-C(4B) -178.1(2) ________________________________________________________________ Table A3.7. Hydrogen bonds for epoxy alcohol 262 [Å and °]. ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ O(1B)-H(1B)...O(5A) 0.78(4) 2.13(4) 2.905(2) 174(4) O(1A)-H(1A)...O(5B)#1 0.75(4) 2.24(4) 2.937(3) 155(4) ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 x-1,y,z-1 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 A3.2 (1) 434 REFERENCES APEX2, Version 2 User Manual, M86-E01078, Bruker Analytical X-ray Systems, Madison, WI, June 2006. (2) Sheldrick, G.M. “SADABS (version 2008/1): Program for Absorption Correction for Data from Area Detector Frames”, University of Göttingen, 2008. (3)     Sheldrick, G. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112. (4) Müller, P. Crystallogr. Rev. 2009, 15, 57. (5) Parsons, S; Flack, H. D; Wagner, T. Acta Crystallogr. 2013, B69, 249. (6) Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.; Towler M.; van de Streek, J. J. Appl. Cryst. 2006, 39, 453.  DEVELOPMENT OF SYNTHETIC STRATEGIES FOR THE TOTAL SYNTHESIS OF ENT-KAURANOID AND DITERPENOID ALKALOID NATURAL PRODUCTS Thesis by Victor Wei-Dek Mak In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2018 (Defended July 17, 2017) ii © 2017 Victor Wei-Dek Mak All Rights Reserved iii To My Mother iv ACKNOWLEDGEMENTS First and foremost, I would like to thank my advisor, Professor Sarah Reisman, for her unwavering support during my time at Caltech. The past five years have been the most formative of my life. Early on, Sarah encouraged a decision to spend more time with my loved ones, and I’m a much better person for it. Undoubtedly, a delicate worklife balance has been crucial for maintaining my sanity, and I am deeply grateful to Sarah for providing flexibility and freedom during my times of need. At the same time, Sarah has always pushed and encouraged my work whenever I needed confidence and motivation. I cherish the time I’ve spent on research so much, and I am truly grateful for the opportunity to contribute to such unbelievably exciting projects in the Reisman laboratory. I must also thank the members of my thesis committee, Professors Brian Stoltz, Greg Fu, and Linda Hsieh-Wilson, for always being incredibly positive and encouraging influences. In particular, Brian has been an especially friendly presence on the 3rd floor of Schlinger. I’ve learned so much from Brian during classes, group meetings, synthesis of the year meetings, as well as yearly committee meetings. For the rest of my career, I will remember his guidance, particularly to think deeply about the motivations behind research. The scientific staff at Caltech has always been outstanding in their support of students and research. I’d like to specifically thank Dr. Scott Virgil for maintaining the Caltech 3CS facility, helping me with prep HPLC, and a high pressure hydrogenation v setup. I must also thank Dr. David VanderVelde for managing such an excellent NMR facility and helping me with NMR experiments throughout the years. I thank all past and present members of the Reisman lab for making it such a dynamic and fun place to grow, both as a scientist and a person. In particular, it was an absolute pleasure to work with Dr. John Yeoman during my first year. I am truly grateful for his patience and guidance. I remember the first time I ran a SmI2-mediated reductive cyclization and obtained a dismal 18% yield, John took the time to show me step-by-step how to properly setup the reaction, and then proceeded to watch me repeat the exact steps he’d just shown me. I must also thank Dr. Kangway Chuang, not just for his friendship, but also for his contributions to the diterpenoid alkaloids project. Either out of sheer brilliance or hard work, Kangway deeply understood the molecules I was working with, and provided guidance throughout. I recall our conversations about metaphotocycloadditions while walking to and from the basketball courts, and the eyeopening realization that it was not a bad idea after all. I will also especially point out Dr. Maddi Kieffer, for helping me so much through the years. Maddi helped me settle down in lab when I first joined, provided invaluable advice during tough times, always supported and encouraged and helped me build confidence, and provided more invaluable advice when I was trying to leave (i.e. job hunting). Lastly, I’d like to thank Alice Wong for her contributions to the diterpenoid alkaloids project during these last few years. It has been very rewarding to see Alice grow as a scientist, and I wouldn’t trust anyone more with the fate of the talatisamine synthesis. I would not have gotten through these past five years if not for those who dragged me out of the lab to do non-lab-related-things. It was incredibly fun playing music with vi Leah Cleary and Anton Dubrovskiy, who both bravely endured the smell of Cottie’s accidents in my apartment during practices. Thank you to the friends who made basketball every week something to look forward to; thank you Kangway Chaung, Haoxuan Wang, Boger Liu, Guy Edouard, Beau Pritchett, Daisuke Saito, and other regulars I’m sure to have missed. Thank you to the Ultimate team who came out to run and throw discs around despite how poorly we’d play; thank you Nick Cowper, Kangway Chaung, Haoxuan Wang, Alice Wong, and Carson Matier. I have come as far as I have because of the support from the terrific instructors and mentors during my early days as a researcher. The chemistry department at UCI was an extremely nurturing environment that fostered my passion for organic chemistry. I will point out Professors Scott Rychnovsky and Liz Jarvo for encouraging my pursuit of graduate school and inspiring me to become a better chemist. Most of all, I must thank my undergraduate advisor, Professor Ken Shea, for his mentorship and wisdom. His calm demeanor towards research and colleagues is something I have always tried to emulate. I must also express my deepest gratitude to Dr. Leah Cleary, who has contributed so much to my career as a scientist. Leah was always fun to work with, and has taught me probably 90% of the chemistry techniques I use on a daily basis. My fondest memories of my undergraduate career are the times I’ve spent in the Shea lab, where I’d learned to embrace the camaraderie between scientists. I am extremely fortunate to have such a loving and supportive family that believes in me. My dad has sacrificed so much for me, and I do not take it for granted that I am able to work on something about which I am passionate. He has also been the one constant during the past few tumultuous years. I will also thank especially my aunt Lori, vii who after my mother’s passing, has made every effort to ensure my well-being. I am grateful to my brother Jordan, who has always, without question or hesitation, helped me with anything I’ve ever needed help with. I am also grateful to my cousin Peter and his partner Rae, who have put in such effort to check up on me every few weeks. It is always an absolute joy to spend time with them, and I truly appreciate the love and support they’ve provided during graduate school. I will also thank Bruce Hsueh for his friendship, patience, and understanding, and also for always enthusiastically willing to spend time with me doing anything, whether it be playing videogames, watching TV, playing sports, or going out for food. Additionally, although he likely cannot comprehend, I will also thank my dog Cottie for preparing me to face each and every day and loving me regardless of how good or bad work is going. Finally, I express my deepest gratitude to Karen for sharing her life with me. Karen is the one who brings value and meaning to everything I do, and she makes every sacrifice I’ve made worth it. Her admirable character often leaves me in awe, and always inspires me to better myself. Karen, thank you for spending every day with me, keeping me alive, growing with me, and sacrificing for me. viii ABSTRACT As part of an ongoing synthetic effort directed towards biologically active entkauranoid natural products, the preparation of two structurally unique natural products, (– )-trichorabdal A and (–)-longikaurin E, is presented. The syntheses intercept an early intermediate from the synthetic route towards the rearranged natural product (–)maoecrystal Z, and thus, represents a unified synthetic strategy to access structurally unique ent-kauranoids. Specifically, the syntheses are enabled by a palladium-mediated oxidative cyclization of a silyl ketene acetal to install a key quaternary center within the bicyclo[3.2.1]octane unit, as well as a reductive cyclization of an aldehyde-lactone to construct the oxabicyclo[2.2.2]octane motif of (–)-longikaurin E. A synthetic strategy to access C19-diterpenoid alkaloids, specifically of the aconitine type, is presented. These highly bridged polycyclic natural products are generally characterized by a substituted piperidyl ring bridging a hydrindane framework that is further attached to a bicyclo[3.2.1]octane. The synthetic strategy relies on the enantioselective synthesis of two bicyclic fragments, which are coupled in a convergent fashion through a 1,2-addition/semipinacol rearrangement sequence to forge a sterically hindered quaternary center. Efficient access to late stage intermediates has enabled the synthesis of the aconitine carbocyclic core, with appropriate functionality for advancement to a selective voltage-gated K+ channel blocker, talatisamine. Additionally, the synthetic strategy described herein is well applicable to the synthesis of related denudatine and napelline type C20-diterpenoid alkaloids. ix PUBLISHED CONTENT AND CONTRIBUTIONS Portions of the work described herein were disclosed in the following publications: Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764. DOI: 10.1021/ja406599a Yeoman, J. T. S.; Cha, J. C.; Mak, V. W.; Reisman, S. E. Tetrahedron 2014, 70, 4070. DOI: 10.1016/j.tet.2014.03071 V.W.M. conducted experiments towards (–)-longikaurin E, and contributed to the preparation of the manuscripts and supporting information. x TABLE OF CONTENTS CHAPTER 1 1 An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 1.1 INTRODUCTION ............................................................................................. 1 1.2 TERPENE BIOSYNTHESIS ................................................................................. 2 1.3 OVERVIEW OF ENT-KAURANOIDS ................................................................. 4 1.3.1 Structure and Biological Activity.......................................................... 4 1.3.2 Ent-Kauranoid Biosynthesis ................................................................. 5 1.4 OVERVIEW OF DITERPENOID ALKALOIDS..................................................... 7 1.4.1 Isolation, Structure, and Biological Activity.......................................... 8 1.4.2 Biosynthesis of Diterpenoid Alkaloids ................................................ 11 1.5 CONCLUDING REMARKS ............................................................................. 13 1.6 NOTES AND REFERENCES ............................................................................. 15 CHAPTER 2 19 Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaruin E 2.1 INTRODUCTION ........................................................................................... 19 2.2 PREVIOUS AND CONCURRENT SYNTHETIC EFFORTS ................................ 20 2.2.1 Fujita’s Relay Synthesis of Enmein ..................................................... 20 xi 2.2.2 Mander’s Synthesis of 15-Desoxyeffusin ............................................ 21 2.2.3 Zhai’s Total Synthesis of Sculponeatin N ........................................... 22 2.3 SYNTHETIC APPROACH ................................................................................ 23 2.3.1 Total Synthesis of (–)-Maoecrystal Z .................................................. 23 2.3.2 Retrosynthesis of (–)-Trichorabdal A and (–)-Longikaurin E ............... 26 2.4 FORWARD SYNTHETIC EFFORTS .................................................................. 27 2.4.1 Development of a Pd(II)-Mediated Oxidative Cyclization.................. 27 2.4.2 Total Synthesis of (–)-Trichorabdal A ................................................ 29 2.4.3 Total Synthesis of (–)-Longikaurin E ................................................... 30 2.5 CONCLUDING REMARKS ............................................................................. 32 2.6 EXPERIMENTAL SECTION .............................................................................. 34 2.6.1 Materials and Methods ...................................................................... 34 2.6.2 Preparative Procedures and Spectroscopic Data ............................... 35 2.7 NOTES AND REFERENCES ............................................................................. 63 APPENDIX 1 67 Spectra Relevant to Chapter 2 CHAPTER 3 114 Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 3.1 INTRODUCTION ......................................................................................... 114 xii 3.2 STRUCTURAL AND BIOSYNTHETIC CONSIDERATIONS ............................ 115 3.3 PRIOR TOTAL SYNTHESES .......................................................................... 116 3.3.1 Wiesner’s Synthesis of C19- and C20-Diterpenoid Alkaloids ............... 116 3.3.2 Gin’s Synthesis of Neofinaconitine .................................................. 122 3.3.3 Sarpong’s Unified Strategy towards C20-, C19-, and C18-Diterpenoid Alkaloids .................................................................................................. 126 3.3.4 Fukuyama’s Synthesis of C19- and C20-Diterpenoid Alkaloids............ 131 3.3.5 Summary of Previous Synthetic Strategies ........................................ 135 3.4 SYNTHETIC APPROACH TO DITERPENOID ALKALOIDS............................ 135 3.5 FORWARD SYNTHETIC EFFORTS ................................................................ 138 3.5.1 Semipinacol Rearrangement Model Studies towards a Tetracyclic Analogue ................................................................................................. 138 3.5.2 Enantioselective Syntheses of Two Bicyclic Fragments ..................... 146 3.5.3 Convergent Fragment Coupling ....................................................... 156 3.5.4 Assembly of the Carbocyclic Core of Talatisamine .......................... 161 3.5.5 Endgame Efforts .............................................................................. 164 3.6 FUTURE DIRECTIONS .................................................................................. 169 3.7 CONCLUDING REMARKS ........................................................................... 171 3.8 EXPERIMENTAL SECTION ............................................................................ 173 3.8.1 Materials and Methods .................................................................... 173 3.8.2 Preparative Procedures and Spectroscopic Data ............................. 174 3.9 NOTES AND REFERENCES ........................................................................... 251 xiii APPENDIX 2 256 Spectra Relevant to Chapter 3 APPENDIX 3 400 X-Ray Crystallography Reports Relevant to Chapter 3 ABOUT THE AUTHOR 435 xiv LIST OF ABBREVIATIONS [α]D angle of optical rotation of plane-polarized light Å angstrom(s) p-ABSA para-acetamidobenzenesulfonyl azide Ac acetyl acac acetylacetonate AIBN azobisisobutyronitrile aq aqueous Ar aryl group atm atmosphere(s) BINOL 1,1'-bi-2,2'-naphthol bipy 2,2'-bipyridine Bn benzyl Boc tert-butoxycarbonyl bp boiling point br broad Bu butyl i-Bu iso-butyl n-Bu butyl or norm-butyl t-Bu tert-butyl BQ 1,4-benzoquinone Bz benzoyl xv c 13 concentration of sample for measurement of optical rotation C carbon-13 isotope /C supported on activated carbon charcoal °C degrees Celcius calc’d calculated CAN ceric ammonium nitrate cat. catalyst Cbz benzyloxycarbonyl cf. consult or compare to (Latin: confer) cis (zusammen) on the same side cm–1 wavenumber(s) CoA Coenzyme A conc. concentrated conv. conversion Cp cyclopentadienyl CSA camphor sulfonic acid Cy cyclohexyl Δ heat or difference δ chemical shift in ppm d doublet d deutero or dextrorotatory D deuterium dba dibenzylideneacetone xvi DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone de novo starting from the beginning; anew DIPEA N,N-diisopropylethylamine DHQ dihydroquinine DHQD dihydroquinidine DIBAL diisobutylaluminum hydride DMAP 4-(dimethylamino)pyridine DME 1,2-dimethoxyethane DMEDA N,N'-dimethylethylenediamine DMF N,N-dimethylformamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMSO dimethylsulfoxide dppe 1,2-bis(diphenylphosphino)ethane dppf 1,1'-bis(diphenylphosphino)ferrocene dr diastereomeric ratio ee enantiomeric excess E methyl carboxylate (CO2CH3) E+ electrophile E trans (entgegen) olefin geometry EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride e.g. for example (Latin: exempli gratia) xvii EI electron impact ent enantiomer of epi epimeric equiv equivalent(s) ESI electrospray ionization Et ethyl et al. and others (Latin: et alii) FAB fast atom bombardment FTIR fourier transform infrared spectroscopy g gram(s) h hour(s) 1H proton [H] reduction HDA hetero-Diels–Alder HFIP hexafluoroisopropanol HMBC heteronuclear multiple-bond correlation spectroscopy HMDS hexamethyldisilazide HMPA hexamethylphosphoramide hν irradiation with light HPLC high performance liquid chromatography HRMS high resolution mass spectrometry Hz hertz IC50 half maximal inhibitory concentration (50%) xviii i.e. that is (Latin: id est) iso isomeric in situ in the reaction mixture J coupling constant in Hz k rate constant kcal kilocalorie(s) kg kilogram(s) L liter or neutral ligand l levorotatory LA Lewis acid LC/MS liquid chromatography–mass spectrometry LDA lithium diisopropylamide m multiplet or meter(s) M molar or molecular ion m meta µ micro m-CPBA meta-chloroperbenzoic acid Me methyl mg milligram(s) MHz megahertz MIC minimum inhibitory concentration min minute(s) mL milliliter(s) xix MM mixed method mol mole(s) MOM methoxymethyl Ms methanesulfonyl (mesyl) MS molecular sieves MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide m/z mass-to-charge ratio NBS N-bromosuccinimide nd not determined NHC N-heterocyclic carbene nm nanometer(s) nM nanomolar NMO N-methylmorpholine N-oxide NMR nuclear magnetic resonance NOE nuclear Overhauser effect NOESY nuclear Overhauser enhancement spectroscopy NPh naphthyl Nu nucleophile o ortho [O] oxidation P peak p para PCC pyridinium chlorochromate xx PDC pyridinium dichromate Ph phenyl pH hydrogen ion concentration in aqueous solution PHAL 1,4-phthalazinediyl diether PIFA [bis(trifluoroacetoxy)iodo]benzene Pin pinacol PivOH pivalic acid pKa acid dissociation constant pm picometer(s) PMB para-methoxybenzyl ppm parts per million PPTS pyridinium para-toluenesulfonate Pr propyl i-Pr isopropyl n-Pr propyl or norm-propyl psi pounds per square inch py pyridine PYR 2,5-diphenyl-4,6-pyrimidinediyl diether q quartet QD Quinidine QN Quinine quant. quantitative R generic (alkyl) group xxi RL large group R rectus RCM ring-closing metathesis recry. recrystallization ref reference Rf retention factor rgt. reagent rt room temperature s singlet or seconds sat. saturated t triplet TBAF tetra-n-butylammonium fluoride TBME tert-butyl methyl ether TBS tert-butyldimethylsilyl TC thiophene-2-carboxylate temp temperature Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TIPS triisopropylsilyl TLC thin layer chromatography TMS trimethylsilyl TOF time-of-flight xxii tol tolyl TPAP tetrapropylammonium perruthenate trans on the opposite side Ts para-toluenesulfonyl (tosyl) UV ultraviolet vide infra see below w/v weight per volume X anionic ligand or halide xs excess Z cis (zusammen) olefin geometry  DEVELOPMENT OF SYNTHETIC STRATEGIES FOR THE TOTAL SYNTHESIS OF ENT-KAURANOID AND DITERPENOID ALKALOID NATURAL PRODUCTS Thesis by Victor Wei-Dek Mak In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2018 (Defended July 17, 2017) ii © 2017 Victor Wei-Dek Mak All Rights Reserved iii To My Mother iv ACKNOWLEDGEMENTS First and foremost, I would like to thank my advisor, Professor Sarah Reisman, for her unwavering support during my time at Caltech. The past five years have been the most formative of my life. Early on, Sarah encouraged a decision to spend more time with my loved ones, and I’m a much better person for it. Undoubtedly, a delicate worklife balance has been crucial for maintaining my sanity, and I am deeply grateful to Sarah for providing flexibility and freedom during my times of need. At the same time, Sarah has always pushed and encouraged my work whenever I needed confidence and motivation. I cherish the time I’ve spent on research so much, and I am truly grateful for the opportunity to contribute to such unbelievably exciting projects in the Reisman laboratory. I must also thank the members of my thesis committee, Professors Brian Stoltz, Greg Fu, and Linda Hsieh-Wilson, for always being incredibly positive and encouraging influences. In particular, Brian has been an especially friendly presence on the 3rd floor of Schlinger. I’ve learned so much from Brian during classes, group meetings, synthesis of the year meetings, as well as yearly committee meetings. For the rest of my career, I will remember his guidance, particularly to think deeply about the motivations behind research. The scientific staff at Caltech has always been outstanding in their support of students and research. I’d like to specifically thank Dr. Scott Virgil for maintaining the Caltech 3CS facility, helping me with prep HPLC, and a high pressure hydrogenation v setup. I must also thank Dr. David VanderVelde for managing such an excellent NMR facility and helping me with NMR experiments throughout the years. I thank all past and present members of the Reisman lab for making it such a dynamic and fun place to grow, both as a scientist and a person. In particular, it was an absolute pleasure to work with Dr. John Yeoman during my first year. I am truly grateful for his patience and guidance. I remember the first time I ran a SmI2-mediated reductive cyclization and obtained a dismal 18% yield, John took the time to show me step-by-step how to properly setup the reaction, and then proceeded to watch me repeat the exact steps he’d just shown me. I must also thank Dr. Kangway Chuang, not just for his friendship, but also for his contributions to the diterpenoid alkaloids project. Either out of sheer brilliance or hard work, Kangway deeply understood the molecules I was working with, and provided guidance throughout. I recall our conversations about metaphotocycloadditions while walking to and from the basketball courts, and the eyeopening realization that it was not a bad idea after all. I will also especially point out Dr. Maddi Kieffer, for helping me so much through the years. Maddi helped me settle down in lab when I first joined, provided invaluable advice during tough times, always supported and encouraged and helped me build confidence, and provided more invaluable advice when I was trying to leave (i.e. job hunting). Lastly, I’d like to thank Alice Wong for her contributions to the diterpenoid alkaloids project during these last few years. It has been very rewarding to see Alice grow as a scientist, and I wouldn’t trust anyone more with the fate of the talatisamine synthesis. I would not have gotten through these past five years if not for those who dragged me out of the lab to do non-lab-related-things. It was incredibly fun playing music with vi Leah Cleary and Anton Dubrovskiy, who both bravely endured the smell of Cottie’s accidents in my apartment during practices. Thank you to the friends who made basketball every week something to look forward to; thank you Kangway Chaung, Haoxuan Wang, Boger Liu, Guy Edouard, Beau Pritchett, Daisuke Saito, and other regulars I’m sure to have missed. Thank you to the Ultimate team who came out to run and throw discs around despite how poorly we’d play; thank you Nick Cowper, Kangway Chaung, Haoxuan Wang, Alice Wong, and Carson Matier. I have come as far as I have because of the support from the terrific instructors and mentors during my early days as a researcher. The chemistry department at UCI was an extremely nurturing environment that fostered my passion for organic chemistry. I will point out Professors Scott Rychnovsky and Liz Jarvo for encouraging my pursuit of graduate school and inspiring me to become a better chemist. Most of all, I must thank my undergraduate advisor, Professor Ken Shea, for his mentorship and wisdom. His calm demeanor towards research and colleagues is something I have always tried to emulate. I must also express my deepest gratitude to Dr. Leah Cleary, who has contributed so much to my career as a scientist. Leah was always fun to work with, and has taught me probably 90% of the chemistry techniques I use on a daily basis. My fondest memories of my undergraduate career are the times I’ve spent in the Shea lab, where I’d learned to embrace the camaraderie between scientists. I am extremely fortunate to have such a loving and supportive family that believes in me. My dad has sacrificed so much for me, and I do not take it for granted that I am able to work on something about which I am passionate. He has also been the one constant during the past few tumultuous years. I will also thank especially my aunt Lori, vii who after my mother’s passing, has made every effort to ensure my well-being. I am grateful to my brother Jordan, who has always, without question or hesitation, helped me with anything I’ve ever needed help with. I am also grateful to my cousin Peter and his partner Rae, who have put in such effort to check up on me every few weeks. It is always an absolute joy to spend time with them, and I truly appreciate the love and support they’ve provided during graduate school. I will also thank Bruce Hsueh for his friendship, patience, and understanding, and also for always enthusiastically willing to spend time with me doing anything, whether it be playing videogames, watching TV, playing sports, or going out for food. Additionally, although he likely cannot comprehend, I will also thank my dog Cottie for preparing me to face each and every day and loving me regardless of how good or bad work is going. Finally, I express my deepest gratitude to Karen for sharing her life with me. Karen is the one who brings value and meaning to everything I do, and she makes every sacrifice I’ve made worth it. Her admirable character often leaves me in awe, and always inspires me to better myself. Karen, thank you for spending every day with me, keeping me alive, growing with me, and sacrificing for me. viii ABSTRACT As part of an ongoing synthetic effort directed towards biologically active entkauranoid natural products, the preparation of two structurally unique natural products, (– )-trichorabdal A and (–)-longikaurin E, is presented. The syntheses intercept an early intermediate from the synthetic route towards the rearranged natural product (–)maoecrystal Z, and thus, represents a unified synthetic strategy to access structurally unique ent-kauranoids. Specifically, the syntheses are enabled by a palladium-mediated oxidative cyclization of a silyl ketene acetal to install a key quaternary center within the bicyclo[3.2.1]octane unit, as well as a reductive cyclization of an aldehyde-lactone to construct the oxabicyclo[2.2.2]octane motif of (–)-longikaurin E. A synthetic strategy to access C19-diterpenoid alkaloids, specifically of the aconitine type, is presented. These highly bridged polycyclic natural products are generally characterized by a substituted piperidyl ring bridging a hydrindane framework that is further attached to a bicyclo[3.2.1]octane. The synthetic strategy relies on the enantioselective synthesis of two bicyclic fragments, which are coupled in a convergent fashion through a 1,2-addition/semipinacol rearrangement sequence to forge a sterically hindered quaternary center. Efficient access to late stage intermediates has enabled the synthesis of the aconitine carbocyclic core, with appropriate functionality for advancement to a selective voltage-gated K+ channel blocker, talatisamine. Additionally, the synthetic strategy described herein is well applicable to the synthesis of related denudatine and napelline type C20-diterpenoid alkaloids. ix PUBLISHED CONTENT AND CONTRIBUTIONS Portions of the work described herein were disclosed in the following publications: Yeoman, J. T. S.; Mak, V. W.; Reisman, S. E. J. Am. Chem. Soc. 2013, 135, 11764. DOI: 10.1021/ja406599a Yeoman, J. T. S.; Cha, J. C.; Mak, V. W.; Reisman, S. E. Tetrahedron 2014, 70, 4070. DOI: 10.1016/j.tet.2014.03071 V.W.M. conducted experiments towards (–)-longikaurin E, and contributed to the preparation of the manuscripts and supporting information. x TABLE OF CONTENTS CHAPTER 1 1 An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 1.1 INTRODUCTION ............................................................................................. 1 1.2 TERPENE BIOSYNTHESIS ................................................................................. 2 1.3 OVERVIEW OF ENT-KAURANOIDS ................................................................. 4 1.3.1 Structure and Biological Activity.......................................................... 4 1.3.2 Ent-Kauranoid Biosynthesis ................................................................. 5 1.4 OVERVIEW OF DITERPENOID ALKALOIDS..................................................... 7 1.4.1 Isolation, Structure, and Biological Activity.......................................... 8 1.4.2 Biosynthesis of Diterpenoid Alkaloids ................................................ 11 1.5 CONCLUDING REMARKS ............................................................................. 13 1.6 NOTES AND REFERENCES ............................................................................. 15 CHAPTER 2 19 Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaruin E 2.1 INTRODUCTION ........................................................................................... 19 2.2 PREVIOUS AND CONCURRENT SYNTHETIC EFFORTS ................................ 20 2.2.1 Fujita’s Relay Synthesis of Enmein ..................................................... 20 xi 2.2.2 Mander’s Synthesis of 15-Desoxyeffusin ............................................ 21 2.2.3 Zhai’s Total Synthesis of Sculponeatin N ........................................... 22 2.3 SYNTHETIC APPROACH ................................................................................ 23 2.3.1 Total Synthesis of (–)-Maoecrystal Z .................................................. 23 2.3.2 Retrosynthesis of (–)-Trichorabdal A and (–)-Longikaurin E ............... 26 2.4 FORWARD SYNTHETIC EFFORTS .................................................................. 27 2.4.1 Development of a Pd(II)-Mediated Oxidative Cyclization.................. 27 2.4.2 Total Synthesis of (–)-Trichorabdal A ................................................ 29 2.4.3 Total Synthesis of (–)-Longikaurin E ................................................... 30 2.5 CONCLUDING REMARKS ............................................................................. 32 2.6 EXPERIMENTAL SECTION .............................................................................. 34 2.6.1 Materials and Methods ...................................................................... 34 2.6.2 Preparative Procedures and Spectroscopic Data ............................... 35 2.7 NOTES AND REFERENCES ............................................................................. 63 APPENDIX 1 67 Spectra Relevant to Chapter 2 CHAPTER 3 114 Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 3.1 INTRODUCTION ......................................................................................... 114 xii 3.2 STRUCTURAL AND BIOSYNTHETIC CONSIDERATIONS ............................ 115 3.3 PRIOR TOTAL SYNTHESES .......................................................................... 116 3.3.1 Wiesner’s Synthesis of C19- and C20-Diterpenoid Alkaloids ............... 116 3.3.2 Gin’s Synthesis of Neofinaconitine .................................................. 122 3.3.3 Sarpong’s Unified Strategy towards C20-, C19-, and C18-Diterpenoid Alkaloids .................................................................................................. 126 3.3.4 Fukuyama’s Synthesis of C19- and C20-Diterpenoid Alkaloids............ 131 3.3.5 Summary of Previous Synthetic Strategies ........................................ 135 3.4 SYNTHETIC APPROACH TO DITERPENOID ALKALOIDS............................ 135 3.5 FORWARD SYNTHETIC EFFORTS ................................................................ 138 3.5.1 Semipinacol Rearrangement Model Studies towards a Tetracyclic Analogue ................................................................................................. 138 3.5.2 Enantioselective Syntheses of Two Bicyclic Fragments ..................... 146 3.5.3 Convergent Fragment Coupling ....................................................... 156 3.5.4 Assembly of the Carbocyclic Core of Talatisamine .......................... 161 3.5.5 Endgame Efforts .............................................................................. 164 3.6 FUTURE DIRECTIONS .................................................................................. 169 3.7 CONCLUDING REMARKS ........................................................................... 171 3.8 EXPERIMENTAL SECTION ............................................................................ 173 3.8.1 Materials and Methods .................................................................... 173 3.8.2 Preparative Procedures and Spectroscopic Data ............................. 174 3.9 NOTES AND REFERENCES ........................................................................... 251 xiii APPENDIX 2 256 Spectra Relevant to Chapter 3 APPENDIX 3 400 X-Ray Crystallography Reports Relevant to Chapter 3 ABOUT THE AUTHOR 435 xiv LIST OF ABBREVIATIONS [α]D angle of optical rotation of plane-polarized light Å angstrom(s) p-ABSA para-acetamidobenzenesulfonyl azide Ac acetyl acac acetylacetonate AIBN azobisisobutyronitrile aq aqueous Ar aryl group atm atmosphere(s) BINOL 1,1'-bi-2,2'-naphthol bipy 2,2'-bipyridine Bn benzyl Boc tert-butoxycarbonyl bp boiling point br broad Bu butyl i-Bu iso-butyl n-Bu butyl or norm-butyl t-Bu tert-butyl BQ 1,4-benzoquinone Bz benzoyl xv c 13 concentration of sample for measurement of optical rotation C carbon-13 isotope /C supported on activated carbon charcoal °C degrees Celcius calc’d calculated CAN ceric ammonium nitrate cat. catalyst Cbz benzyloxycarbonyl cf. consult or compare to (Latin: confer) cis (zusammen) on the same side cm–1 wavenumber(s) CoA Coenzyme A conc. concentrated conv. conversion Cp cyclopentadienyl CSA camphor sulfonic acid Cy cyclohexyl Δ heat or difference δ chemical shift in ppm d doublet d deutero or dextrorotatory D deuterium dba dibenzylideneacetone xvi DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCE 1,2-dichloroethane DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone de novo starting from the beginning; anew DIPEA N,N-diisopropylethylamine DHQ dihydroquinine DHQD dihydroquinidine DIBAL diisobutylaluminum hydride DMAP 4-(dimethylamino)pyridine DME 1,2-dimethoxyethane DMEDA N,N'-dimethylethylenediamine DMF N,N-dimethylformamide DMPU 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone DMSO dimethylsulfoxide dppe 1,2-bis(diphenylphosphino)ethane dppf 1,1'-bis(diphenylphosphino)ferrocene dr diastereomeric ratio ee enantiomeric excess E methyl carboxylate (CO2CH3) E+ electrophile E trans (entgegen) olefin geometry EDCI N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride e.g. for example (Latin: exempli gratia) xvii EI electron impact ent enantiomer of epi epimeric equiv equivalent(s) ESI electrospray ionization Et ethyl et al. and others (Latin: et alii) FAB fast atom bombardment FTIR fourier transform infrared spectroscopy g gram(s) h hour(s) 1H proton [H] reduction HDA hetero-Diels–Alder HFIP hexafluoroisopropanol HMBC heteronuclear multiple-bond correlation spectroscopy HMDS hexamethyldisilazide HMPA hexamethylphosphoramide hν irradiation with light HPLC high performance liquid chromatography HRMS high resolution mass spectrometry Hz hertz IC50 half maximal inhibitory concentration (50%) xviii i.e. that is (Latin: id est) iso isomeric in situ in the reaction mixture J coupling constant in Hz k rate constant kcal kilocalorie(s) kg kilogram(s) L liter or neutral ligand l levorotatory LA Lewis acid LC/MS liquid chromatography–mass spectrometry LDA lithium diisopropylamide m multiplet or meter(s) M molar or molecular ion m meta µ micro m-CPBA meta-chloroperbenzoic acid Me methyl mg milligram(s) MHz megahertz MIC minimum inhibitory concentration min minute(s) mL milliliter(s) xix MM mixed method mol mole(s) MOM methoxymethyl Ms methanesulfonyl (mesyl) MS molecular sieves MTT 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide m/z mass-to-charge ratio NBS N-bromosuccinimide nd not determined NHC N-heterocyclic carbene nm nanometer(s) nM nanomolar NMO N-methylmorpholine N-oxide NMR nuclear magnetic resonance NOE nuclear Overhauser effect NOESY nuclear Overhauser enhancement spectroscopy NPh naphthyl Nu nucleophile o ortho [O] oxidation P peak p para PCC pyridinium chlorochromate xx PDC pyridinium dichromate Ph phenyl pH hydrogen ion concentration in aqueous solution PHAL 1,4-phthalazinediyl diether PIFA [bis(trifluoroacetoxy)iodo]benzene Pin pinacol PivOH pivalic acid pKa acid dissociation constant pm picometer(s) PMB para-methoxybenzyl ppm parts per million PPTS pyridinium para-toluenesulfonate Pr propyl i-Pr isopropyl n-Pr propyl or norm-propyl psi pounds per square inch py pyridine PYR 2,5-diphenyl-4,6-pyrimidinediyl diether q quartet QD Quinidine QN Quinine quant. quantitative R generic (alkyl) group xxi RL large group R rectus RCM ring-closing metathesis recry. recrystallization ref reference Rf retention factor rgt. reagent rt room temperature s singlet or seconds sat. saturated t triplet TBAF tetra-n-butylammonium fluoride TBME tert-butyl methyl ether TBS tert-butyldimethylsilyl TC thiophene-2-carboxylate temp temperature Tf trifluoromethanesulfonyl TFA trifluoroacetic acid THF tetrahydrofuran TIPS triisopropylsilyl TLC thin layer chromatography TMS trimethylsilyl TOF time-of-flight xxii tol tolyl TPAP tetrapropylammonium perruthenate trans on the opposite side Ts para-toluenesulfonyl (tosyl) UV ultraviolet vide infra see below w/v weight per volume X anionic ligand or halide xs excess Z cis (zusammen) olefin geometry Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 1 Chapter 1 An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 1.1 INTRODUCTION Terpenoid natural products are one of the largest classes of biologically active small molecules, and hold importance in areas of flavors, fragrances, poisons, and medicines. 1 The Isodon diterpenes, which encompass the ent-kauranoids, possess important biological properties such as antibacterial and anticancer activity. Further investigations of these natural products and analogues as medical treatments have been hampered by the lack of efficient synthetic routes. The biosynthetically related diterpenoid alkaloids also remain relatively understudied with respect to their syntheses, even though a significant number of the natural products possess biological activity involving modulation of voltage-gated ion channels. In this chapter, the rich history of ent-kauranoid and diterpenoid alkaloids is discussed in terms of biosynthesis, Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 2 distribution, structure, and biological activity with the aim of understanding motivations behind the surge of synthetic studies in recent years. 1.2 TERPENE BIOSYNTHESIS In nature, linear hydrocarbons undergo cyclizations, rearrangements, and oxidations to create terpenoids. The building blocks of these linear hydrocarbons are C5 isoprenyl monomers (3 and 4) derived from acetyl coenzyme A (acetyl-CoA, 1) or deoxyxylulose (2), and are produced by the biosynthetic mevalonate or deoxyxylulose pathways (Figure 1.1).2 The monomers (3 and 4) are stitched together to form linear, pyrophosphorylated polyenes of varying lengths, such as geranyl pyrophosphate (5), farnesyl pyrophosphate (6), squalene (8) and so on, and in turn afford terpenes belonging to general classes such as monoterpenes (C10), sesquiterpenes (C15), diterpenes (C20), and triterpenes (C30, e.g. steroids). Cyclizations and rearrangements can form varieties of carbocyclic skeletons, and subsequent oxidations result in an even larger degree of diversity. The biosynthesis of monoterpenes from geranyl pyrophosphate (5) is used as an example to demonstrate the complexity and diversity exhibited by the natural products. 5, which contains only two prenyl units, can undergo cyclization and/or rearrangement to afford seven unique carbocyclic skeletons (Figure 1.2). Polyenes containing more prenyl units would provide an even greater number of unique carbocyclic skeletons. Oxidation of the carbocycles generates another degree of complexity, as exemplified by the many menthane type monoterpene natural products. Additionally, with larger terpenes such as sesquiterpenes and diterpenes, there are more possible sites for oxidation. Thus, the 3 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids complexity and diversity of terpenoid natural products increase exponentially with each additional prenyl unit. mevalonate pathway O Me C5 isoprenyl monomers SCoA Me acetyl-CoA (1) OPP deoxyxylulose pathway OH Me O Me isopentyl diphosphate (IPP, 3) OP Me isomerase OPP dimethyl allyl diphosphate (DMAPP, 4) OH deoxyxylulose (2) Linear polyene precursors Me Me Me Me Me Me Me Me OPP squalene (8) geranyl pyrophosphate (5) Me Me Me Me Me Me Me Me Me Me Me Me OPP OPP geranylgeranyl pyrophosphate (7) farnesyl pyrophosphate (6) Figure 1.1. Biosynthesis of terpene precursors. Me OPP Me Me geranyl pyrophosphate (5) menthane type pinane type Me Me bornane type fenchane type Me isocamphane type carane type Me Me O [O] thujane type OH + more OH menthane type Me limonene Me Me menthol Figure 1.2. Biosynthesis of monoterpenes. O Me Me Me pulegone carvone Me Me carvacrol Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 4 OVERVIEW OF ENT-KAURANOIDS 1.3 The Isodon diterpenoids are a large family of natural products that are principally based on the structure of the diterpene ent-kaurene. The first study of Isodon extracts dates back to 1910,3 and the first isolation of an Isodon diterpenoid was achieved in 1958.4e–g Since then, more than 600 Isodon diterpenoids have been isolated, with the family exhibiting structural diversity in the form of oxygenation patterns and rearranged frameworks.5 The structural homology between many ent-kauranoids suggests the benefit of a unified synthetic strategy to access this biologically active family of natural products. Plants from the genus Isodon have long been used for medical purposes in East Asian countries, and the isolated diterpenoids have exhibited antibacterial and antitumor properties. 1.3.1 Structure and Biological Activity The vast majority of Isodon diterpenoids share the same carbocyclic skeleton as ent-kaurene (9, Figure 1.3). Oxidation of the skeleton returns oxygenated natural products such as adenanthin (10), and others with bridging oxygen heterocycles, as in 7,20-epoxy type longikaurin E (11). The 6,7-seco-ent-kauranoids represent the largest group of products deviating from the ent-kaurene carbocyclic skeleton, and are derived from oxidative scission of the C6–C7 bond of their 7,20-epoxy- precursors. Representative members of this type include trichorabdals A and B (12 and 13), sculponeatin N (14), and enmein (15), which has undergone translactonization at C1/C7. More exotically rearranged products have also been discovered, as exemplified by maoecrystals V and Z (16 and 17). 5 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 3 Me 18 OH 1 2 10 9 11 7 Me 6 Me 8 12 4 5 20 19 14 15 H Me 16 17 O O H Ac O Me O OH Me O O OAc O O OH 1 O 7 O enmein (15) Me O O O H R HO O trichorabdal A (12: R = H) trichorabdal B (13: R = OAc) H H Me 20 sculponeatin N (14) Me longikaurin E (11) OH Me 6 O O Me O H O OH Me adenanthin (10) Me Me HO O OAc Me O Me OAc 13 ent-kaurene (9) H O Me maoecrystal V (16) H HO Me OAc O O O maoecrystal Z (17) Figure 1.3. Ent-kaurene (9) and representative ent-kauranoids. Most of the biologically active ent-kauranoids share a common α,β-unsaturated carbonyl as part of a bridging cyclopentane D-ring. This structural motif is a pharmacaphore that is crucial for biological activity of the natural products, and possibly acts through electrophilicity of the Michael acceptor for covalent modification.6 In early studies on structure-activity relationships (SAR), Fujita and coworkers reported that hydrogenation of the enone moiety significantly weakened antitumor and antibacterial activity of ent-kauranoids and derivatives.4bc,7 Furthermore, adenanthin (10) has been shown to selectively inhibit peroxiredoxin enzymes by covalent modification of a key cysteine residue, while its saturated analog was found to be biologically inactive.8 1.3.2 Ent-Kauranoid Biosynthesis The diterpene ent-kaurene (9) is known to arise from enzyme-mediated cyclizations and rearrangements of geranylgeranyl diphosphate (7, Figure 1.4).9 An initial cyclization mediated by copalyl diphosphate synthase affords the bicyclic product 18, and a second cyclization mediated by kaurene synthase B results in rearrangements to 6 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids eventually provide ent-kaurene (9). Hong and Tantillo have also proposed concerted biosynthetic pathways that avoid secondary carbocations.10 OPP Me H copalyl DPP synthase Me H kaurene synthase B Me Me Me Me OPP Me Me geranylgeranyl diphosphate (7) Me copalyl diphosphate (18) Me Me Me Me Me 19 Me Me 20 H Me Me ent-kaurene (9) Figure 1.4. Biosynthesis of ent-kaurene (9). Enzymatic oxidations of ent-kaurene (99) return natural products that are classified based on oxidation at C20. Notably, 7,20-epoxy-ent-kauranoids of the general structure 21 are prone to undergo oxidative cleavage of the C6–C7 bond to afford 6,7seco-ent-kauranoids (22, Figure 1.5). The rearranged natural product, maoecrystal Z (17, see Figure 1.3), likely arises from a retro-aldol reaction from the 6,7-seco type (22 and intramolecular aldol cyclization of the resulting enolate (23) to tetracycle 24. This hypothesis is further supported by studies from Fujita and coworkers, who demonstrated that trichorabdal B (13) rearranged to tetracycle 25 under basic conditions (Figure 1.5b).4c From the ent-kaurene framework, sequences of oxidation, C6–C7 bond cleavage, and skeletal rearrangements ultimately produce the over 600 known structurally distinct ent-kauranoids. 7 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids (a) [O] ent-kaurene (9) HO OH Me Me 6 20 oxidative cleavage H Me 7 O OH O O 6 Me O 7,20-epoxy type (21) skeletal rearrangement Me O Me Me O H Me NaOH, MeOH H AcO O O O HO retro-Dieckmann/ aldol reaction trichorabdal B (13) O O O O H HO Me O rearranged type (24) 23 (b) 7 6,7-seco type (22) H O HO Me AcO OMe HO OH O O O 25 Figure 1.5. (a) Biosynthesis and rearrangement of ent-kauranoids. (b) Methoxidemediated rearrangement of trichorabdal B (13). 1.4 OVERVIEW OF DITERPENOID ALKALOIDS The ent-atisane and ent-kaurene diterpenes are widely considered as the biogenetic precursors to all diterpenoid alkaloids. This family alkaloids share structural features similar to those of diterpenoids, but differ from “true alkaloids” in that the carbocyclic cores are derived from terpene biosynthesis, rather than α-amino acid precursors. The diterpenoid alkaloids are divided into three general categories based on the number of carbons in the molecular framework: C20-, C19-, and C18-diterpenoid alkaloids; and these are further divided into subclasses based on the connectivity of their skeletons (e.g. hetidines, hetisines, atisanes, etc…).11 As of July 2008, about 400 C20-, 700 C19-, and 80 C18-diterpenoids have been isolated. In past literature, the diterpenoid alkaloids are often referred to as the Aconitum alkaloids, as they were primarily isolated from the Aconitum genus of plants.12 However, 8 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids these widespread alkaloids have now been isolated from Delphinium, Consolida, and Spiraea genera of plants as well. These plants have long been used in traditional Chinese and Japanese medicine for their antiarrhythmic, antipyretic, and analgesic properties. Indeed, diterpenoid alkaloids possess a wide range of biological activities, namely antiinflammatory, anticancer, antiepileptiform, antihypertensive, and antiarrhythmic properties. With many of the natural products possessing important pharmacological activity, strong interest in the synthesis of their complex structures has sustained over the decades since their first structural elucidation. 1.4.1 Isolation, Structure, and Biological Activity The diterpenoid alkaloids are primarily isolated from the Aconitum and Delphinium genera of plants. Isolates from these plants have been known for centuries, and extracts containing aconitine (“aconite”) have been used throughout history as local anesthetic, but more commonly as a poison for hunting or warfare purposes. It has therefore acquired colloquial names such as “queen of all poisons,” and “wolf’s bane,” while its appearance has evoked nicknames such as “monkshood” or “devil’s helmet”. Despite the history of practical use, the chemical structures of diterpenoid alkaloids remained unknown until Wiesner’s seminal report in 1954. 13 Before the advent of NMR, structural elucidation heavily relied on oxidation and dehydrogenation experiments, leading to the proposed structures of C20-diterpenoid alkaloids veatchine (25) and garryine (26, Figure 1.6). The pharmacological and medicinal properties aconitine (33), one the most well known alkaloids, has been known since 1833.14 However, the structure 9 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids was not fully elucidated until 1971, after decades of extensive chemical and X-ray crystallographic studies.15 (a) C20-diterpenoid alkaloids. OH A Me H OH Me Me E N O OH Me 15 6 N O H O OH Ac H N H O N 20 veatchine (25) garryine (26) Me OH OH Me N Me N Et guan-fu base A (28) hetisine types O HO OH OH HO OH Me Me N H H delcarduchol (30) hetidine type H N Et O O napelline (29) napelline type OAc OH kobusine (27) veatchine types 13 14 H atisine (31) atisine type denudatine (32) denudatine type (b) C19 - and C18 -diterpenoid alkaloids. HO MeO OMe 18 MeO N Et OBz OH OMe AcO OH aconitine (33) OMe 1 OH MeO 18 N Et OMe HO talatisamine (34) C19 aconitine types OMe O 4 AcHN O 6 N Et OMe OH OMe HO lappaconitine (35) C18 lappaconitine type Figure 1.6. Representative Diterpenoid Alkaloids. Many of the C20-diterpenoid alkaloids structurally resemble to ent-atisane and entkaurene diterpenes, as one might predict based on their biosynthetic pathways. For example, the hetisine, hetidine, atisine, and denudatine types (i.e. 27, 28, 31–32, Figure 1.6) all bear a bicyclo[2.2.2]octane, while the veatchine and napelline types (i.e. 25, 26, 29) bear a bicyclo[3.2.1]octane. The C19-diterpenoid alkaloids, which are biogenetically derived from their C20 counterparts, typically possess a rearranged hexacyclic framework that lacks resemblance to any diterpene equivalent. Lastly, the C18-diterpenoid alkaloids share the same hexacyclic core as their C19 precursors, but lack the exocyclic C18 moiety. Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 10 A basic tertiary amine is common to all classes of diterpenoid alkaloids, although the nitrogen is also found in the form of lactams, hemiaminals, and cyclic imines. Among all classes, the 3-azabicyclo[3.3.1]nonane that constitutes the AE-ring system is another highly conserved structural feature. The pharmacological properties of the diterpenoid alkaloids span a wide range, which most notably include anti-inflammatory, analgesic, and antiarrhythmic effects. Although they are notorious for their poisonous properties, several diterpenoid alkaloids have been used in East Asian medicines. The C20-diterpenoid alkaloid, guan-fu base A (28), and its derivatives have been used for its anti-inflammatory and antiarrhythmic effects, and the C20–C14–C13 aminoalcohol subunit was determined to be a pharmacaphore. 16 Derivatives of kobusine (27) were also tested for antifibrillatory activity, and it was concluded that free hydroxyl groups, especially the C6 alcohol, and aromatic esters at C15 were important for biological activity.17 A number of C19- and C18-diterpenoid alkaloids have been studied for their antiinflammatory, analgesic, and antiarrhythmic effects. 3-Acetylaconitine, lappaconitine (35), and crassicauline A have all been clinically used in China as non-narcotic analgesic drugs, and lappaconitine (35) has been used in Russia as an antiarrhythmic drug.18 Broad SAR studies revealed that aromatic ester functionalities at C1, C4, C6, and C14 are crucial for biological activity, in addition to the basicity of the tertiary amine.19 Ameri categorized the alkaloids in to three subgroups based on structure and biological activity,20 and summarized the following: (1) diesters such as aconitine (33) suppress inactivation of voltage-gated Na+ channels by binding to the α-subunit of the protein channel, and are the most toxic, (2) monoester alkaloids such as lappaconitine (35) block Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 11 voltage-gated Na+ channels, are competitive antagonists, and are considerably less toxic, (3) natural products lacking ester groups are the least toxic, but are reported to still have antiarrhythmic action, suggesting affinities to various subtypes of the α-subunit of the sodium channel. Talatisamine (34) was found to block voltage-gated K+ channels, and demonstrated an in vitro neuroprotective effect against β-amyloid oligomers induced cytotoxicity in cortical neurons.21 1.4.2 Biosynthesis of Diterpenoid Alkaloids Although relatively few studies on biosynthesis have been performed,22 it is generally accepted that the diterpenoid alkaloids are biogenetically derived from the diterpenes ent-kaurene and ent-atisane.23 As depicted in Figure 1.7, oxidation of both parent diterpenes and incorporation of serine in the form of β-aminoethanol24 directly provides the C20 veatchine and atisine type alkaloids, respectively. The exact order of oxidation and the point of amination still remain unknown. From the veatchine type alkaloid, a Mannich reaction can form the C7–C20 bond of the napelline type, or interconversion via Wagner–Meerwein rearrangement can produce the atisine type as well. From the atisine type alkaloids, a Mannich reaction can form the C7–C20 bond of the denudatine type alkaloids, with a final Wagner–Meerwein rearrangement providing the napelline type alkaloids. 12 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids OH OH Me 12 13 20 + serine 16 Mannich reaction N N 7 Me OH Me Me (O) ent-kaurene (9) veatchine type Me Me napelline type Wagner–Meerwein rearrangement Wagner–Meerwein rearrangement OH (O) Me + serine Mannich reaction OH OH N OH N Me Me Me Me (O) ent-atisane atisine type Me denudatine type Figure 1.7. Postulated Biosynthesis of several C20-Diterpenoid Alkaloids. From the C20 atisine, denudatine, and napelline type alkaloids, three pathways are postulated to provide the C19-, and in turn the C18-diterpenoid alkaloids.12b In the atisine pathway, Wagner–Meerwein rearrangement affords rearranged framework A, after which oxidative scission of the exocyclic olefin provides the C19 proaconine (7,17-seco) type alkaloids. An aza-Prins reaction then forges the C7–C17 bond of the C19 aconitine type alkaloids. Alternatively, the denudatine pathway involves a Wagner–Meerwein rearrangement to provide rearranged type B, which provides the C19 aconitine type alkaloids after oxidative scission of the exocyclic olefin. Currently, there is one known alkaloid of the rearranged type B, actaline, which lends credence to this biosynthetic pathway.25 In 1975, Kodama et al. proposed the napelline pathway to the C19-diterpenoid alkaloids that involves two sequential Wagner–Meerwein rearrangements of the C20 napelline type alkaloids.26 Based on the broad distribution of denudatine and napelline type alkaloids in plants of the Aconitum genus, the denudatine and napelline pathways are 13 Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids considered to be the major pathways to C19-diterpenoid alkaloids.27 Functionalizations including hydroxylation, methylation, and esterification of the skeletal frameworks contribute largely to the high number and complexity of the C19 diterpenoid alkaloids. As the C18-diterpenoid alkaloids often occur naturally with their C19 counterparts, it is also logical to conclude they are produced by removal of the C18 methylene unit of the aconitine type alkaloids. OPP N –H2O –CH2 Wagner–Meerwein rearrangement O N Me N OH Me Me Me Me C 20 atisine type Me C 20 rearranged type (A) C19 protoaconine type aza-Prins OPP N Wagner–Meerwein rearrangement O –CH2 N Me N OH Me Me OH Me Me C 20 denudatine type Me C 20 rearranged type (B) C19 aconitine type Wagner–Meerwein rearrangement –CH2 OPP O Wagner–Meerwein rearrangement N OPP Me Me N N OH Me Me C 20 napelline type C 20 rearranged type (C) OH Me H C18 lappaconine type Figure 1.8. Postulated Biosynthesis of C19-Diterpenoid Alkaloids. 1.5 CONCLUDING REMARKS The Isodon diterpenes comprise over 600 structurally diverse natural products possessing numerous frameworks and oxidation patterns. Many of the biologically active Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 14 members share the α,β-unsaturated carbonyl moiety that is hypothesized to covalently modify target proteins. Though historically there have been strikingly few reports of synthetic studies towards ent-kauranoids, renewed interest in their antibacterial and anticancer properties have resulted in numerous total syntheses accomplished in the last decade. These synthetic studies will be discussed, alongside our own syntheses, in the following chapter. The diterpenoid alkaloids possess incredibly complex structures that represent significant challenges to synthetic chemists. As these natural products are found in traditional East Asian medicines, it comes as no surprise that they possess significant and compelling biological activity, and has provided commercialized antiarrhythmic drugs. The identification of talatisamine as a novel voltage-gated K+ channel blocker represents a novel discovery that suggests there is still unknown biological activity within this class of natural products. Efficient access to these natural products remains an elusive goal in the field of total synthesis. Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids 1.6 (1) 15 NOTES AND REFERENCES Breitmaier, E. Terpenes: Flavors, Fragrances, Pharmaca, Pheromones; WileyVCH: Weinheim, Germany, 2006. (2) Dewick, P. M. Medicinal Natural Products: A Biosynthetic Approach. John Wiley & Sons, Ltd, 2002. (3) Yagi, S. J. Kyoto Med. Soc., 1910, 7, 30. (4) Isolation of select Isodon (also known as Rabdiosa) natural products: Maoecrystal Z: (a) Han, Q.-B.; Cheung, S.; Tai, J.; Qiao, C.-F.; Song, J.-Z.; Tso, T.-F.; Sun, H.-D.; Xu, H.-X. Org. Lett. 2006, 8, 4727. Trichorabdal A: (b) Node, M.; Sai, M.; Fuji, K.; Fujita, E.; Shingu, T.; Watson, W. H.; Grossie, D. Chem. Lett. 1982, 2023. Trichorabdal B: (c) Fujita, E.; Fuji, K.; Sai, M.; Node, M.; Watson, W. H.; Zabel, V. J. Chem. Soc., Chem. Commun. 1981, 899. Longikaurin E: (d) Fujita, T.; Takeda, Y.; Shingu, T. Heterocycles, 1981, 16, 227. Enmein: (e) Takahashi, M.; Fujita, T.; Koyama, Y. Yakugaku Zasshi, 1985, 78, 699. (f) Ikeda, T.; Kanatomo, S. Yakugaku Zasshi 1958, 78, 1128. (g) Naya, K. Nippon Kagaku Zasshi, 1958, 79, 885. Maoecrystal V: (h) Li, S.-H.; Wang, J.; Niu, X.-M.; Shen, Y.-H.; Zhang, H.-J.; Sun, H.-D.; Li, M.-L.; Tian, Q.-E.; Lu, Y.; Cao, P.; Zheng, Q.-T. Org. Lett. 2004, 6, 4327. Adenanthin: (i) Xu, Y.-L.; Sun, H.-D.; Wang, D.Z.; Iwashita, T.; Komura, H.; Kozuka, M.; Naya, K.; Kubo, I. Tetrahedron Lett. 1987, 28, 499. Sculponeatin N: (j) Li, X.; Pu, J.-X.; Weng, Z.-Y.; Zhao, Y.; Zhao, Y.; Xiao, W.-L.; Sun, H.-D. Chem. Biodiversity 2010, 7, 2888. (5) Sun, H.-D.; Huang, S.-X.; Han, Q.-B. Nat. Prod. Rep. 2006, 23, 673. Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids (6) 16 (a) Serafimova, I. M.; Pufall, M. A.; Krishnan, S.; Duda, K.; Cohen, M. S.; Maglathlin, R. L.; McFarland, J. M.; Miller, R. M.; Frödin, M.; Taunton, J. Nat. Chem. Biol. 2012, 8, 471. (b) Gersch, M.; Kreuzer, J.; Sieber, S. A. Nat. Prod. Rep. 2012, 29, 659. (7) (a) Fujita, E.; Nagao, Y.; Kaneko, K.; Nakazawa, S.; Kuroda, H. Chem. Pharm. Bull. 1976, 24, 2118. (b) Fuji, K.; Node, M.; Sai, M.; Fujita, E.; Takeda, S.; Unemi, N. Chem. Pharm. Bull. 1989, 37, 1472. (8) Liu, C.-X.; Yin, Q.-Q.; Zhou, H.-C.; Wu, Y.-L.; Pu, J.-X.; Xia, L.; Liu, W.; Huang, X.; Jiang, T.; Wu, M.-X.; He, L.-C.; Zhao, Y.-X.; Wang, X.-L.; Xiao, W.L.; Chen, H.-Z.; Zhao, Q.; Zhou, A.-W.; Wang, L.-S.; Sun, H.-D.; Chen, G.-Q. Nat. Chem. Biol. 2012, 8, 486. (9) Bohlmann, J.; Meyer-Gauen, G.; Croteau, R. Proc. Natl. Acad. Sci. USA 1998, 95, 4126. (10) (a) Hong, Y. J.; Tantillo, D. J. J. Am. Chem. Soc. 2010, 132, 5375; (b) Tantillo, D. J. Nat. Prod. Rep. 2011, 28, 1035. (11) Wang, F.-P.; Chen, Q.-H.; Liu, X.-Y. Nat. Prod. Rep. 2010, 27, 529. (12) (a) Pelletier, S. W.; Mody, N. V. The Structure and Synthesis of C19-Diterpenoid Alkaloids in The Alkaloids; Manske, R. H. F.; Rodrigo, R. G. A., Ed.; Academic Press, Inc: New York, 1979; Vol. 17, p. 1–103. (b) Wang, F.-P.; Chen, Q.-H. The C19-Diterpenoid Alkaloids. in The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Elsevier Science: New York, 2010; Vol. 69, p. 1–577. Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids (13) 17 Wiesner, K.; Armstrong, R.; Bartlett, M. F.; Edwards, J. A. J. Am. Chem. Soc. 1954, 76, 6068. (14) Geiger, P. L. Ann. 1833, 7, 269. (15) (a) Bachelor, F. W.; Brown, R. F. C.; Buchi, G. Tetrahedron Lett. 1960, 1, 1. (b) Birbaum, K. B.; Wiesner, K.; Jay, E. W. K.; Jay, L. Tetrahedron Lett. 1971, 13, 867. (16) (a) Wang, R. B.; Peng, S. X.; Hua, W. Y. Acta Pharm. Sinica 1993, 23, 583. (b) Ren, Y.; Peng, S. X.; Hua, W. Y.; Zhu, D. Y. J. China. Pharm. Univ. 1996, 27, 261. (17) (a) Wada, K.; Ishzuki, S.; Mori, T.; Fujihara, E.; Kauahara, N. Biol. Pharm. Bull. 1998, 21, 140. (b) Wada, K.; Ishzuki, S.; Mori, T.; Fujihara, E.; Kauahara, N. Biol. Pharm. Bull. 2000, 23, 607. (18) Vakhitova, Y. V.; Farafontova, E. I.; Khisamutdinova, R. Y.; Yunusov, V. M.; Tsypysheva, I. P.; Yunusov, M. S. Russ. J. Bioorg. Chem. 2013, 39, 92. (19) (a) Salimov, B. T.; Kuzibaeva, Z. K.; Dzhakhangirov, F. N. Chem. Nat. Compds. 1996, 32, 366. (b) Dzhakhangirov, F. N.; Sultankhodzhaev, M. N.; Tashkhodzha, B.; Salimov, B. T. Chem. Nat. Compds. 1997, 33, 190. (c) Wang, J.-L.; Shen, X.L.; Chen, Q.-H.; Gong, Q.; Wang, W.; Wang, F.-P. Chem. Pharm. Bull. 2009, 57, 801. (20) Ameri, A. Prog. Neurobiol. 1998, 56, 211. Chapter 1 – An Introduction to Ent-Kauranoids and Diterpenoid Alkaloids (21) 18 (a) Song, M.-K.; Liu, H.; Jiang H.-L.; Yue, J.-M.; Hu, G.-Y.; Chen, H.-Z. Neuroscience 2008, 155, 469. (b) Wang, Y.; Song, M.; Hou, L.; Yu, Z.; Chen, H. Neurosci. Lett. 2012, 518, 122. (22) (a) Herbert, E. J.; Kirby, G. W. Tetrahedron Lett. 1963, 4, 1505. (b) Benn, M. N.; May, J. Experientia 1964, 20, 252. (c) Frost, J. M.; Hale, R. L.; Waller, G. R.; Zalkov, L. H.; Girota, N. N. Chem. Ind. 1967, 320. (23) Xiao, P. G.; Wang, F. P.; Gao, F.; Yan, L. P.; Chen, D. L.; Liu, Y. Acta Phytotaxon. Sin. 2006, 44, 1. (24) Zhao, P. Z.; Gao, S.; Fan, L. M.; Nie, J. C.; He, H. P.; Zeng, Y.; Shen, Y. M.; Hao, X. J. J. Nat. Prod. 2009, 72, 645. (25) Nishanov, A. A.; Tashkhozhaev, B.; Sultankhodzhaev, M. I.; Ibragimov, B. T.; Yunusov, M. S. Chem. Nat. Compds. 1989, 25, 32. (26) Kodama, M.; Karihara, H.; Ito, S. Tetrahedron Lett. 1975, 16, 1301. (27) Wang, F. P.; Liang, X. T. C20-Diterpenoid Alkaloids in The Alkaloids: Chemistry and Biology; Cordell, G. A., Ed.; Elsevier Science, New York, 2002; Vol. 59, p. 1–280. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 19 Chapter 2 Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E† 2.1 INTRODUCTION In 2011, our group reported the total synthesis of the rearranged ent-Kauranoid maoecrystal Z. Key to the synthesis was a spirolactone intermediate that was prepared in good yield and excellent diastereoselectivity via a Ti(III)-mediated reductive coupling reaction. Given that several biologically active ent-kauranoids possess a spirocyclic lactone or lactol moiety, we set out to explore whether the spirolactone intermediate could be used for the synthesis of the more general 6,7-seco framework and its biogenetically related 7,20-epoxy type frameworks. This chapter introduces the state of the art prior to and concurrent with our synthetic efforts. A detailed account of our total †"The research discussed within this chapter was completed in collaboration with Dr. John T. S. Yeoman. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 20 syntheses of (–)-trichorabdal A and (–)-longikaurin E via a common intermediate is described. This work, taken together with our synthesis of (–)-maoecrystal Z, represents a unified synthetic strategy to access structurally distinct ent-kauranoid natural products. 2.2 PREVIOUS AND CONCURRENT SYNTHETIC EFFORTS Synthetic efforts relating to 6,7-seco-ent-kauranoids are discussed in this section with the aim of contextualizing our synthetic efforts with prior state of the art. Several syntheses of ent-kauranoid natural products followed our communication on the total synthesis of (–)-trichorabdal A and (–)-longikaurin E;1 for the sake of brevity, these syntheses will not be reviewed in this section. 2.2.1 Fujita’s Relay Synthesis of Enmein In light of their compelling biological activity and structural complexity, several research groups have reported total syntheses of 6,7-seco-ent-kauranoids. Perhaps the most challenging synthetic aspect of these diterpenoids is the formation of the two quaternary centers, which include the C8 quaternary center and the C10 quaternary center contained within the central spirolactone. As early as 1974, Fujita reported the total synthesis of enmein (15) through an optically active relay compound (Figure 2.1).2 In the synthesis, the C8 quaternary center was introduced via enolate alkylation. Thiol ether 37 was accessed in 12 steps from phenanthrene derivative 36. Deprotection of thiol ether 37 and ozonolysis afforded a ketoaldehyde that underwent a sodium methoxide-mediated aldol reaction to form bicyclo[3.2.1]octane 38 of the ent-kaurene core. After 21 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E advancement to alkene 39, ozonolysis cleaved the C6–C7 bond to form the 6,7-seco framework of 40, which was advanced a further 18 steps to enmein (15). H MeO 2C SBu 1. KOH, EtOH 12 steps 8 OMe O O MeO Me Me 36 O 8 steps O Me OH H Me 6 HO 7 39 H 2. O 3; DMS O (43% yield, 3 steps) CH2N 2 O O Me MeO Me O H 10 H O 3. NaOMe OH Me 37 O 3; Jones reagent; 8 OH Me Me OH O 38 OH Me 6 O O 20 O 6 OH O Me O 7 1 OMe 40 O 7 O enmein (15) Figure 2.1. Key transformations in Fujita’s relay synthesis of enmein (15). Mander’s Synthesis of 15-Desoxyeffusin 2.2.2 More than a decade later after Fujita’s studies, Mander reported the synthesis of 15-desoxy derivatives of effusin and longikaurin C (Figure 2.2).3 Similar to Fujita’s strategy, oxidative cleavage of the C6–C7 bond of a lactol precursor provided access to the seco-ent-karanoid framework. To construct the bicyclo[3.2.1]octane, α-diazoketone 41 was treated with trifluoroacetic acid to afford dienone 42 through an intramolecular aromatic alkylation. A further 12 steps provided lactone 43, which smoothly underwent intramolecular α-alkylation to furnish ent-kauranoid framework 44 after desilylation and oxidation. This intermediate was advanced to 15-desoxylongikaurin C (45), and oxidative cleavage of the C6–C7 bond upon exposure to periodic acid afforded the 6,7seco type desoxyeffusin (46) in a biomimetic fashion. Notably, oxidation of C15 on both 45 and 46 to afford the corresponding natural products was not achieved at the time. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 22 O CF3CO2H N2 MeO (88% yield) OMe 12 steps O 8 O OMe 41 42 H Br H 1. LDA, THF 2. TBAF OMOM O OMOM H 10 steps Me 3. PDC O Me H OTBS O (82% yield, 3 steps) 43 O O 44 H H Me OH 6 AcO 7 O OH H 5IO 6 Me Et 2O AcO 15 O O O (94% yield) 15-desoxylongikaurin C (45) H 15-desoxyeffusin (46) Figure 2.2. Mander’s synthesis of 15-desoxy analogues. 2.2.3 Zhai’s Total Synthesis of Sculponeatin N Zhai and colleagues recently disclosed a concise total synthesis of sculponeatin N (14) that utilizes a radical cyclization to build the bicyclo[3.2.1]octane unit (Figure 2.3).4 Beginning with known diester 47, a silyl diene unit was appended, and a reduction/acylation sequence provided 48 as an intramolecular Diels–Alder cycloaddition precursor. Heating to 190 °C in the presence of a radical scavenger simultaneously constructed the B and C-rings, and after silylation, provided tricycle 49 in 76% yield over two steps. The C8 quaternary center of 51 was introduced via alkylation of the lactone with 2,3-dibromopropene (50). In a crucial step of the synthesis, exposure of 51 to triethylborane and tris(trimethylsilyl)silane rapidly furnished 6,7-seco-ent-kauranoid core 52. Lastly, allylic oxidation and desilylation provided sculponeatin N (14) in just 13 steps from diester 47. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E TMS 6 steps Me Me O CO2Me 47 LDA, HMPA, THF, –78 °C; H O TBSO 50 Br O Br 49 O H O TBSO 3. 1 M HCl, THF O TBSO O Br Et 3B (TMS)3SiH PhH, 25 °C O (68% yield) 51 1. SeO2, TBHP 2. Dess–Martin Me Me (76% yield, 2 steps) Me Me (88% yield) H 2. TBSCl, imidazole O 48 O H Me Me 1. BHT, PhMe, 190 °C; p-TsOH, 120 °C; K 2CO3, MeOH Me Me CO2Me 23 H Me HO (80% yield, 3 steps) 52 O O Me O sculponeatin N (14) Figure 2.3. Zhai’s total synthesis of sculponeatin N (14). 2.3 SYNTHETIC APPROACH 2.3.1 Total Synthesis of (–)-Maoecrystal Z Our interest in the 6,7-seco-ent-kauranoids was piqued by maoecrystal Z (17), which possesses a unique rearranged skeleton.5 In 2011, our group reported the total synthesis of (–)-maoecrystal Z (17) that featured, among other key steps, a dialdehyde cyclization cascade to form the tetracyclic core.6 The synthetic strategy was partially guided by Fujita’s studies that showed treatment of trichorabdal B (13) initiated a retroDieckmann–aldol sequence to form the tetracyclic framework of 17. 7 In the retrosynthetic analysis, 17 was envisioned to arise from a SmII-initiated cascade cyclization of 54 through Sm-enolate 53 (Figure 2.4). Dialdehyde 54 would arise from Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 24 alkylation with alkyl iodide 55 of the key spirolactone 56 that is found within the skeleton of many ent-kauranoids. cascade cyclization H Me H H HO Me OAc O H H Me O O Me H O maoecrystal Z (17) O H Me O SmIII O SmIII O O Me H 53 O H O 54 H I OTBS + Me TBSO Me 55 O O 56 Figure 2.4. Retrosynthetic analysis of (–)-maoecrystal Z (17). In the forward direction, (–)-γ-cyclogeraniol (57) was converted to the silyl ether and treated with m-CPBA to form epoxide 58 as an inconsequential mixture of diastereomers (Figure 2.5). After much optimization, it was found that spirolactone 56 could be accessed diastereoselectively through a titanocene-mediated coupling with trifluoroethyl acrylate. Alkylation and oxidation afforded enoate 59, which was deprotected and treated with Dess–Martin periodinane to form the cyclization precursor, dialdehyde 54. In the key step of the synthesis, exposure of dialdehyde 54 to SmI2 and LiBr with t-BuOH as a proton source furnished a single diastereomer of tetracycle 60. This reaction likely proceeds through ketyl formation at C12, undergoing radical cyclization and further reduction to form Sm-enolate 53 (see Figure 2.4). A subsequent aldol reaction affords the central 5-membered ring, overall providing two new rings and setting four stereocenters in a single step. Lastly, bis-acetylation to diacetate 61 followed 25 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E by ozonolysis and α-methylenation provided enal 62, which was monodeprotected to afford maoecrystal Z (17). 1. TBSCl, imidazole Me Me OH (– )- γ-cyclogeraniol (57) 58 3 : 1 dr 1. O 3, CH2Cl2, –78 °C; Et 3N workup 2. [Me 2NCH 2]I Et 3N, CH2Cl2 (80% yield, 2 steps) s-collidine•HCl THF Me O O 56 single diastereomer H 1. H 2SiF6, 0 °C Me O 2. DMP O OTBS 59 H Me Ac2O TMSOTf OH CH2Cl2, 0 °C O H O O Me H O H O 54 H Me Ac O Me OAc O O (74% yield) 60 2 rings 4 stereogenic centers 61 H Me Ac H 12 Me (86% yield, 2 steps) 12 HO Me O (54% yield) Me TBSO (76% yield) Me TBSO 2. KHMDS, 0 °C PhSeBr, –78 °C; 30% H 2O 2, 0 °C THF, –78 °C H Cp2TiCl2, Zn OTBS (90% yield) 1. LHMDS, 55 THF/HMPA (4:1) 0 to 23 °C SmI2, LiBr t-BuOH Me Me 2. m-CPBA NaHCO 3 CO2CH2CF 3 O H H O Me OAc O O 62 O 1 M NaOH MeOH/H 2O (1:1) (38% yield) Me H HO Me OAc O O O (– )-maoecrystal Z (17) Figure 2.5. Total synthesis of (–)-maoecrystal Z (17). Our group’s total synthesis of (–)-maoecrystal Z (17) proceeded in 12 synthetic steps from (–)-γ-cyclogeraniol (57). The successful utilization of the key spirolactone 56 prompted our investigations to the biogenetically related ent-kauranoids (–)-trichorabdal A (12) and (–)-longikaurin E (11). Ultimately, spirolactone 56 would serve as an important building block for the completion of structurally distinct ent-kauranoid natural products. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 26 Retrosynthesis of (–)-Trichorabdal A and (–)-Longikaurin E 2.3.2 Retrosynthetically, 11 and 12 were both envisioned to arise from exo-olefin 63 (Figure 2.6). To access (–)-longikaurin E (11), we hoped to forge the central oxabicyclo[2.2.2]octane via the reductive cyclization of a C6-aldehyde precursor.8 The bicyclo[3.2.1]octane motif of 63 would arise through a transition metal-mediated oxidative cyclization reaction of silyl ketene acetal 64. Although the oxidative cyclization of silyl enol ethers is well precedented,9,10 there were no examples of transition metalmediated oxidative cyclizations between silyl ketene acetals and simple olefins that generated all-carbon quaternary centers reported prior to our studies.11 Mindful of this challenge, we were nonetheless eager to employ such a strategy for the assembly of this pivotal intermediate, as it was anticipated that the Sm(II)-mediated cyclization chemistry devised en route to (–)-maoecrystal Z (17) would enable the facile synthesis of tricycle 64 from aldehyde 65 and intermediate 59. Thus, the strategy would enable the divergent synthesis of three architecturally unique ent-kauranoids via a common precursor. H Me H O O Me O HO O Me (– )-trichorabdal A (12) H Sm-mediated reductive cyclization O OH Me Pd-mediated oxidative cyclization H H O Me O OR O Me TBSO H Me OSiR'3 O 63 64 7 Me 6 O OH Sm-mediated reductive cyclization OAc (– )-longikaurin E (11) TBSO H Me RO H H HO Me OAc O H H O maoecrystal Z (17) O H Me TBSO Me TBSO O Me Me O 59 O O H O 65 Figure 2.6. Retrosynthesis of (–)-trichorabdal A (12) and (–)-longikaurin E (11). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 2.4 FORWARD SYNTHETIC EFFORTS 2.4.1 Development of a Pd(II)-Mediated Oxidative Cyclization 27 To investigate the proposed oxidative cyclization, we needed to prepare silyl ketene acetal 64 from enoate 59 (Figure 2.7). The more sterically accessible silyl ether of 59 was deprotected and oxidized to afford aldehyde 66. Treatment with a mixture of SmI2 and LiBr in THF in the presence of t-BuOH at low temperature formed the cyclization product 67 as a single diastereomer in 57% yield. MOM-protection of the secondary alcohol of 67 allowed for smooth conversion to silyl ketene acetal 64 upon deprotonation and trapping with TBSCl. It was found that use of silyl protecting groups gave lower yields of silyl ketene acetal 64, presumably due to 1,3-diaxial interactions that made deprotonation at C8 challenging. O 1. n-Bu4NHSO 4 p-TsOH, MeOH 59 2. DMP, CH2Cl2 SmI2, LiBr t-BuOH H Me TBSO THF, –78 °C Me O (77% yield, 2 steps) HO H H Me O MOMCl n-Bu 4NI, DIPEA DMF, 45 °C Me TBSO H Me (91% yield) O 68 O (57% yield) 66 MOMO H H Me TBSO O 67 H KHMDS TBSCl, DMPU 8 THF, –78 °C O MOMO H Me TBSO H Me (85% yield) O OTBS 64 Figure 2.7. Preparation of silyl ketene acetal 64. With oxidative cyclization precursor 64 in hand, a survey of conditions for the key oxidative cyclization step was conducted. Upon exposure of 64 to 10 mol % Pd(OAc)2 in DMSO at 45 °C under an air atmosphere, we were delighted to isolate tetracycle 69, albeit in only 7% yield (Table 1, entry 1). Fortunately, the use of 28 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E stoichiometric Pd(OAc)2 substantially improved both conversion and the yield of 69 (entry 2), and a survey of reaction conditions was conducted. The desired transformation does proceed in MeCN at ambient temperature (entry 3); however, increased side product formation is observed. Other solvents (e.g., PhMe, glyme, dioxane, t-BuOH, DMF) yielded only traces of 69. Other palladium sources also performed poorly (entries 4–6): for example, the major product when using PdCl2 and AgBF4 (entry 6) was methyl ketone 70, via Wacker oxidation. No desaturated products from Saegusa–Ito-type pathways were observed.12 H Me TBSO Me MOMO H H Pd II O O OMOM TBS DMSO, 45 °C air Me TBSO 64 Me TBSO O Me O OMOM Me H O H Me O 69 O 70 Entry Pd source (equiv) Additive (equiv) Yield 69 (%)a 1 Pd(OAc)2 (0.1) -- 7 2 Pd(OAc)2 (1.0) -- 35 3b Pd(OAc)2 (1.0) -- 28c 4 Pd(TFA)2 (1.0) -- 19 5 PdCl2 (1.0) -- 0 6 PdCl2 (1.0) AgBF4 (2.0) 5d 7e Pd(OAc)2 (1.0) H2O (5.0) 38 8 Pd(OAc)2 (1.0) K2CO3 (5.0) 0 9 Pd(OAc)2 (1.0) AcOH (0.5) 56 10 Pd(OAc)2 (0.1) AcOH (0.5) 7 11 Pd(OAc)2 (1.0) AcOH (1.0) 31 12 Pd(OAc)2 (1.0) p-TsOH (0.5) 46 13 Pd(OAc)2 (1.0) BzOH (0.5) 32 14 Pd(OAc)2 (1.0) PivOH (0.5) 40 a Isolated yield. bReaction conducted in MeCN at 23 °C. cProduct isolated as an inseparable 4.3:1 mixture with an olefin isomerization side product. d13% yield of methyl ketone 70 was also isolated. eRun under a N2 atmosphere. Table 2.1. Reaction optimization of the oxidative cyclization of 64. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 29 High variability in both the yield and purity of 69 upon attempts to increase reaction scale beyond a few milligrams prompted an examination of the roles of adventitious water and Brønsted acid. Indeed, similar reaction conditions with water and Brønsted acid have been used to promote Wacker-type oxidation of terminal olefins.13 Control experiments demonstrated that water had little effect on product formation (entry 7), whereas the addition of bases such as K2CO3 inhibits the reaction (entry 8). On the other hand, the use of 0.5 equiv AcOH as an additive afforded 69 in 56% yield (entry 9) with a much cleaner reaction profile, a result reproducible on preparative scales. Neither an increased amount of AcOH nor the use of other acids examined were found to further improve the yield. To the best of our knowledge, this represents the first example of a Pd-mediated oxidative cyclization of a silyl ketene acetal to generate an all-carbon quaternary center. 2.4.2 Total Synthesis of (–)-Trichorabdal A Having now established the carbon framework present in many 6,7-seco-ent- kauranoids, the remaining steps for the synthesis of 12 included installation of the exoenone and C6 aldehyde. Ozonolysis of 69 and subsequent α-methylenation using bis(dimethylamino)methane and acetic anhydride delivered β-ketolactone 72 (Figure 2.8).14 Notably, the analogous two-step procedure using Eschenmoser’s salt provided significantly diminished yields of 72. Exposure to 6 M aqueous HCl in dioxane at 45 °C smoothly effected global deprotection, and selective oxidation of the C6 primary alcohol was accomplished using catalytic TEMPO and PhI(OAc)2,15 delivering (–)-trichorabdal A (12).16 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E H Me TBSO H O 3, CH2Cl2, –94 °C; O Me then PPh 3 OMOM O Me TBSO O DMF, 95 °C Me (69% yield) H Me TBSO Me 2NCH 2NMe 2, Ac2O O OMOM O 69 O Me OMOM O 72 (82% yield) 71 H 1. HCl (aq) dioxane, 45 °C O 30 Me H 2. TEMPO, PhI(OAc) 2 CH2Cl2 O O Me O O HO (– )-trichorabdal A (12) (73% yield, 2 steps) Figure 2.8. Total synthesis of (–)-trichorabdal A (12). Total Synthesis of (–)-Longikaurin E 2.4.3 With the synthesis of 12 complete, we turned our attention to the aldehydelactone reductive coupling required for the synthesis of (–)-longikaurin E (11). Treatment of exo-olefin 69 with 6 M aqueous HCl in dioxane at 45 °C resulted in global deprotection to afford diol 73; subsequent oxidation with catalytic TEMPO and PhI(OAc)2 likewise proceeded smoothly (Figure 2.9). Aldehyde 74 was acetylated using acetic anhydride and DMAP to furnish 75, and a screen of reaction parameters for the proposed reductive cyclization was conducted. H Me TBSO H HCl (aq) O dioxane, 60 °C Me Me HO OMOM O Me 73 H Me H Ac2O, DMAP O O CH2Cl2 OH O (89% yield) 69 TEMPO PhI(OAc) 2 O Me H O OH CH2Cl2 (58% yield, 2 steps) 74 Figure 2.9. Synthesis of aldehyde-lactone 75. Me O O Me H O 75 OAc Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 31 H OH Me H Me O O Me SmI2 additives Me H O H H Me 75 OAc 76 THF OAc O OH Me HO Me O OH OAc O Me 77 O OAc 78 Entry Equivs SmI2 Additives (equivs) Temperature (°C) Yielda (brsm) 1 5.0 LiCl (50), t-BuOH (1.0) –78 no reaction 2 5.0 LiBr (50), t-BuOH (1.0) –78 no reaction 3 5.0 t-BuOH (1.0) –78 no reaction 4 5.0 HMPA (50), t-BuOH (1.0) –78 0%b 5 5.0 LiCl (50), t-BuOH (1.0) 0 54% 78 6 5.0 LiBr (50), t-BuOH (1.0) 0 38% 78 7 5.0 t-BuOH (1.0) 0 25% 76 (100%) 8 2.2 -- 23 55% 76 (75%) 2.4 -- 23 55% 76 (62%) t-BuOH (1.0) 23 72% 77 9 10 a c 5.0 b c Isolated yield. Complex mixture. Run to full consumption of 75. Table 2.2. Optimization of Sm-mediated pinacol-type coupling. Surprisingly, treatment of aldehyde-lactone 75 with LiCl, LiBr, or no lithium salt in the presence of t-BuOH at –78 °C (Table 2.2, entries 1–3) led to recovery of starting material, while use of a bulkier additive, HMPA, resulted in a complex mixture of products (entry 4). The use of lithium salts with t-BuOH at higher temperature induced reduction of the aldehyde to alcohol 78 with no recovered starting material (entries 5–6). Fortunately, omitting the lithium salts at 0 °C gave 20% yield of desired hydroxyl-lactol 76 (entry 7). Further raising the temperature to 23 °C improved conversion, while utilizing less equivalents of SmI2, and excluding the proton source lowered the amount of 32 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E side-products. Overall, this resulted in a 55% isolated yield of the desired product (76), along with 27% yield of recovered starting material (entry 8). The remainder of the mass balance was attributed to C6-deoxy lactol 77 and over-reduction side products. Attempts to push the reaction to completion, for example by raising the equivalents of SmI2, resulted in larger amounts of side-product 77 (entry 9). In fact, running the reaction to full consumption of 75 gave lactol 77 in 72% yield (entry 10). Completion of the total synthesis from hydroxyl-lactol 76 proceeded via ozonolysis and α-methylenation under previously described conditions (Figure 2.10). Notably, a significant amount of an epoxide product was observed in the ozonolysis of 76. Formation of this epoxide was suppressed by using lower temperatures, down to –94 °C. Lastly, α-methylenation of ketone 79 delivered (–)-longikaurin E (11) in 67% yield.17 This represents the first total synthesis of a 7,20-epoxy-ent-kauranoid natural product. H H OH Me Me O 3, DCM, –94 °C O OH 76 OAc then PPh 3 (66% yield) O Me 2NCH 2NMe 2 Ac2O OH Me Me O OH 79 OAc DMF, 95 °C (67% yield) H O OH Me Me O OH OAc (– )-longikaurin E (11) Figure 2.10. Total synthesis of (–)-longikaurin E (11). 2.5 CONCLUDING REMARKS In summary, a unified synthetic strategy to prepare three unique ent-kauranoid frameworks from unsaturated lactone 59 has been established. The first total synthesis of (–)-trichorabdal A (12) and (–)-longikaurin E (11) proceeded in 15 and 17 steps and 3.2% and 1.0% overall yield, respectively, from (–)-γ-cyclogeraniol (57). The pivotal transformations that enabled these syntheses include a new PdII-mediated oxidative Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 33 cyclization of a silyl ketene acetal (64) to form an all-carbon quaternary center, as well as a SmII-mediated pinacol-type coupling to forge the oxabicyclo[2.2.2]octane of 11. Taken with our group’s total synthesis of (–)-maoecrystal Z (17), we have demonstrated the synthetic utility of single-electron chemistry in diastereoselectively forming vicinal stereocenters in complex polycyclic systems and have also established a non-biomimetic synthetic relationship among three architecturally distinct ent-kaurane diterpenoids. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 2.6 EXPERIMENTAL SECTION 2.6.1 Materials and Methods 34 Unless otherwise stated, reactions were performed under an inert atmosphere (dry N2 or Ar) with freshly dried solvents utilizing standard Schlenk techniques. Glaswarewas oven-dried at 120 °C for a minimum of four hours, or flame-dried utilizing a Bunsen burner under high vacuum. Tetrahydrofuran (THF), methylene chloride (CH2Cl2), acetonitrile (MeCN), tert-butyl methyl ether (TBME), benzene (PhH), and toluene (PhMe) were dried by passing through activated alumina columns. Triethylamine (Et3N) and N,N-Diisopropylethylamine (DIPEA) were distilled over calcium hydride, 1,3Dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (DMPU) and hexamethylphosphoramide (HMPA) were distilled over calcium hydride under reduced pressure, and dimethylsulfoxide (DMSO) was dried over 4 Å MS for at least 48 hours prior to use. Unless otherwise stated, chemicals and reagents were used as received. All reactions were monitored by thin-layer chromatography using EMD/Merck silica gel 60 F254 precoated plates (0.25 mm) and were visualized by UV, p-anisaldehyde, KMnO4, or CAM staining staining. Flash column chromatography was performed using silica gel (SiliaFlash® P60, particle size 40-63 microns [230 to 400 mesh]) purchased from Silicycle. Optical rotations were measured on a Jasco P-2000 polarimeter using a 100 mm path-length cell at 589 nm. 1H and 13C NMR spectra were recorded on a Bruker Avance III HD with Prodigy cryoprobe (at 400 MHz and 101 MHz respectively), a Varian 400 MR (at 400 MHz and 101 MHz, respectively), a Varian Inova 500 (at 500 MHz and 126 MHz, respectively), or a Varian Inova 600 (at 600 MHz and 150 MHz, respectively), and are reported relative to internal CHCl3 (1H, δ = 7.26) and CDCl3 (13C, δ = 77.0). Data for 35 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 1 H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, app = apparent. IR spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm–1). HRMS were acquired using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI), atmospheric pressure chemical ionization (APCI), or mixed (MM) ionization mode. Preparative HPLC was performed with an Agilent 1100 Series HPLC utilizing an Agilent Eclipse XDB-C18 5µm column (9.4 x 250 mm). Preparative Procedures and Spectroscopic Data 2.6.2 Preparation of aldehyde 66: TBSO Me Me MeOH, 0 °C O TBSO 59 O O HO n-Bu4NHSO 4 p-TsOH DMP Me Me DCM O TBSO S1 O Me Me O TBSO (77% yield, 2 steps) O 66 To a solution of enoate 59 (1.94 g, 3.43 mmol) in 35 mL MeOH cooled to 0 °C was added n-Bu4NHSO4 (128 mg, 0.378 mmol, 0.11 equiv) and p-TsOH (26 mg, 0.14 mmol, 0.04 equiv). After stirring at 0 °C for 1.5 h, the reaction mixture was diluted with sat. NaHCO3 (25 mL) and concentrated in vacuo to remove MeOH. The aqueous layer was then extracted with EtOAc (3 x 15 mL). The combined organic extracts were then washed with brine (15 mL), dried over Na2SO4, and concentrated in vacuo to provide crude alcohol S1. Crude S1 was immediately dissolved in DCM (35 mL) and Dess– Martin periodinane (2.91 g, 6.87 mmol, 2.0 equiv) was added. After stirring at ambient Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 36 temperature for 30 min, sat. NaHCO3 (20 mL) and sat. Na2S2O3 (20 mL) were added and the biphasic mixture was stirred vigorously until both layers became clear (20 min). The layers were separated and the aqueous phase was extracted with DCM (3 x 15 mL). The combined organic extracts were washed with brine (15 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (10 to 12% EtOAc/Hex) to provide aldehyde 66 as a clear gum (1.18 g, 77% yield from 59). 1 H NMR (500 MHz, CDCl3): δ 9.71 (t, J = 2.0 Hz, 1H), 6.39 (s, 1H), 5.78 – 5.66 (m, 1H), 5.09 – 4.99 (m, 2H), 4.48 (dd, J = 11.2, 1.9 Hz, 1H), 4.40 (dd, J = 11.2, 1.4 Hz, 1H), 3.81 – 3.71 (m, 2H), 2.48 – 2.26 (m, 4H), 2.20 – 2.10 (m, 2H), 2.01 (dt, J = 13.9, 7.6 Hz, 1H), 1.84 (d, J = 13.6 Hz, 1H), 1.69 – 1.49 (m, 2H), 1.48 – 1.39 (m, 2H), 1.25 (td, J = 13.0, 4.3 Hz, 1H), 1.14 (td, J = 13.0, 4.4 Hz, 1H), 1.01 (s, 3H), 0.89 (s, 3H), 0.86 (s, 9H), 0.02 (s, 6H) 13 C NMR (126 MHz, CDCl3): δ 202.5, 164.8, 155.6, 135.6, 126.2, 117.6, 69.9, 61.3, 55.5, 47.3, 42.0, 39.7, 38.6, 36.0, 33.1, 33.0, 32.8, 32.1, 25.8, 23.2, 18.3, 18.1, -5.5, -5.6. FTIR (thin film/NaCl): 3421, 3076, 2927, 2855, 2716, 1728, 1713, 1471, 1393, 1255, 1164, 1150, 1104, 1068, 995, 913, 838, 776 cm–1. HRMS: (MM: ESI–APCI) calc’d for C26H45O4Si [M + H]+ 449.3082, found 449.3067. [!]!" ! = –33.4° (c = 1.23, CHCl3). An analytical sample of alcohol S1 was obtained (63% yield) by SiO2 chromatography (30% EtOAc/Hex): Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 1 37 H NMR (500 MHz, CDCl3): δ 6.37 (s, 1H), 5.73 (dddd, J = 16.8, 10.4, 7.7, 6.5 Hz, 1H), 5.07 – 4.98 (m, 2H), 4.51 (dd, J = 11.3, 2.1 Hz, 1H), 4.41 (dd, J = 11.3, 1.5 Hz, 1H), 3.83 – 3.71 (m, 3H), 3.67 (dt, J = 11.0, 6.4 Hz, 1H), 2.36 (ddd, J = 13.9, 5.6, 1.3 Hz, 1H), 2.16 – 2.07 (m, 1H), 2.04 (dd, J = 14.0, 8.2 Hz, 1H), 2.01 – 1.92 (m, 2H), 1.91 – 1.78 (m, 2H), 1.66 – 1.49 (m, 3H), 1.49 – 1.34 (m, 3H), 1.32 – 1.21 (m, 1H), 1.21 – 1.09 (m, 1H), 1.02 (s, 3H), 0.92 (s, 3H), 0.87 (s, 9H), 0.03 (s, 6H); 13 C NMR (126 MHz, CDCl3): δ 165.2, 154.6, 136.3, 127.6, 116.8, 70.0, 61.5, 60.6, 55.6, 42.1, 40.0, 38.2, 35.7, 35.3, 33.3, 33.3, 33.0, 32.8, 25.8, 23.3, 18.4, 18.0, -5.5, -5.6; FTIR (thin film/NaCl): 3447, 3074, 2952, 2928, 2856, 1718, 1472, 1462, 1395, 1363, 1256, 1165, 1150, 1105, 1069, 995, 909, 838, 776; HRMS: (MM: ESI–APCI) calc’d for C26H47O4Si [M + H]+ 451.3238, found 451.3251. [!]!" ! = –44.6° (c = 1.21, CHCl3); Preparation of tricycle 67: O Me Me THF, –78 °C O TBSO 66 HO SmI2, LiBr t-BuOH H H Me TBSO H Me O (57% yield) O O 67 Fresh SmI2 was prepared according to the following procedure:18 A flame-dried flask was charged with finely ground samarium (Aldrich, 1.30 g, 8.64 mmol, 1.7 equiv) and was briefly flame-dried in vacuo. Once cooled, THF (50 mL) was added under argon followed by diiodoethane (1.40 g, 4.96 mmol, 1.0 equiv) with vigorous stirring for 3 h at ambient temperature. The deep blue solution (~0.1M in SmI2) was allowed to settle for at least 10 min prior to use. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 38 A solution of aldehyde 66 (0.676 g, 1.51 mmol) and t-BuOH (0.145 mL, 1.51 mmol, 1.0 equiv) in 150 mL THF was cooled to –78 °C. Inside a glovebox, a separate flame-dried flask was charged with LiBr (3.27 g, 38 mmol, 25 equiv), removed from the glovebox, and to this flask was added freshly prepared 0.1 M SmI2 in THF (38 mL, 3.8 mmol, 2.5 equiv) and stirred vigorously for 2 min. While stirring continued, the resulting homogenous purple solution was added to the aldehyde solution via cannula. After 45 min at –78 °C, sat. NaHCO3 (60 mL), sat. Na2S2O3 (60 mL) and Rochelle salt (10 g) were added, and the mixture was extracted with EtOAc (3 x 80 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (9 to 12% EtOAc/Hex) to afford tricycle 67 as a white foam (0.385 g, 57% yield). 1 H NMR (500 MHz, CDCl3): δ 5.80 – 5.68 (m, 1H), 5.04 – 4.94 (m, 2H), 4.55 (br s, 1H), 4.47 (d, J = 11.4 Hz, 1H), 4.24 (dd, J = 11.5, 1.4 Hz, 1H), 3.72 (dd, J = 11.4, 4.1 Hz, 1H), 3.67 (dd, J = 11.3, 3.3 Hz, 1H), 2.85 (td, J = 12.3, 3.4 Hz, 1H), 2.45 (dtd, J = 13.2, 3.6, 2.0 Hz, 1H), 2.04 – 1.84 (m, 5H), 1.79 – 1.71 (m, 2H), 1.69 (t, J = 3.8 Hz, 1H), 1.56 – 1.36 (m, 4H), 1.27 (td, J = 12.7, 4.9 Hz, 1H), 1.09 (ddd, J = 14.2, 12.5, 2.2 Hz, 1H), 1.01 (s, 3H), 0.98 (t, J = 12.0 Hz, 1H), 0.88 (s, 3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 174.2, 136.2, 116.3, 73.2, 65.5, 60.0, 51.5, 46.6, 41.9, 40.9, 40.8, 39.5, 35.4, 35.1, 34.1, 33.7, 30.6, 27.8, 25.9, 23.6, 18.4, 18.1, -5.5, -5.6. FTIR (thin film/NaCl): 3461, 3075, 2927, 2856, 1716, 1471, 1463, 1394, 1362, 1256, 1220, 1064, 1046, 994, 911, 837, 776, 734 cm–1. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 39 HRMS: (MM: ESI–APCI) calc’d for C26H47O4Si [M + H]+ 451.3238, found 451.3236. [!]!" ! = –11.3° (c = 2.26, CHCl3). Preparation of MOM ether 68: MOMCl i-Pr2NEt n-Bu4NI HO H H Me TBSO H Me O DMF, 45 °C O 67 (91% yield) MOMO H Me TBSO H H Me O O 68 A solution of tricycle 67 (0.315 g, 0.699 mmol), n-Bu4NI (26 mg, 70 µmol, 0.1 equiv), DIPEA (0.73 mL, 4.2 mmol, 6.0 equiv), and MOMCl (92% tech., 0.29 mL, 3.5 mmol, 5.0 equiv) in 3.5 mL DMF was heated to 45 °C. After stirring for 6 h at 45 °C, the reaction mixture was cooled to room temperature and diluted with sat. NaHCO3 (5 mL) and extracted with Et2O (3 x 5 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude residue was chromatographed on SiO2 (7 to 9% EtOAc/Hex) to afford methoxymethyl ether 68 as a clear gum (0.315 g, 91% yield). 1 H NMR (500 MHz, CDCl3): δ 5.81 – 5.69 (m, 1H), 5.05 – 4.98 (m, 1H), 4.98 (t, J = 1.2 Hz, 1H), 4.68 (d, J = 6.7 Hz, 1H), 4.62 (d, J = 6.7 Hz, 1H), 4.50 (d, J = 11.4 Hz, 1H), 4.37 (dt, J = 3.7, 1.8 Hz, 1H), 4.24 (dd, J = 11.4, 1.4 Hz, 1H), 3.74 (dd, J = 11.4, 4.1 Hz, 1H), 3.67 (dd, J = 11.4, 3.3 Hz, 1H), 3.40 (s, 3H), 2.87 (td, J = 12.3, 3.5 Hz, 1H), 2.47 (dtd, J = 13.1, 3.7, 2.1 Hz, 1H), 2.09 – 1.86 (m, 5H), 1.86 – 1.72 (m, 2H), 1.69 (t, J = 3.7 Hz, 1H), 1.64 – 1.40 (m, 4H), 1.28 – 1.18 (m, 1H), 1.08 – 0.96 (m, 4H), 0.90 (s, 3H), 0.89 (s, 9H), 0.05 (s, 3H), 0.05 (s, 3H). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 13 40 C NMR (126 MHz, CDCl3): δ 173.9, 136.2, 116.3, 95.1, 73.3, 71.4, 59.8, 56.3, 51.4, 47.0, 42.1, 40.8, 39.6, 36.4, 36.1, 35.3, 34.1, 33.9, 31.2, 27.4, 25.9, 23.5, 18.3, 18.1, -5.5, -5.6. FTIR (thin film/NaCl): 3074, 2951, 2927, 2855, 1731, 1472, 1462, 1389, 1361, 1256, 1202, 1149, 1085, 1063, 1045, 918, 838, 776 cm–1. HRMS: (MM: ESI–APCI) calc’d for C28H51O5Si [M + H]+ 495.3500, found 495.3510. [!]!" ! = –22° (c = 0.76, CHCl3). Preparation of silyl ketene acetal 64: MOMO H Me TBSO KHMDS THF, 0 °C; H H Me O 68 O then –78 °C, DMPU, TBSCl (85% yield) MOMO H Me TBSO H Me O OTBS 64 *Note: 1-methyl-2-pyrrolidinone (NMP; distilled from CaH2) can be readily substituted for DMPU affording identical product yields. To a solution of KHMDS (0.106 g, 0.534 mmol, 2.0 equiv) in 5 mL THF cooled to 0 °C was added MOM ether 68 (0.132 g, 0.267 mmol) dropwise as a solution in THF (3 mL + 1 mL rinse). After stirring at 0 °C for 30 min, the reaction mixture was cooled to –78 °C and DMPU (1.0 mL) was added dropwise. After stirring 5 min, TBSCl (80 mg in 1 mL THF, 0.53 mmol, 2.0 equiv) was added and cooling was maintained at –78 °C. After 1 h, the reaction mixture was warmed to 0 °C, diluted with ice-cold pentane (10 mL) and ice-cold sat. NaHCO3 (5 mL). The layers were separated and the aqueous was extracted with ice-cold pentane (2 x 5 mL). The combined organic layers were washed Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 41 with brine (3 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on Florisil (3% EtOAc/Hex with 0.5% Et3N) to afford silyl ketene acetal 64 as a clear gum (0.139 g, 85% yield). 1 H NMR (500 MHz, CDCl3): δ 5.77 (ddt, J = 17.2, 10.2, 7.1 Hz, 1H), 5.02 – 4.93 (m, 2H), 4.68 (d, J = 6.8 Hz, 1H), 4.63 (d, J = 6.8 Hz, 1H), 4.04 (dd, J = 11.4, 2.9 Hz, 1H), 3.99 (d, J = 10.3 Hz, 1H), 3.92 (dt, J = 3.8, 1.8 Hz, 1H), 3.84 (dd, J = 10.4, 1.5 Hz, 1H), 3.81 (dd, J = 11.4, 2.6 Hz, 1H), 3.36 (s, 3H), 2.69 (ddd, J = 13.2, 4.3, 2.1 Hz, 1H), 2.22 (s, 1H), 2.15 (dq, J = 13.8, 2.7 Hz, 1H), 2.02 – 1.87 (m, 2H), 1.79 – 1.66 (m, 2H), 1.59 – 1.39 (m, 4H), 1.31 – 1.15 (m, 2H), 1.05 (s, 3H), 1.02 (s, 3H), 1.00 – 0.93 (m, 2H), 0.93 (s, 9H), 0.90 (s, 9H), 0.13 (s, 6H), 0.03 (s, 3H), 0.03 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 148.5, 137.2, 115.5, 95.8, 82.8, 74.7, 71.9, 61.7, 56.3, 50.1 (br), 45.8, 41.2, 38.5 (br), 38.2, 37.7, 33.8, 33.6, 32.9, 32.8, 30.4 (br), 28.1, 26.0, 25.8, 19.5, 18.1, 18.0, -4.2, -4.4, -5.7, -5.9. FTIR (thin film/NaCl): 3075, 2952, 2929, 2857, 1713, 1472, 1463, 1361, 1250, 1166, 1150, 1099, 1047, 1035, 989, 910, 870, 839, 783 cm–1. HRMS: (MM: ESI–APCI) calc’d for C34H65O5Si2 [M + H]+ 609.4365, found 609.4354. [!]!" ! = –82.6° (c = 1.50, CHCl3). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 42 Preparation of tetracycle 69: MOMO H Me TBSO Pd(OAc) 2 AcOH H Me O OTBS 64 DMSO, 45 °C air (56% yield) H Me TBSO O Me O OMOM 69 A solution of silyl ketene acetal 64 (0.139 g, 0.228 mmol), Pd(OAc)2 (52 mg, 0.23 mmol, 1.0 equiv), and AcOH (6.9 mg in 0.10 mL DMSO, 0.11 mmol, 0.5 equiv) in 9 mL DMSO was heated to 45 °C in an open flask. After stirring under air for 6 h at 45 °C, the reaction mixture was cooled to room temperature, diluted with 1M HCl (10 mL) and extracted with Et2O (4 x 6 mL). The combined organic extracts were washed with brine (3 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (7 to 9% EtOAc/Hex) to afford tetracycle 69 as a clear gum (63 mg, 56% yield). 1 H NMR (600 MHz, CDCl3): δ 4.98 (s, 1H), 4.94 (s, 1H), 4.65 (d, J = 6.7 Hz, 1H), 4.62 (d, J = 6.8 Hz, 1H), 4.53 (s, 2H), 4.13 (q, J = 4.4 Hz, 1H), 3.79 (dd, J = 11.4, 5.0 Hz, 1H), 3.71 (dd, J = 11.7, 2.0 Hz, 1H), 3.40 (s, 3H), 2.68 (d, J = 5.0 Hz, 1H), 2.58 (d, J = 16.6 Hz, 1H), 2.47 – 2.42 (m, 2H), 2.30 – 2.22 (m, 2H), 2.19 (d, J = 16.3 Hz, 1H), 1.89 (dd, J = 11.8, 3.9 Hz, 1H), 1.78 (d, J = 14.0 Hz, 1H), 1.73 – 1.68 (m, 1H), 1.49 – 1.41 (m, 3H), 1.37 (dd, J = 14.5, 4.5 Hz, 1H), 1.30 – 1.24 (m, 1H), 1.02 (s, 3H), 0.94 (s, 3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.04 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 175.4, 157.0, 106.1, 96.0, 72.9, 71.5, 60.7, 56.1, 53.4, 52.2, 52.1, 42.9, 42.4, 41.4, 35.9, 35.8, 34.4, 34.4, 30.9, 30.6, 25.9, 23.7, 18.3, 18.2, -5.5, -5.5. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 43 FTIR (thin film/NaCl): 3583, 2926, 2853, 1739, 1464, 1388, 1252, 1232, 1147, 1082, 1046, 837, 776 cm–1. HRMS: (MM: ESI–APCI) calc’d for C28H49O5Si [M + H]+ 493.3344, found 493.3355. [!]!" ! = +23.0° (c = 0.305, CHCl3). Optimization of reaction parameters: General procedure for oxidative cyclization of 64 to 69 (Table 2.1). A vial was charged with silyl ketene acetal 64 (10 mg, 16 µmol), Pd(II) salt, additive, and solvent (0.65 mL), placed under an atmosphere of O2, N2, or air, and heated to the desired temperature. Following the cessation of reaction progress as indicated by LC-MS or TLC analysis, the mixture was cooled to room temperature and diluted with 1M HCl (1 mL) and Et2O (1 mL). The layers were separated and the aqueous layer was extracted further with Et2O (3 x 0.5 mL). The combined organic extracts were washed with brine (0.5 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (7 to 9% EtOAc/Hex) to afford pure tetracycle 69. Preparation of methyl ketone 70: MOMO H Me TBSO H Pd(MeCN) 4(BF4)2 H Me O 68 O DMSO, 45 °C air MOMO H Me TBSO O H Me H Me (26% yield) O O 70 *Note: Methyl ketone 70 was initially isolated as a side product during optimization experiments for the conversion of 64 to 69 (Table 2.1, entry 6, 13% yield). Independent preparation was accomplished using the following procedure. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 44 A solution of MOM ether 68 (16 mg, 32 µmol) and Pd(MeCN)4(BF4)2 (14 mg, 32 µmol, 1.0 equiv) in DMSO (1.3 mL) was heated at 45 °C in an open vial. After stirring under air for 3 h, the reaction mixture was cooled to room temperature and diluted with 1M HCl (2 mL) and extracted with Et2O (3 x 2 mL). The combined organic extracts were washed with brine (1 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (10 to 20% EtOAc/Hex) to afford methyl ketone 70 as a clear gum (4.3 mg, 26% yield). 1 H NMR (500 MHz, CDCl3): δ 4.76 (d, J = 6.8 Hz, 1H), 4.64 (d, J = 6.8 Hz, 1H), 4.50 (d, J = 11.4 Hz, 1H), 4.37 (dt, J = 3.8, 1.8 Hz, 1H), 4.25 (dd, J = 11.4, 1.4 Hz, 1H), 3.74 (dd, J = 11.4, 4.0 Hz, 1H), 3.67 (dd, J = 11.4, 3.3 Hz, 1H), 3.45 (s, 3H), 2.94 (td, J = 12.3, 3.6 Hz, 1H), 2.46 – 2.37 (m, 2H), 2.38 – 2.23 (m, 2H), 2.13 (s, 3H), 2.09 (dq, J = 14.1, 3.2 Hz, 1H), 1.99 – 1.88 (m, 2H), 1.81 – 1.73 (m, 1H), 1.68 (t, J = 3.7 Hz, 1H), 1.59 – 1.42 (m, 4H), 1.29 – 1.19 (m, 1H), 1.11 – 1.03 (m, 1H), 1.02 (s, 3H), 0.90 (s, 3H), 0.88 (s, 9H), 0.05 (s, 3H), 0.05 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 207.5, 173.6, 95.0, 73.4, 70.7, 59.9, 56.5, 51.4, 50.1, 46.8, 42.1, 39.6, 36.3, 36.0, 35.3, 34.1, 33.9, 30.5, 27.4, 27.1, 25.9, 23.6, 18.4, 18.1, -5.5, -5.5. FTIR (thin film/NaCl): 2951, 2926, 2855, 1732, 1716, 1471, 1463, 1361, 1251, 1206, 1148, 1084, 1063, 1045, 918, 837, 776 cm–1. HRMS: (MM: ESI–APCI) calc’d for C28H51O6Si [M + H]+ 511.3449, found 511.3465. [!]!" ! = –15° (c = 0.22, CHCl3). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 45 Preparation of ketolactone 71: H H O 3, DCM, –94 °C Me TBSO O Me O 69 OMOM then PPh 3 /polystyrene –94 to 23 °C Me TBSO (69% yield) O O Me O OMOM 71 A solution of tetracycle 69 (30.0 mg, 60.9 µmol) in 6 mL DCM was cooled to –94 °C (liq. N2/acetone) at which time ozone was gently bubbled through the solution (O2 flow rate = 1/8 L/min, 1 setting on ozone generator) for 10 min. The solution was purged with argon for 5 min, polystyrene-bound PPh3 (3 mmol/g loading, 200 mg, 0.61 mmol, 10 equiv) was then added. The reaction was slowly warmed to room temperature over 30 min. After stirring for 3 h, the suspension was filtered through celite and concentrated in vacuo. The crude residue was chromatographed on SiO2 (15 to 20% EtOAc/Hex) to afford ketolactone 71 as a clear gum (20.9 mg, 69% yield). 1 H NMR (500 MHz, CDCl3): δ 4.69 (d, J = 6.7 Hz, 1H), 4.61 (d, J = 6.7 Hz, 1H), 4.59 (d, J = 11.5 Hz, 1H), 4.39 (d, J = 11.4 Hz, 1H), 4.27 (br s, 1H), 3.69 (d, J = 11.3 Hz, 1H), 3.64 (dd, J = 11.7, 6.1 Hz, 1H), 3.41 (s, 3H), 2.83 (d, J = 10.8 Hz, 1H), 2.73 – 2.62 (m, 2H), 2.48 (ddd, J = 18.4, 6.9, 1.4 Hz, 1H), 2.44 – 2.31 (m, 2H), 2.13 (dd, J = 18.4, 3.7 Hz, 1H), 2.07 (t, J = 13.1 Hz, 1H), 1.75 – 1.65 (m, 2H), 1.53 – 1.37 (m, 3H), 1.32 (dd, J = 15.4, 4.4 Hz, 1H), 1.29 – 1.21 (m, 1H), 1.03 (s, 3H), 0.88 (s, 3H), 0.87 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 214.1, 171.3, 96.2, 72.9, 70.0, 60.4, 57.4, 56.4, 51.4, 48.2, 47.1, 43.1, 42.5, 35.2, 34.3, 34.2, 32.5, 29.1, 27.1, 25.9, 23.6, 18.2, 18.0, -5.5, -5.5. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 46 FTIR (thin film/NaCl): 2952, 2928, 2856, 1750, 1726, 1471, 1464, 1390, 1236, 1148, 1094, 1047, 959, 945, 915, 838, 778 cm–1. HRMS: (MM: ESI–APCI) calc’d for C27H47O6Si [M + H]+ 495.3136, found 495.3147. [!]!" ! = +8.2° (c = 0.99, CHCl3). Preparation of enone 72: H Me TBSO Me 2N O Me O H Ac2O O OMOM 71 NMe 2 DMF, 95 °C Me TBSO O O Me O OMOM 72 A solution of ketolactone 71 (19.2 mg, 38.8 µmol), bis(dimethylamino)methane (0.40 mL, 2.9 mmol, 75 equiv), acetic anhydride (0.40 mL, 4.2 mmol, 109 equiv) and 0.40 mL DMF was heated to 95 °C in a sealed vial. After stirring at 95 °C for 1 h, the reaction mixture was cooled to room temperature, diluted with sat. NaHCO3 (1 mL) and extracted with DCM (3 x 1 mL). The combined organic extracts were washed with sat. NaHCO3 (0.5 mL) and brine (0.5 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (10 to 15% EtOAc/Hex) to afford enone 72 as a clear gum (16.1 mg, 82% yield). 1 H NMR (500 MHz, CDCl3): δ 5.98 (s, 1H), 5.46 (s, 1H), 4.69 (d, J = 6.7 Hz, 1H), 4.61 (d, J = 6.7 Hz, 1H), 4.60 (d, J = 11.5 Hz, 1H), 4.37 (d, J = 11.5 Hz, 1H), 4.24 (br s, 1H), 3.66 (d, J = 11.4 Hz, 1H), 3.58 (dd, J = 11.4, 6.1 Hz, 1H), 3.42 (s, 3H), 3.13 (ddt, J = 9.6, 5.0, 1.0 Hz, 1H), 2.85 (d, J = 12.1 Hz, 1H), 2.68 (s, 1H), 2.45 (dd, J = 15.2, 9.3 Hz, 1H), 2.31 (dd, J = 12.3, 4.7 Hz, 1H), 1.93 (t, J = 13.8 Hz, 1H), 1.75 (d, J = 14.4 Hz, 1H), 1.68 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 47 (d, J = 5.1 Hz, 1H), 1.58 (dd, J = 15.1, 4.7 Hz, 1H), 1.54 – 1.39 (m, 3H), 1.30 – 1.20 (m, 1H), 1.03 (s, 3H), 0.88 (s, 3H), 0.84 (s, 9H), 0.01 (s, 3H), -0.02 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 201.0, 171.3, 150.0, 118.1, 96.4, 73.0, 69.3, 60.4, 56.9, 56.4, 51.9, 48.0, 43.7, 42.5, 36.9, 34.4, 34.3, 34.3, 29.7, 29.6, 26.0, 23.7, 18.3, 18.0, 5.6, -5.6. FTIR (thin film/NaCl): 2952, 2928, 2855, 1744, 1719, 1462, 1389, 1366, 1261, 1235, 1147, 1122, 1092, 1047, 989, 932, 838, 778 cm–1. HRMS: (MM: ESI–APCI) calc’d for C28H47O6Si [M + H]+ 507.3136, found 507.3145. [!]!" ! = +27.6° (c = 1.02, CHCl3). Preparation of diol S2: H H O 6M aq. HCl Me TBSO O Me O 72 OMOM dioxane 45 °C (99% yield) Me HO O O Me O OH S2 To a solution of enone 72 (16.1 mg, 31.8 µmol) in 0.90 mL dioxane was added 0.70 mL 6M HCl (aq), and the mixture was stirred at 45 °C. After 75 min, the reaction mixture was cooled to room temperature, carefully diluted with sat. NaHCO3 (3 mL) and DCM (3 mL) and stirred until cessation of bubbling (10 min). The layers were separated and the aqueous layer was extracted with DCM (3 x 2 mL). The combined organic extracts were washed with sat. NaHCO3 (1 mL) and brine (1 mL), dried over Na2SO4, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (50 to 65% EtOAc/Hex) to afford diol S2 as a white solid (11.0 mg, 99% yield). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 1 48 H NMR (500 MHz, CDCl3): δ 6.01 (s, 1H), 5.48 (s, 1H), 4.63 (d, J = 11.5 Hz, 1H), 4.55 (br s, 1H), 4.32 (dd, J = 11.4, 1.2 Hz, 1H), 3.79 (dd, J = 11.4, 1.8 Hz, 1H), 3.65 (dd, J = 11.4, 6.3 Hz, 1H), 3.16 (ddt, J = 8.8, 4.9, 1.1 Hz, 1H), 3.00 (d, J = 12.2 Hz, 1H), 2.65 (d, J = 3.2 Hz, 1H), 2.31 (ddd, J = 12.2, 4.8, 1.4 Hz, 1H), 2.14 (ddd, J = 15.1, 8.9, 1.9 Hz, 1H), 2.11 – 2.01 (m, 1H), 1.87 – 1.79 (m, 2H), 1.76 (d, J = 6.1 Hz, 1H), 1.56 – 1.43 (m, 4H), 1.37 – 1.27 (m, 2H), 1.07 (s, 3H), 0.88 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 201.3, 171.2, 149.7, 118.2, 69.5, 66.1, 60.1, 56.8, 51.7, 47.3, 43.4, 42.0, 34.6, 34.3, 33.9, 30.2, 30.1, 29.7, 24.0, 18.1. FTIR (thin film/NaCl): 3434, 2921, 2848, 1734, 1700, 1457, 1390, 1357, 1260, 1124, 1039, 1021, 928, 836, 749 cm–1. HRMS: (MM: ESI–APCI) calc’d for C20H29O5 [M + H]+ 349.2010, found 349.2014. [!]!" ! = +14° (c 0.16, CHCl3). Preparation of (–)-trichorabdal A (12): H Me HO O TEMPO PhI(OAc) 2 O Me O S2 OH DCM H Me H O O Me O O (74% yield) OH (– )-trichorabdal A (12) To a solution of diol S2 (11.0 mg, 31.6 µmol) in 1.6 mL DCM was added 2,2,6,6tetramethylpiperidine 1-oxyl (1.0 mg, 6.3 µmol, 0.1 equiv) and iodobenzene diacetate (14.2 mg, 44.2 µmol, 1.4 equiv). After stirring for 3.5 h at ambient temperature, the reaction mixture was diluted with sat. NaHCO3 (0.5 mL) and sat. Na2S2O3 (0.5 mL). The layers were separated, the aqueous layer was extracted with DCM (3 x 1 mL), the combined organic extracts were washed with brine (1 mL), dried over Na2SO4, filtered Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 49 through a small plug of silica gel, and concentrated in vacuo. The crude residue was purified by preparative reverse phase HPLC (40 to 70% MeCN/H2O, 10 minute gradient, tR=6.8 min) to afford (–)-trichorabdal A (12) as a white solid (8.1 mg, 74% yield). 1 H NMR (600 MHz, pyridine-d5, at 60 °C): δ 10.06 (d, J = 4.3 Hz, 1H), 6.49 (s, 1H), 6.01 (s, 1H), 5.38 (s, 1H), 5.12 (d, J = 11.4 Hz, 1H), 4.88 – 4.64 (m, 1H), 4.65 – 4.60 (m, 1H), 3.46 (d, J = 11.8 Hz, 1H), 3.13 (dd, J = 8.9, 4.6 Hz, 1H), 2.91 (d, J = 4.3 Hz, 1H), 2.64 – 2.57 (m, 1H), 2.48 – 2.38 (m, 3H), 2.04 – 1.95 (m, 1H), 1.78 (dd, J = 14.8, 5.0 Hz, 1H), 1.68 – 1.59 (m, 1H), 1.52 – 1.42 (m, 2H), 1.27 – 1.19 (m, 1H), 1.04 (s, 3H), 0.99 (s, 3H); 13 C NMR (126 MHz, pyridine-d5, at 60 °C): δ 205.3, 201.5, 171.1, 150.9, 117.6, 70.8, 65.0, 60.9 (br), 56.9 (br), 47.9 (br), 42.7 (br), 42.1, 40.3 (br), 35.3, 34.3, 32.4, 31.6, 28.6, 25.9 (br), 18.7. FTIR (thin film/NaCl): 3467, 2922, 2849, 1744, 1711, 1647, 1490, 1459, 1391, 1349, 1271, 1238, 1180, 1124, 1079, 1038, 1024, 928, 850, 730 cm–1. HRMS: (MM: ESI–APCI) calc’d for C20H27O5 [M + H]+ 347.1853, found 347.1837. [!]!" ! = –61° (c 0.12, EtOH). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 50 1 H NMR comparison table for trichorabdal A (12). Natural*16 Natural Natural Synthetic Synthetic (400 MHz, (600 MHz, C5D5N, 40 °C) C5D5N, 60 °C) δ (ppm) mult J (Hz) δ (ppm) mult 10.03 d, 1H 3 10.06 d, 1H 6.05 s, 1H 6.01 s, 1H 5.35 s, 1H 5.38 s, 1H 5.10 ABq, 1H 12 5.12 d, 1H 4.71 ABq, 1H 12 4.72 m, 1H 4.60 m, 1H 4.62 m, 1H 3.45 d, 1H 12 3.46 d, 1H 3.12 dd, 1H 10,4 3.13 dd, 1H 2.90 d, 1H 3 2.91 d, 1H 1.00 s, 3H 1.04 s, 3H 0.95 s, 3H 0.99 s, 3H * No further 1H signals were reported. Synthetic J (Hz) 4.3 11.4 11.8 8.9, 4.6 4.3 - Δ (ppm) +0.03 –0.04 +0.03 +0.02 +0.01 +0.02 +0.01 +0.01 +0.01 +0.04 +0.04 13 C NMR comparison table for trichorabdal A (12).** Natural16 Synthetic (100 MHz, C5D5N, 60 °C) (126 MHz, C5D5N, 60 °C) δ (ppm) δ (ppm) 204.5 205.3 200.7 169.5 150.6 117.1 70.7 64.9 60.7 56.7 47.8 42.7 42.0 40.3 35.2 34.2 32.3 31.5 28.4 26.0 18.6 201.5 171.1 150.9 117.6 70.8 65.0 60.9 56.9 47.9 42.7 42.1 40.3 35.3 34.3 32.4 31.6 28.6 25.9 18.7 Δ (ppm) +0.8 +0.8 +0.6 +0.3 +0.5 +0.1 +0.1 +0.2 +0.2 +0.1 0.0 +0.1 0.0 +0.1 +0.1 +0.1 +0.1 +0.2 –0.1 +0.1 ** It should be noted that conformational flexibility of the natural product results in significant broadening of some carbon signals, even at elevated temperatures. For discussion of the conformational equilibria of these structures, see Osawa et al.16 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 51 Preparation of diol 73: H H 6M aq. HCl Me TBSO O Me O 69 OMOM dioxane 45 °C Me HO O Me (89% yield) O OH 73 To a solution of tetracycle 69 (59.2 mg, 0.120 mmol, 1.0 equiv) in 3.7 mL dioxane was added 2.8 mL 6M HCl(aq). The resulting solution was heated to 45 °C and stirred for 30 min. The reaction mixture was then cooled to 0 °C and diluted with sat. NaHCO3 (10 mL) and DCM (10 mL) and stirred until bubbling ceased (15 min). The layers were separated, and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic extracts were washed with brine (40 mL), dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (40 to 50% EtOAc/Hex) to provide diol 73 (35.9 mg, 89% yield). 1 H NMR (500 MHz, CDCl3): δ 4.98 – 4.95 (m, 2 H), 4.46 (br s, 2H), 4.40 (dtd, J = 6.6, 5.2, 3.6 Hz, 1H), 3.87 (dt, J = 11.5, 4.5 Hz, 1H), 3.82 (dt, J = 11.5, 2.9 Hz, 1H), 2.64 (d, J = 5.2 Hz, 1H), 2.60 (ddt, J = 16.6, 5.4, 2.6 Hz, 1H), 2.52 – 2.43 (m, 2H), 2.37 (td, J = 13.3, 4.3 Hz, 1H), 2.26 (br s, 1 H), 2.22 (dq, J = 16.2, 2.0 Hz, 1H), 1.97 (dtd, J = 14.2, 6.4, 1.2 Hz, 1H), 1.90 (t, J = 3.6 Hz, 1H), 1.88 – 1.81 (m, 3H), 1.66 (ddt, J = 14.2, 5.2, 1.9 Hz, 1H), 1.52 – 1.41 (m, 3H), 1.31 (ddd, J = 14.1, 13.1, 4.3 Hz, 1H), 1.05 (s, 3H), 0.92 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 175.5, 156.1, 106.3, 71.7, 66.4, 60.6, 54.0, 53.0, 51.4, 42.5, 41.7, 40.4, 39.7, 36.5, 34.4, 34.1, 31.5, 31.4, 23.5, 18.4. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 52 FTIR (NaCl/thin film): 3246, 2929, 2872, 2848, 1734, 1459, 1388, 1353, 1298, 1242, 1087, 1044, 1023, 997, 989 cm–1. HRMS: (ESI+) calc’d for C20H31O4 [M + H]+ 335.2217, found 335.2228. [!]!" ! = –28° (c = 0.66, CHCl3). Preparation of acetate 75. H Me HO TEMPO PhI(OAc) 2 O Me O 73 OH DCM H Me O Ac2O DMAP O Me H O 74 OH DCM H Me O O Me H O (58% yield, 2 steps) OAc 75 To a solution of diol 73 (35.2 mg, 0.105 mmol, 1.0 equiv) in DCM (5.3 mL) was added PhI(OAc)2 (47.6 mg, 0.148 mmol, 1.4 equiv) and 2,2,6,6-tetramethylpiperidine 1oxyl (3.3 mg, 21 µmol, 0.20 equiv). The resulting solution was stirred for 4.5 h, and then diluted with sat. Na2S2O3 (20 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide crude aldehyde 74. The crude residue was chromatographed on SiO2 (25% EtOAc/Hex) to provide 25.4 mg 74 (~85% purity, contaminated with ketoaldehyde from over-oxidation). Impure 74 was dissolved in DCM (7.6 mL), and Ac2O (36 µL, 0.38 mmol, 5.0 equiv) and DMAP (93 mg, 0.76 mmol, 10 equiv) were added. The solution was stirred at ambient temperature until TLC indicated full consumption of starting material (30 min). The reaction mixture was then diluted with sat. NaHCO3 (20 mL) and DCM (20 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 53 chromatographed on SiO2 (20% EtOAc/Hex) to provide acetate 75 (22.8 mg, 58% yield from 73). 1 H NMR (500 MHz, CDCl3): δ 9.93 (d, J = 4.4 Hz, 1H), 5.27 (q, J = 5.0 Hz, 1H), 4.99 (m, 2H), 4.84 (br d, J = 9.3 Hz, 1H), 4.68 (d, J = 11.8 Hz, 1H), 2.65 – 2.54 (m, 1H), 2.46 (q, J = 6.1 Hz, 1H), 2.39 (d, J = 4.4 Hz, 1H), 2.33 – 2.17 (m, 3H), 2.07 (s, 3H), 2.01 – 1.87 (m, 3H), 1.82 – 1.67 (m, 1H), 1.66 – 1.49 (m, 3H), 1.28 – 1.16 (m, 2H), 1.14 (s, 3H), 1.04 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 205.1, 174.2, 169.7, 155.0, 107.3, 70.4, 67.7, 62.5, 53.2, 51.9, 41.9, 41.7, 40.4, 36.5, 36.1, 34.5, 33.7, 30.6, 29.6, 23.8, 21.8, 18.2. FTIR (NaCl/thin film): 3079, 2953, 2849, 2751, 1735, 1712, 1654, 1462, 1371, 1231, 1085, 1071, 1036, 914 cm–1. HRMS: (ESI+) calc’d for C22H31O5 [M + H]+ 375.2166, found 375.2175. ![!]!" ! = –6.9° (c = 0.42, CHCl3). An analytical sample of aldehyde 74 was obtained (65% yield) by preparative reverse phase HPLC (45% to 70% MeCN/H2O, 10 minute gradient, tR = 7.0 min). 1 H NMR (600 MHz, CDCl3): δ 9.95 (d, J = 5.4 Hz, 1H), 4.99 (s, 1H), 4.95 (t, J = 2.4 Hz, 1H), 4.88 (br s, 1H), 4.71 (d, J = 11.8 Hz, 1H), 4.25 (dq, J = 5.4, 3.5 Hz, 1H), 2.64 (d, J = 5.4 Hz, 1H), 2.59 – 2.53 (m, 1H), 2.51 – 2.47 (m, 1H), 2.46 – 2.35 (m, 2H), 2.17 (dq, J = 16.3, 2.0 Hz, 1H), 2.00 (d, J = 3.0 Hz, 1H), 1.96 (dt, J = 13.5, 6.6 Hz, 1H), 1.90 – Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 54 1.82 (m, 2H), 1.63 – 1.54 (m, 4H), 1.50 (dt, J = 13.2, 3.5 Hz, 1H), 1.31 (m, 1H), 1.18 (s, 3H), 1.00 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 206.6, 174.9, 155.5, 107.6, 71.3, 66.0, 63.4, 53.5, 53.5, 41.9, 41.2, 40.6, 39.5, 36.2, 34.4, 33.6, 31.4, 29.9, 23.6, 18.4. FTIR (NaCl/thin film): 3467, 2990, 2946, 2844, 2717, 1718, 1653, 1465, 1390, 1280, 1233, 1201, 1117, 1088, 1025, 881 cm–1. HRMS: (ESI+) calc’d for C20H29O4 [M + H]+ 333.2060, found 333.2070. [!]!" ! = –65.4° (c = 0.37, CHCl3). Preparation of hydroxylactol 76: H Me H SmI2 O O Me H O 75 OAc OH Me THF (55% yield, 75% brsm) Me O OH OAc 76 To a solution of 75 (4.4 mg, 12 µmol, 1.0 equiv) in THF (0.27 mL) was added freshly prepared 0.1 M SmI2 (0.23 mL, 23 µmol, 2.0 equiv). The solution was stirred until the reaction turned from blue to green (ca. 1.5 h). The reaction mixture was then diluted with sat. NaHCO3 (1 mL), sat. Na2S2O3 (1 mL), and DCM (2 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 x 2 mL). The organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (17% to 25% EtOAc/Hex) to provide recovered 75 (1.2 mg, 27% yield) and hydroxylactol 76 (2.4 mg, 55% yield). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 1 55 H NMR (500 MHz, CDCl3): δ 6.16 – 6.14 (m, 1H), 5.14 (ddd, J = 5.8, 4.1, 1.9 Hz, 1H), 5.11 (dd, J = 2.6, 1.2 Hz, 1H), 4.23 (dd, J = 9.1, 1.9 Hz, 1H), 4.10 (dd, J = 9.1, 1.8 Hz, 1H), 4.03 (dd, J = 7.3, 1.9 Hz, 1H), 2.59 (s, 1H), 2.50 – 2.42 (m, 2H), 2.40 (d, J = 1.9 Hz, 1H), 2.29 (dt, J = 8.9, 4.2 Hz, 1H), 2.17 – 2.09 (m, 2H), 2.06 (s, 3H), 1.75 (dt, J = 5.7, 1.5 Hz, 1H), 1.67 (dd, J = 11.7, 3.6 Hz, 1H), 1.51 – 1.41 (m, 3H), 1.39 – 1.32 (m, 3H), 1.27 – 1.22 (m, 2H), 1.12 (s, 3H), 1.09 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 169.9, 155.2, 113.0, 97.5, 75.4, 69.3, 69.1, 62.0, 57.3, 53.7, 46.7, 41.3, 37.2, 34.4, 34.2, 34.0, 33.6, 29.9, 27.2, 22.6, 22.0, 18.5. FTIR (NaCl/thin film): 3436, 2927, 2851, 1733, 1648, 1443, 1376, 1264, 1237, 1210, 1073, 1029 cm–1. HRMS: (ESI+) calc’d for C20H29O3 [M – OAc]+ 317.2111, found 317.2119. [!]!" ! = –47.2° (c = 0.30, CHCl3). Preparation of lactol 77: H Me O SmI2 t-BuOH O Me H O 75 OAc THF (72% yield) H Me Me O OH OAc 77 To a solution of aldehyde 75 (5.0 mg, 13 µmol, 1.0 equiv) in THF (1.3 mL) was added t-BuOH (1.3 µL, 13 µmol, 1.0 equiv) and freshly prepared 0.1 M SmI2 (0.67 mL, 67 µmol, 5.0 equiv) dropwise over 1 min. The resulting solution was stirred until the reaction turned from blue to green (ca. 6 h), and then diluted with sat. NaHCO3 (5 mL), sat. Na2S2O3 (5 mL), and DCM (10 mL). The layers were separated and the aqueous layer was extracted with DCM (3 x 10 mL). The organic extracts were dried over Na2SO4, Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 56 filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (25% to 33% EtOAc/Hex) to provide lactol 77 (3.6 mg, 72% yield). 1 H NMR (500 MHz, CDCl3): δ 5.18 (dd, J = 2.7, 1.5 Hz, 1H), 5.14 (td, J = 6.0, 1.6 Hz, 1H), 4.92 – 4.90 (m, 1H), 4.23 (s, 2H), 2.60 (dd, J = 13.9, 11.1 Hz, 1H), 2.56 (ddt, J = 15.6, 5.1, 2.3 Hz, 1H), 2.41 (s, 1H), 2.40 (ddt, J = 11.9, 3.2, 1.0 Hz, 1H), 2.29 (dt, J = 9.6, 4.7 Hz, 1H), 2.15 (ddt, J = 15.7, 9.5, 1.3 Hz, 1H), 2.12 (ddt, J = 15.7, 3.0, 1.5 Hz, 1H), 2.06 (s, 3H), 1.91 (dd, J = 14.0, 8.6 Hz, 1H), 1.64 (ddt, J = 11.6, 4.0, 1.0 Hz, 1H), 1.58 (d, J = 5.3 Hz, 1H), 1.52 – 1.47 (m, 2H), 1.45 – 1.32 (m, 3H), 1.29 (dtd, J = 13.7, 3.3, 1.5 Hz, 1H), 1.19 (td, J = 13.4, 5.1 Hz, 1H), 1.11 (td, J = 12.7, 4.0 Hz, 1H), 1.10 (s, 3H), 0.89 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 170.1, 156.7, 105.5, 97.3, 69.1, 68.8, 61.1, 53.4, 49.2, 45.3, 40.8, 37.3, 36.0, 33.9, 33.7, 32.7, 32.0, 30.4, 27.1, 22.0, 21.1, 18.6. FTIR (NaCl/thin film): 3402, 2929, 1729, 1646, 1444, 1366, 1236, 1210, 1182, 1101, 1044, 915 cm–1. HRMS: (ESI+) calc’d for C20H29O2 [M – OAc]+ 301.2162, found 301.2164. [!]!" ! = –135° (c = 0.30, CHCl3). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 57 Preparation of primary alcohol 78: H Me O SmI2 LiCl, t-BuOH O Me H O 75 OAc THF, 0 °C H Me HO O Me O (54% yield) OAc 78 Freshly prepared 0.1 M SmI2 (0.17 mL, 17 µmol, 5.0 equiv) was added directly to a vial charged with LiCl (7.2 mg, 170 µmol, 50 equiv) and stirred until the solution had turned emerald green and all solids were dissolved (< 10 min). The resulting solution was added dropwise via cannula into a solution of aldehyde 75 (1.3 mg, 3.5 µmol, 1.0 equiv) and a solution of t-BuOH in THF (0.01 M, 0.35 mL, 3.5 µmol, 1.0 equiv) stirring at 0 °C. Stirring continued until the reaction turned yellow (35 min). The reaction mixture was diluted with sat. NaHCO3 (1 mL), sat. Na2S2O3 (1 mL), and H2O (0.5 mL), then Rochelle salt (100 mg) and EtOAc (2 mL) were added. The layers were separated, and the aqueous layer extracted with EtOAc (3 x 2 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (20 to 25% EtOAc/Hex) to afford alcohol 78 (0.7 mg, 54% yield). 1 H NMR (500 MHz; CDCl3): δ 5.47 (ddd, J = 5.4, 4.5, 3.4 Hz, 1H), 4.96 (t, J = 2.4 Hz, 1H), 4.90 (t, J = 1.9 Hz, 1H), 4.57 (d, J = 11.5 Hz, 1H), 4.46 (d, J = 11.5 Hz, 1H), 3.82 (d, J = 11.8 Hz, 1H), 3.73 (dt, J = 10.9, 4.7 Hz, 1H), 2.81 (d, J = 4.3 Hz, 1H), 2.65 (ddt, J = 16.8, 5.8, 2.7 Hz, 1H), 2.45 (q, J = 6.8 Hz, 1H), 2.36 (dd, J = 11.9, 2.7 Hz, 1H), 2.24 (dq, J = 16.9, 2.2 Hz, 1H), 2.08 – 2.02 (m, 1H), 2.07 (s, 3H), 1.99 (dd, J = 12.2, 4.8 Hz, 1H), 1.86 (d, J = 13.6 Hz, 1H), 1.67 – 1.57 (m, 2H), 1.53 – 1.45 (m, 4H), 1.28 – 1.24 (m, 1H), 1.19 (td, J = 14.3, 5.3 Hz, 1H), 1.05 (s, 3H), 0.90 (s, 3H). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 13 58 C NMR (126 MHz, CDCl3): δ 174.7, 170.1, 156.5, 105.2, 70.4, 68.0, 60.3, 53.3, 52.4, 51.2, 42.8, 42.4, 40.9, 37.4, 35.8, 34.3, 34.2, 30.2, 30.0, 23.7, 21.9, 18.1. IR (NaCl/thin film): 3463, 2951, 2925, 2868, 2848, 1737, 1729, 1651, 1460, 1447, 1388, 1372, 1233, 1181, 1083, 1021 cm–1. HRMS: (ESI+) calc’d for C20H29O3 [M – OAc]+ 317.2117, found 317.2105. [!]!" ! = –7.5° (c = 0.16, CHCl3). General procedure for reductive cyclization of aldehyde 75 (Table 2.2): To a flask charged with aldehyde 75 (1.3 mg, 3.5 µmol, 1.0 equiv) was added one of the following: 0.35 mL THF; 0.35 mL 10 mM t-BuOH /THF solution (3.5 µmol, 1.0 equiv); 0.35 mL THF and 30 uL HMPA (0.175 mmol, 50 equiv) and maintained at the indicated temperature. Inside a glove box, an oven-dried vial was charged with LiCl or LiBr (170 µmol, 50 equiv) or naught, and removed from the glove box, or not. Freshly prepared 0.1 M SmI2 was added directly to the reaction vessel dropwise, or to the vial containing LiX, which was stirred for 1–10 min until all solids were dissolved, and the resulting solution then added dropwise via cannula to the reaction vessel. Following addition of SmI2 or SmI2/LiX, the reaction was allowed to stir at the indicated temperature until the appearance of a yellow solution (35–55 min). At this point, the reaction was diluted with sat. NaHCO (1 mL), sat. Na2S2O3 (1 mL), and H2O (0.5 mL), and Rochelle salt (100 mg) and EtOAc (2 mL) were added. The layers were separated, and the aqueous extracted with EtOAc (3 x 2 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 59 chromatographed on SiO2 (17% to 33% EtOAc/Hex) to afford hydroxylactol 76, lactol 77, primary alcohol 78, or recovered aldehyde 75. Preparation of ketolactol 79: H H O 3, DCM, –94 °C OH Me Me O OH OAc 76 then PPh 3 /polystyrene –94 to 23 °C (66% yield) O OH Me Me O OH OAc 79 A solution of lactol 76 (4.4 mg, 12 µmol, 1.0 equiv) in DCM (2 mL) was cooled to –94 °C (liq. N2/acetone), and ozone was gently bubbled through the solution (O2 flow rate = 1/8 L/min, 1 setting on ozone generator) for 10 min. The solution was purged with argon for 10 min, and then polystyrene-bound PPh3 (3 mmol/g loading, 39 mg, 0.12 mmol, 10 equiv) was added. After 25 min, the reaction was warmed to 0 °C and stirred for 30 min, and finally warmed to room temperature and stirred for an additional 30 min. The solution was filtered through a pad of celite and concentrated in vacuo. The crude residue was chromatographed on SiO2 (33% EtOAc/Hex) to afford ketolactol 79 (2.9 mg, 66% yield). 1 H NMR (500 MHz, CDCl3): δ 5.63 (d, J = 12.0 Hz, 1H), 5.24 (td, J = 4.9, 1.4 Hz, 1H), 4.16 (dd, J = 9.4, 1.9 Hz, 1H), 4.09 (dd, J = 9.3, 1.7 Hz, 1H), 3.79 (dd, J = 12.0, 7.5 Hz, 1H), 3.53 (s, 1H), 2.71 (ddd, J = 12.4, 4.0, 1.3 Hz, 1H), 2.70 – 2.65 (m, 1H), 2.50 (ddd, J = 18.7, 7.1, 1.6 Hz, 1H), 2.30 – 2.24 (m, 2H), 2.18 (dd, J = 18.6, 4.0 Hz, 1H), 2.10 (s, 3H), 1.59 (dd, J = 4.9, 1.2 Hz, 1H), 1.54 – 1.42 (m, 3H), 1.38 – 1.33 (m, 2H), 1.26 – 1.21 (m, 3H), 1.13 (s, 3H), 1.11 (s, 3H). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 13 60 C NMR (126 MHz, CDCl3): δ 222.7, 169.7, 94.8, 74.7, 68.9, 68.1, 59.6, 58.8, 53.6, 49.3, 41.3, 36.9, 35.9, 33.9, 33.7, 30.6, 29.1, 25.9, 22.5, 21.9, 18.3. FTIR (NaCl/thin film): 3338, 2924, 2870, 1728, 1446, 1373, 1306, 1238, 1212, 1061, 1021, 939 cm–1. HRMS: (ESI+) calc’d for C21H31O6 [M + H]+ 379.2115, found 379.2123. ![!]!" ! = –86° (c = 0.30, CHCl3). Preparation of (–)-longikaurin E (11): H Me 2N O Me Me NMe 2 Ac2O OH DMF, 95 °C O OH 79 OAc (67% yield) H O OH Me Me O OH OAc (– )-longikaurin E (11) To a solution of 79 (2.6 mg, 6.9 µmol, 1.0 equiv) in DMF (0.23 mL) was added bis(dimethylamino) methane (0.23 mL, 1.7 mmol, 240 equiv) and Ac2O (0.23 mL, 2.1 mmol, 300 equiv), and the resulting mixture was stirred at 95 °C for 45 min in a sealed vial. After cooling to room temperature, the solution was diluted with 1M HCl (2 mL) and extracted with Et2O (3 x 4 mL). The combined organic extracts were dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was chromatographed on SiO2 (33% EtOAc/Hex) to afford (–)-longikaurin E (11) (1.8 mg, 67% yield). 1 H NMR (500 MHz, CDCl3): δ 6.00 (t, J = 0.9 Hz, 1H), 5.84 (d, J = 12.0 Hz, 1H), 5.47 (t, J = 0.8 Hz, 1H), 5.27 (ddd, J = 5.5, 4.5, 1.1 Hz, 1H), 4.13 (dd, J = 9.3, 1.4 Hz, 1H), 4.10 (dd, J = 9.3, 1.9 Hz, 1H), 3.87 (dd, J = 12.0, 8.1 Hz, 1H), 3.53 (s, 1H), 3.13 (dd, J = 9.4, 4.7 Hz, 1H), 2.71 (dd, J = 12.3, 0.8 Hz, 1H), 2.31 (ddd, J = 16.2, 9.3, 1.0 Hz, 1H), Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 61 2.21 (ddd, J = 12.2, 4.6, 1.2 Hz, 1H), 2.11 (s, 3H), 1.79 (ddt, J =16.0, 5.5, 1.1 Hz, 1H), 1.62 (d, J = 4.0 Hz, 1H), 1.51 – 1.42 (m, 2H), 1.39 – 1.33 (m, 2H), 1.32 – 1.20 (m, 3H), 1.15 (s, 3H), 1.13 (s, 3H). 13 C NMR (126 MHz, CDCl3): δ 208.4, 169.7, 151.7, 118.5, 95.0, 74.8, 69.1, 68.0, 58.5, 58.5, 53.7, 41.4, 38.0, 37.1, 34.1, 33.7, 33.6, 31.3, 26.3, 22.8, 21.9, 18.4. FTIR (NaCl/thin film): 3270, 2953, 2918, 2854, 1727, 1714, 1644, 1504, 1372, 1373, 1264, 1241, 1167, 1057, 940 cm–1. HRMS: (ESI+) calc’d for C22H31O6 [M + H]+ 391.2115, found 391.2125. !" ![!]!" ! = –51° (c = 0.30, C5H5N); [!]! = –39° (c = 0.17, CHCl3). Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 62 1 H NMR comparison table for longikaurin E (11). Natural*17 Natural Natural Synthetic (CDCl3) (CDCl3, 500 δ (ppm) mult J (Hz) MHz) δ (ppm) 5.26 dd, 1H 4.5, 4.5 5.27 4.11 br s, 2H 4.13 4.10 3.91 dd, 1H 12, 8 3.87 2.09 s, 3H 2.11 1.71 – 1.88 m** 1.79 1.62 1.25 1.14 1.12 m** m** s, 3H s, 3H - 1.62 1.20 – 1.32 1.15 1.13 13 C NMR comparison table for longikaurin E (11). Natural* 17 Synthetic (CDCl3) (CDCl3, 126 MHz) δ (ppm) δ (ppm) Δ (ppm) 208.4 208.4 0.0 169.6 169.7 +0.1 151.7 151.7 0.0 118.2 118.5 +0.3 95.0 95.0 0.0 74.5 74.8 +0.3 68.9 69.1 +0.2 68.1 68.0 –0.1 * No further 1H or 13C signals were reported. ** Integrations not reported. Synthetic Synthetic mult J (Hz) ddd, 1H dd, 1H dd, 1H dd, 1H s, 3H ddt, 1H 5.5, 4.5, 1.1 9.3, 1.4 9.3, 1.9 12.0, 8.1 16.0, 5.5, 1.1 4.0 - d, 1H m, 3H s, 3H s, 3H Δ (ppm) +0.01 –0.04 +0.02 0.00 +0.01 +0.01 Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 2.7 (1) 63 NOTES AND REFERENCES (a) Lu, P.; Gu, Z.; Zakarian, A. J. Am. Chem. Soc. 2013, 135, 14552. (b) Cherney, E. C.; Green, J. C.; Baran, P. S. Angew. Chem., Int. Ed. 2013, 52, 9019. (c) Zhu, L.; Luo, J.; Hong, R. Org. Lett. 2014, 16, 2162. (d) Moritz, B. J.; Mack, D. J.; Tong, L.; Thomson, R. J. Angew. Chem., Int. Ed. 2014, 53, 2988. (e) Lazarski, K. E.; Moritz, B. J.; Thomson, R. J. Angew. Chem., Int. Ed. 2014, 53, 10588. (f) Lu, P.; Mailyan, A.; Gu, Z.; Guptill, D. M.; Wang, H.; Davies, H. M. L.; Zakarian, A. J. Am. Chem. Soc. 2014, 136, 17738. (g) Liu, W.; Li, H.; Cai, P.-J.; Wang, Z.; Yu, Z.-X.; Lei, X. Angew. Chem., Int. Ed. 2016, 55, 3112. (h) Cernijenko, A.; Risgaard, R.; Baran, P. S. J. Am. Chem. Soc. 2016, 138, 9425. (i) Zhao, X.; Li, W.; Wang, J.; Ma, D. J. Am. Chem. Soc. 2017, 139, 2932. (j) He, C.; Hu, J.; Wu, Y.; Ding, H. J. Am. Chem. Soc. 2017, 139, 6098. (2) (a) Fujita, E.; Shibuya, M.; Nakamura, S.; Okada, Y.; Fujita, T. J. Chem. Soc., Chem. Commun. 1972, 1107. (b) Fujita, E.; Shibuya, M.; Nakamura, S.; Okada, Y.; Fujita, T. J. Chem. Soc., Perkin Trans. 1 1974, 165. (3) 13-desoxyeffusin: (a) Kenny, M. J.; Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1986, 27, 3923. (b) Kenny, M. J.; Mander, L. N.; Sethi, S. P. Tetrahedron Lett. 1986, 27, 3927. Semisynthesis of longirabdolactone: (c) Adamson, G.; Mander, L. N. Aust. J. Chem. 2003, 56, 805. (4) Pan, Z.; Zheng, C.; Wang, H.; Chen, Y.; Li, Y.; Cheng, B.; Zhai, H. Org. Lett. 2014, 16, 216. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E (5) 64 Han, Q.-B.; Cheung, S.; Tai, J.; Qiao, C.-F.; Song, J.-Z.; Tso, T.-F.; Sun, H.-D.; Xu, H.-X. Org. Lett. 2006, 8, 4727. (6) Cha, J. Y.; Yeoman, J. T.; Reisman, S. E. J. Am. Chem. Soc. 2011, 133, 14964. (7) Fujita, E.; Fuji, K.; Sai, M.; Node, M.; Watson, W. H.; Zabel, V. J. Chem. Soc., Chem. Commun. 1981, 899. (8) Seminal reports of SmII-mediated pinacol couplings: (a) Namy, J. L.; Souppe, J.; Kagan, H. B. Tetrahedron Lett. 1983, 24, 765. (b) Molander, G. A.; Kenny, C. J. Org. Chem. 1988, 53, 2132. Selected examples of SmII-mediated ketone-ester reductive couplings: (c) Hasegawa, E.; Okamoto, K.; Tanikawa, N.; Nakamura, M.; Iwaya, K.; Hoshi, T.; Suzuki, T. Tetrahedron Lett. 2006, 47, 7715. (d) Liu, Y.; Zhang, Y. Tetrahedron Lett. 2001, 42, 5745. (e) Iwaya, K.; Nakamura, M.; Hasegawa, E. Tetrahedron Lett. 2002, 43, 5067. (f) Iwaya, K.; Tamura, M.; Nakamura, M.; Hasegawa, E. Tetrahedron Lett. 2003, 44, 9317. (g) Li, H.; Fu, B.; Wang, M. A.; Li, N.; Liu, W. J.; Xie, Z. Q.; Ma, Y. Q.; Qin, Z. Eur. J. Org. Chem. 2008, 1753. Other examples of ketone-ester reductive couplings: (h) Miyazaki, T.; Maekawa, H.; Yonemura, K.; Yamamoto, Y.; Yamanaka, Y.; Nishiguchi, I. Tetrahedron 2011, 67, 1598. (i) Kise, N.; Arimoto, K.; Ueda, N. Tetrahedron Lett. 2003, 44, 6281. (9) Seminal reports of stoichiometric PdII-mediated silyl enol ether oxidative cyclizations: (a) Ito, Y.; Aoyama, H.; Hirao, T.; Mochizuki, A.; Saegusa, T. J. Am. Chem. Soc. 1979, 101, 494. (b) Kende, A. S.; Roth, B.; Sanfilippo, P. J. J. Am. Chem. Soc. 1982, 104, 1784. For the development of PdII-catalyzed Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 65 cyclizations, see: (c) Toyota, M.; Wada, T.; Fukumoto, K.; Ihara, M. J. Am. Chem. Soc. 1998, 120, 4916. (d) Toyota, M.; Rudyanto, M.; Ihara, M. J. Org. Chem. 2002, 67, 3374. For a review, see: (e) Toyota, M.; Ihara, M. Synlett 2002, 1211. Selected synthetic examples: (f) Kende, A. S.; Roth, B.; Sanfilippo, P. J.; Blacklock, T. J. J. Am. Chem. Soc. 1982, 102, 5808. (g) Jeker, O. F.; Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 3474. (h) Nicolaou, K. C.; Tria, G. S.; Edmonds, D. J.; Kar, M. J. Am. Chem. Soc. 2009, 131, 15909. (i) Varseev, G. N.; Maier, M. E. Angew. Chem., Int. Ed. 2009, 48, 3685. (j) Toyota, M.; Sasaki, M.; Ihara, M. Org. Lett. 2003, 5, 1193. (k) Toyota, M.; Odashima, T.; Wada, T.; Ihara, M. J. Am. Chem. Soc. 2000, 122, 9036. (10) For the preparation of similar bridged ring systems by AuI-catalyzed cyclizations of alkynyl silyl enol ethers, see: (a) Staben, S. T.; Kennedy-Smith, J. J.; Huang, D.; Corkey, B. K.; LaLonde, R. L.; Toste, F. D. Angew. Chem., Int. Ed. 2006, 45, 5991. (b) Huwyler, N.; Carreira, E. M. Angew. Chem., Int. Ed. 2012, 51, 13066. (c) Lu, Z.; Li, Y.; Deng, J.; Li, A. Nature Chem. 2013, 5, 679. (11) For the formation of all-carbon quaternary centers from silyl enol ether precursors, see references 19b, d, f, and g. For diester, ketoester, and lactam-ester precursors, see: (a) Takeda, K.; Toyota, M. Tetrahedron 2011, 67, 9909. For ketonitrile precursors, see: (b) Kung, L.-R.; Tu, C.-H.; Shia, K.-S.; Liu, H.-J. Chem. Commun. 2003, 2490. For the formation of a tertiary center via PdIImediated oxidative cyclization of a silyl ketene acetal, see: (c) Hibi, A.; Toyota, M. Tetrahedron Lett. 2009, 50, 4888. Chapter 2 – Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 66 (12) Ito, Y.; Hirao, T.; Saegusa, T. J. Org. Chem. 1978, 43, 1011. (13) Wang, Y.-F.; Gao, Y.-R.; Mao, S.; Zhang, Y.-L.; Guo, D.-D.; Yan, Z.-L.; Guo, S.H.; Wang, Y.-Q. Org. Lett. 2014, 16, 1610. (14) (a) DeSolms, S. J. J. Org. Chem. 1976, 41, 2650. (b) Taylor, E. C.; Shvo, Y. J. Org. Chem. 1968, 33, 1719. (15) De Mico, A.; Margarita, R.; Parlanti, L.; Vescovi, A.; Piancatelli, G. J. Org. Chem. 1997, 62, 6974. (16) Spectroscopic data obtained were consistent with isolation data reported by Node and coworkers: (a) Node, M.; Sai, M.; Fuji, K.; Fujita, E.; Shingu, T.; Watson, W. H.; Grossie, D. Chem. Lett. 1982, 2023. For additional spectroscopic data, see also (b) Fuji, K.; Node, M.; Sai, M.; Fujita, E.; Takeda, S.; Unemi, N. Chem. Pharm. Bull. 1989, 37, 1472. (c) Fuji, K.; Node, M.; Sai, M.; Fujita, E.; Shingu, T.; Watson, W. H.; Grossie, D. A.; Zabel, V. Chem. Pharm. Bull. 1989, 37, 1465. (d) Yunlong, X.; Ming, W. Phytochemistry 1989, 28, 1978. (e) Osawa, K.; Yasuda, H.; Maruyama, T.; Morita, H.; Takeya, K.; Itokawa, H. Phytochemistry 1994, 36, 1287. (17) Spectroscopic data obtained were consistent with isolation data reported by Fujita and coworkers: Fujita, T.; Takeda, Y.; Shingu, T. Heterocycles, 1981, 16, 227. (18) Reisman, S. E.; Ready, J. M.; Hasuoka, A.; Smith, C. J.; Wood, J. L. J. Am. Chem. Soc. 2006, 128, 1448. Appendix 1 – Spectra Relevant to Chapter 2 67 Appendix 1 Spectra Relevant to Chapter 2: Total Syntheses of Ent-Kauranoids (–)-Trichorabdal A and (–)-Longikaurin E 10 9 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 2.500 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7127407 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 40 sec Sample #13, Operator: yeomanjo 8 7 6 5 TBSO 4 O S1 0.99 1.03 Me Me O 3.09 1.08 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: May 31 2012 2.09 HO 3 2 1.06 1.08 4.13 Sample Name: jtsy-viii-101 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-viii-101 FidFile: PROTON01 1 0.48 3.21 3.24 1.76 1.16 3.22 2.93 9.85 jtsy-viii-101 ppm Appendix 1 – Spectra Relevant to Chapter 2 68 6.08 1.00 1.05 1.03 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 512 repetitions OBSERVE C13, 125.6528709 MHz DECOUPLE H1, 499.7152303 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 1.0 Hz FT size 65536 Total time 17 min 180 Sample #13, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 31 2012 Sample Name: jtsy-viii-101 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-viii-101 FidFile: CARBON01 jtsy-viii-101 160 140 120 TBSO Me Me O 100 S1 HO 80 O 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 69 10 0.94 9 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 2.500 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7127410 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 40 sec Sample #48, Operator: yeomanjo 8 7 6 5 TBSO Me Me 2.03 O 4 66 O O 3 2 2.01 1.04 0.96 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: May 30 2012 1 2.08 2.01 1.05 0.99 2.98 2.91 9.41 Sample Name: jtsy-viii-097 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-viii-097 FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 70 6.03 3.97 2.00 0.94 1.01 0.99 0.96 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 512 repetitions OBSERVE C13, 125.6528718 MHz DECOUPLE H1, 499.7152303 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 17 min 180 Sample #48, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 30 2012 Sample Name: jtsy-viii-097 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-viii-097 FidFile: CARBON01 160 140 120 100 TBSO Me Me O 80 66 O O 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 71 10 9 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 2.500 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7225128 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 40 sec Sample #20, Operator: yeomanjo 8 7 6 5 2.24 Me TBSO 4 Me 67 1.08 1.08 1.03 1.03 1.03 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Mar 15 2012 O H 3 H O 1.00 HO 2 1 2.05 1.16 4.55 4.30 8.84 H ppm 2.98 3.00 Sample Name: jtsy-vii-089char Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-vii-089char FidFile: PROTON01 Appendix 1 – Spectra Relevant to Chapter 2 72 2.17 1.09 4.49 5.45 1.03 1.08 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 512 repetitions OBSERVE C13, 125.6553299 MHz DECOUPLE H1, 499.7250019 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 17 min 180 Sample #20, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Mar 15 2012 Sample Name: jtsy-vii-089char Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-vii-089char FidFile: CARBON01 160 140 120 100 Me TBSO Me 67 HO 80 H O H O 60 H 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 73 10 9 8 7 6 Me 1.05 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 2.500 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7225195 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 40 sec 5 68 2.14 Me TBSO H O H O 1.01 1.01 1.02 1.01 1.02 Sample #14, Operator: yeomanjo 4 3 2 5.32 MOMO H 1 3.87 3.12 9.25 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Feb 14 2012 ppm 3.03 3.09 Sample Name: jtsy-vii-191char Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-vii-191char FidFile: PROTON01 Appendix 1 – Spectra Relevant to Chapter 2 74 1.36 2.13 1.04 3.35 1.01 1.00 3.14 1.03 1.02 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 512 repetitions OBSERVE C13, 125.6553270 MHz DECOUPLE H1, 499.7250019 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 17 min 180 Sample #14, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Feb 14 2012 Sample Name: jtsy-vii-191char Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-vii-191char FidFile: CARBON01 160 140 Me 120 Me TBSO O H H 100 68 MOMO H O 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 75 10 9 8 7 6 Me 1.01 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 2.500 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7225125 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 40 sec 5 64 2.00 Me TBSO H O 4 OTBS 0.91 1.00 0.97 1.95 Sample #20, Operator: yeomanjo 3 2 0.88 0.95 1.93 MOMO H 1 4.37 2.99 3.68 9.37 10.19 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Feb 28 2012 ppm 5.77 2.76 3.40 Sample Name: jtsy-vii-231plug Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-vii-231plug FidFile: PROTON01 Appendix 1 – Spectra Relevant to Chapter 2 76 3.84 1.89 0.92 2.93 0.98 0.98 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 1700 repetitions OBSERVE C13, 125.6553261 MHz DECOUPLE H1, 499.7250019 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 1.0 Hz FT size 65536 Total time 58 min 180 Sample #20, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Feb 28 2012 Sample Name: jtsy-vii-231plug Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-vii-231plug FidFile: CARBON01 160 140 Me TBSO Me 120 64 MOMO H O H 100 OTBS 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 77 10 9 Relax. delay 2.000 sec Pulse 45.0 degrees Acq. time 3.000 sec Width 7995.2 Hz 8 repetitions OBSERVE H1, 499.7049152 MHz DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 0 min 40 sec Sample #46, Operator: yeomanjo 8 7 6 5 69 O 0.99 0.97 Me O 4 OMOM 0.90 Me TBSO 0.99 1.14 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Jan 23 2013 3 2 0.90 1.02 2.02 2.04 1.06 H 1 3.21 3.01 10.43 Sample Name: jtsy-ix-081B-f23-39 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-081B-f23-39 FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 78 6.73 3.07 1.07 2.64 0.94 0.98 1.01 3.01 2.10 2.03 220 200 Relax. delay 0.100 sec Pulse 45.0 degrees Acq. time 1.043 sec Width 31421.8 Hz 48000 repetitions OBSERVE C13, 125.6871022 MHz DECOUPLE H1, 499.8513810 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 2.0 Hz FT size 65536 Total time 15 hr, 14 min Temp. 25.0 C / 298.1 K Operator: yeomanjo 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Jan 12 2012 FidFile: jtsy-vii-125-c13 Sample directory: Sample Name: jtsy-vii-125 Data Collected on: daytona.caltech.edu-inova500 Archive directory: 160 140 Me 120 Me TBSO H O 69 O 100 80 OMOM 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 79 Me TBSO Me H 69 O O OMOM Appendix 1 – Spectra Relevant to Chapter 2 80 Me TBSO Me H 69 O O OMOM Appendix 1 – Spectra Relevant to Chapter 2 81 Me TBSO Me H 69 O O OMOM Appendix 1 – Spectra Relevant to Chapter 2 82 Me TBSO Me H 69 O O OMOM Appendix 1 – Spectra Relevant to Chapter 2 83 10 9 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 3.000 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7049153 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 44 sec 8 7 Me TBSO 6 Me 79 O H 5 O Me 0.93 0.99 1.03 0.95 0.98 Sample #46, Operator: yeomanjo 4 O 3 0.90 H 2 1.90 1.99 3.01 1.10 1.18 0.90 1.07 1.04 6.35 MOMO H 1 2.52 1.08 3.38 3.07 10.32 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Jun 13 2013 ppm 3.41 3.28 Sample Name: jtsy-ix-199f30-35 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-199f30-35 FidFile: PROTON01 Appendix 1 – Spectra Relevant to Chapter 2 84 3.00 1.00 1.00 220 200 Relax. delay 0.100 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 3000 repetitions OBSERVE C13, 125.6509014 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 2.0 Hz FT size 65536 Total time 57 min 180 Sample #46, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Jun 13 2013 Sample Name: jtsy-ix-199f30-35 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-199f30-35 FidFile: CARBON01 160 Me 140 Me TBSO H O 120 79 MOMO H H O 100 Me O 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 85 10 9 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 3.000 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7049151 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 44 sec Sample #32, Operator: yeomanjo 8 7 6 Me TBSO Me O 5 71 O 4 OMOM 0.86 0.92 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Mar 5 2013 3 2 1.08 0.90 O 1 3.37 12.80 H ppm 3.03 3.01 0.96 2.00 Sample Name: jtsy-ix-133Bf15-23 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-133Bf15-23 FidFile: PROTON01 Appendix 1 – Spectra Relevant to Chapter 2 86 1.53 1.33 3.19 1.13 1.79 0.84 1.94 1.06 1.91 3.17 0.91 0.91 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 1000 repetitions OBSERVE C13, 125.6509033 MHz DECOUPLE H1, 499.7074131 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 1.0 Hz FT size 65536 Total time 34 min 180 Sample #32, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Mar 5 2013 Sample Name: jtsy-ix-133Bf15-23 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-133Bf15-23 FidFile: CARBON01 160 140 Me TBSO 120 Me H O 71 O O 100 OMOM 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 87 10 9 8 7 6 0.92 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 3.000 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7049151 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 44 sec Me 72 O 5 OMOM 0.99 1.99 O 0.87 0.94 Sample #39, Operator: yeomanjo Me TBSO 0.96 O 4 3 1.00 H 2 1 3.31 3.67 9.73 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Feb 13 2013 ppm 3.17 2.96 Sample Name: jtsy-ix-107 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-107 FidFile: PROTON01 Appendix 1 – Spectra Relevant to Chapter 2 88 2.42 0.88 1.03 1.02 2.04 3.19 0.92 0.93 0.86 0.91 0.90 0.88 3.20 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 1000 repetitions OBSERVE C13, 125.6509014 MHz DECOUPLE H1, 499.7074131 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 1.0 Hz FT size 65536 Total time 34 min 180 Sample #39, Operator: yeomanjo Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Feb 13 2013 Sample Name: jtsy-ix-107 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-107 FidFile: CARBON01 160 140 Me TBSO Me O 72 O 120 H O 100 OMOM 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 89 10 9 Relax. delay 10.000 sec Pulse 45.0 degrees Acq. time 3.000 sec Width 8000.0 Hz 8 repetitions OBSERVE H1, 499.7049151 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 65536 Total time 1 min 44 sec 8 7 6 5 Me HO Me 1.01 1.01 Sample #39, Operator: yeomanjo 1.01 O 4 S2 O O OH 3 1.02 1.00 H 2 1.06 1.07 1.10 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Feb 15 2013 1 3.25 1.01 0.99 1.00 Sample Name: jtsy-ix-115f16-35 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-115f16-35 FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 90 3.64 2.15 1.09 1.83 3.91 2.53 1.01 1.01 220 200 Relax. delay 0.100 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 20000 repetitions OBSERVE C13, 125.6871032 MHz DECOUPLE H1, 499.8513810 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 3.0 Hz FT size 65536 Total time 6 hr, 20 min Temp. 25.0 C / 298.1 K Operator: yeomanjo 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Feb 17 2013 FidFile: jtsy-ix-115f16-35 Sample directory: Sample Name: jtsy-ix-115f16-35 Data Collected on: daytona.caltech.edu-inova500 Archive directory: 160 140 Me HO Me O S2 O 120 H O 100 OH 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 91 9 8 7 6 5 Me O O 4 0.92 O OH 3 (– )-trichorabdal A (12) H 0.91 10 0.95 Me 0.98 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.708 sec Width 9594.6 Hz 8 repetitions OBSERVE H1, 599.6348295 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 0 min 22 sec 0.96 O 0.91 3.15 Temp. 60.0 C / 333.1 K Operator: yeomanjo 1.02 H 2 0.82 Pulse Sequence: PROTON (s2pul) Solvent: pyridine Data collected on: Mar 13 2013 1 0.99 3.06 3.11 Sample Name: jtsy-ix-143prep Data Collected on: fid.caltech.edu-inova600 Archive directory: /home/yeomanjo/vnmrsys/data Sample directory: jtsy-ix-143prep FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 92 1.00 1.00 2.01 0.52 1.18 1.00 0.85 220 200 Relax. delay 0.100 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 13000 repetitions OBSERVE C13, 125.6870252 MHz DECOUPLE H1, 499.8512260 MHz Power 39 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 5.0 Hz FT size 65536 Total time 4 hr, 7 min Temp. 60.0 C / 333.1 K Operator: yeomanjo 180 Pulse Sequence: CARBON (s2pul) Solvent: pyridine Data collected on: Mar 15 2013 FidFile: jtsy-ix-143prep-c13 Sample directory: Sample Name: jtsy-ix-143prep Data Collected on: daytona.caltech.edu-inova500 Archive directory: 160 140 120 H Me O O O O OH 100 80 60 (– )-trichorabdal A (12) Me H 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 93 (– )-trichorabdal A (12) Me H H Me O O O O OH Appendix 1 – Spectra Relevant to Chapter 2 94 (– )-trichorabdal A (12) Me H H Me O O O O OH Appendix 1 – Spectra Relevant to Chapter 2 95 (– )-trichorabdal A (12) Me H H Me O O O O OH Appendix 1 – Spectra Relevant to Chapter 2 96 (– )-trichorabdal A (12) Me H H Me O O O O OH Appendix 1 – Spectra Relevant to Chapter 2 97 10 9 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 2.621 sec Width 6250.0 Hz 16 repetitions OBSERVE H1, 499.7049153 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 0 min 58 sec 8 7 6 5 Me O 4 73 O 1.00 1.02 Sample #27, Operator: vmak Me HO 2.00 H OH 3 2 1.08 1.01 3.04 1.73 1.94 1.05 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: May 1 2013 1 3.13 2.93 Sample Name: VWM2-007-c2f13-24 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-007-c2f13-24 FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 98 3.16 1.08 2.15 2.02 1.08 1.96 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 1000 repetitions OBSERVE C13, 125.6509033 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 1.0 Hz FT size 65536 Total time 34 min Sample #27, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 1 2013 Sample Name: VWM2-007-c2f13-24 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-007-c2f13-24 FidFile: CARBON01 160 Me 140 Me HO H O 120 73 O OH 100 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 99 0.94 10 9 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.705 sec Width 9611.9 Hz 8 repetitions OBSERVE H1, 599.6357305 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 0 min 22 sec Temp. 25.0 C / 298.1 K Operator: vmak 8 7 6 5 2.07 0.80 1.04 Pulse Sequence: PROTON (s2pul) Solvent: CDCl3 Data collected on: May 9 2013 Me H 1.02 4 Me O H O 74 O 3 OH 2 1.05 1.10 1.13 1.87 1.05 0.90 1.18 2.00 Sample Name: VWM2-019 Data Collected on: fid.caltech.edu-inova600 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-019 FidFile: PROTON01 1 4.17 1.09 1.17 3.00 3.18 VWM2-019 ppm Appendix 1 – Spectra Relevant to Chapter 2 100 220 200 Relax. delay 0.500 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 2250 repetitions OBSERVE C13, 125.6509043 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 4.0 Hz FT size 65536 Total time 58 min Sample #22, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 9 2013 Sample Name: VWM2-019-comb Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-019-comb FidFile: CARBON01 160 140 120 100 80 60 Me H Me O H O 40 74 O 20 OH 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 101 0.93 10 9 Relax. delay 2.000 sec Pulse 45.0 degrees Acq. time 2.048 sec Width 8000.0 Hz 32 repetitions OBSERVE H1, 499.7049153 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 2 min 10 sec 8 7 6 5 Me H 2.07 0.77 1.04 Sample #35, Operator: vmak O 75 O 4 Me O H 3 OAc 2 0.98 1.08 1.00 1.00 2.13 3.12 2.96 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: May 7 2013 1 1.84 3.09 3.13 Sample Name: VWM2-017-f14-19 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-017-f14-19 FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 102 1.08 6.57 1.00 220 200 Relax. delay 0.500 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 2250 repetitions OBSERVE C13, 125.6509033 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 4.0 Hz FT size 65536 Total time 58 min Sample #21, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 9 2013 Sample Name: VWM2-021-comb Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-021-comb FidFile: CARBON01 160 140 Me Me O 120 H H O 75 O 100 OAc 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 103 10 9 8 7 6 Me Me O OH OAc 4 5 76 OH 1.04 0.99 Relax. delay 2.000 sec Pulse 45.0 degrees Acq. time 2.621 sec Width 6250.0 Hz 32 repetitions OBSERVE H1, 499.7049149 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 2 min 28 sec H 1.07 0.97 0.98 Sample #33, Operator: vmak 3 2 0.98 2.08 1.03 1.08 2.20 3.14 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: May 17 2013 1 3.42 3.09 2.13 3.01 3.02 Sample Name: VWM2-033c Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-033c FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 104 1.06 1.10 0.96 220 200 Relax. delay 0.100 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 3000 repetitions OBSERVE C13, 125.6509004 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 57 min Sample #33, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 17 2013 Sample Name: VWM2-033c Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-033c FidFile: CARBON01 160 140 Me 120 Me H OAc 100 O OH 76 OH 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 105 10 9 Relax. delay 2.000 sec Pulse 45.0 degrees Acq. time 2.621 sec Width 6250.0 Hz 128 repetitions OBSERVE H1, 499.7049153 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 9 min 53 sec 8 7 6 5 1.00 1.00 0.99 Sample #36, Operator: vmak Me 4 O OH OAc 77 2.04 Me H 3 2 2.04 1.01 2.26 3.21 1.08 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Jun 5 2013 1 1.07 1.13 2.11 3.19 1.07 1.07 3.00 2.93 Sample Name: VWM2-025-652013 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-025-652013 FidFile: PROTON02 ppm Appendix 1 – Spectra Relevant to Chapter 2 106 2.11 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 8000 repetitions OBSERVE C13, 125.6509021 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 4 hr, 33 min Sample #36, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Jun 5 2013 Sample Name: VWM2-025-652013 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-025-652013 FidFile: CARBON01 160 140 Me 120 Me H 77 OAc 100 O OH 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 107 10 9 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 3.000 sec Width 8000.0 Hz 32 repetitions OBSERVE H1, 499.6951455 MHz DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 2 min 8 sec 8 7 6 Me 5 Me HO O 78 O 1.05 1.00 0.97 Sample #18, Operator: vmak 1.00 1.00 H 4 OAc 1.03 1.02 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Jan 21 2014 3 2 4.22 1.21 1.06 Sample Name: VWM3-063 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM3-063 FidFile: PROTON05 1 1.69 1.66 3.35 3.23 VWM3-063 ppm Appendix 1 – Spectra Relevant to Chapter 2 108 2.32 4.34 1.06 1.05 1.02 0.98 0.99 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 5000 repetitions OBSERVE C13, 125.6484443 MHz DECOUPLE H1, 499.6976415 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 2.0 Hz FT size 65536 Total time 2 hr, 50 min Sample #18, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Jan 21 2014 Sample Name: VWM3-063 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM3-063 FidFile: CARBON01 VWM3-063 160 140 Me HO Me O 78 O 120 H 100 OAc 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 109 10 9 8 7 6 Me 0.97 5 Me 1.00 O 4 O OH OAc 79 OH 0.99 1.00 Relax. delay 2.000 sec Pulse 45.0 degrees Acq. time 2.621 sec Width 6250.0 Hz 64 repetitions OBSERVE H1, 499.7049153 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 4 min 56 sec H 1.01 Sample #22, Operator: vmak 3 2 2.13 1.06 2.99 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Jun 13 2013 1 1.02 1.06 2.28 2.00 3.83 3.01 3.06 Sample Name: VWM2-063-f24-41 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-063-f24-41 FidFile: PROTON01 ppm Appendix 1 – Spectra Relevant to Chapter 2 110 1.03 2.15 0.94 220 200 Relax. delay 0.100 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 3100 repetitions OBSERVE C13, 125.6509011 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 1.0 Hz FT size 65536 Total time 59 min Sample #34, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: May 24 2013 Sample Name: VWM2-043-f26-36 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-043-f26-36 FidFile: CARBON01 160 140 Me Me O 100 O OH OAc 79 OH 120 H 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 111 10 9 8 7 6 0.99 O OH OAc 5 4 (– )-longikaurin E (11) Me 1.02 0.97 1.04 Relax. delay 2.000 sec Pulse 45.0 degrees Acq. time 2.621 sec Width 6250.0 Hz 128 repetitions OBSERVE H1, 499.7049153 MHz DATA PROCESSING Line broadening 0.2 Hz FT size 32768 Total time 9 min 53 sec Me 1.00 O 0.91 Sample #35, Operator: vmak 0.99 1.00 OH 3 0.99 H 1 2 1.06 1.02 2.99 Pulse Sequence: PROTON (s2pul) Solvent: cdcl3 Data collected on: Jun 23 2013 1.05 1.01 2.21 2.04 2.84 3.02 3.06 Sample Name: VWM2-067-c2 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-067-c2 FidFile: PROTON06 ppm Appendix 1 – Spectra Relevant to Chapter 2 112 1.02 220 200 Relax. delay 1.000 sec Pulse 45.0 degrees Acq. time 1.042 sec Width 31446.5 Hz 12500 repetitions OBSERVE C13, 125.6509014 MHz DECOUPLE H1, 499.7074131 MHz Power 40 dB continuously on WALTZ-16 modulated DATA PROCESSING Line broadening 0.5 Hz FT size 65536 Total time 7 hr, 7 min Sample #20, Operator: vmak 180 Pulse Sequence: CARBON (s2pul) Solvent: cdcl3 Data collected on: Jun 22 2013 Sample Name: VWM2-067-c2 Data Collected on: indy.caltech.edu-inova500 Archive directory: /home/vmak/vnmrsys/data Sample directory: VWM2-067-c2 FidFile: CARBON01 160 Me OH O OH O OAc 140 120 100 (– )-longikaurin E (11) Me H 80 60 40 20 0 ppm Appendix 1 – Spectra Relevant to Chapter 2 113 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 114 Chapter 3 Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 3.1 INTRODUCTION The diterpenoid alkaloids have garnered much attention from the synthetic community due to their structural complexity and compelling biological activity.1 Early efforts in the 1960s were directed towards classic targets such as C20 veatchine2 and atisine type alkaloids,3 and later, pioneering work towards C19 aconitine type alkaloids.4 More recently, synthetic studies towards more complex C20 hetidine and hetisine type alkaloids have sparked a new interested in the field,5 specifically towards the C18 and C19 natural products. This chapter reviews completed total syntheses of natural products that bear the aconitine core (e.g. C18- and C19-diterpenoid alkaloids), as well as syntheses of related C20-diterpenoid alkaloids employing divergent strategies. Lastly, a detailed account of our own progress towards talatisamine, a C19 aconitine type alkaloid, is Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 115 presented, as well as a unified strategy to access C20 denudatine and napelline type alkaloids in a non-biomimetic manner. 3.2 STRUCTURAL AND BIOSYNTHETIC CONSIDERATIONS A major challenge in the synthesis of diterpenoid alkaloids is construction of the highly caged polycyclic framework. The C18- and C19-diterpenoid alkaloids possess a complex hexacyclic skeleton that is abundantly decorated with oxygenated functionality (Figure 3.1). Specifically, a piperidyl E-ring bridges the hydrindane AF-ring system, that is adjoined to a bicyclo[3.2.1] CD-rings through the central cyclohexyl B-ring. The AF/B-C rings also constitute a 6/7/5-ring system rearranged from a 6/6/6-phenanthrene core. The natural products possess at least 11 contiguous stereocenters that include two quaternary centers at C4 and C11 at the bridgehead positions of the AE bicycle. Ring labelling and atom numbering 13 12 17 2 Et 1 A NE 3 4 19 C 14 9 D 10 11 F 5 6 2 3 16 18 4 A 1 19 R B 8 15 NEt 5 11 10 17 6 12 7 9 7 8 NEt R E F B 15 C 18 R 14 13 OMe MeO OMe D 16 NEt OH MeO N Et H OMe HO talatisamine (34) HO HO OMe Figure 3.1. Structural depictions of C19-Diterpenoid Alkaloids Although there have only been a handful of completed syntheses of C19- and C18diterpenoid alkaloids, several reports, most of which detail approaches to the AEF or CD 116 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine rings, have been published.6 A majority of the successful syntheses have employed Diels–Alder cycloadditions to form a [2.2.2]-bicycle and Wagner–Meerwein rearrangement to generate the [3.2.1]-bicyclic CD-ring system. These strategies have relied on the biomimetic rearrangement of the C20 denudatine skeleton into the C19 aconitine framework. Chemical evidence for this transformation was first demonstrated by Johnston and Overton, who were able to convert atisine to derivative 80, containing a tosylate leaving group (Figure 3.2). 7 Gas phase pyrolysis at 500 °C successfully converted the [2.2.2]-bicycle into the [3.2.1]-bicycle of 81 in 77% yield. Wiesner also achieved a solution phase Wagner–Meerwein rearrangement several years later, in a tricyclic model system.4b Under solvolytic conditions, tosylate 82 underwent rearrangement to tricycles 83 as a 1:1 mixture of olefins. This biomimetic conversion was key to their strategy to access C19 aconitine and C20 napelline type alkaloids. Johnston and Overton (1971) NAc Me 0.5 mmHg 500 °C Wiesner (1975) Me 2N (77% yield) TsO O 80 NH NAc Me TsO O 81 X OMe 82 X = -OCH2CH2O- NMe 2 DMSO 180 °C O O (85% yield) OMe 83 1:1 olefin isomers Figure 3.2. Chemical support for biomimetic Wagner–Meerwein rearrangements. 3.3 PRIOR TOTAL SYNTHESES 3.3.1 Wiesner’s Synthesis of C19- and C20-Diterpenoid Alkaloids Wiesner’s landmark synthesis of talatisamine (34) in 1974 constitutes the first total synthesis of a C19-diterpenoid alkaloid.4a Implementation of the Wagner–Meerwein Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 117 rearrangement in the more complex context of total synthesis proved challenging, but was eventually accomplished during the late stage of the synthesis. The synthesis begins with an initial Diels–Alder cycloaddition between bicycle 84 and diene 85 afforded two diastereomeric tricycles that were independently advanced to sulfonamide 86 (Figure 3.3).4b Deprotonation by sodium hydride and cyclization afforded the piperidine ring, and after mesylate reduction and methylation, provided aromatic intermediate 87. At this stage, a dissolving metal reduction, amine acylation, and olefin isomerization afforded enone 88, which readily underwent [2 + 2] cycloaddition with allene to furnish cyclobutane 89. Another three steps involving oxidative cleavage of the exocyclic olefin, generated cyclobutanol 90, and upon exposure to Brønsted acid, underwent a retro-aldol reaction to ketoaldehyde 91 and intramolecular aldol cyclization to provide the [2.2.2]bicycle of atisine framework 92. A further seven steps were required to install the tosylate leaving group of 93 in the requisite stereochemical configuration. With tosylated atisine analogue 93, the biomimetic Wagner–Meerwein rearrangement would forge the [3.2.1]-bicyclic CD-rings of talatisamine (34). Under previously described conditions employing a tetramethylguanidine base at elevated temperatures, 93 underwent rearrangement to presumably produce carbocationic intermediate 94, and subsequently, an equimolar mixture of olefinic isomers 95 and 96 (Figure 3.4). Although the rearrangement proceeded in good overall yield, isomer 95 could not be advanced in a productive manner; only isomer 96 was carried forward to pentacycle 97. Upon mercuric acetate-mediated oxidation, a biomimetic aza-Prins cyclization formed the last C7–C17 bond, completing the first total synthesis of a C19diterpenoid alkaloid, talatisamine (34). 118 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine OMs MsO OAc CN H 18 steps OMe NHMs + OMe NMs MeO 1. NaH 2. Red-Al 3. NaH, MeI OAc OMe OMe 84 85 86 OMe NAc MeO 1. Na/NH 3 2. Ac2O 87 OMe 1. HO(CH 2)2OH 2. OsO 4, NaIO 4 hυ 3. HCl, MeOH 88 3. NaBH 4 O 89 OMe NAc MeO X = –OCH2CH2O– O OMe NAc 7 steps X = –OCH2CH2O– O O 92 X OH 90 MeO OMe NAc MeO HCl 91 OMe NAc MeO OMe NAc MeO TsO O OH X OMe 93 Figure 3.3. Synthesis of Wagner–Meerwein rearrangement precursor 93. NH OMe NAc MeO Me 2N TsO OMe NAc MeO OMe NAc MeO NMe 2 + DMSO 180 °C X OMe OMe NAc MeO O X = –OCH2CH2O– O 93 O OMe 94 OMe NEt MeO 3 steps 17 96 7 O O O OMe 95 (40% yield) OMe NEt MeO OMe NEt MeO Hg(OAc) 2 H H 2O (40% yield) HO OMe 97 OMe 96 (40% yield) HO OMe 98 Figure 3.4. Wiesner’s total synthesis of talatisamine (34). HO HO 34 OMe 119 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine In an effort to improve the synthesis, Wiesner and coworkers hypothesized that performing the biomimetic rearrangement with the C7–C17 bond in place would preclude the unproductive, strained olefin isomer 95. Accordingly, they began synthetic efforts towards 13-desoxydelphonine (99), which possesses a C6-methoxy group. Olefin 100 was synthesized in 11 steps from o-cresol, and then engaged in an aziridination and azasemipinacol rearrangement of 101 to form the C7–C17 bond (aconitine numbering) of acetamide 102 (Figure 3.5). A 20-step sequence appended a cyclohexyl ring bearing a methyl ester (103), and another 5 steps involving lactam formation provided aromatic intermediate 104. Most importantly, this intermediate (104) possesses the C7–C17 bond that was absent in their first generation synthesis of talatisamine (34). H NAc NHAc 17 CO2Me 1. TMSN3 CO2Me 2. Ac2O, AcOH 85 °C Me MeO Me 7 101 102 O AcO NHAc 20 steps OMe 17 O MOMO 7 MeO O OMe 103 MeN Me O 5 steps OAc MeO AcOH (75% yield) 100 11 steps from o-cresol Me MeO CO2Me MeO OMe O NMe OMe 17 17 MeO 7 OMe MOMO 7 MeO 104 MOMO OH Figure 3.5. Synthesis of pentacyclic aromatic intermediate 104. From aromatic intermediate 104, the endgame strategy mirrors that of their synthesis of talatisamine (34), however with the C7–C17 bond in place, significant improvements were observed. Rather than a reductive dearomatization, three steps involving oxidative dearomatization of arene 104 provided diene 105 as a mixture of 120 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine diastereomers and brominated/unbrominated products (Figure 3.6). The mixture of products underwent an intermolecular Diels–Alder cycloaddition with benzyl vinyl ether, and after global reduction with zinc metal, afforded a single hexacyclic product 106 that comprises the C20 denudatine framework. Elaboration of 106 to hexacyclic intermediate 107 required 12 steps, thereby installing a bromide leaving group for the crucial rearrangement. Under previously described conditions, the Wagner–Meerwein rearrangement of bromide 107 proceeded smoothly to afford aconitine framework 108 as a single isomer in 89% yield. This rearrangement is a significant improvement from their previous synthesis, which provided a 1:1 mixture of olefinic isomers. A final four steps involving deprotection, reductions, and hydrations provided 13-desoxydelphonine (99). The fourth generation synthetic strategy obviated the low yielding aza-Prins cyclization, since the C7–C17 bond was formed at a relatively early stage in the synthesis. This seminal work leveraged the conversion of denudatine framework 107 into the aconitine framework 108, a finding that would be pivotal for the success of future syntheses. OMe O NMe MeO 3 steps 104 1. MeO R OBn MeO O O O O 106 105 R = H, Br (2:1) OMe O NMe MeO OMe O NMe MeO N O OMe O H Br 107 DMSO/o-xylene 180 °C (89% yield) OMe NMe MeO 4 steps N MeO 12 steps OBn 2. Zn, AcOH O OMe O NMe MeO H MeO O O HO OMe 108 H MeO HO OMe 13-desoxydelphonine (99) Figure 3.6. Wiesner’s total synthesis of 13-desoxydelphonine (99). 121 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine During the course of Wiesner’s work towards C19 aconitine type alkaloids, his group also explored the biomimetic conversion of the denudatine scaffold to the napelline scaffold through a similar Wagner–Meerwein rearrangement (Figure 3.7).8 Denudatine framework 109 was synthesized in a fashion analogous to the previously described synthesis of 13-desoxydelphonine (99). By installing a leaving group at C13 instead of C15, rearrangement of mesylate 109 occurred readily under reflux in acetic acid to furnish triacetate 110. This was advanced three steps to triketone 111, which constituted a formal synthesis of napelline (29) based on their earlier work.8c Me OAc O NEt OMs O Me 15 OAc OAc Me AcOH Me N Et MsO OAc Me O Me reflux 13 O (95% yield) OAc N Et 109 110 O 3 steps Ac OAc O Me Me Me O HO OH O OH N Et N Et 111 napelline (29) Figure 3.7. Wiesner’s total synthesis of napelline (29). Wiesner’s work towards the synthesis of C19- and C20-diterpenoid alkaloids was initially part of a structural elucidation effort, but undoubtedly inspired future syntheses that also feature elegant use of Wagner–Meerwein rearrangements for conversions of denudatine scaffolds to aconitine scaffolds. Although Wiesner’s syntheses cannot be held to the same standards as modern total synthesis, their influence on the field is incredibly significant, as the diterpenoid alkaloids remain formidable targets for total synthesis, even with modern synthetic methods. 122 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Gin’s Synthesis of Neofinaconitine 3.3.2 The next total synthesis of a diterpenoid alkaloid possessing the aconitine core came nearly four decades after Wiesner’s work. In Gin’s posthumous synthesis of the C18-diterpenoid alkaloid neofinaconitine (112), a convergent strategy was employed to assemble the aconitine scaffold and to access to synthetic material for stereochemical/structural confirmation.9 Notably, the synthesis did not utilize the same Wagner–Meerwein rearrangement as the past and future syntheses. In their retrosynthetic analysis, Gin and coworkers envisioned forming the C7–C8 bond of neofinaconitine (112) through a radical cyclization and the C11 quaternary center through an intramolecular Mannich reaction at C17 (Figure 3.8). The deconstructed polycycle 113 could be accessed in a convergent manner by Diels–Alder cycloaddition of dihydroazepinone 114 and siloxydiene 115. The fused cyclopropane of 115 could be prepared by another unusual Diels–Alder cycloaddition between siloxydiene 116 and cyclopropene 117. O NH 2 O OMe NEt O MeO 2C Mannich reaction 11 17 11 7 7 8 MeO O HO 8 radical cyclization OMe 17 Et N O CO2Me NEt Br 17 azepinone Diels–Alder H 7 H Br 11 O 8 MeO neofinaconitine (112) OR MeO OR 113 TBSO Et N cyclopropene Diels–Alder O CO2Me Br TBSO + + OMe 114 MeO 115 OTIPS 116 Figure 3.8. Gin’s retrosynthetic analysis of neofinaconitine (112). OR 117 123 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine O + OTIPS 118 119 [6 steps] 120 N Br 2. HBr/AcOH C6H 5F, 0 °C 122 Br (62% yield, 2 steps) OTIPS Et N (1 : 1.6) OTIPS 121 (desired) OMe O Me 1. TBAF, THF MeO MeO OTIPS MeO OMe N 4 steps + 0 °C MeO O TBSO TBSO Et 3N TBSOTf MeO 123 Et N O CO2Me 114 Br (87% yield) 1. MgBr Br 2. TBSOTf, KHMDS THF, –78 °C MeO (77% yield, 2 steps) 124 Et N CO2Me H O Br MeO TBSO O H SnCl4, 4 Å MS MeCN Me 126 single isomer 1. OsO 4, NMO, THF/H2O then Pb(OAc) 4 O CO2Me Br H H O 2. DBU, toluene (57% yield, 2 steps) MeO 127 O Figure 3.9. Convergent assembly of Mannich cyclization precursor 127. The C/D bicycle was generated at an early stage in the synthesis through a Diels– Alder cycloaddition between cyclopropene 119 and a siloxydiene generated in situ from cyclopentene 118 (Figure 3.9). This produced two isomeric cycloadducts 120 and 121 in a 1:1.6 ratio, in favor of the desired isomer. This mixture was advanced four steps to Weinreb amide 122, which was ultimately isolable as a single isomer. Since the cyclopropylmethyl silyl ether moiety of 122 was detrimental to diastereoselectivity of the ensuing azepinone Diels–Alder, it was converted to homoallyl bromide 123, which served as an α,β-unsaturated ketone precursor. Addition of vinyl-Grignard and silyl ether formation provided siloxydiene 124 as a single olefin isomer. With the homoallylic bromide of 124, it was suspected that the sterically large bromine atom would hinder the 124 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine “back” face of the diene and restrict rotation, thereby improving the diastereofacial selectivity. Remarkably, Diels–Alder cycloaddition with azepinone 114 in the presence of tin tetrachloride provided cycloadduct 126 in 87% yield as a single product. Lastly, homoallyl bromide 126 was converted to enone 127 by oxidative scission of the exocyclic olefin, followed by β-elimination of the bromide. Et N 17 Br CO2Me H 7 O O O H 1 11 8 O Br Tf2NH 7 CO2Me Et 3 N 17 1 CH2Cl2 8 O O MeO 2C 7 H 8 O MeO MeO 2C 1. TMSOTf, Et 3N 2. PhSeCl, 0 °C MeO 1. LiBH 4, THF 133 PhH, 80 °C O O NEt O MeO 2C NEt 1. Pd/C, H 2, EtOAc 2. NaBH 4, MeOH, 0 °C H 3. MeI, KOt-Bu, THF 0 °C H O MeO MeO HO O (30% yield, 3 steps) 132 NH 2 O OMe O NEt HO OMe NEt O 3 steps H H 2. CrO3, H 2SO4 (aq) (40% yield, 2 steps) O 129 131 OMe O (99% yield) MeO 3. NaIO 4, THF/H2O OMe O NEt HO 8 O MeO 2C (51% yield, 3 steps) H Bu 3SnH, AIBN 128 130 4 N 7 (66% yield, 2 steps) O NEt CO2Me Et 2. MsCl, Et 3N CH2Cl2, 50 °C O MeO O 127 1. CAN, CH 3CN H 2O, 60 °C 11 (75% yield) MeO Br MeO HO OMe 134 MeO HO OMe neofinaconitine (112) Figure 3.10. Gin’s total synthesis of neofinaconitine (112). The assembly of the aconitine core required two crucial C–C bond formations. The C11–C17 bond was to be formed by an intramolecular Mannich-type N-acyliminium cyclization, and the C7–C8 bond was to be formed by an intramolecular radical cyclization. Protonation of enamide 127 with triflimide produced an N-acyliminium ion that underwent Mannich reaction with a C1–C11 enol to forge the desired C11–C17 bond Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 125 (Figure 3.10). Unfortunately, the C1 ketone underwent cyclization onto the D-ring enone to forge the unproductive C8–O bond of 128. Cleavage of this undesired C8–O bond required three steps, and was accomplished by allylic oxidation at C3, followed by mesylation and elimination to produce bis-enone 129. Remarkably, the radical cyclization proceeded smoothly to construct the C7–C8 bond of the aconitine core (130) in quantitative yield. To date, this remains the most expedient synthesis of the full aconitine scaffold. The remainder of the synthesis necessitated functional group interconversions to establish alcohol and methyl ether stereocenters, oxidative truncation of the C4 methyl ester, and selective acylation of the resulting C4 alcohol. The tertiary alcohol at C8 was introduced utilizing the D-ring ketone of 130 (Figure 3.10). Silyl enol formation and selenation provided an α-selenide that underwent oxidation/elimination by treatment with sodium meta-periodate. The transiently generated bridgehead olefin (131) readily underwent hydration to provide tertiary alcohol 132. Hydrogenation, borohydride reduction, and methylation provided 133 in 30% yield over three steps. Although this sequence terminated with a low yielding, non-selective bis-methylation, an efficient protocol involving global methylation and formal C8-OMe demethylation was developed in subsequent semisynthetic studies. From C19 acontine scaffold 133, borohydride reduction of the methyl ester was followed by oxidative truncation to provide the C4 alcohol of the C18-diterpenoid alkaloids (134). Finally, amide reduction and acylation provided neofinaconitine (112) in an additional three steps. Structural assignment of the synthetic material was also confirmed through relay synthesis from the C19-diterpenoid alkaloid condelphine. Gin’s synthesis of neofinaconitine (112) showcases the advantages 126 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine of a non-biomimetic, convergent strategy for the synthesis of highly caged, polycyclic frameworks. Sarpong’s Unified Strategy towards C20-, C19-, and C18Diterpenoid Alkaloids 3.3.3 Wiesner’s landmark syntheses of C19 aconitine type and C20 napelline type alkaloids demonstrated the viability of biomimetic conversions of denudatine scaffolds to napelline and aconitine scaffolds in total synthesis. These conversions would be employed once again in the synthesis of weisaconitine D (135) and liljestrandinine (154), which Sarpong reported as the first strategy to access both C18- and C19-diterpenoid alkaloids.10 In contrast to Gin’s synthesis of neofinaconitine (112), which oxidatively truncates the C4–C18 bond of a C19-framework,9 Sarpong’s synthesis excludes C18 for the synthesis of 135, and modularly constructs the C4–C18 bond of C19-diterpenoid alkaloid 154. In their retrosynthetic analysis of 135, the B-ring was identified as the maximally bridged ring, and was disconnected, along with the C/D-rings, to arene-olefin 136 (Figure 3.11). The maximally bridged piperidine E-ring of 136 was disconnected at the C19–N bond to arrive at hydrindane 137. This bicycle would serve as the divergence point for C19- and C20-diterpenoid alkaloids, which require quaternization at C4. Bicycle 137 would arise from a Diels–Alder cycloaddition between diene 138 and enone 139. H OMe NEt 4 OMe NEt H OMe OMe 4 B HO EtO OMe weisaconitine D (135) + CN MeO TBSO O MeO 2C E H HO TBSO 136 137 138 Figure 3.11. Sarpong’s retrosynthetic analysis of weisaconitine D (135). 139 127 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine The synthesis of weisaconitine D (135) proceeded in 30 steps from diene 138, which itself is available in five steps from commercial materials (Figure 3.12). A Diels– Alder cycloaddition between 138 dienophile 139 provided a cycloadduct that was hydrogenated to give bicycle 140. The ketone of 140 was converted to the vinyl triflate, which underwent cross-coupling with sodium cyanide to yield α,β-unsaturated nitrile 131 in 70% yield over the two steps. Next, a Rh-catalyzed conjugate addition with in situ generated lithium boronate 142 simultaneously generated two adjacent stereocenters in 143. The nitrile was stereospecifically converted to the carbamate through a Hoffmann rearrangement, with additional steps providing mesylate 144. Subjection to potassium tert-butoxide then effected intramolecular alkylation to forge the piperidine ring of 145 in 76% yield. Methoxymethyl ether cleavage and oxidative dearomatization afforded the intramolecular Diels–Alder substrate 146. OMe O MeO 2C + OMe 1. toluene, 110 °C 2. Pd/C, H 2, EtOAc TBSO (70% yield, 2 steps) TBSO 138 (70% yield, 2 steps) 140 OMe Li(MeO) 3B OMe OMOM CO2Me CN OMe TBSO H 141 2. CuI, NaCN, Pd(PPh 3)4 H 139 CO2Me CN 1. LiHMDS, PhNTf 2 CO2Me O 142 TBSO [RhCOD(OH)] 2 H 2O, 100 °C H 7 steps OMe OMOM 143 (60% yield) OMe H N MsO OMe H O THF 0 °C to rt MeO (76% yield) 144 MOMO H KOt-Bu OMe NCO 2Me O (98% yield, 2 steps) MOM H 1. HCl, i-PrOH 2. PhI(OAc) 2 NaHCO 3, MeOH MeO OMe NCO 2Me MeO MeO O 145 Figure 3.12. Preparation of intramolecular Diels–Alder precursor 146. 146 128 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Dienone 146 readily underwent cycloaddition in refluxing para-xylene to produce the bicyclo[2.2.2] moiety of 147 (Figure 3.13). Four functional group manipulations provided alcohol 148, and exposure to triflic anhydride generated an intermediate triflate that underwent the key Wagner–Meerwein rearrangement to forge the [3.2.1]-bicycle of 149. The rearrangement produced a single product, even though two isomeric alcohols are possible; presumably, the allylic isomer of 149 is precluded due to ring strain from a bridgehead olefin. Another eight steps were required to install the final C–O bond, the Nethyl group, and the C16 methoxy group of weisaconitine D (135). OMe NCO 2Me H OMe p-xylene MeO 150 °C MeO O (77% yield) NCO 2Me H 4 steps MeO O HO OMOM 147 148 OMe 146 1. Tf2O, Py, CH2Cl2 –78 °C to rt OMe NCO 2Me H OMe NCO 2Me H 8 steps OMe NEt H 2. DBU, DMSO, 120 °C (55% yield, 2 steps) MOMO HO 149 HO EtO 16 OMe weisaconitine D (135) C18 lappaconitine type Figure 3.13. Sarpong’s total synthesis of weisaconitine D (135). Extension of this strategy to the synthesis of C19- and C20-diterpenoid alkaloids necessitated quaternization at C4. To this end, alcohol 150 was oxidized under Swern conditions to the aldehyde (not shown) to facilitate α-functionalization (Figure 3.14). Unfortunately, attempts to alkylate the aldehyde were unfruitful, leading to decomposition or alkylation from the undesired α-face. Ultimately, an aldol-Cannizzaro sequence was developed to access a 1,3-diol that was subsequently mesylated to afford 129 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine bis-mesylate 151 with the C4 stereocenter ablated. At this stage, intramolecular Nalkylation provided the piperidine ring of tetracycle 152, and mesylate displacement with methoxide afforded the C18 methoxy group of 153. This was advanced to C19- diterpenoid alkaloid liljestrandinine (154) in a further 12 steps analogous to the weisaconitine D (135) synthesis. OMe OMe MsO 4 H N OMe H HO O MeO 1. DMSO, (COCl)2 Et 3N MsO 4 H N OMe H O 2. KOH, CH2O 3. MsCl, Py KOt-Bu THF, 50 °C MeO (78% yield, 3 steps) MOMO MsO 18 4 OMe NCO 2Me 1. NaOMe, MeOH MeO 2. K 2CO3, ClCO2Me (26% yield, 3 steps) MOMO 151 4 OMe NCO 2Me 12 steps 18 120 °C MeO MOMO 150 MeO MeO MOMO HO 152 OMe NEt 4 153 HO liljestrandinine (154) C19 aconitine type Figure 3.14. Sarpong’s total synthesis of liljestrandinine (154). By establishing a protocol to functionalize C4, bis-mesylate 151 is well suited for advancement to C20 denudatine type alkaloids.11 Optimal conditions for piperidine ring formation were identified using potassium hydride instead of potassium tert-butoxide, providing 154 in a substantially improved 83% yield (Figure 3.15). Reductive cleavage of the C18 mesylate to the methyl group and oxidative dearomatization/intramolecular Diels–Alder cycloaddition were accomplished in four steps to furnish hexacycle 155, which possesses the bicyclo[2.2.2] moiety of the denudatine type alkaloids. A final seven 130 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine steps of functional group interconversions provided cochlearenine (156), as well as Noxidized and C17-veratroylated natural analogues. OMe MsO MsO MsO H N OMe H O MeO Me NCO 2Me O MeO 155 O Me MeO NCO 2Me 4 steps MOMO 154 H OMe O 7 steps O Me O OH OH OH OMe N OMe DMF 151 OMe MeO 18 (83% yield) MOMO Me KH OMe 4 N Me cochlearenine (156) C 20 denudatine type Figure 3.15. Sarpong’s total synthesis of cochlearenine (156). The installation of stereocenters relies completely on diastereocontrol from stereocenters established in the initial Diels–Alder cycloaddition that forms the hydrindane unit. Thus, an enantioselective variant of the transformation would render the syntheses asymmetric. For this purpose, dienophile 157 was synthesized and utilized in a Cu-catalyzed enantioselective Diels–Alder cycloaddition with diene 138, providing cycloadduct 158 in 92% enantiomeric excess. The carbonylcarbamate functionality could be converted to the methyl ester by subjection to bismuth(III) triflate in methanol, and after re-protection of the silyl ether in the same pot, provides hydrindane 159 thereby intercepting an early intermediate in the syntheses. Sarpong’s synthetic strategy targets C18-, C19-, and C20-diterpenoid alkaloids in a modular fashion through C4 quaternization and biomimetic Wagner–Meerwein rearrangements of denudatine frameworks to aconitine frameworks. Specifically, by 131 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine diverging at an early stage in the synthesis through arene olefin 150 (see Figure 3.14), the strategy demonstrate that C18 variants need not necessarily derive from C19 or C20 variants through C4–C18 bond scission. These syntheses also highlight the potential of de novo syntheses to access biogenetically related diterpenoid alkaloids. OMe O O O TBSO R PhMe/CH 2Cl2, –20 °C 157 (68% yield) >20:1 dr, 92% ee 138 Me Ln = OMe [Cu-Ln ](OTf)2 (20 mol%) OMe N H + O t-Bu H Me O N O TBSO N t-Bu Bi(OTf) 3, MeOH then Et 3N, imid. TBSCl (63% yield) 158 (R = (CO)NHCO2Me) 159 (R = CO2Me) Figure 3.16. Enantioselective [4 + 2] for the synthesis of hydrindane 159. 3.3.4 Fukuyama’s Alkaloids Synthesis of C19- and C20-Diterpenoid In 2014, Fukuyama reported the first total synthesis of a C20 denudatine type alkaloid, lepenine (160).12 In their follow up study, an intermediate in their synthesis was advanced to the C19 aconitine type alkaloid, cardiopetaline (162), by employing a microwave-assisted Wagner–Meerwein rearrangement. 13 Both lepenine (160) and cardiopetaline (162) were accessed from common intermediate 161 (Figure 3.17). Retrosynthetically, lepenine (160) was proposed to arise from arene 163. Ultimately, their sequence for installing the bicyclo[2.2.2] moiety mirrored that of Wiesner’s fourth generation synthesis of 13-desoxydelphonine (99, see Figure 3.6). The C7–C20 bond (denudatine numbering) of 163 could be constructed by an intramolecular Mannich cyclization between the ketone of 164 and an in situ generated iminium ion. 132 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Coincidentally, the analogous C11–C17 bond of neofinaconitine (112) is also constructed by an intramolecular Mannich cyclization in Gin’s synthesis.9 The tricyclic core of 164 could be stereoselectively generated by an intramolecular Diels–Alder cycloaddition of 165, which possesses only a single stereogenic center. OH Me HO OH OH Me OH OMe NEt Me OH NEt Me OMe N N Me O MeO Me lepenine (160) C 20 denudatine type 161 common intermediate O Mannich reaction 7 Me O 20 HO HO cardiopetaline (162) C19 aconitine type OMe H OH OH H H OH Me 163 OMe OMe OMe N Et O H NHEt 164 O Me O O 165 Figure 3.17. Divergent strategy for lepenine (160) and cardiopetaline (162). The first stereogenic center is derived from L-lactic acid methyl ester. In two steps (not shown), allylic alcohol 166 was synthesized, and a tandem Johnson–Claisen rearrangement/Claisen rearrangement occurred upon refluxing in triethylorthoacetate to afford trans-olefin 167 in 85% yield (Figure 3.18). Mesylation, ozonolysis/reduction, and pivaloylation provided pivalate 168, which was determined to have an enantiomeric excess of 91%, indicating successful chirality transfer during the Claisen rearrangement. Friedel–Crafts acylation of an intermediate carboxylic acid afforded tetralone 169, which was advanced four steps to Diels–Alder precursor 170. In the subsequent cycloaddition, heating in the presence of a radical scavenger successfully constructed the phenanthrene 133 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine core of 171. At this stage, crystallization of intermediate 171 provided enantiomerically pure material. OMe O Me EtO 2C (EtO)3CMe, reflux 1. MsCl, Et 3N, 0 °C 2. O 3, then NaBH 4 OH 166 EtO 2C (58% yield, 3 steps) OPiv 167 168 91% ee OMe 1. LiOH, MeOH THF, 0 °C O OMe OMs 4 steps OMs BHT PhCN, 160 °C 2. TFAA, TFA OPiv (82% yield, 2 steps) O 169 O OMs H (84% yield) Me 170 OMe O H NEt O Alloc 171 recrystallized to >99% ee 2. AcCl/MeOH, then PhI(OAc) 2 (84% yield, 2 steps) OH Me N Et Pd(PPh 3)4, AcOH H CH2Cl2, reflux O (75% yield) Me OMe N Et OMs 173 172 OMe O OMe 174 O H OMs O 1. KOH, then NaBH 4 OMe 4 steps Me Me OMs 3. PivCl, Py, DMAP Me (85% yield) OH OMe OMe 4-NO2C6H 4OH (5 mol%) ethylene (70 bar) CH2Cl2, 70 °C (84% yield) OH Me N Et O OMe OMe 175 Figure 3.18. Synthesis of denudatine core 175. In four steps, the olefin of 171 was hydrated, and the bridging lactone is converted to aminoaldehyde 172. Upon Pd-catalyzed removal of the Alloc group, an intramolecular Mannich reaction occurred to provided pentacycle 173 in 75% yield. This single step constructs two bridged ring systems in the piperidine ring and bicyclo[2.2.1] moiety. From 173, cleavage of the mesylate, in situ borohydride reduction, and oxidative dearomatization then afforded ortho-quinone monoketal 174. Heating 174 under an 134 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine ethylene atmosphere smoothly furnished the bicyclo[2.2.2] system of 175, which constitutes the C20 denudatine core. OH NEt Me OH Me MeO O N Et 175 OMe O OMe 8 steps OMe 10 steps lepenine (160) NEt 1. µwave, MeOH 150 °C Me OMOM NEt O 176 (71% yield, 2 steps) OH NEt Me H 2SO4 (aq) 110 °C 2. NaBH(OAc)3 AcOH, 40 °C PhO 2S HO OH N Et OMOM Me OH Me HO OMe 177 (86% yield) HO HO cardiopetaline (162) Figure 3.19. Fukuyama’s total syntheses of lepenine (160) and cardiopetaline (162). With the denudatine core 175 in place, eight steps of standard functional group manipulations including hydration of the olefin and methylenation provided C20 denudatine type alkaloid, lepenine (160, Figure 3.19). In order to access the C19- diterpenoid alkaloid scaffold, 175 was converted to sulfonyloxirane 176 in 10 steps. The epoxide underwent a microwave-assisted Wagner–Meerwein rearrangement, and upon reduction, provided the alcohol of aconitine core 177. Finally, methoxymethyl ether cleavage and formal demethylation at C8 was accomplished by heating in aqueous sulfuric acid, providing cardiopetaline 162 in 86% yield. Although Fukuyama’s studies appear to draw heavily from Wiesner’s fourth generation methods,4f synthesis of the analogous aromatic intermediate was significantly improved, and the strategy successfully transferred asymmetry from the chiral pool. Additionally, a new additive- Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 135 free method for the Wagner–Meerwein rearrangement was identified for sulfonyloxirane 176. Summary of Previous Synthetic Strategies 3.3.5 Wiesner’s pioneering studies heavily influenced future syntheses. The salient transformation of Wiesner’s, Sarpong’s, and Fukuyama’s syntheses is a biomimetic Wagner–Meerwein rearrangement that transforms a denudatine scaffold to an aconitine scaffold. The requisite bicyclo[2.2.2] systems were constructed using inter- and intramolecular Diels–Alder cycloadditions. However, as demonstrated in the three syntheses, stereoselective installation of the necessary leaving groups required long sequences of minimally productive functional group manipulations. Thus, syntheses that construct the CD-[3.2.1]-bicycle in a non-biomimetic fashion may circumvent these issues. Although Gin’s synthesis of neofinaconitine (112) certainly addresses these challenges, the initial cyclopropene [4 + 2] cycloaddition proceeds with poor regioselectively, providing a 1:1.6 mixture of inseperable isomers. Our group’s synthetic strategy, described in the next sections, represents a distinct approach to the aconitine core. 3.4 SYNTHETIC APPROACH TO DITERPENOID ALKALOIDS A majority of the diterpenoid alkaloids possess a common structural motif in the AEF tricycle (Figure 3.20). This motif is comprised of a hydrindane framework (A/F rings) that is bridged by a substituted piperidyl ring (E ring). This tricycle is conjoined to a [3.2.1]-bicycle in the aconitine and napelline type alkaloids (e.g. 34 and 29) and a 136 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine [2.2.2]-bicycle in the denudatine type alkaloids (e.g. 160). We sought to identify a synthetic approach that would access these highly bridged polycyclic structures with a unified strategy. Talatisamine (34) was chosen as an initial target due to its compelling biological activity as a selective voltage-gated K+ channel blocker. In a convergent manner, the central 6-membered B ring can be retrosynthetically disconnected to two polycycles of similar complexity: the AEF-rings (178) and the CD-[3.2.1]-bicycle (179). Analogous disconnections are envisioned for napelline (29), which possesses a [3.2.1]bicycle with different relative connectivity to the AEF tricycle, and lepenine (160), which possesses a [2.2.2]-bicycle. Notably, the C20-diterpenoid alkaloids bear an additional quaternary center at C8 that represents another major synthetic challenge for attachment to the F-ring. Nevertheless, we anticipate that development of a convergent synthesis of talatisamine (34), specifically through conjoining the two polycycles 178 and 179, will be highly informative for the synthesis of C20 napelline and denudatine type alkaloids. OMe A MeO E OH Me F N Et OMe A N Et talatisamine (34) C19 aconitine type A OMe NEt E F B C HO H lepenine (160) C 20 denudatine type OMe MeO NEt D OMe 8 N Et H HO HO OH F E 8 napelline (29) C 20 napelline type convergent fragment coupling OH A OH Me F E HO MeO HO OH + HO 178 HO OMe 179 Figure 3.20. Synthetic strategy to convergently access diterpenoid alkaloids. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 137 In order to achieve a truly convergent fragment coupling, enantioselective syntheses of both fragments must be developed. Furthermore, in addition to the bridged polycyclic structure, another major challenge for the synthesis of talatisamine (34) are the 12 contiguous stereocenters, including two quaternary centers at C4 and C11. In our retrosynthetic analysis, a key disconnection of the piperidine E-ring, through a lactam intermediate, to secondary amine 180 simplifies the construction of the C4 quaternary center to the facile α-functionalization of a diester (Figure 3.21). The secondary amine of 180 could be introduced via reductive amination of ketone 181, which provides a functional handle to bisect the central B-ring at both α-positions of the ketone. Specifically, it was envisioned that an intramolecular aldol of diketone 182 would close the central B-ring, and a semipinacol rearrangement would construct the hindered C10– C11 bond and C11 quaternary center of 182 via epoxy alcohol 183. Epoxy alcohol 183 is the direct product of a convergent fragment coupling between vinyl lithium 184 and epoxyketone 185. This strategy streamlines the synthesis of bridged polycyclic compounds by enabling the coupling of two relatively complex fragments through the robust chemistry of 1,2-additions into ketones. The subsequent semipinacol rearrangement exploits the enthalpically favorable ring-opening of epoxides as a driving force for the formation of a hindered quaternary center,14 and in this case, ultimately enables the crucial retrosynthetic disconnection of the C10–C11 bond, resulting in a highly convergent synthetic plan. 138 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine OMe NEt MeO E lactam formation/ reduction MeO 2C 4 OMe CO2Me NHEt reductive amination OMe CO2Me O MeO 2C B H H HO HO HO OMe MeO 2C 11 10 17 H OMe HO 180 talatisamine (34) C19 aconitine type OH CO2Me O HO semipinacol rearrangement MeO 2C MeO 2C H intramolecular aldol HO OMe 181 O 11 17 O MeO 2C MeO 2C H OH 1,2-addition 10 O Li O 185 + OR' HO O OMe 182 HO OMe 183 RO OMe 184 Figure 3.21. Retrosynthetic analysis of talatisamine (34). 3.5 FORWARD SYNTHETIC EFFORTS In the following sections, our synthetic efforts towards C19-diterpenoid alkaloid talatisamine (34) are described. A racemic route to epoxyketone 185 was developed first, and this was used in a model system to explore the 1,2-addition/semipinacol rearrangement sequence as well as the intramolecular aldol and reductive amination steps. Subsequently, enantioselective routes to epoxyketone 185 and [3.2.1]-bicycles were developed and employed in the 1,2-addition/semipinacol rearrangement sequence to convergently couple both fragments. Lastly, efforts to complete the total synthesis of talatisamine (34) are detailed. 3.5.1 Semipinacol Rearrangement Model Studies towards a Tetracyclic Analogue Our first task was to establish proof of concept for a convergent fragment coupling towards diterpenoid alkaloids beginning with the synthesis of the AEF tricycle. 139 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Thus, a racemic route to epoxyketone 185 was devised (Figure 3.22). Beginning with dimethyl malonate (186), alkylation with commercially available alkyl bromide 187 followed by Michael addition with 2-cyclopenten-1-one (188) forged the first quaternary center of 189 in modest yield. Exposure to aqueous hydrochloric acid at elevated temperature resulted in ketal deprotection and intramolecular aldol condensation to afford enone 190 in 84% yield. This three-step procedure efficiently constructs the hydrindane framework (AF rings) from cheap and readily available starting materials in a scalable manner. O 1. NaH, n-Bu4NI 187, THF, reflux MeO 2C 2 (66% yield, 2 steps) 186 O MeO 2C MeO 2C 2. NaOMe, 188 MeOH, 0 °C MeO 2C HCl (aq) O 189 MeO 2C MeO 2C H acetone 70 °C O 190 (84% yield) O O S N Br OH 191 O MeCN/H 2O (67% yield) MeO 2C MeO 2C H 192 O O O Br 187 188 O Et 3N Br CH2Cl2 MeO 2C MeO 2C H (99% yield) 185 O O Figure 3.22. Racemic synthesis of epoxyketone 185. In order to establish the epoxide stereochemistry with the trans-fused ring junction, enone 190 was converted to bromohydrin 182 by treatment with Nbromosaccharin (191) in the presence of water.15 This transformation presumably occurs by initial formation of a bromonium ion on the β-face, followed by nucleophilic addition of water from the α-face at the less substituted position. Other brominating reagents, such as N-bromosuccinimide, tetrabutylammonium tribromide, pyridinium tribromide, and bromine, were unsuccessful in activating the olefin of 190; N-bromosaccharin 140 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine appears to be electrophilic enough to activate the non-nucleophilic olefin of 190. Although this transformation did not occur with perfect regio- or stereocontrol, the major isomer 192 was separated from other isomers during purification by crystallization. Attempts to improve the selectivity by modifying reaction parameters (temperature, equivalents of water, etc.) were also unfruitful. Nonetheless, the bromohydration of enone 190 was easily scalable and permitted the diastereoselective synthesis of epoxyketone 185. The last transformation was accomplished by simple exposure to triethylamine base to facilitate epoxide ring closure. Nucleophilic epoxidation of enone 190 was also explored, but did not provide isolable products; this method would also hypothetically produce the undesired cis-ring junction. O Br 1. PBr 3, DMF 2. NaBH 4 193 Br + TIPSO 195 (1.0 equiv) CH2Cl2 HO 194 (50% yield, 2 steps) MeO 2C MeO 2C H 185 (1.0 equiv) [Si]–Cl imidazole O RO (76% yield) 195 (R = TIPS) (76% yield) 196 (R = TMS) t-BuLi, then 185 O Br THF, –94 °C (72% yield) O MeO 2C MeO 2C H OH TIPSO 197 Figure 3.23. Synthesis of semipinacol rearrangement precursor 197. Vinyl halides readily undergo lithium-halogen exchange and addition into carbonyls, and vinylic functionality is known to have good migratory aptitude. Therefore, vinyl bromide 195 was chosen as an appropriate model compound, as it possesses a 5membered ring that resembles the aconitine C-ring as well as a pendant silyl ether for the intramolecular aldol step (Figure 3.23). The synthesis of vinyl bromide 195 commenced 141 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine with a known two-step procedure engaging cyclopentanone (193) with Vilsmeier salt and in situ vinyl-bromide formation, followed by borohydride reduction to produce vinyl bromide 194.16 The allylic alcohol was then silyl protected to afford the corresponding silyl ethers 195 and 196 in good yield. Lithium-halogen exchange of vinyl bromide 195 using tert-butyllithium at low temperature provided the alkenyllithium, and addition of one equivalent of epoxyketone 185 afforded tertiary alcohol 197 as a single diastereomer in 72% yield. It was crucial to perform the 1,2-addition by inverse addition at –94 °C, as exposing the in situ generated vinyllithium to higher temperatures resulted in competing Wurtz dimerization. Nevertheless, cyclopentene 195 was successfully coupled to epoxyketone 185 while simultaneously establishing the requisite anti-relationship between the migrating cyclopentene and the epoxide of 197. OR O MeO 2C MeO 2C H OH OR MeO 2C Lewis acid MeO 2C MeO 2C H CH2Cl2 TIPSO CO2Me O O OTIPS OTIPS 197 198 Entry Lewis acid Additive Temperature Result 1 ZnBr2 -- rt no reaction 2 AlMe3 -- –78 °C to rt no reaction 3 AlMe2Cl -- –78 °C to rt chlorohydrin 4 EtAlCl2 -- –78 °C to rt chlorohydrin 5 BF3•OEt2 -- –45 °C fluorohydrin 6 TiCl4 -- –78 °C to rt decomposition 7 Yb(OTf)3 -- rt desilylation 8 Sc(OTf)3 -- –78 °C to rt decomposition 9 TMSOTf -- –78 °C decomposition 10 TMSOTf 2,6-lutidine 0 °C 90% yield (R = TMS) Table 3.1. Screen of Lewis acids for semipinacol rearrangement of 197. 142 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine With an established protocol for the coupling of vinyl halides with epoxyketone 185, we investigated the key semipinacol rearrangement to determine the feasibility of the proposed strategy to construct the challenging C11 quaternary center. For this purpose, a broad screen of common Lewis acids was conducted on epoxy alcohol 197 in dichloromethane (Table 3.1). Several common Lewis acids failed to promote reactivity (entries 1 and 2), while others promoted non-specific decomposition of the substrate (entries 6, 8, and 9) or desilylation (entry 7). Interestingly, alkylaluminum chlorides and boron trifluoride resulted in nucleophilic epoxide ring opening to halohydrins instead of semipinacol rearrangement (entries 3–5). In an attempt to protect the tertiary alcohol of 197, it was discovered that subjection to TMSOTf in the presence of 2,6-lutidine directly afforded the desired rearrangement product 198 in 90% yield (entry 10). Presumably, the amine base acts to buffer the triflic acid formed in the alcohol protection step, and excess TMSOTf facilitates semipinacol rearrangement of the in situ generated silyl ether. The use of a stronger base, such as triethylamine, resulted in further conversion of ketone 198 to the silyl enol ether. Br + TMSO t-BuLi, then 185 O MeO 2C MeO 2C H O THF, –94 °C O MeO 2C MeO 2C H OTMS 196 (1.0 equiv) 185 (1.0 equiv) 199 OTMS MeO 2C CO2Me O then TMSOTf 2,6-lutidine, 0 °C (54% yield) 200 OTMS Figure 3.24. One pot 1,2-addition and semipinacol rearrangement. OLi 143 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Further highlighting the utility of this convergent fragment coupling strategy, the 1,2-addition and semipinacol rearrangement could be performed in a single vessel (Figure 3.24). Thus, lithium-halogen exchange of vinyl bromide 196 with tert-butyllithium followed by addition of epoxyketone 185 produces intermediate lithium alkoxide 199. After warming the reaction temperature to 0 °C, TMSOTf and 2,6-lutidine are added to the reaction mixture, resulting in rapid semipinacol rearrangement to afford 54% yield of 200 in a single step. This remarkable transformation provides rearrangement product 200 as a single diastereomer from one equivalent of each coupling partner. This method enables the efficient construction of the aconitine C11 quaternary center directly from vinyl halides and epoxyketone 185, and demonstrates potential for the synthesis of C20diterpenoid alkaloids as well. MeO 2C OTMS OTMS OTMS CO2Me O CO2Me O CO2Me O MeO 2C AcOH (aq) THF OTMS MeO 2C DMP CH2Cl2 (97% yield) OH 200 H (81% yield) O 201 202 OTMS CO2Me O MeO 2C KOt-Bu THF, –78 °C OTMS MOMCl, n-Bu4NI i-Pr2NEt DMF, 45 °C OH (83% yield >20:1 dr) OMOM H 2SiF6 MeCN, 0 °C (94% yield) 204 OH CO2Me O OMe Me 3OBF 4 Proton sponge CO2Me O MeO 2C CH2Cl2 OMOM (71% yield) 205 OMOM (91% yield) 203 MeO 2C CO2Me O MeO 2C OMe EtNH 2, Ti(Oi-Pr)4 CO2Me NHEt MeO 2C 17 then NaBH 4, EtOH OMOM (90% yield) 206 207 Figure 3.25. Investigations on intramolecular aldol and reductive amination steps. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 144 We next attempted to investigate the intramolecular aldol and reductive amination steps. Because difficulty was encountered in differentiating the primary triisopropyl (TIPS) ether and secondary trimethylsilyl (TMS) ether of 198, bis-TMS ether 200 was used for further model studies (Figure 3.25). Exposure of 200 to aqueous acetic acid in tetrahydrofuran resulted in selective deprotection of the primary silyl ether to alcohol 201 in excellent yield. Oxidation using Dess–Martin periodinane provided ketoaldehyde 202, which was poised to undergo intramolecular aldol reaction. Treatment of ketoaldehyde 202 with hexamethyldisilazide bases produced aldol product 203 in variable diasteomeric ratios, but nevertheless forging the central B-ring in good yield. The yield and diastereomeric ratio was improved when potassium tert-butoxide was employed, providing aldol product 203 in 83% yield and >20:1 diastereoselectivity. However, the relative configuration was not determined at this stage since β-hydroxyketone 203 underwent spontaneous epimerization upon standing (likely through a retro-aldol/aldol process) and desilylation. The alcohol was promptly protected as the methoxymethyl ether (204) and desilylated using hexafluorosilicic acid to reveal the C1 alcohol (205). Reductive amination on ketone 205 proved to be intractable at the time, possibly due to the free alcohol at C1; we therefore sought to methylate the alcohol to the methyl ether present in talatisamine (34). Methylation attempts under basic conditions were met with limited success, resulting in decomposition likely stemming from retro-aldol of the βhydroxyketone. The use of trimethyloxonium tetrafluoroborate and Proton sponge provided methyl ether 206 in 71% yield. With ketone 206 in hand, treatment with ethylamine in the presence of a titanium tetraisopropoxide led to complete conversion to Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 145 an intermediate iminium ion (observed by LCMS). Dilution of the reaction mixture with ethanol and addition of sodium borohydride resulted in reduction to secondary amine 207. Rigorous analysis of 2D NMR data revealed that the newly formed C17 stereocenter possessed the undesired configuration for lactam ring closure to the piperidine E-ring. Although unexpected, this finding can be rationalized by steric encumberance imposed by the pseudoaxial MOM-ether. The model studies discussed thus far validated our synthetic approach and demonstrated that both C4 and C11 quaternary centers could be accessed in a rapid sequence from commercially available starting materials. Specifically, hydrindane 185 was readily available in just five steps from dimethyl malonate (186) using operationally simple chemistry. With the model system (vinyl bromide 196), 1,2-addition and semipinacol rearrangement were accomplished in a single step, thereby establishing an efficient means to couple both fragments in a convergent fashion and directly forge the challenging C11 quaternary center. This short sequence also enabled important investigations of subsequent key steps, including an intramolecular aldol cyclization to create the central B-ring and reductive amination to afford the secondary amine, albeit in the undesired configuration. Ultimately, tetracyclic analogue 207 possesses four of the six rings present in talatisamine (34), and was synthesized in 12 steps from dimethyl malonate (186). Although these studies were compelling, they did not yet address the challenge of [3.2.1]-bicyclic CD-ring system or the enantioselective syntheses of both fragments described in the retrosynthetic analysis. 146 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Enantioselective Syntheses of Two Bicyclic Fragments 3.5.2 The most straightforward manner to render the epoxyketone (185) route asymmetric was to employ an enantioselective Michael addition between α-substituted malonate 208 and cyclopenten-1-one (188) to intercept ketone 189 (Figure 3.26). Only one such method has been reported, by the Shibasaki group, utilizing an elaborate lanthanum-bound linked-BINOL catalyst.17 Attempts to utilize this chemistry were met with initial success, but reproducibility issues hampered future use since the catalyst quality varied depending on the batch of lanthanum from commercial vendors. Another limiting factor was the high catalyst loading (10 mol%) of the non-recoverable linkedBINOL ligand, which was synthesized in seven steps from (S)-BINOL. O O + (S,S)-La-linked-BINOL (10 mol%) DME/HFIP, 4 °C, 84 h MeO 2C CO2Me 208 O O O 188 (61% yield, 98% ee) irreproducible 2 MeO 2C MeO 2C H 189 O O O La O O O H (S,S)-La-linked-BINOL (7 steps from (S)-BINOL) Figure 3.26. Catalytic enantioselective Michael addition of 208 and 188. An alternative route utilized another procedure developed by Shibasaki (Figure 3.27).18 An enantioselective Michael addition between dimethyl malonate (186) and cyclopenten-1-one (188) was catalyzed by GaNa-(S)-BINOL and sodium tert-butoxide to deliver α-functionalized malonate 209 in 92% yield and 91% enantiomeric excess. The reaction is proposed to occur through attack of a sodium enolate onto the bimetallic catalyst, coordination of the α,β-unsaturated ketone to the Ga center, and Michael addition via an organized transition state to generate the new stereogenic center. This 147 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine reaction was reproducible and scalable, and also did not require cryogenic temperatures. The remainder of the sequence resembles the racemic route with minimal adjustments. Protection of ketone 209 under standard conditions provided ketal 210, which was alkylated with alkyl bromide 187 to forge the C4 quaternary center of bis-ketal 211. Heating in aqueous hydrochloric acid and acetone resulted in ketal deprotection and intramolecular deprotection to intercept enone 190. Bromohydration was again achieved with N-bromosaccharin (191) and water. Notably, purification by recrystallization effectively enriched the enantiomeric excess to >99%, thereby providing enantiopure material. Epoxide ring closure proceeded uneventfully to afford epoxyketone 185 in six steps from dimethyl malonate (186). MeO 2C O + GaNa-(S)-BINOL (10 mol%) NaOt-Bu (7 mol%) 186 188 O H O O O NaH, n-Bu4NI O 2 THF, reflux HCl (aq) O MeO 2C MeO 2C H (78% yield, 98% brsm) 210 benzene, reflux (83% yield) 209 O Br MeO 2C O H (92% yield, 91% ee) 187 MeO 2C MeO 2C THF/Et2O, rt MeO 2C ethylene glycol p-TsOH MeO 2C O 211 acetone, 70 °C (67% yield) OH MeO 2C MeO 2C H 190 NBSac (191) O MeCN/H 2O (62% yield) recrystallized to >99% ee MeO 2C MeO 2C H 192 Et 3N Br O CH2Cl2 MeO 2C MeO 2C H (99% yield) O O 185 Figure 3.27. Alternative enantioselective route to epoxyketone 185. We envisioned utilizing a meta-photocycloaddition for the synthesis of the bicyclo[3.2.1]octane fragment, as it is an established method for the construction of 148 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine bicyclic compounds in total 19 synthesis. However, intermolecular meta- photocycloadditions, particularly with anisole (212) and electron rich olefins (e.g. 213) are known to react with poor regioselectivity in the cyclopropane ring-forming step as well as poor endo/exo selectivity, forming up to four isomeric products (Figure 3.28).20 Sugimura et al. have devised a valuable solution to this problem by joining the arene and olefin reactants with a chiral tether as in 216.21 Irradiation of arene olefin 216 at 254 nm resulted in photocycloaddition to initially produce the 6-substituted product 217, which subsequently underwent vinyl-cyclopropane rearrangement to form the 7-substituted product 218. In typical systems, these two isomeric products undergo photoequilibration. However, 6-substituted photoadduct 217 absorbs more strongly at 254 nm, resulting in a complete shift in equilibrium to produce 7-substituted photoadduct 218 in 70% isolated yield. Sugimura advanced cyclopropane 218 to enantiomerically pure bicyclo[3.2.1]octane 220 in a five step sequence involving cyclopropane ring-opening. meta-photocycloaddition OMe OR H OMe H OR + 212 213 non-selective formation of four isomeric products Me Me R S O O H hυ Me hν (254 nm) Me 6 vinylcyclopropane rearrangement H 7 O H Me H OR O OH O 7 6 7-substituted (218) 1. (HOCH2)2, p-TsOH 2. PCC HO 3. K 2CO3, MeOH O (67% yield, 3 steps) O H Me (70% yield) Me 2. Hg(OAc)2, H 2O then NaBH 4 (45–50% yield, 2 steps) H 215 O 6 1. H 2, Pd/C H 214 6-substituted (217) 216 + 7 Me pentane H O H OMe H O 219 Figure 3.28. Sugimura’s diastereoselective meta-photocycloaddition. 220 149 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine We sought to employ Sugimura’s method for construction of enantiopure [3.2.1]bicycles for the synthesis of talatisamine (34). Rather than reducing the olefin of photoadduct 218, we plan to instead engage it in an electrophilic ring opening of the neighboring cyclopropane, which would also be assisted by the ether substituent (Figure 3.29). Photoadduct 218 can therefore undergo Grob fragmentation to produce oxocarbenium ion 221, which would hydrolyze to form ketone 222. Tether cleavage would proceed identically to Sugimura’s sequence, and functional group interconversions of the resulting alcohol would produce vinyl bromide 223. This sequence could potentially provide access to a variety of enantiopure [3.2.1]-bicycles bearing a vinylic anion (e.g. 224–226) for 1,2-addition and semipinacol rearrangement into epoxyketone 185, and functionality on the 3-carbon bridge to facilitate B-ring formation. H E+ E H Me electrophile (E+ ) O Me H 218 O H Me Me H Li–halogen exchange tether cleavage O O 221 Br OH H 2O O Me O Me 222 Li Li E Li H FGI's RO E 223 RO H RO 224 Cl 225 O RO 226 Figure 3.29. Forward plan for elaborating photoadduct 218. The synthesis of photoadduct 218 was performed using procedures modified from Sugimura’s initial report.21a Beginning with commercially available (2R,4R)-pentanediol (227), a Mitsunobu reaction with phenol provided the aryl ether, and Hg(II)-catalyzed vinylation with ethyl vinyl ether provided arene olefin 216 (Figure 3.30). Although 150 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Sugimura’s studies were conducted on small scale, we were able to obtain comparable yields of the meta-photocycloaddition on 1.5 g scale after optimization of the reaction setup. Because the reaction profiles were generally clean, reactions could be run in 1.5 g batches, concentrated to crude mixtures, and combined with future batches for a single purification to provide multigram quantities of photoadduct 218. H Me R R OH 227 Me OH 1. phenol (1.1 equiv) DIAD, PPH 3, THF Me R S O O 2. Hg(OAc) 2 (20 mol%) OEt 45 °C Me 216 (55% yield, 2 steps) hν (254 nm) pentane 25 °C, 27 h (1.5 g batches, 67% avg. yield) O Me H O H Me 218 Figure 3.30. Scalable synthesis of photoadduct 218. Our first attempts to advance photoadduct 218 were through protonation of the olefin with Brønsted acid (Figure 3.31). The 6-substituted product 217 could be isolated at partial conversions of the meta-photocycloaddition, and subjection to aqueous hydrochloric acid at elevated temperatures provided ketone 228 in 37% yield. However, attempts to optimize this reaction were unfruitful, and ultimately this substrate was not pursued because the photocycloaddition could not be easily optimized for selective synthesis of 6-substituted adduct 217. Under similar conditions, the 7-substituted adduct 218 surprisingly afforded diene 229. Although one can surmise this occurs by elimination of the tether to form a C6–C7 olefin, evidence supported the intermediacy of cyclopropylcarbinyl cation 230. For instance, diene 229 was not observed in acidolysis of the 6-substituted adduct 217, as one would expect from elimination at C6/C7. At room temperature, ketalization of the ketone of 229 was observed, indicating that the free alcohol of intermediate 230 can ketalize prior to hydrolysis. Similar results were reported 151 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine by Fenton and Gilbert, who found that treatment of 7-acetate-substituted metaphotoadducts with acidic methanol resulted in formation of ketone 229 as well.22 In an attempt to harness this reactivity, vinyl bromide 230, the product of metaphotocycloaddition of aryl bromide 231, could potentially undergo acidolysis to directly afford bicyclo[3.2.1]octane 232. This would significantly shorten the synthetic route, as it effects tether cleavage and vinyl bromide formation in a single step to provide a functionalized fragment that can be used directly in the 1,2-addition/semipinacol rearrangement sequence. Unfortunately, preliminary experiments with aryl bromide 230 did not deliver photoadduct 231, and instead resulted in significant polymer formation. Future studies are still warranted, particularly with other aryl functionalities that can be rapidly advanced to a vinyl anion equivalent. Me Me H O H OH HCl (aq) O O H O (37% yield) 6-substituted (217) 6 H 6 via: HCl (aq) O H H+ 7 O O 6 H 6 7 HO O (yield nd) Me 229 H O H Me 230 7-substituted (218) H H 7 dioxane, 40 °C Me Me H 228 7 H O H 7 Me 6 Me Me via: 6 THF, 60 °C 7 Me Me Br Br Me hν (254 nm) O O O Br Me 230 H O 231 Figure 3.31. Acidolysis of meta-photoadducts. Me H 3O+ Me O H O Me 232 152 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Subsequent attempts to functionalize photoadduct 218 involved halogenation of the olefin (Figure 3.32). Treatment with N-chlorosaccharin in THF and water resulted in formation of allylic chloride 233 in 84% yield. Protection of the ketone and oxidation of the tether provided ketone 234 in 80% yield over two steps. Cleavage of the tether required low temperatures to prevent further fragmentation of the [3.2.1]-bicycle, and was accomplished with potassium hexamethyldisilazide at –78 °C to afford alcohol 235. DMP oxidation then delivered ketone 236. Unfortunately, ketone 236 could not be advanced to vinyl bromide 237 due to the labile allylic chloride, and therefore this substrate was not further pursued. Me H NCSac O Me H O Me 218 Me OH 1. O TMSOTf (20 mol%) 2. DMP, NaHCO 3, CH2Cl2 THF/H2O H (84% yield) O Cl Me Me O O O O (80% yield, 2 steps) 233 KHMDS Cl 234 Br O HO THF, –78 °C OTMS TMSO DMP, NaHCO 3 O CH2Cl2 O (56% yield) Cl (53% yield) 235 O O O Cl 236 O Cl 237 Figure 3.32. Synthesis of a chlorinated bicyclo[3.2.1]octane. In hopes that an allylic ether would be less labile than the chloride, photoadduct 218 was epoxidized with m-CPBA produced an intermediate epoxide (238) that was immediately activated with Brønsted acid to furnish allylic alcohol 239 in 79% yield (Figure 3.33).23 In order to differentiate both secondary alcohols of 239, the allylic alcohol would be selectively protected as part of a 1,3-diol. Therefore, reduction with sodium borohydride in the presence of cerium trichloride furnished 1,3-diol 240 as a 153 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine single diastereomer in 91% yield. Interestingly, borohydride reduction of 239 in the absence of cerium trichloride provided a 1 : 2.3 mixture of diols 240 and 244, favoring the anti-diastereomer 244. The formation of 244 could proceed by directed delivery of the hydride by the allylic alcohol of 239. The oxophilic cerium salt likely chelates to the hydroxyl groups, thereby preventing the directed hydride delivery and providing triol 240 as a single diastereomer. Attempts to protect the syn-diastereomer 240 as the acetonide were met with complications relating to hydrolysis of the allylic alcohol under acidic conditions, resulting in non-selective formation of allyl ethers 241 and 242, and further fragmentation to arene 243. Efforts to synthesize other acetals were largely unfruitful due to the tendency of the allyl alcohol to undergo hydrolysis and fragmentation. H H H H Me O O CH2Cl2, rt H Me H O Me MeOH, –78°C (79% yield) O 239 Me Me Me 2C(OMe)2 p-TsOH (10 mol%) O (91% yield) OH 238 Me OH NaBH 4, CeCl3•7H2O O H Me 218 Me OH HCl (aq) m-CPBA O Me O Me OH Me O Me OH O + + O CH2Cl2, rt OH 240 O OMe OH OH OH 241 OMe 242 243 Me tentative assignments based on 1 H NMR and LCMS Me Me Me OH O NaBH 4 Me OH Me O OH OH 239 O + MeOH, 0 °C O Me HO OH 240 (29% yield) OH OH 244 (67% yield) Figure 3.33. Epoxidation of photoadduct 218 and elaboration to triol 240. Me 154 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine In order to circumvent the lability of allyl alcohol 240, silylene protection at low temperatures mitigated hydrolysis, providing siliconide 245 in 91% yield (Figure 3.34). Oxidation of the tether with DMP, elimination mediated by KHMDS, and another oxidation afforded bicyclic ketone 248, which was also converted to triflate 249 under standard conditions for subsequent investigations. Me Me Me OH t-Bu2Si(OTf)2 2,6-lutidine O Me OH Me O O OH OH (91% yield) O DMP, NaHCO 3 CH2Cl2, rt CH2Cl2, –78 °C 240 Me O Si O 245 t-Bu t-Bu O Si O t-Bu (99% yield) 246 t-Bu TfO O HO KHMDS THF, –78 °C (89% yield) KHMDS PhNTf 2 DMP, NaHCO 3 O Si O t-Bu t-Bu 247 CH2Cl2, rt (91% yield) THF, –78 °C O Si O t-Bu t-Bu 248 (95% yield) O Si O t-Bu t-Bu 249 Figure 3.34. Silylene protection and advancement to bicyclic triflate 249. With the functionalized bicyclo[3.2.1]octane in place, efforts were directed towards conversion to a vinyl anion precursor for the following 1,2-addition. For ketone 248, Shapiro conditions and triphenyl phosphite-halogen-based conditions failed to provide isolable samples of vinyl bromide 250.24,25 Barton’s method for preparation of vinyl iodides by oxidation of intermediate hydrazones successfully delivered vinyl iodide 251, albeit in a modest 39% yield.26 Vinyl triflate 249 could also be used for the preparation of vinyl bromide 250 and vinyl stannane 252. Under Pd-catalyzed conditions reported by Buchwald, vinyl bromide 250 was formed in low yield, possibly due to competing deprotection of the silylene group at high temperature.27 Coupling of the vinyl 155 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine triflate with stannyl cuprates provided tributylstannane 252 in a moderate 50% yield, but was hampered by scalability issues. 28 Ultimately, the highest yielding procedure employed a Pd-catalyzed Stille cross-coupling with hexamethylditin to produce vinyl stannane 253.29 Although this stannane could be used directly in the 1,2-addition, the crude material was converted to vinyl iodide 251 due to safety concerns regarding volatile tetra-alkylstannane byproducts. Nevertheless, this two-step procedure efficiently and reliably provided multigram quantities of vinyl iodide 251 to enable subsequent investigations on the 1,2-addition and semipinacol rearrangement. O [KF, KOAc, or K 3PO 4 ] KBr (2.0 equiv) Pd 2dba3 (2.5 mol%) t-BuBrettPhos(7.5 mol%) Br • i. TrisNHNH2 ii. n-BuLi, (BrCF2)2 dioxane, 130 °C –or– O Si O t-Bu t-Bu TfO O Si O t-Bu t-Bu • P(OPh) 3, Br 2, Et 3N –60 to 45 °C 248 O Si O t-Bu (26–32% yield) t-Bu 249 250 I Bu 3Sn NH 2NH 2, Et 3N EtOH, 55 °C then t-BuNC(NMe 2)2 I 2, THF, 90 °C (39% yield) LDA, Bu 3SnH, then CuCN O Si O t-Bu t-Bu 251 O Si O t-Bu t-Bu then 249 –25 °C 252 Me 3Sn TfO Me 6Sn2, LiCl Pd(PPh 3)4 THF, 70 °C O Si O t-Bu t-Bu 249 (50% yield) I I2 O Si O t-Bu t-Bu CH2Cl2 (80% yield, 2 steps) 253 subjected crude Figure 3.35. Preparation bicyclic vinyl anion precursors. O Si O t-Bu t-Bu 251 156 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Convergent Fragment Coupling 3.5.3 In consideration of the fragment coupling between bicyclic vinyllithium 254 and epoxyketone 185, 1,2-addition should provide epoxyalcohol 255, and semipinacol rearrangement should generate rearranged product 256 (Figure 3.36). Based on earlier model studies, we anticipated that the allyl ether moiety of 256 might undergo ionization to allyl cation 257, which upon enol ether formation, is poised to undergo cationic cyclization to furnish the carbocyclic core (258) of the aconitine alkaloids. This hypothesis was supported by investigations of epoxy alcohol 259, which underwent rearrangement with concomitant elimination of the allyl ether moiety, presumably through allyl cation 260, to provide diene products such as 261. Li 1,2-addition O MeO 2C MeO 2C H O MeO 2C MeO 2C H OH + O semipinacol rearrangement O X O 185 254 OTMS CO2Me O MeO 2C 255 MeO 2C OTMS CO2Me OR O X O cationic cyclization MeO 2C OTMS CO2Me O H O X O O X O LA 256 257 O MeO 2C MeO 2C H TMSOTf 2,6-lutidine OH HO 258 MeO 2C OTMS OTMS CO2Me O CO2Me O MeO 2C CH2Cl2, 0 °C TMSO OPg OTMS 259 260 OTMS 261 Figure 3.36. Proposed cationic cyclization for carbocyclic core 258. 157 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine I MeO 2C MeO 2C H 185 Conditions O O MeO 2C MeO 2C H O OH + O Si O t-Bu t-Bu O Si O t-Bu t-Bu 251 262 Entry Conditions Yield 262 (%) Notes 1 t-BuLi (2.0 equiv), THF, –78 °C; then 185, –94 °C 55 inverse additiona 2 PhLi (2.0 equiv), THF, –78 °C; then 185, –94 °C 50 inverse additiona 3 t-BuLi (3.0 equiv) added into 185 and 251, THF, –94 °C 50 “one-pot” conditionsb 4 t-BuLi (2.0 equiv), THF, –78 °C; solution added to 185, –94 °C 72 normal additionc 5 t-BuLi (2.0 equiv), THF, –78 °C; then HMPA, 185, –94 °C 0 only protodehalogenation 6 t-BuLi (2.0 equiv), THF, –78 °C; added to CeCl3/THF; then 185 51 -- 7 t-BuLi (2.0 equiv), TMEDA/THF, –78 °C; then 185, –94 °C 47 -- 8 t-BuLi (2.0 equiv), TMEDA/hexane, –78 °C; then 185, toluene, –94 °C 0 only protodehalogenation 9 i-PrMgCl•LiCl (1.1 equiv), THF, rt; then 185, –94 °C 0 only protodehalogenation 10 i-PrMgCl•LiCl (1.1 equiv), toluene, rt; then 185, rt 0 only protodehalogenation a Inverse addition: epoxyketone 185 added to pre-stirred solution of vinyllithium (t-BuLi/251). b “One-pot” conditions: t-BuLi added directly to solution of 185 and 251. c Normal addition: pre-stirred solution of vinyllithium (t-BuLi/251) added to epoxyketone 185. Table 3.2. 1,2-addition optimization for tertiary alcohol 262. 158 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Under previously developed conditions for 1,2-addition into epoxyketone 185, reaction with bicyclic vinyl iodide 251 furnished epoxy alcohol 262 in 55% yield (Entry 1, Table 3.2). Other reagents for lithium-halogen exchange such as phenyllithium failed to increase the yield, as did single pot conditions in which tert-butyllithium was added directly to a mixture of epoxyketone 185 and vinyl iodide 251 (Entries 2 and 3). Although the conditions in Entry 1 were developed to prevent Wurtz coupling of the model system discussed in Section 3.5.1, it was discovered that bicycle 251 did not undergo the same dimerization and thus did not require inverse addition. Normal addition of the intermediate vinyllithium into a pre-cooled solution of epoxyketone 185 at –94 °C delivered epoxy alcohol 262 in 72% yield on a 1.6 g scale (entry 4). A survey of additives including HMPA, CeCl3, and TMEDA provided lower yields or protodehalogenation (Entries 6–8). Iodine/magnesium exchange with “turbo Grignard” also exclusively resulted in protodehalogenation of 251, likely by α-deprotonation of epoxyketone 185 (Entries 9 and 10).30 MeO 2C MeO 2C H O OH TMSOTf amine base MeO 2C MeO 2C H O OTMS CO2Me O MeO 2C OTMS CH2Cl2 262 O Si O t-Bu t-Bu MeO 2C OTMS CO2Me O 263 MeO 2C O Si O t-Bu O Si O t-Bu t-Bu t-Bu 264 (<33% yield) OTMS OTMS CO2Me O CO2Me O MeO 2C MeO 2C OTMS CO2Me O H O Si O LA t-Bu t-Bu 265 OR RO NR 3 266 amine base = Et 3N or 2,6-lutidine RO 267 2,6-tBu2-4-Me-pyridine 258 not observed Figure 3.37. Semipinacol rearrangement of 262 and side product formation. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 159 At this juncture, extensive efforts were directed to achieve the proposed cationic cyclization. Standard conditions for semipinacol rearrangement necessitated TMSOTf as the Lewis acid, and an amine base to buffer the reaction media from triflic acid generated in situ. At low temperatures (below 0 °C), rapid protection of tertiary alcohol 262 to the silyl ether 263 occurred (Figure 3.37). Approaching room temperature, semipinacol rearrangement to 264 was observed; however, this was formed as a mixture with other side-products, and purification returned <33% yield of semipinacol product 264. When the reactions were allowed to reach full conversion, tentatively assigned products 266 and 267 were observed. These products are proposed to arise from the intermediate allyl cation 265. With triethylamine or 2,6-lutidine as bases, ammonium/lutidinium products 266 were observed by 1H NMR; we speculate that these may arise from nonregioselective attack of the base onto allyl cation 265. With the non-nucleophilic base 2,6-ditert-butyl-4-methylpyridine, ortho-substituted styrene 267 was observed by 1H NMR; this may occur by rearrangement of allyl cation 265 through an elaborate mechanism in which the [3.2.1]-bicycle is fragmented (as in Figure 3.33). Unfortunately, no products containing silyl enol ethers or cationic cyclization product 258 were observed during the course of these studies. MeO 2C MeO 2C H O OH TMSOTf, Et 3N MeO 2C MeO 2C H O OTMS CH2Cl2, –10 °C 262 O Si O t-Bu t-Bu (97% yield) 263 Figure 3.38. Trimethylsilyl protection of epoxy alcohol 263. O Si O t-Bu t-Bu Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 160 Although we were initially discouraged by these results, we remained optimistic since the semipinacol rearrangement occurred readily at room temperature. We elected to devise a procedure for efficient preparation of semipinacol product 264. For these studies, epoxy alcohol 262 was protected as silyl ether 263 with TMSOTf at –10 °C (Figure 3.38). Since this reaction was clean and high yielding, we posited that low temperatures mitigated ionization of the allyl ether moiety. To this effect, we optimized the semipinacol rearrangement of silyl ether 263 at low temperatures using a stronger Lewis acid, TMSNTf2, and non-nucleophilic base, 2,6-ditert-butyl-4-methylpyridine, to preclude N-silylation (Table 3.3).31 At –78 °C, low yields of rearrangement product 264 were obtained at extended reaction times, but the reaction profile and yield improved with shorter reaction times (Entries 1 and 2). Lowering the reaction temperature and time even further provided improved yields of up to 90% (Entries 3 and 4). However, with one equivalent of Lewis acid, the reaction scaled poorly, and the yield diminished to as low as 59% on a 280 mg scale (Entries 5–7). We reasoned that use of silyl ether 263 as the rearrangement substrate negated the need for a full equivalent of TMSNTf2, which could in fact be regenerated in situ. Using catalytic amounts of Lewis acid successfully delivered semipinacol product 264 in quantitative yield, and tolerated elevated temperatures and extended reaction times (Entry 8). Additionally, this reaction was highly scalable, providing semipinacol product 264 in 97% yield on a 1.2 g scale (Entry 9). The coupling epoxyketone 185 with bicyclo[3.2.1]octane 251 currently proceeds in three steps. However, the sequence is efficient, occurring in an overall 67% yield. The ability to reliably advance multigram quantities of epoxyketone 185 and bicycle 251 161 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine to semipinacol product 264 proved to be crucial for enabling subsequent studies towards talatisamine (34). MeO 2C MeO 2C H O OTMS TMSNTf2 2,6-t-Bu2-4-MePy OTMS CO2Me O MeO 2C CH2Cl2 263 O Si O t-Bu O Si O t-Bu t-Bu t-Bu 264 Equivs Temperature TMSNTf2 (°C) 10 mg 1.0 –78 45 min <25 2 10 mg 1.0 –78 60 sec 50 3 10 mg 1.0 –94 85 sec 82 4 10 mg 1.0 –94 10 sec 90 5 75 mg 1.0 –94 10 sec 88 6 150 mg 1.0 –94 10 sec 82 7 280 mg 1.0 –94 10 sec 59 8 10 mg 0.10 –70 to 0 2.5 hr 99 9 1.2 g 0.10 –70 15 min 97 Entry Scale 1 Time Isolated yield 264 (%) Table 3.3. Semipinacol rearrangement optimization of silyl ether 263. 3.5.4 Assembly of the Carbocyclic Core of Talatisamine At this juncture, several options were explored to advance semipinacol rearrangement product 264 to the carbocyclic core of talatisamine (34), which required construction of the final C7–C8 bond to complete the central B-ring. We first explored a radical cyclization of α-bromoketone 268 onto the D-ring olefin (Figure 3.39). 162 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Deprotonation of ketone 264 with LiHMDS and addition of NBS provided bromoketone 268 in 82% yield. To our dismay, an extensive survey of reaction conditions to effect the desired 6-exo radical cyclization failed to deliver carbocyclic core 269. Instead, all attempts returned starting material (268) or the hydrodebromination product (264). It was unclear to us at that juncture whether cyclization to radical 271 was unfavorable due to resonance-stabilized radical 270, or if cyclization suffered from poor polarity matching. OTMS CO2Me O MeO 2C OTMS CO2Me O MeO 2C LHMDS, NBS (82% yield) O Si O t-Bu t-Bu 268 OTMS CO2Me O OTMS CO2Me O MeO 2C • O Si O t-Bu t-Bu 270 B radical cyclization t-Bu 264 MeO 2C MeO 2C 6-exo Br THF, –78 °C O Si O t-Bu OTMS CO2Me O • O Si O t-Bu t-Bu 271 X O Si O t-Bu t-Bu 269 Conditions attempted: • Bu 3SnH, AIBN, PhH, 80 °C • Bu 3SnH, AIBN (syringe pump addn), PhH, 80 °C • (TMS)3SiH, AIBN (syringe pump addn), PhH, 80 °C • (TMS)3SiH, ACHN (syringe pump addn), PhMe, 110 °C • DLP, t-dodecanethiol, Et 3SiH, cyclohexane, 85 °C • Bu 6Sn2, h υ (halogen lamp), PhH, 80 °C • Ph3Sn–SC(S)OEt, Bu 3SnH, AIBN, PhH, 80 °C Figure 3.39. Survey of 6-exo radical cyclization conditions for pentacycle 269. Reflecting on the success of the intramolecular aldol reaction in the model system (see Section 3.5.1), we elected to perform an intramolecular Michael addition to complete the aconitine carbocyclic core. To this end, selective deprotection of silylene 264 was accomplished using HF•pyridine to deliver diol 272 in 98% yield (Figure 3.40). Under conditions developed by Steves and Stahl, allylic oxidation occurred to afford α,β- 163 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine unsaturated ketone 273 in good yield, although over-oxidation to the diketone was occasionally observed at prolonged reaction times, resulting in slightly diminished yields.32 Protection of the secondary alcohol provided the corresponding methoxymethyl ether of 274 in 84% yield. Treatment of 274 with tert-butoxide base at low temperature resulted in an intramolecular Michael addition to furnish pentacycle 275, thereby completing the central B-ring of the aconitine carbocycle. OTMS CO2Me O MeO 2C OTMS CO2Me O MeO 2C HF•Py MeCN O Si O t-Bu t-Bu (84–98% yield) OH OH OH 272 264 OTMS CO2Me O MeO 2C O 273 OTMS CO2Me O MeO 2C B KOt-Bu DMF, 55 °C (84% yield) OTMS CO2Me O MeO 2C MeCN (98% yield) MOMCl, n-Bu4NI i-Pr2NEt Cu(MeCN) 4OTf, ABNO, NMI, MeObpy THF, –78 °C O MOMO (quantitative crude) 274 O MOMO 275 Figure 3.40. Intramolecular Michael addition for carbocyclic core 275. Completion of the aconitine carbocycle 275 marks the successful implementation of our convergent fragment coupling strategy. In our retrosynthetic analysis, the principle disconnections were bisection across the central B-ring. We have thus demonstrated that the aconitine core can be assembled in a convergent manner by constructing the C10–C11 bond via semipinacol rearrangement and the C7–C8 bond via intramolecular Michael addition. 164 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Endgame Efforts 3.5.5 From aconitine carbocycle 275, the remaining hurdles for the total synthesis of talatisamine (34) include hydrogenation of the bridgehead olefin, installation of the C8 alcohol, and construction of the piperidine E-ring. Guided by Gin’s synthesis of neofinaconitine (112), we elected to install the C8 alcohol through oxy-Michael addition of an intermediate α,β-unsaturated ketone.9 Deprotonation of diketone 275 occured chemoselectively α to the C16 ketone to afford α-selenide 276 in 80% yield (Figure 3.41). Oxidation of a selenide possessing a free C1 alcohol resulted in rupture of the central B-ring through the C7–C8 bond via a retro-aldol process. However, with the C1 TMS-ether, β-hydroxyketone 277 was furnished in 44% yield. As in Gin’s system, we propose that selenoxide elimination occurs to generate an intermediate enone, which is rapidly hydrated to relieve strain in the bridgehead olefin. MeO 2C OTMS CO2Me O 1 MeO 2C LiHMDS, PhSeCl THF, –78 °C MOMO 16 275 O (80% yield) OTMS CO2Me O 8 7 SePh O MOMO 276 1 MeO 2C n-Bu4NIO 4 CH2Cl2 (44% yield) OTMS CO2Me O 8 MOMO HO 7 O 277 Figure 3.41. Initial investigation of oxy-Michael addition for the C8-alcohol. During these studies, we observed that the C1 silyl ether was labile and occasionally underwent spontaneous deprotection. For this reason, silyl ether 275 was converted to lactone 278 by exposure to trifluoroacetic acid (Figure 3.42). Hydrogenation of the bridgehead olefin proceeded smoothly under standard conditions to provide saturated product 279 in 96% yield over two steps.33 Selenation of the ketone 165 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine afforded α-selenide 280, and oxidation with sodium meta-periodate yielded tertiary alcohol 281 in moderate yield. However, because the substrate lacks alkene functionality, oxidation of the selenide could proceed under ozonolytic conditions without complication. This also allowed the use of methanol as both the solvent and nucleophile for the oxy-Michael addition. As such, ozonolysis of 280 in methanol followed by addition of pyridine, which accelerated selenoxide elimination, furnished C8-methyl ether 282 in 88% yield. The methyl ether would serve as a protecting group for the C8 alcohol of talatisamine (34), since selective formal demethylation at the position is known to occur through a carbocation intermediate.34 MeO 2C OTMS CO2Me O O MeO 2C TFA O CH2Cl2 O MOMO 275 O (96% yield, 2 steps) O O O THF, –78 °C O NaIO 4 SePh O O THF/H2O (51% yield) O MOMO 279 MeO 2C O O O MOMO 278 MeO 2C (88% yield) H EtOH/EtOAc MOMO LiHMDS, PhSeCl O MeO 2C H 2 (1 atm) Pd/C O MOMO 280 HO O 281 O3 MeOH, –78 °C O MeO 2C O O then pyridine –78 °C to rt (89% yield) MOMO MeO O 282 Figure 3.42. Functionalization to C8-methoxylated lactone 282. Alongside several functional group manipulations, the last challenge is to install the piperidine E-ring of talatisamine (34). The original proposal was to implement a 166 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine reductive amination of the C17 ketone. Unfortunately, preliminary experiments showed that chemoselective reduction of the C17 ketone of 282 proceeded stereoselectively from the α-face, providing alcohol 283 in 66% yield (Figure 3.43). The diastereoselectivity of this reduction is conflicting with lactam formation, since hypothetical reduction of C17 imine 284 would provide β-disposed secondary amine 285, which is geometrically unable to undergo cyclization with the lactone carbonyl to form lactam 286. This outcome forced us to devise a new scheme for installing the piperidine E-ring. O MeO 2C O O MeO 2C NaBH 4 O 17 OH O EtOH/THF, 0 °C MOMO MeO O (66% yield) MOMO 282 O MeO 2C NEt O 17 MOMO MeO 284 O NaBH 4 undesired diastereoselectivity MeO O 283 O MeO 2C NHEt OH O NEt H MeO 2C O * MOMO MeO O * MOMO 285 HO O 286 Figure 3.43. Unexpected diastereoselectivity for reduction of the C17 ketone. An important note regarding the lactone functionality is that it differentiates the C18 and C19 carbonyls, which were formerly both methyl esters. As part of the oxabicyclo[2.2.2] system, the lactone also bears an substantial degree of ring strain. We therefore sought to engage the lactone in an aminolysis reaction with ethylamine. When treated with ethylamine in THF at room temperature, lactone 282 underwent aminolysis to afford amide 287 in 69% yield (Figure 3.44). Alternatively, the aminolysis could be performed in the same pot as the selenoxide elimination reaction, affording amide 287 in 167 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 87% yield from α-selenide 280. From amide 287, a final C17–N bond formation through a nucleophilic displacement would complete the full framework of talatisamine (34). The C17 ketone of 287 could again be chemo- and diastereoselectively reduced with sodium borohydride to produce diol 288. However, we were unable to mesylate the C17 alcohol of 288, as mesylation of the C1 alcohol and amide activation often occurred competitively. O MeO 2C OH O NHEt O MeO 2C O EtNH 2 O THF MOMO MeO O (69% yield) MOMO 282 O MeO 2C O3 MeOH, –78 °C O O SePh O 287 O MeO 2C EtNH 2 then pyridine –78 °C to rt THF MOMO 280 MeO (87% yield) O MOMO 282 1 MeO 2C NaBH 4 OH O NHEt OH 17 OH O NHEt O MeO 2C O O O MOMO MeO MsCl –or– Ms 2O MeO O 287 OH O NHEt OMs MeO 2C OH O NEt MeO 2C 17 EtOH/THF 0 °C (65% yield) MOMO MeO 288 O MOMO MeO O 289 MOMO MeO O 290 Figure 3.44. Initial investigations on lactone aminolysis. Due to the difficulties encountered with diol 288, alcohol 283 was mesylated instead, as it lacks the problematic the C1 alcohol and C18 amide (Figure 3.45). Standard mesylation conditions employing triethylamine or pyridine with mesyl chloride or mesyl anhydride in dichloromethane provided no reaction at room temperature, and returned 168 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine intractable reaction profiles at prolonged reaction times or higher temperatures. Interestingly, the use of n-butyllithium or LiHMDS at low temperatures for alkoxide formation prior to mesylation resulted in conversion to cyclic mesyl acetal 291, which was disappointingly inert to aminolysis conditions. Switching to a potassium counterion in KOt-Bu and KHMDS provided moderate conversions to desired mesylate 293. These results are promising, and further optimization of this mesylation step is required. n-BuLi or LiHMDS MsCl O MeO 2C O O OH (>50% conversion) MOMO 283 O O OMs MeO MOMO MeO MOMO 291 O MeO H 2NEt O THF, –78 °C MeO 2C H KHMDS Ms 2O OMs O H 2NEt OH O NHEt OMs MeO 2C neat THF, –78 °C (32% yield, 46% brsm) OMs 292 O MeO 2C OH O NHEt H MeO 2C MOMO MeO 293 O (88% yield) MOMO MeO O 294 Figure 3.45. Preliminary results for mesylation and aminolysis of lactone 283. With mesylate 293 in hand, subjection to neat ethylamine in a sealed vessel produced aminolysis product 294 in 88% yield. Amide 294 is poised to undergo intramolecular cyclization and mesylate displacement to produce aconitine core. A preliminary screen of conditions has thus far proved unsuccessful. If accomplished, the resulting lactam possesses all the functionality required for advancement to talatisamine (34), and remaining steps include global reduction of the carbonyl functional groups, global methylation, and deprotection of the MOM ether and C8-methoxy group; all of these transformations are well precedented based on previous syntheses. Preliminary Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 169 investigations to forge aconitine core 290 have revealed a surprising reluctance of amide 293 to undergo intramolecular cyclization. Basic conditions have led to side products arising from enolization and elimination of the C8-methoxy group, while acidic conditions have failed to induce reactivity in 293. Preliminary experiments have also suggested that solvolytic conditions, such as those employed by Wiesner and Sarpong, may result in ionization of the mesylate and lactam formation.4,10 Further efforts to this end are required for the total synthesis of talatisamine (34). OH O NHEt OMs MeO 2C OH O NEt MeO 2C • NaH, DMF, 0 °C • NaH, THF, rt to 50 °C • K 2CO3, MeOH, 40 °C • KOt-Bu, THF, 0 °C to rt MOMO MeO O MOMO 294 MeO 290 O • AcOH, MeCN, 40 °C * DBU, DMSO/o-xylene, 180 °C Figure 4.46. Preliminary investigations on lactam ring closure. 3.6 FUTURE DIRECTIONS Immediate objectives will focus on the final challenge of amide cyclization of mesylate 294 to form lactam 290, as well as optimization of the mesylation step (Figure 3.47). Should these efforts be successful, the remaining steps to access talatisamine (34) are straightforward. Global reduction with lithium aluminum hydride in refluxing dioxane should provide triol 295, and subsequent methylation should afford protected intermediate 296. Lastly, as demonstrated by Pelletier, Gin, and Fukuyama, subjection to aqueous sulfuric acid at high temperature should result in cleavage of the methoxymethyl ether and formal demethylation at C8 to produce talatisamine (34).34 170 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine OH O NHEt OMs MeO 2C MOMO MeO OH O NEt MeO 2C DBU LiAlH 4 DMSO, 140 °C dioxane reflux O MOMO 294 MeO O MOMO 290 H 2SO4 (aq) THF reflux 110 °C MeO OH OMe NEt MeO NaH, MeI MOMO MeO 295 OMe NEt MeO OH NEt HO OMe 296 HO HO OMe talatisamine (34) Figure 3.47. Proposed completion of talatisamine (34). As a long-term objective, we propose to implement the convergent fragment coupling strategy in the synthesis of denudatine and napelline type C20-diterpenoid alkaloids. The piperidine rings of napelline (29) and lepenine (160) can be retrosynthetically deconstructed to amides 297 and 299, respectively. Scission across the central ring through the bonds shown in red lead to [3.2.1]- and [2.2.2]-bicyclic vinyllithiums 298 and 300. Enantioselective syntheses of both bicyclic fragments also require development, but epoxyketone 185 can serve as the precursor to the AF rings of napelline (29) and lepenine (160). Successful syntheses of these alkaloids would validate the approach as a unified strategy to access C19- and C20-diterpenoid alkaloids, and access to C18-diterpenoid alkaloids may also be possible by oxidative scission of the C4–C18 bond as demonstrated in Gin’s synthesis of neofinaconitine (112).9 171 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Me HO OH A HO OH OH F Li MeO 2C HO OH OH E N Et EtHN O napelline (29) C 20 napelline type Me OH A E N Et 297 HO OH OH MeO 2C F R O H HO OH O 298 O O 185 H EtHN lepenine (160) C 20 denudatine type MeO 2C MeO 2C H OH Li R H O 299 300 Figure 3.47. Retrosynthetic analysis of C20-diterpenoid alkaloids. 3.7 CONCLUDING REMARKS The C19-diterpenoid alkaloids represent highly challenging targets for total synthesis and test the limits of current state-of-the-art methods and strategies. Syntheses by Wiesner, Sarpong, and Fukuyama have thoroughly established the [4 + 2] cycloaddition and biomimetic Wagner–Meerwein rearrangement as a viable method to construct the aconitine skeleton.4,10,13 These syntheses have also shown that biogenetically related C20-diterpenoid alkaloids can be accessed via common intermediates. On the other hand, Gin’s synthesis of the C18 neofinaconitine (112) has demonstrated that a non-biomimetic approach can lead to a relatively expedient synthesis of the aconitine core.9 Our approach to talatisamine (34) showcases the advantages of a convergent strategy to couple two relatively complex, chiral fragments. Scalable and enantioselective syntheses of epoxyketone 185 and bicyclo[3.2.1]octane 251 have been developed, and novel application of a 1,2-addition/semipinacol rearrangement sequence has successfully constructed the hindered C11 quaternary center of the diterpenoid alkaloids. This Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 172 approach has enabled efficient access to the carbocyclic core of the C19 aconitine type alkaloids, with requisite functionalities in place for advancement to talatisamine (34). Additionally, the coupling of additional bicyclic fragments with epoxyketone 185 via the 1,2-addition/semipinacol rearrangement method can possibly provide access to a range of C20-diterpenoid alkaloids possessing a common AEF tricycle, as in napelline (29) and lepenine (160). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 3.8 EXPERIMENTAL SECTION 3.8.1 Materials and Methods 173 Unless otherwise stated, reactions were performed under an inert atmosphere (dry N2 or Ar) with freshly dried solvents utilizing standard Schlenk techniques. Glaswarewas oven-dried at 120 °C for a minimum of four hours, or flame-dried utilizing a Bunsen burner under high vacuum. Tetrahydrofuran (THF), methylene chloride (CH2Cl2), acetonitrile (MeCN), tert-butyl methyl ether (TBME), benzene (PhH), and toluene (PhMe) were dried by passing through activated alumina columns. Triethylamine (Et3N) and N,N-diisopropylethylamine (DIPEA) were distilled over calcium hydride prior to use. Unless otherwise stated, chemicals and reagents were used as received. All reactions were monitored by thin-layer chromatography using EMD/Merck silica gel 60 F254 precoated plates (0.25 mm) and were visualized by UV, p-anisaldehyde, KMnO4, or CAM staining. Flash column chromatography was performed using silica gel (SiliaFlash® P60, particle size 40-63 microns [230 to 400 mesh]) purchased from Silicycle. Optical rotations were measured on a Jasco P-2000 polarimeter using a 100 mm path-length cell at 589 nm. 1H and 13C NMR spectra were recorded on a Bruker Avance III HD with Prodigy cryoprobe (at 400 MHz and 101 MHz respectively), a Varian 400 MR (at 400 MHz and 101 MHz, respectively), a Varian Inova 500 (at 500 MHz and 126 MHz, respectively), or a Varian Inova 600 (at 600 MHz and 150 MHz, respectively), and are reported relative to internal CHCl3 (1H, δ = 7.26) and CDCl3 (13C, δ = 77.0). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Multiplicity and qualifier abbreviations are as follows: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, app = apparent. IR 174 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer and are reported in frequency of absorption (cm–1). HRMS were acquired using an Agilent 6200 Series TOF with an Agilent G1978A Multimode source in electrospray ionization (ESI), or mixed (MM) ionization mode, or obtained from the Caltech Mass Spectral Facility in fast-atom bombardment mode (FAB). 3.8.2 Preparative Procedures and Spectroscopic Data Preparation of diester 208: MeO 2C O O + MeO 2C O O THF, reflux MeO 2C 186 NaH, n-Bu4NI Br MeO 2C 187 (78% yield) 208 In a 250-mL, round-bottomed flask equipped with a reflux condenser, NaH (60% dispersion in mineral oil, 1.05 g, 43.7 mmol, 1.17 equiv) was suspended in THF (44 mL) and cooled to 0 °C. To this suspension was added dimethyl malonate (186, 5.0 mL, 43.7 mmol, 1.17 equiv) dropwise with a vent needle to allow pressure release caused by H2 evolution. The reaction was then warmed to room temperature with stirring for 30 minutes, after which n-Bu4NI (1.38 g, 3.74 mmol, 0.10 equiv) and 2-(2-bromoethyl)-1,3dioxolane (187, 4.4 mL, 37.4 mmol, 1.0 equiv) was added. The solution was heated to reflux and stirred for 4 h, and then quenched by addition of sat. NH4Cl (100 mL). The aqueous phase was extracted with Et2O (3 x 200 mL), and the combined organic extracts were washed with 1 N HCl (100 mL) and brine (100 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (20 to 23% EtOAc in hexanes) provided diester 208 (6.76 g, 29.1 mmol, 78% yield) as a colorless oil. 175 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 H NMR (400 MHz, CDCl3): δ 4.88 (t, J = 4.5 Hz, 1H), 4.00 – 3.91 (m, 2H), 3.90 – 3.80 (m, 2H), 3.74 (s, 6H), 3.47 (t, J = 7.5 Hz, 1H), 2.08 – 2.01 (m, 2H), 1.74 – 1.68 (m, 2H). Preparation of racemic ketal 189: O MeO 2C O O O + NaOMe MeOH, 0 °C MeO 2C 208 188 O (85% yield) MeO 2C MeO 2C O (±)-189 In a 500-mL, round-bottomed flask, Na (2.18 g, 94.9 mmol, 1.1 equiv) was added to MeOH (110 mL). After consumption of the solid Na, the solution was cooled to 0 °C, and a solution of diester 208 (20.0 g, 86.3 mmol, 1.0 equiv) in MeOH (30 mL) was added via cannula, followed by dropwise addition of a solution of 2-cyclopenten-1-one (188, 7.95 mL, 94.9 mmol, 1.1 equiv) in MeOH (30 mL) over 20 minutes. The reaction was stirred for an additional 2 h, and then quenched with sat. NH4Cl (300 mL). The mixture was concentrated in vacuo to remove MeOH, and the resulting solution was extracted with EtOAc (3 x 150 mL). The combined organic extracts were washed with brine (150 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (20% acetone in hexanes) afforded ketal 189 (23.1 g, 73.5 mmol, 85% yield) as a white solid. 1 H NMR (400 MHz, CDCl3):
4.85 (td, J = 4.4, 0.9 Hz, 1H), 4.01 – 3.91 (m, 2H), 3.89 – 3.80 (m, 2H), 3.74 – 3.73 (m, 6H), 2.85 – 2.74 (m, 1H), 2.48 (dd, J = 18.5, 7.6 Hz, 1H), 2.31 (dd, J = 17.2, 8.4 Hz, 1H), 2.25 – 2.11 (m, 3H), 2.08 – 2.03 (m, 2H), 1.73 – 1.58 (m, 3H). 176 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 C NMR (101 MHz, CDCl3): δ 217.4, 170.9, 170.8, 103.7, 59.4, 52.4, 52.4, 41.1, 40.2, 38.5, 28.9, 27.7, 24.9. FTIR (NaCl, thin film): 2956, 2890, 1743, 1730, 1451, 1435, 1407, 1222, 1147, 1036 cm-1. HRMS: (FAB) calc’d for C15H23O7 [M + H]+ 315.1444, found 315.1438. Preparation of allylic alcohol 194: O Br PBr 3 DMF 0 °C to rt 193 Br NaBH 4 EtOH O S3 (50% yield, 2 steps) HO 194 In a 1-L, round-bottomed flask, PBr3 (14.3 mL, 153 mmol, 2.7 equiv) was added via syringe to a solution of DMF (14.0 mL, 181 mmol, 3.2 equiv) in CH2Cl2 (80 mL) at 0 °C. After stirring for 1 h, a solution of cyclopentanone (193, 5.0 mL, 56.5 mmol, 1.0 equiv) in CH2Cl2 (30 mL, 10 mL rinse) was added via cannula. The reaction was allowed to warm to ambient temperature, and stirred for an additional 21 h. The reaction was cooled again to 0 °C, and quenched carefully with sat. NaHCO3 (500 mL). Solid NaHCO3 was added periodically as needed until bubbling ceased. The resulting mixture was extracted with Et2O (3 x 250 mL), and the combined organic extracts were washed with H2O (2 x 500 mL) and brine (500 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (15% EtOAc in hexanes) to afford bromoenal S3 (ca. 5.8 g), which was used in the next step without rigorous removal of solvent. In a 500-mL, round-bottomed flask, bromoenal S3 (ca. 5.8 g) was dissolved in EtOH (33 mL) and cooled to 0 °C. NaBH4 (1.5 g, 39.8 mmol, 1.2 equiv) was added, and Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 177 the reaction was stirred for 1 h. The reaction was quenched with H2O (200 mL), and the mixture was concentrated in vacuo to remove ethanol. The resulting aqueous solution was extracted with Et2O (3 x 200 mL), and the combined organic extracts were washed with brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (15% EtOAc in hexanes) afforded allylic alcohol 194 (5.05 g, 28.5 mmol, 50% yield over two steps) as a colorless oil. Spectroscopic data for bromoenal S3 and allylic alcohol 194 matched that reported in the literature.16 Caution: Bromoenal S3 was found to decompose exothermically upon standing for several hours. It could be safely stored as a solution in Et2O in a –20 °C freezer, but in most cases was immediately used in subsequent reactions. Bromoenal S3: 1 H NMR (300 MHz, CDCl3): δ 9.90 (s, 1H), 2.94 – 2.86 (m, 4H), 2.57 – 2.49 (m, 4H), 2.02 (pd, J = 7.9, 1.1 Hz, 4H). Allylic alcohol 194: 1 H NMR (300 MHz, CDCl3): δ 4.29 – 4.21 (m, 2H), 2.73 – 2.59 (m, 2H), 2.54 – 2.40 (m, 2H), 1.97 (tt, J = 8.3, 6.6 Hz, 2H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 178 Preparation of silyl ethers 195 and 196: Br TIPSCl or TMSCl imidazole CH2Cl2 HO 194 Br RO (76% yield) 195 (R = TIPS) (76% yield) 196 (R = TMS) In a 200-mL, round-bottomed flask, allylic alcohol 194 (5.05 g, 28.5 mmol, 1.0 equiv) and imidazole (4.66 g, 68.5 mmol, 2.4 equiv) were dissolved in DMF (57 mL). To this solution was added TMSCl (4.34 mL, 34.2 mmol, 1.2 equiv), and the reaction was stirred for 12 h. The reaction was quenched with sat. NaHCO3 (100 mL) and H2O (100 mL), and extracted with Et2O (3 x 200 mL). The combined organic extracts were washed with H2O (200 mL) and brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude oil was purified by silica gel chromatography (0.5% Et3N/5% EtOAc in hexanes) to afford TMS ether 196 (5.44 g, 21.8 mmol, 76% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 4.24 (tt, J = 1.6, 1.0 Hz, 2H), 2.67 – 2.61 (m, 2H), 2.46 – 2.38 (m, 2H), 1.99 – 1.90 (m, 2H), 0.13 (s, 9H). 13 C NMR (126 MHz,CDCl3): δ 139.8, 116.8, 60.4, 40.3, 32.4, 21.5, -0.4. FTIR (NaCl, thin film): 2953, 2922, 2852, 1655, 1443, 1319, 1246, 1091, 1023 cm-1. HRMS: (FAB) calc’d for C9H17BrOSiNa [M + Na]+ 271.0130, found 217.0144. The same procedure was used to prepare TIPS ether 195: 1 H NMR (500 MHz, CDCl3): δ 4.35 (tq, J = 1.7, 0.9 Hz, 2H), 2.68 – 2.62 (m, 2H), 2.52 – 2.45 (m, 2H), 1.99 – 1.91 (m, 2H), 1.18 – 1.10 (m, 3H), 1.10 – 1.04 (m, 18H). 13 C NMR (126 MHz, CDCl3): δ 140.7, 115.2, 61.4, 40.2, 32.3, 21.5, 18.0, 12.0. 179 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine FTIR (NaCl, thin film): 2960, 2941, 2892, 2866, 1657, 1463, 1383, 1369, 1104, 1066 cm-1. HRMS: (FAB) calc’d for C15H28BrOSi [M + H – H2]+ 331.1093, found 331.1089. Preparation of epoxy alcohol 197: Br + TIPSO 195 MeO 2C MeO 2C H 185 t-BuLi, then 185 O O O MeO 2C MeO 2C H OH THF, –94 °C TIPSO (72% yield) 197 In a 10-mL, round-bottomed flask, a solution of vinyl bromide 195 (54.3 mg, 0.186 mmol, 1.0 equiv) in THF (0.93 mL) was added to a solution of t-BuLi (220 µL, 0.373 mmol, 2.0 equiv) in THF (0.93 mL) at –94 °C. After stirring for 15 min, a solution of epoxyketone 185 (50.0 mg, 0.186 mmol, 1.0 equiv) in THF (0.93 mL) was added. The reaction was stirred for an additional hour, and then quenched with H2O (5 mL). The mixture was extracted with Et2O (3 x 5 mL), and the combined organic extracts were washed with brine (15 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (11% EtOAc in hexanes) afforded epoxy alcohol 197 (64.5 mg, 0.134 mmol, 72% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3):
4.58 (dt, J = 2.8, 1.5 Hz, 2H), 3.75 (s, 3H), 3.71 (s, 3H), 3.29 (d, J = 3.6 Hz, 1H), 2.99 (s, 1H), 2.65 (dd, J = 12.3, 5.7 Hz, 1H), 2.57 – 2.49 (m, 2H), 2.49 – 2.24 (m, 6H), 2.06 – 1.91 (m, 4H), 1.86 – 1.70 (m, 2H), 1.63 – 1.54 (m, 1H), 1.14 – 1.07 (m, 3H), 1.07 – 1.03 (m, 18H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 180 C NMR (126 MHz, CDCl3): δ 171.9, 170.2, 139.4, 136.5, 77.1, 72.1, 60.6, 57.5, 55.0, 52.9, 52.1, 46.3, 39.5, 35.4, 35.0, 29.0, 24.6, 22.0, 21.5, 18.0, 12.0. FTIR (NaCl, thin film): 3493, 2946, 2888, 2865, 1740, 1730, 1463, 1434, 1368, 1305, 1245, 1092, 1062 cm-1. HRMS: (ESI) calc’d for C28H46NaO7Si [M + Na]+ 545.2905, found 545.2906. Preparation of ketone 198: O MeO 2C MeO 2C H OH CH2Cl2, 0 °C TIPSO OTMS OTMS TMSOTf 2,6-lutidine MeO 2C MeO 2C MeO 2C H O OTIPS (90% yield) 197 CO2Me O OTIPS 198 In a 10-mL, round-bottomed flask, epoxy alcohol 197 (94.2 mg, 0.180 mmol, 1.0 equiv) was dissolved in CH2Cl2 (2 mL) and cooled to 0 °C. 2,6-lutidine (63 µL, 0.541 mmol, 3.0 equiv) was added, followed by TMSOTf (65 µL, 0.360 mmol, 2.0 equiv). The reaction was stirred for 15 min, and then quenched with sat. NaHCO3 (5 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (7% EtOAc in hexanes) afforded ketone 198 (95.8 mg, 0.161 mmol, 90% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3): δ 4.21 (s, 1H), 4.12 (d, J = 12.2 Hz, 1H), 3.98 (d, J = 12.2 Hz, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 3.44 (dd, J = 12.7, 7.5 Hz, 1H), 2.62 – 2.54 (m, 1H), 2.45 (dt, J = 15.7, 7.5 Hz, 2H), 2.39 – 2.08 (m, 6H), 1.94 – 1.76 (m, 3H), 1.77 – 1.64 (m, 2H), 1.14 – 1.08 (m, 3H), 1.08 – 1.04 (m, 18H), 0.05 (s, 9H). 181 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 C NMR (126 MHz, CDCl3): δ 220.1, 170.9, 170.8, 139.2, 135.4, 70.3, 61.4, 57.3, 56.1, 52.6, 52.5, 45.7, 38.7, 36.5, 35.0, 28.3, 23.5, 21.5, 19.0, 17.9, 11.9, -0.1. FTIR (NaCl, thin film): 2950, 2892, 2866, 1743, 1462, 1405, 1278, 1278, 1252, 1208, 1169, 1094, 1070, 1020 cm-1. HRMS: (ESI) calc’d for C22H33O6Si [M – OTIPS]+ 421.2041, found 421.2031. Preparation of ketone 200 directly from epoxyketone 185: OTMS Br + TMSO 196 (1.0 equiv) MeO 2C MeO 2C H 185 (1.0 equiv) t-BuLi, then 185 THF, –94 °C O O CO2Me O MeO 2C then TMSOTf 2,6-lutidine, 0 °C OTMS (54% yield) 200 In a 50-mL, round-bottomed flask, vinyl bromide 196 (130 mg, 0.522 mmol, 1.0 equiv) was dissolved in THF (5.2 mL) and cooled to –94 °C (acetone/liquid N2). t-BuLi (0.61 mL, 1.7 M in pentane, 1.04 mmol, 2.0 equiv) was added, and the reaction was stirred for 10 min. In a separate flask, a solution of epoxyketone 185 (140 mg, 0.522 mmol, 1.0 equiv) in THF (5.2 mL) was prepared and added slowly, down the side of the flask, to the first reaction flask. The reaction was stirred for 30 min while allowing the acetone/liquid N2 bath to expire (not exceeding 0 °C). The cooling bath was replaced with an ice bath (0 °C), and then 2,6-lutidine (0.18 mL, 1.57 mmol, 3.0 equiv) was added, followed by TMSOTf (0.19 mL, 1.04 mmol, 2.0 equiv). The reaction was stirred for 20 min, and then another portion of 2,6-lutidine (0.18 mL, 1.57 mmol, 3.0 equiv) was added, followed by another portion of TMSOTf (0.19 mL, 1.04 mmol, 2.0 equiv). The reaction was stirred an additional 20 min, then quenched with sat. NaHCO3 (20 mL). The mixture was extracted with CH2Cl2 (3 x 20 mL), and the combined organic extracts were dried 182 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (5 to 7% EtOAc in hexanes) to provide ketone 200 (142.7 mg, 0.279 mmol, 54% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3): δ 4.21 (s, 1H), 3.98 (d, J = 12.6 Hz, 1H), 3.88 (d, J = 12.8 Hz, 1H), 3.72 (s, 3H), 3.64 (s, 3H), 3.38 (dd, J = 12.8, 7.5 Hz, 1H), 2.48 – 2.25 (m, 6H), 2.25 – 2.08 (m, 3H), 1.93 – 1.64 (m, 5H), 0.11 (s, 9H), 0.05 (s, 9H). 13 C NMR (126 MHz, CDCl3): δ 220.0, 170.8, 170.8, 138.6, 136.0, 70.4, 60.4, 57.3, 56.1, 52.6, 52.6, 45.8, 38.8, 36.7, 35.2, 28.3, 23.5, 21.6, 19.0, -0.1, -0.6. FTIR (NaCl, thin film): 2954, 2904, 2848, 1743, 1460, 1434, 1405, 1252, 1209, 1169, 1072, 1021 cm-1. HRMS: (ESI) calc’d for C22H33O6Si [M – OTMS]+ 421.2041, found 421.2045. Preparation of allylic alcohol 201: MeO 2C OTMS OTMS CO2Me O CO2Me O AcOH (aq) MeO 2C OTMS MeO 2C E OH O THF OTMS 200 (97% yield) OH 201 S4 (E = CO2Me) In a 10-mL, round-bottomed flask, bis-silyl ether 200 (120 mg, 0.235 mmol, 1.0 equiv) was dissolved in THF (2.4 mL). Aqueous AcOH (0.7 mL, 1.0 M, 0.700 mmol, 3.0 equiv) was added, and the reaction was stirred for 45 min. The reaction was then quenched by addition of sat. NaHCO3 (10 mL), and the aqueous phase was extracted with CH2Cl2 (3 x 10 mL). The combined organic layers were dried over Na2SO4, filtered, and Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine concentrated in vacuo. 183 Purification by silica gel chromatography (33% EtOAc in hexanes) afforded an equilibrium mixture of allylic alcohol 201 and cyclic hemiketal S4 (100 mg, 0.228 mmol, 97% yield) as a white foam. FTIR (NaCl, thin film): 3479, 2953, 2847, 1739, 1734, 1643, 1445, 1434, 1402, 1251, 1172, 1099, 1075 cm-1. HRMS: (ESI) calc’d for C22H33O6Si [M – OH]+ 421.2041, found 421.2043. Key NMR signals for allylic alcohol 201: 1 H NMR (500 MHz, CDCl3): δ 4.31 (d, J = 16.5 Hz, 1H), 4.17 (dt, J = 16.1, 2.7 Hz, 1H), 3.87 (t, J = 5.5 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.09 (t, J = 9.1 Hz, 1H), 0.15 (s, 9H). 13 C NMR (126 MHz, CDCl3): δ 221.8, 171.9, 170.9, 134.1, 134.1, 0.4. Key NMR signals for cyclic hemiketal S4: 1 H NMR (500 MHz, CDCl3): δ 4.25 (s, 1H), 3.99 (dd, J = 12.4 6.1 Hz, 1H), 3.89 (dd, J = 14.0, 4.8 Hz), 3.76 (s, 3H), 3.71 (s, 3H), 3.36 (dd, J = 12.8, 7.5 Hz, 1H), 0.09 (s, 9H). 13 C NMR (126 MHz, CDCl3): δ 171.0, 170.5, 139.3, 138.1, 106.9, 0.1. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 184 Preparation of ketoaldehyde 202: MeO 2C OTMS OTMS CO2Me O CO2Me O DMP MeO 2C CH2Cl2 OH 201 H (81% yield) O 202 In a 25-mL, round-bottomed flask, allylic alcohol 201 (203.4 mg, 0.464 mmol, 1.0 equiv) was dissolved in CH2Cl2 (4.6 mL). Dess–Martin periodinane (393.4 mg, 0.927 mmol, 2.0 equiv) was added, and the reaction was stirred for 1 h. The reaction was then quenched by addition of sat. NaHCO3 (5 mL) and sat. Na2S2O3 (5 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (25% EtOAc in hexanes) afforded ketoaldehyde 202 (163.7 mg, 0.375 mmol, 81% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 9.77 (s, 1H), 4.39 (s, 1H), 3.73 (s, 3H), 3.64 (s, 3H), 3.45 (dd, J = 12.6, 7.7 Hz, 1H), 2.78 – 2.63 (m, 3H), 2.60 – 2.34 (m, 4H), 2.25 – 2.07 (m, 2H), 1.95 – 1.72 (m, 4H), 1.67 (tdd, J = 14.4, 3.5, 2.0 Hz, 1H), 0.07 (s, 9H). 13 C NMR (126 MHz, CDCl3): δ 218.6, 188.4, 171.0, 170.4, 162.1, 138.6, 70.1, 58.9, 56.5, 52.8, 52.7, 47.6, 38.9, 38.8, 31.8, 28.2, 23.8, 21.7, 19.2, -0.1. FTIR (NaCl, thin film): 2954, 2851, 2756, 1740, 1660, 1594, 1579, 1460, 1434, 1252, 1171, 1099, 1060, 1023 cm-1. HRMS: (ESI) calc’d for C22H33O7Si [M + H]+ 437.1990, found 437.1982. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 185 Preparation of tetracycle 203: MeO 2C OTMS OTMS CO2Me O CO2Me O KOt-Bu THF, –78 °C H O MeO 2C OH (83% yield, >20:1 dr) 202 203 In a 10-mL, round-bottomed flask, ketoaldehyde 202 (40.0 mg, 91.6 µmol, 1.0 equiv) was dissolved in THF (1.8 mL) and cooled to –78 °C. To this solution was added KOt-Bu (101 µL, 1 M in THF, 0.101 mmol, 1.1 equiv), and the reaction was stirred for 5 min at –78 °C. The reaction was quenched by addition of sat. NaHCO3 (2 mL), and the mixture was extracted with CH2Cl2 (3 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (40% EtOAc in hexanes) to afford alcohol 203 (33.1 mg, 75.8 µmol, 83% yield) as a white solid. Note: The aldol product 203 is unstable to long term storage, as it slowly undergoes epimerization at the allylic alcohol (likely through retro-aldol/aldol) and cleavage of the silyl ether. It is also unstable to un-neutralized CDCl3, and thus NMR’s are often contaminated with epimeric/diol side products. The direct aldol product 203 was most often carried onto the next step crude without purification. 1 H NMR (400 MHz, CDCl3): δ 4.26 (s, 1H), 3.99 (dd, J = 9.1, 6.6 Hz, 1H), 3.74 (s, 3H), 3.68 (s, 3H), 2.62 – 2.50 (m, 3H), 2.52 – 2.42 (m, 1H), 2.42 (dd, J = 9.9, 2.3 Hz, 1H), 2.28 – 2.12 (m, 3H), 2.01 – 1.89 (m, 4H), 1.81 – 1.73 (m, 2H), 1.63 (ddd, J = 14.3, 10.0, 1.9 Hz, 1H), 0.12 (s, 9H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 186 C NMR (101 MHz, CDCl3): δ 211.7, 172.2, 170.5, 147.1, 138.1, 78.1, 70.7, 57.3, 55.1, 52.9, 52.3, 51.7, 44.4, 32.6, 31.6, 29.5, 27.4, 26.7, 23.1, 0.9. FTIR (NaCl, thin film): 3445, 2954, 2851, 1738, 1732, 1652, 1435, 1252, 1059, 841 cm-1. HRMS: (ESI) calc’d for C22H33O7Si [M + H]+ 437.1990, found 437.1994. Preparation methoxymethyl ether 204: OTMS CO2Me O MeO 2C OH 203 OTMS MOMCl, n-Bu4NI i-Pr2NEt CO2Me O MeO 2C DMF, 45 °C (91% yield) OMOM 204 In a 1-dram vial, allylic alcohol 203 (8.4 mg, 19.2 µmol, 1.0 equiv) was dissolved in DMF (0.20 mL). To this solution was sequentially added n-Bu4NI (1.4 mg, 3.9 µmol, 0.20 equiv), i-Pr2NEt (20 µL, 0.115 mmol, 6.0 equiv), and MOMCl (7.3 µL, 96.2 µmol, 5.0 equiv). The reaction was heated to 45 °C and stirred for 13 h, and then quenched with sat. NaHCO3 (2 mL). The mixture was extracted with CH2Cl2 (3 x 1 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (40% EtOAc in hexanes) to afford methoxymethyl ether 204 (8.4 mg, 17.5 µmol, 91% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 4.79 (d, J = 7.1 Hz, 1H), 4.69 (d, J = 7.1 Hz, 1H), 4.25 (t, J = 2.5 Hz, 1H), 4.00 (dd, J = 10.2, 5.4 Hz, 1H), 3.73 (s, 3H), 3.67 (s, 3H), 3.43 (s, 3H), 2.63 (ddd, J = 8.6, 3.2, 1.9 Hz, 1H), 2.60 – 2.41 (m, 4H), 2.25 – 2.10 (m, 3H), 2.00 – 1.90 (m, 3H), 1.88 – 1.71 (m, 2H), 1.63 – 1.56 (m, 1H), 0.10 (s, 9). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 187 C NMR (101 MHz, CDCl3): δ 209.5, 172.3, 170.4, 147.4, 135.7, 95.5, 82.5, 70.2, 57.3, 55.4, 54.6, 52.9, 52.3, 47.7, 44.5, 32.9, 31.6, 29.1, 27.3, 26.3, 23.0, 0.9. FTIR (NaCl, thin film): 2953, 2847, 1755, 1732, 1462, 1453, 1434, 1251, 1150, 1099, 1024 cm-1. HRMS: (ESI) calc’d for C24H36KO8Si [M + K]+ 519.1811, found 519.1813. Preparation of alcohol 205: OTMS CO2Me O MeO 2C OMOM OH H 2SiF6 CO2Me O MeO 2C MeCN, 0 °C OMOM (94% yield) 204 205 In a 1-dram vial, silyl ether 204 (8.4 mg, 17.5 µmol, 1.0 equiv) was dissolved in MeCN (0.35 mL) and cooled to 0 °C. H2SiF6 (20–25 wt%, 11.2 µL, 17.5 µmol, 1.0 equiv) was added, and the reaction was stirred for 10 minutes before quenching with sat. NaHCO3 (1 mL). The mixture was extracted with CH2Cl2 (3 x 1 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford pure alcohol 205 (6.7 mg, 16.4 µmol, 94% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 4.79 (d, J = 7.2 Hz, 1H), 4.69 (d, J = 7.0 Hz, 1H), 4.33 – 4.26 (m, 1H), 4.28 (d, J = 11.2 Hz, 1H), 3.82 (td, J = 11.6, 5.1 Hz, 1H), 3.73 (s, 3H), 3.68 (s, 3H), 3.44 (s, 3H), 2.82 – 2.69 (m, 2H), 2.65 – 2.51 (m, 1H), 2.51 – 2.41 (m, 1H), 2.37 (ddd, J = 14.5, 8.6, 1.8 Hz, 1H), 2.27 – 2.13 (m, 3H), 2.10 – 1.91 (m, 3H), 1.86 (td, J = 14.0, 2.7 Hz, 1H), 1.64 (ddd, J = 14.4, 9.9, 2.0 Hz, 1H), 1.46 (qd, J = 13.7, 2.3 Hz, 1H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 188 C NMR (101 MHz, CDCl3): δ 217.5, 171.7, 170.8, 147.4, 136.8, 95.6, 82.8, 71.4, 57.7, 55.5, 53.8, 52.8, 52.5, 47.9, 45.0, 32.9, 31.9, 30.2, 28.1, 27.6, 22.7. FTIR (NaCl, thin film): 3491, 2953, 2892, 2849, 1741, 1732, 1453, 1435, 1298, 1286, 1260, 1215, 1151, 1098, 1080, 1056, 1035, 1024 cm-1. HRMS: (ESI) calc’d for C19H23O6 [M – OCH2OCH3]+ 347.1489, found 347.1484. Preparation of methyl ether 206: OH CO2Me O MeO 2C OMOM OMe Me 3OBF 4 Proton sponge CO2Me O MeO 2C CH2Cl2 OMOM (71% yield) 205 206 In an N2-filled glovebox, alcohol 205 (30.0 mg, 73.4 µmol, 1.0 equiv), Me3OBF4 (32.6 mg, 0.220 mmol, 3.0 equiv), and Proton sponge (63.0 mg, 0.294 mmol, 4.0 equiv) were dissolved in CH2Cl2 (0.5 mL) in a 1-dram vial. The vial was sealed with a Teflon cap, brought out of the glovebox, and stirred for 36 h. The reaction mixture was then filtered directly through a short plug of silica, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (60% EtOAc in hexanes) to afford methyl ether 206 (22.1 mg, 52.3 µmol, 71% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 4.77 (d, J = 7.1 Hz, 1H), 4.65 (d, J = 7.1 Hz, 1H), 4.26 (s, 1H), 3.74 (s, 3H), 3.66 (s, 3H), 3.44 – 3.39 (m, 4H), 3.35 (s, 3H), 2.71 (ddd, J = 8.6, 3.5, 2.0 Hz, 1H), 2.65 – 2.54 (m, 1H), 2.53 – 2.45 (m, 1H), 2.38 (dd, J = 9.9, 2.1 Hz, 1H), 2.34 – 2.15 (m, 3H), 2.09 – 1.90 (m, 3H), 1.85 (ddd, J = 14.3, 12.5, 3.3 Hz, 1H), 1.66 – 1.51 (m, 3H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 189 C NMR (101 MHz, CDCl3): δ 209.6, 172.1, 170.3, 146.9, 136.3, 95.4, 82.1, 79.2, 57.7, 57.1, 55.5, 54.5, 52.9, 52.3, 47.6, 44.8, 33.1, 31.7, 30.0, 26.7, 22.7, 22.0. FTIR (NaCl, thin film): 2952, 2849, 1752, 1732, 1452, 1437, 1258, 1238, 1214, 1149, 1105, 1024 cm-1. HRMS: (ESI) calc’d for C22H30NaO8 [M + Na]+ 445.1833, found 445.1844. Preparation of amine 207: OMe CO2Me O MeO 2C OMOM OMe EtNH 2, Ti(Oi-Pr)4 CO2Me NHEt MeO 2C then NaBH 4, EtOH OMOM (90% yield) 206 207 In a ½-dram vial, EtNH2 (36 µL, 2.0 M in THF, 72 µmol, 3.0 equiv) and Ti(OiPr)4 (37 µL, 0.125 mmol, 6.0 equiv) were added to ketone 206 (10.0 mg, 23.7 µmol, 1.0 equiv). After stirring for 2 h, the mixture was diluted with EtOH (0.47 mL), and NaBH4 (9.0 mg, 0.238 mmol, 10 equiv) was added. The reaction mixture was stirred for an additional 2 h, and then concentrated in vacuo. The resulting residue was dissolved in CH2Cl2 and quenched by addition of sat. NaHCO3 (1 mL) and Rochelle’s salt (ca. 30 mg), and then stirred for 1 h. The layers were separated, and the aqueous phase was extracted CH2Cl2 (3 x 1 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford amine 207 (9.6 mg, 21.3 µmol, 90% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 4.74 (d, J = 6.8 Hz, 1H), 4.60 (d, J = 6.8 Hz, 1H), 3.74 (s, 3H), 3.73 – 3.68 (m, 1H), 3.70 – 3.56 (m, 4H), 3.38 (s, 3H), 3.23 (s, 3H), 3.20 – 3.11 190 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine (m, 1H), 2.79 – 2.56 (m, 4H), 2.56 – 2.45 (m, 3H), 2.33 – 2.03 (m, 4H), 1.89 (p, J = 7.4 Hz, 2H), 1.72 – 1.59 (m, 2H), 1.37 (dd, J = 13.7, 9.7 Hz, 1H), 1.04 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 172.9, 170.8, 145.6, 133.5, 95.2, 77.4, 76.0, 61.5, 56.6, 56.4, 55.3, 52.9, 52.4, 49.0, 47.6, 42.8, 38.7, 33.4, 31.1, 28.9, 24.0, 21.7, 21.5, 15.3. FTIR (NaCl, thin film): 3346, 2951, 2888, 2847, 2824, 1738, 1732, 1463, 1457, 1436, 1372, 1262, 1236, 1198, 1148, 1096, 1029, 988, 917 cm-1. HRMS: (ESI) calc’d for C24H38NO7 [M + H]+ 452.2643, found 452.2634. Preparation of diester 209: MeO 2C O + THF/Et2O, rt MeO 2C 186 GaNa-(S)-BINOL (10 mol%) NaOt-Bu (7 mol%) 188 48 mmol scale: 92% yield, 91% ee 160 mmol scale: 76% yield, 77% ee MeO 2C MeO 2C O H 209 Preparation of GaNa-(S)-BINOL solution (0.05 M in 9:1 THF:Et2O):18 In a 500-mL, round-bottomed flask, a solution of NaOt-Bu (3.29 g, 34.2 mmol, 4.0 equiv) in THF (60 mL) was added to a solution of (S)-BINOL (4.90 g, 17.1 mmol, 2.0 equiv) in THF (52 mL), and the resulting mixture was stirred for 30 minutes. This was then cannulated into a solution of GaCl3 (1.51 g, 8.55 mmol, 1.0 equiv) in THF (43 mL) and Et2O (17 mL). This mixture was stirred for 2 h, and then allowed to stand un-agitated for at least 22 h. Enantioselective Michael addition: A solution of GaNa-(S)-BINOL (96 mL, 0.05 M in 9:1 THF:Et2O, 4.80 mmol, 0.10 equiv) was transferred via syringe to a 500mL, round-bottomed flask. To this was added a solution of NaOt-Bu (323 mg, 3.36 mmol. 0.07 equiv) in THF (7.5 mL), followed by dimethyl malonate (186, 5.5 mL, 48 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 191 mmol, 1.0 equiv) and 2-cyclopenten-1-one (188, 4.0 mL, 48 mmol, 1.0 equiv). The reaction was stirred for 37 h, then quenched with 1 N HCl (300 mL). The mixture was extracted with EtOAc (3 x 200 mL), and the combined organic extracts were washed with brine (300 mL), dried over Na2SO4, filtered, and concentrated in vacou. Vacuum distillation of the crude residue afforded diester 209 (9.44 g, 44.1 mmol, 92% yield) as a colorless oil. Spectroscopic data matched that reported in the literature.35 1 H NMR (300 MHz, CDCl3): δ 3.77 (s, 3H), 3.75 (s, 3H), 3.38 (d, J = 9.4 Hz, 1H), 2.95 – 2.78 (m, 1H), 2.51 (dd, J = 18.4, 7.7 Hz, 2H), 2.43 – 2.13 (m, 3H), 2.01 (ddd, J = 18.4, 11.1, 1.3 Hz, 1H), 1.74 – 1.59 (m, 1H). Diester 209 was carried forward to enone 190, where enantiomeric excess was determined to be 91%: SFC data for racemic enone 190: Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 192 SFC data for enantioenriched enone 190 (three steps from diester 209): Large-scale preparation of diester 209: The above protocol was reproduced using 160 mmols of dimethyl malonate (186) and 160 mmols of 2-cyclopenten-1-one (188), affording a 76% yield of diester 209 in 77% ee. [!]!" ! = –46° (c = 0.84, CHCl3). SFC data for racemic diester 209: Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 193 SFC data for enantioenriched diester 209 prepared on 160 mmol scale: Preparation of ketal 210: MeO 2C MeO 2C ethylene glycol p-TsOH O H 209 benzene, reflux (83% yield) MeO 2C MeO 2C O H O 210 In a 50-mL, round-bottomed flask equipped with a reflux condenser and Dean– Stark trap, ketone 209 (1.33 g, 6.19 mmol, 1.0 equiv) was dissolved in toluene (21 mL). To this solution was added ethylene glycol (0.70 mL, 12.4 mmol, 2.0 equiv) and pTsOH•H2O (120 mg, 0.619 mmol, 0.10 equiv), and the reaction was heated to reflux for 48 h. The reaction was then cooled to room temperature and washed with sat. NaHCO3 (2 x 50 mL). The organic phase was dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (25% EtOAc in hexanes) provided ketal 210 (1.33 g, 5.15 mmol, 83% yield) as a colorless oil. 194 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 H NMR (400 MHz, CDCl3): δ 3.93 – 3.84 (m, 1H), 3.72 (s, 3H), 3.71 (s, 3H), 3.31 (d, J = 10.2 Hz, 1H), 2.75 – 2.62 (m, 1H), 2.08 (ddd, J = 13.7, 8.0, 1.2 Hz, 1H), 1.99 – 1.86 (m, 2H), 1.85 – 1.75 (m, 1H), 1.56 (dd, J = 13.6, 9.5 Hz, 1H), 1.48 – 1.36 (m, 1H). 13 C NMR (101 MHz, CDCl3): δ 169.0, 168.9, 117.0, 64.3, 64.2, 56.7, 52.4, 52.4, 40.6, 36.8, 35.5, 28.2. FTIR (NaCl, thin film): 2956, 2885, 1754, 1734, 1435, 1316, 1216, 1151, 1079, 1017, 947 cm-1. HRMS: (PMM) calc’d for C12H19O6 [M + H]+ 259.1176, found 259.1169. [!]!" ! = +2.2° (c = 1.4, CHCl3). Preparation of bis-ketal 211: 187 Br MeO 2C MeO 2C O O O THF, reflux H O (78% yield, 98% brsm) 210 O O NaH, n-Bu4NI MeO 2C MeO 2C H O O 211 In a 250-mL, round-bottomed flask equipped with a reflux condenser, NaH (60% dispersion in mineral oil, 1.42 g, 35.6 mmol, 1.2 equiv) was washed with hexanes (3 x 10 mL), then cooled to 0 °C. A solution of diester 210 (7.66 g, 29.6 mmol, 1.0 equiv) in THF (70 mL, followed by 3 x 10 mL rinse) was added, and the reaction was heated to 70 °C with stirring for 25 min. n-Bu4NI (1.09 g, 2.96 mmol, 0.10 equiv) and 2-(2bromoethyl)-1,3-dioxolane (187, 5.22 mL, 44.5 mmol, 1.5 equiv) were added sequentially, and the reaction was heated to reflux for 15 h. The reaction was then quenched by addition of sat. NH4Cl (50 mL) and H2O (50 mL). The mixture was 195 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine extracted with CH2Cl2 (3 x 250 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (35 to 40% EtOAc in hexanes) afforded recovered starting material 210 (1.56 g, 20% recovery) and bis-ketal 211 (7.26 g, 23.1 mmol, 78% yield, 98% based on recovered starting material) as a colorless oil. 1 H NMR (500 MHz, CDCl3): δ 4.83 (td, J = 4.5, 1.9 Hz, 1H), 3.97 – 3.81 (m, 8H), 3.71 (s, 3H), 3.71 (s, 3H), 2.70 – 2.60 (m, 1H), 2.05 – 1.95 (m, 3H), 1.91 – 1.80 (m, 2H), 1.80 – 1.66 (m, 2H), 1.64 – 1.50 (m, 3H). 13 C NMR (126 MHz, CDCl3): δ 171.2, 171.1, 116.6, 103.9, 64.9, 64.9, 64.2, 64.1, 59.8, 52.2, 52.1, 40.4, 38.0, 35.3, 29.0, 27.9, 25.4. FTIR (NaCl, thin film): 2954, 2915, 2877, 1728, 1434, 1227, 1141, 1024 cm-1. HRMS: (FAB) calc’d for C17H27O8 [M + H]+ 359.1706, found 359.1716. [!]!" ! = –0.69° (c = 0.60, CHCl3). Preparation of enone 190: O O HCl (aq) MeO 2C MeO 2C H 211 O O acetone, 70 °C MeO 2C MeO 2C H O (67% yield) 190 In a 200-mL, round-bottomed flask equipped with a reflux condenser, bis-ketal 211 (7.26 g, 23.1 mmol, 1.0 equiv) was dissolved in acetone (92 mL). Aqueous HCl (23.1 mL, 2 N, 46.2 mmol, 2.0 equiv) was added, and the reaction was heated to 70 °C with stirring for 7 h. The reaction was then quenched with sat. NaHCO3 (100 mL) and 196 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine partially concentrated in vacuo to remove acetone. The resulting mixture was extracted with CH2Cl2 (3 x 150 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (25% EtOAc in hexanes) to afford enone 190 (3.91 g, 15.5 mmol, 67% yield) as a white solid. 1 H NMR (500 MHz, CDCl3): δ 6.70 (q, J = 3.8 Hz, 1H), 3.79 (s, 3H), 3.68 (s, 3H), 3.11 (qdd, J = 7.4, 3.5, 2.1 Hz, 1H), 2.53 – 2.37 (m, 4H), 2.32 – 2.22 (m, 2H), 2.11 – 2.00 (m, 1H), 1.99 – 1.90 (m, 1H). 13 C NMR (126 MHz, CDCl3): δ 204.6, 171.9, 169.5, 137.1, 131.3, 55.1, 52.7, 52.2, 42.8, 37.8, 29.4, 23.9, 23.3. FTIR (NaCl, thin film): 3022, 2956, 2898, 2848, 1732, 1659, 1451, 1434, 1283, 1256, 1214, 1174, 1143, 1064 cm–1. HRMS: (FAB) calc’d for C13H17O5 [M + H]+ 253.1076, found 253.1076. [!]!" ! = –34° (c = 1.7, CHCl3). Preparation bromohydrin 192: O O S N Br OH MeO 2C MeO 2C H 190 191 O O MeCN/H 2O (62% yield) MeO 2C MeO 2C H Br O 192 A 250-mL, round-bottomed flask was charged with enone 190 (3.91 g, 15.5 mmol, 1.0 equiv), MeCN (64 mL), and H2O (12 mL), followed lastly by N- Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 197 bromosaccharin (191, 5.28 g, 20.1 mmol, 1.3 equiv). The reaction was stirred for 6.5 h, then quenched by addition of sat. Na2S2O3 (150 mL). The mixture was extracted with Et2O (3 x 250 mL), and the combined organic extracts were washed with sat. NaHCO3 (2 x 150 mL), brine (150 mL), dried over MgSO4, filtered, and concentrated in vacuo to afford a crude white solid. This was dissolved in Et2O (600 mL) at 35 °C. Ca. 300 mL was concentrated off, and then hexanes (300 mL) was added. The solution was concentrated until ca. 300 mL of solvent remained, with white solids suspended within. The solvent was decanted into a Büchner funnel, washing the flask carefully with hexanes. The residual solids in the flask were collected, affording bromohydrin 192 (3.37 g, 9.65 mmol, 62% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 4.39 – 4.32 (m, 1H), 3.77 (s, 3H), 3.75 (s, 3H), 3.10 (ddd, J = 12.2, 5.8, 1.5 Hz, 1H), 2.80 – 2.68 (m, 2H), 2.58 – 2.45 (m, 1H), 2.43 – 2.32 (m, 2H), 2.32 – 2.16 (m, 2H), 2.11 – 1.96 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 211.6, 171.3, 171.1, 76.5, 55.5, 53.0, 52.5, 47.9, 42.2, 36.2, 28.2, 27.6, 21.3. FTIR (NaCl, thin film): 3436, 2998, 2955, 2847, 1748, 1732, 1435, 1403, 1252, 1213, 1152, 1091, 1073, 1056, 980 cm-1. HRMS: (FAB) calc’d for C13H18BrO6 [M + H]+ 349.0287, found 349.0275. [!]!" ! = –49° (c = 0.17, CHCl3). 198 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine Preparation of epoxyketone 185: OH MeO 2C MeO 2C H Et 3N Br O 192 CH2Cl2 (99% yield) MeO 2C MeO 2C H O O 185 In a 250-mL, round-bottomed flask, bromohydrin 192 (3.35 g, 9.59 mmol, 1.0 equiv) was dissolved in CH2Cl2 (96 mL). Et3N (1.60 mL, 11.5 mmol, 1.2 equiv) was added, and the reaction was stirred for 9 h. The mixture was loaded directly onto a column of silica gel (slurried in hexanes), and purification by chromatography (100% hexanes, then 40% EtOAc in hexanes) afforded epoxyketone 185 (2.54 g, 9.47 mmol, 99% yield) as a white solid. 1 H NMR (500 MHz, CDCl3): δ 3.76 (s, 1H), 3.76 – 3.73 (m, 4H), 2.93 (dd, J = 12.5, 5.8 Hz, 1H), 2.67 (qd, J = 11.7, 7.4 Hz, 1H), 2.58 (ddd, J = 18.7, 7.6, 1.6 Hz, 1H), 2.48 – 2.28 (m, 4H), 2.12 – 2.01 (m, 1H), 1.72 – 1.61 (m, 1H). 13 C NMR (126 MHz, CDCl3): δ 212.0, 171.4, 169.8, 63.0, 56.1, 55.2, 53.1, 52.4, 43.8, 38.4, 29.3, 23.0, 21.7. FTIR (NaCl/thin film): 3006, 2956, 2903, 2848, 1755, 1732, 1453, 1434, 1408, 1372, 1306, 1251, 1214, 1176, 1139, 1058, 890 cm-1. HRMS: (FAB) calc’d for C13H17O6 [M + H]+ 269.1025, found 269.1050. [!]!" ! = –171° (c = 0.60, CHCl3). 199 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine SFC data for racemic epoxyketone 185: SFC data for enantiopure epoxyketone 185: Preparation of aryl ether S5: Me Me HO Me + OH OH 227 DIAD, PPh 3 Me OH O THF (58% yield) S5 In a 1-L, round-bottomed flask equipped with an addition funnel, (2R, 4R)pentanediol (227, 7.39 g, 71.0 mmol, 1.0 equiv), phenol (7.35 g, 78.1 mmol, 1.1 equiv), and PPh3 (22.3 g, 85.1 mmol, 1.2 equiv) were dissolved in THF (375 mL). A solution of Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 200 DIAD (16.8 mL, 85.1 mmol, 1.2 equiv) in THF (100 mL) was prepared in another flask, and transferred to the addition funnel. The DIAD solution was added dropwise to the vigorously stirring reaction over 25 min, and the resulting solution was stirred for an additional 24 h and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (15% EtOAc in hexanes) afforded arene S5 (7.4 g, 41 mmol, 52% yield). Spectroscopic data matched that reported by Sugimura et al.21 1 H NMR (500 MHz, CDCl3): δ 7.31 – 7.26 (m, 2H), 6.99 – 6.91 (m, 3H), 4.61 (dqd, J = 8.6, 6.0, 4.4 Hz, 1H), 4.06 (dqt, J = 8.9, 6.1, 2.7 Hz, 1H), 2.56 (s, 1H), 1.95 (dt, J = 14.4, 8.8 Hz, 1H), 1.70 (ddd, J = 14.4, 4.5, 3.1 Hz, 1H), 1.31 (d, J = 6.0 Hz, 3H), 1.23 (d, J = 6.2 Hz, 3H). Preparation of arene olefin 216: Me Me Me OH O Hg(OAc) 2 (20 mol%) Me O O OEt 45 °C S5 (>95% yield) 216 In a 250-mL, round-bottomed flask equipped with a reflux condenser, arene S5 (3.90 g, 21.6 mmol, 1.0 equiv) was dissolved in ethyl vinyl ether (108 mL), and Hg(OAc)2 (689 mg, 2.16 mmol, 0.10 equiv) was added. The mixture was heated to reflux and stirred for 18 h, at which point another portion of Hg(OAc)2 (689 mg, 2.16 mmol, 0.10 equiv) was added. After stirring for another 15 h at reflux, the reaction was quenched by addition of sat. NaHCO3 (100 mL). The layers were separated, and the aqueous phase was extracted with Et2O (3 x 200 mL). The combined organic extracts Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 201 were washed with brine (200 mL), dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by filtering over a short plug of silica (eluting with 10% EtOAc/1% Et3N in hexanes) to provide arene olefin 216 (4.5 g, 21.8 mmol, 100% yield) as a colorless oil. Spectroscopic data matched that reported by Sugimura et al.21 1 H NMR (400 MHz, CDCl3): δ 7.31 – 7.24 (m, 2H), 6.97 – 6.86 (m, 3H), 6.34 (dd, J = 14.2, 6.6 Hz, 1H), 4.52 (h, J = 6.2 Hz, 1H), 4.33 (dd, J = 14.2, 1.6 Hz, 1H), 4.12 (h, J = 6.3 Hz, 1H), 4.03 (dd, J = 6.7, 1.6 Hz, 1H), 2.20 (dt, J = 13.9, 6.9 Hz, 1H), 1.65 (dt, J = 14.0, 6.0 Hz, 1H), 1.33 (d, J = 6.1 Hz, 3H), 1.25 (d, J = 6.2 Hz, 3H). Preparation of 7-substituted meta-photoadduct 218: H Me Me O O 216 hν (254 nm) pentane 25 °C (1.5 g batches, 67% avg. yield) O Me H O H Me 218 In a 1-L, round-bottomed quartz flask, arene olefin 216 (1.5 g, 7.3 mmol, 1.0 equiv) was dissolved in pentane (700 mL). This solution was sparged with Ar for 75 min, then irradiated with stirring using a Honeywell 254 nm lamp for 27 h. The temperature was deliberately maintained at 25 °C using ventilation fans. Upon completion, the reaction was concentrated in vacuo to afford a crude residue. This procedure was repeated for a total of 5 batches. All 5 crude batches were combined and purified by silica gel chromatography (9% EtOAc in hexanes) to afford 7-substituted 202 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine photoadduct 218 (5.0 g, 24.2 mmol, 67% average yield over 5 batches) as a white solid. Spectroscopic data matched that reported by Sugimura et al.21 1 H NMR (300 MHz, CDCl3): δ 5.63 (ddt, J = 5.5, 2.7, 1.0 Hz, 1H), 5.44 (dd, J = 5.5, 1.7 Hz, 1H), 4.49 (dd, J = 7.0, 2.5 Hz, 1H), 4.31 (p, J = 6.5 Hz, 1H), 4.06 (p, J = 6.5 Hz, 1H), 3.26 (dd, J = 8.4, 2.8 Hz, 1H), 2.52 – 2.42 (m, 3H), 2.34 (dt, J = 17.4, 7.4 Hz, 1H), 2.10 (ddd, J = 14.6, 7.0, 0.9 Hz, 1H), 1.60 (d, J = 17.5 Hz, 1H), 1.23 (d, J = 6.3 Hz, 6H). Preparation of 6-substituted meta-photoadduct 217: H Me Me Me O O 216 H hν (254 nm) pentane Me H O + O O Me H O H Me 217 (42% yield) 218 (24% yield) H A 500-mL, round-bottomed quartz flask was charged with arene olefin 216 (244 mg, 1.18 mmol, 1.0 equiv) and pentane (250 mL). The solution was degassed by sparging with argon for 30 minutes. The reaction was then irradiated with stirring using a Honeywell 254 nm lamp for 21.5 h. The reaction was then concentrated in vacuo, and purified by silica gel chromatography (7 to 9% EtOAc in hexanes) to provide 6substituted photoadduct 217 (101.3 mg, 0.491 mmol, 42% yield) and 7-substituted photoadduct 218 (59.1 mg, 0.287 mmol, 24% yield). Spectroscopic data matched that reported by Sugimura et al.21 Note: No extra precautions were taken to prevent heating of this reaction by the irradiation lamp. This caused polymeric material to form on the inner wall of the flask, Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 203 which interfered with light penetration, and thereby effectively diminished conversion of 217 to 218 via vinyl cyclopropane rearrangement to allow isolation of 6-substituted photoadduct 217. 1 H NMR (300 MHz, CDCl3): δ 5.59 (ddd, J = 5.6, 2.4, 0.7 Hz, 1H), 5.42 (ddd, J = 5.7, 2.8, 1.6 Hz, 1H), 4.25 (dtd, J = 9.9, 7.3, 6.8, 5.7 Hz, 1H), 4.16 – 4.07 (m, 1H), 4.02 (tt, J = 7.4, 5.6 Hz, 1H), 3.85 (t, J = 2.6 Hz, 2H), 2.34 (ddt, J = 8.2, 2.2, 1.2 Hz, 1H), 2.09 (ddt, J = 8.4, 6.3, 1.1 Hz, 1H), 1.95 – 1.80 (m, 2H), 1.59 (d, J = 15.3 Hz, 1H), 1.50 (ddd, J = 13.9, 3.0, 1.4 Hz, 1H), 1.22 (d, J = 6.3 Hz, 3H), 1.20 (d, J = 6.4 Hz, 3H). Preparation of [3.2.1]-bicycle 228: Me H Me Me H O HCl (aq) Me OH O THF, 60 °C O H (37% yield) 217 O 228 To a 1-dram vial containing 6-substituted photoadduct 217 (18.0 mg, 87.3 µmol, 1.0 equiv) was added THF (0.87 mL) and aqueous HCl (3 M, 0.15 mL, 0.436 mmol, 5.0 equiv). The vial was sealed and heated to 60 °C for 16 h, then quenched by addition of sat. NaHCO3 (3 mL). The mixture was extracted with CH2Cl2 (3 x 3 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (40% EtOAc in hexanes) provided [3.2.1]bicycle 228 (7.3 mg, 32.5 µmol, 37% yield) as a colorless oil. Spectroscopic data matched that reported by Sugimura et al.21 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 204 H NMR (400 MHz, CDCl3): δ 5.88 (dddd, J = 9.4, 7.0, 2.5, 1.0 Hz, 1H), 5.48 (dddd, J = 9.2, 3.7, 2.8, 0.8 Hz, 1H), 4.10 (dd, J = 8.5, 4.4 Hz, 1H), 3.98 – 3.88 (m, 1H), 3.73 – 3.62 (m, 1H), 2.97 (ddt, J = 17.9, 5.2, 2.6 Hz, 1H), 2.86 (s, 1H), 2.68 (dd, J = 13.3, 8.4 Hz, 1H), 2.65 – 2.57 (m, 2H), 2.39 (dt, J = 4.6, 2.0 Hz, 1H), 1.92 (dt, J = 13.1, 5.5 Hz, 1H), 1.67 – 1.58 (m, 1H), 1.50 (ddd, J = 14.5, 4.1, 2.7 Hz, 1H), 1.17 (d, J = 6.1 Hz, 3H), 1.15 (d, J = 6.4 Hz, 3H). Preparation of [3.2.1]-bicycle 229: H HCl (aq) O Me H 218 O Me H dioxane, 40 °C O (yield nd) 229 To a 1-dram vial containing 7-substituted photoadduct 218 (4.2 mg, 20.4 µmol, 1.0 equiv) was added dioxane (0.20 mL) and aqueous HCl (3 M, 70 µL, 0.204 mmol, 10.0 equiv). The vial was sealed and heated to 40 °C for 3 h, then quenched by addition of sat. NaHCO3 (1 mL). The mixture was extracted with CH2Cl2 (3 x 1 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. 1 H NMR of the crude residue showed signals for a major product that were consistent with those reported for known [3.2.1]-bicycle 229.36 Diagnostic signals in crude 1H NMR (500 MHz, CDCl3): δ 6.68 (dd, J = 6.8, 3.0 Hz, 1H), 6.21 (dd, J = 6.9, 3.0 Hz, 1H), 6.07 – 6.01 (m, 2H), 5.51 – 5.46 (m, 1H) 2.82 – 2.74 (m, 3H), 2.52 – 2.46 (m, 1H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 205 Preparation of allylic chloride 233: Me H NCSac O Me H O H Me 218 Me OH O THF/H2O (84% yield) O Cl 233 In a 50-mL, round-bottomed flask, photoadduct 218 (250 mg, 1.21. mmol, 1.0 equiv) was dissolved in THF (10 mL) and H2O (2 mL). N-chlorosaccharin (317 mg, 1.45 mmol, 1.2 equiv) was added, and the reaction was stirred for 1.5 h. The reaction was then quenched by addition of sat. NaHCO3 (5 mL) and sat. Na2S2O3 (5 mL) and extracted with CH2Cl2 (3 x 30 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (45 to 50% EtOAc in hexanes) to afford allylic chloride 233 (267 mg, 1.03 mmol, 84% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 5.94 (dd, J = 9.1, 7.2 Hz, 1H), 5.79 (ddd, J = 9.0, 3.9, 1.3 Hz, 1H), 4.88 (dd, J = 3.8, 3.2 Hz, 1H), 4.04 (dd, J = 7.3, 1.2 Hz, 1H), 3.90 (dqt, J = 9.2, 6.2, 3.0 Hz, 1H), 3.70 (dqd, J = 8.6, 6.0, 4.6 Hz, 1H), 2.80 (dt, J = 7.4, 1.2 Hz, 1H), 2.73 (ddq, J = 8.0, 3.1, 1.5 Hz, 1H), 2.30 (d, J = 2.8 Hz, 1H), 2.25 (ddd, J = 15.0, 7.4, 1.7 Hz, 1H), 2.15 (ddt, J = 14.9, 8.2, 1.3 Hz, 1H), 1.64 (dt, J = 14.4, 8.7 Hz, 1H), 1.48 (ddd, J = 14.4, 4.6, 3.3 Hz, 1H), 1.17 (d, J = 3.1 Hz, 3H), 1.15 (d, J = 3.0 Hz, 3H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 206 Preparation of ketal S6: Me Me TMSO OH O OTMS TMSOTf (20 mol%) CH2Cl2 O Cl 233 (90% yield) Me Me OH O O O Cl S6 In a 25-mL, round-bottomed flask, ketone 233 (267 mg, 1.03 mmol, 1.0 equiv) and 1,2-bis(trimethylsiloxy)ethane (0.50 mL, 2.06 mmol, 2.0 equiv) were dissolved in CH2Cl2 (10 mL). To this solution was added TMSOTf (37 µL, 0.206 mmol, 0.20 equiv). The reaction was stirred for 15 h, and then quenched with sat. NaHCO3 (10 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide pure ketal S6 (282 mg, 0.931 mmol, 90% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 6.03 (ddd, J = 9.5, 7.1, 0.8 Hz, 1H), 5.75 (ddd, J = 9.3, 3.6, 1.4 Hz, 1H), 4.48 – 4.42 (m, 1H), 4.44 (s, 1H), 4.09 – 3.99 (m, 4H), 4.00 – 3.88 (m, 1H), 3.72 (dd, J = 8.3, 3.0 Hz, 1H), 3.65 (dqd, J = 11.9, 5.9, 2.7 Hz, 1H), 2.48 (td, J = 7.5, 1.8 Hz, 2H), 2.11 (ddd, J = 14.7, 8.6, 3.2 Hz, 1H), 1.95 (dd, J = 14.7, 8.3 Hz, 1H), 1.66 – 1.52 (m, 1H), 1.49 (dt, J = 14.8, 2.1 Hz, 1H), 1.15 (dd, J = 6.3, 1.0 Hz, 3H), 1.11 (d, J = 5.9 Hz, 3H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 207 Preparation of ketone 234: Me Me OH Me O DMP, NaHCO 3 CH2Cl2 O O S6 Cl (89% yield) Me O O O O Cl 234 A 25-mL, round-bottomed flask was charged with alcohol S6 (282 mg, 0.931 mmol, 1.0 equiv), NaHCO3 (313 mg, 3.73 mmol, 4.0 equiv), and CH2Cl2 (9.3 mL). To this solution was added Dess–Martin periodinane (790 mg, 1.86 mmol, 2.0 equiv). The reaction was stirred for 12 h, and then quenched with sat. NaHCO3 (10 mL) and sat. Na2S2O3 (10 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 25 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (40% EtOAc in hexanes) afforded ketone 234 (249 mg, 0.828 mmol, 89% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 6.04 (ddd, J = 9.4, 7.4, 0.9 Hz, 1H), 5.71 (ddd, J = 9.4, 3.5, 1.4 Hz, 1H), 4.45 (ddd, J = 3.5, 2.0, 0.9 Hz, 1H), 4.03 – 3.94 (m, 4H), 3.89 (dqd, J = 8.2, 6.1, 4.6 Hz, 1H), 3.65 (dd, J = 8.2, 3.5 Hz, 1H), 2.78 (dd, J = 15.8, 8.2 Hz, 1H), 2.50 (dd, J = 7.4, 1.9 Hz, 1H), 2.44 (ddt, J = 7.8, 3.0, 1.7 Hz, 1H), 2.35 (dd, J = 15.8, 4.6 Hz, 1H), 2.20 (s, 3H), 2.03 (dddd, J = 14.3, 7.8, 3.5, 0.8 Hz, 1H), 1.94 (dd, J = 14.4, 8.2 Hz, 1H), 1.13 (d, J = 6.1 Hz, 3H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 208 Preparation of alcohol 235: Me Me O HO O KHMDS THF, –78 °C O O O O Cl Cl (56% yield) 234 235 In a 25-mL, round-bottomed flask, ketone 234 (249 mg, 0.828 mmol, 1.0 equiv) was dissolved in THF (8.3 mL) and cooled to –78 °C. KHMDS (2.5 mL, 0.5 M in toluene, 1.24 mmol, 1.5 equiv) was added, and then reaction was warmed to 0 °C. After stirring for 30 min, the reaction was quenched with sat. NH4Cl (5 mL) and H2O (5 mL) and extracted with CH2Cl2 (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (40% EtOAc in hexanes) afforded alcohol 235 (100 mg, 0.462 mmol, 56% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 6.02 (ddd, J = 9.5, 7.2, 0.8 Hz, 1H), 5.72 (ddd, J = 9.4, 3.7, 1.5 Hz, 1H), 4.44 (ddd, J = 3.8, 2.2, 0.8 Hz, 1H), 4.12 – 3.99 (m, 4H), 3.91 (ddd, J = 12.3, 5.7, 4.1 Hz, 1H), 3.22 (d, J = 12.3 Hz, 1H), 2.53 – 2.48 (m, 1H), 2.41 (dd, J = 7.2, 1.9 Hz, 1H), 2.02 (dd, J = 5.5, 4.0 Hz, 2H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 209 Preparation of ketone 236: O HO DMP, NaHCO 3 O CH2Cl2 O O Cl (53% yield) 235 O Cl 236 A 25-mL, round-bottomed flask was charged with alcohol 235 (98.0 mg, 0.452 mmol, 1.0 equiv), NaHCO3 (152 mg, 1.81 mmol, 4.0 equiv), and CH2Cl2 (5 mL). To this solution was added Dess–Martin periodinane (384 mg, 0.905 mmol, 2.0 equiv). The reaction was stirred for 15 h, and then quenched with sat. NaHCO3 (5 mL) and sat. Na2S2O3 (5 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 15 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (25% EtOAc in hexanes) afforded ketone 236 (51.7 mg, 0.241 mmol, 53% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 5.97 (ddd, J = 9.2, 3.6, 0.8 Hz, 1H), 5.89 (dd, J = 9.3, 7.5 Hz, 1H), 4.64 (dd, J = 3.6, 1.3 Hz, 1H), 4.17 – 3.96 (m, 4H), 2.94 (dtt, J = 7.5, 1.4, 0.7 Hz, 1H), 2.82 – 2.72 (m, 2H), 2.20 (dt, J = 19.0, 4.6 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 204.4, 128.7, 125.9, 110.3, 65.4, 64.3, 60.1, 53.8, 44.9, 41.9. FTIR (NaCl, thin film): 3043, 2965, 2895, 1753, 1628, 1478, 1407, 1380, 1346, 1312, 1213, 1146, 1097, 1055, 1003, 948, 918 cm-1. HRMS: (FAB) calc’d for C10H12ClO3 [M + H]+ 215.0475, found 215.0454. [!]!" ! = +544° (c = 1.0, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 210 Preparation of allylic alcohol 239: H Me m-CPBA, CH2Cl2 O Me H O H Me Me OH O then HCl (aq) (79% yield) 218 O OH 239 A 1-L, round-bottomed flask was charged with photoadduct 218 (7.26 g, 35.2 mmol, 1.0 equiv) and CH2Cl2 (350 mL), and cooled to 0 °C. m-CPBA (7.89 g, 35.2 mmol, 1.0 equiv) was added, and the reaction was stirred for 30 min at 0 °C, then warmed to room temperature. After stirring for an additional 90 min at room temperature, 2 N HCl (70 mL, 140 mmol, 4.0 equiv) was added, and the biphasic mixture was stirred vigorously. After 30 min, the reaction was quenched by careful addition of sat. NaHCO3 (200 mL), and stirred until bubbling ceased (ca. 30 min). The layers were separated, and the aqueous phase was extracted with EtOAc (8 x 300 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel chromatography (45 to 50% acetone in hexanes) afforded allylic alcohol 239 (6.7 g, 28 mmol, 79% yield) as a colorless oil. Note: The product is highly water soluble, and thus requires rigorous extraction with a polar solvent such as EtOAc. 1 H NMR (400 MHz, CDCl3): δ 5.97 (dd, J = 9.0, 7.2 Hz, 1H), 5.77 (ddd, J = 9.0, 3.8, 1.2 Hz, 1H), 4.59 (s, 1H), 4.02 (dd, J = 6.1, 2.2 Hz, 1H), 3.90 (dqd, J = 9.2, 6.2, 3.0 Hz, 1H), 3.70 (dqd, J = 8.8, 6.0, 4.3 Hz, 1H), 2.79 (dd, J = 7.2, 1.5 Hz, 1H), 2.67 – 2.53 (m, 211 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 2H), 2.31 (br s, 1H), 2.18 – 2.05 (m, 2H), 1.62 (dt, J = 14.4, 8.9 Hz, 1H), 1.48 (ddd, J = 14.5, 4.4, 3.1 Hz, 1H), 1.16 (d, J = 3.8 Hz, 3H), 1.14 (d, J = 4.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 213.9, 131.4, 129.6, 81.1, 75.2, 73.9, 67.0, 51.6, 49.5, 45.9, 32.2, 23.6, 20.0. FTIR (NaCl, thin film): 3400, 2969, 2933, 1753, 1458, 1447, 1376, 1329, 1120, 1080, 1048, 926 cm-1. HRMS: (FAB) calc’d for C13H21O4 [M + H]+ 241.1440, found 241.1421. [!]!" ! = –6.2° (c = 1.0, CHCl3). Preparation of triol 240: Me Me OH Me NaBH 4, CeCl3•7H2O O Me OH O MeOH, –78°C O 239 OH (89% yield) 240 OH OH In a 1-L, round-bottomed flask, ketone 239 (6.7 g, 28 mmol, 1.0 equiv) and CeCl3•7H2O (15.6 g, 41.8 mmol, 1.5 equiv) were dissolved in MeOH (280 mL). The solution was then cooled to –78 °C, and NaBH4 (1.27 g, 33.5 mmol, 1.2 equiv) was added. After stirring for 2 h at –78 °C, the reaction was quenched with 1 M NaOH (200 mL), and concentrated in vacuo to remove MeOH. The aqueous phase was extracted with EtOAc (8 x 250 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Filtration of the crude residue over a short plug of silica (eluting with 50% acetone in hexanes) afforded triol 240 (6.1 g, 25 mmol, 89% yield) as a white solid. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 212 Note: The product is highly water soluble, and thus requires rigorous extraction with a polar solvent such as EtOAc. 1 H NMR (400 MHz, CDCl3):
5.88 (ddt, J = 9.9, 3.7, 1.7 Hz, 1H), 5.74 (dd, J = 9.4, 7.0 Hz, 1H), 4.46 (s, 1H), 3.97 (dqd, J = 8.9, 6.3, 2.7 Hz, 1H), 3.85 (br s, 1H), 3.77 – 3.67 (m, 3H), 3.62 (br s, 2H), 2.63 – 2.58 (m, 1H), 2.46 (appar s, 1H), 1.77 (td, J = 4.7, 4.1, 1.7 Hz, 2H), 1.63 – 1.47 (m, 2H), 1.15 (d, J = 6.1 Hz, 3H), 1.12 (d, J = 6.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 129.7, 126.5, 78.3, 75.4, 72.0, 71.7, 68.1, 45.5, 45.4, 40.8, 33.8, 23.4, 20.1. FTIR (NaCl, thin film): 3369, 3032, 2967, 2934, 1757, 1642, 1447, 1420, 1376, 1318, 1180, 1084, 1033, 970, 934 cm-1. HRMS: (FAB) calc’d for C13H23O4 [M + H]+ 243.1596, found 243.1616. [!]!" ! = –6.2° (c = 1.0, CHCl3). Preparation of triol 244: Me Me Me OH O NaBH 4 Me OH Me O OH OH 239 H O + MeOH, 0 °C O Me HO OH 240 (29% yield) OH H 244 (67% yield) W-coupling observed in OH COSY (4.20 ppm, 3.91 ppm) In a 1-dram vial, ketone 239 (9.2 mg, 38 µmol, 1.0 equiv) was dissolved in MeOH (0.38 mL) and cooled to 0 °C. NaBH4 (2.9 mg, 77 µmol, 2.0 equiv) was added, and the reaction was stirred for 15 minutes, then diluted with acetone (1 mL) and concentrated in vacuo. The resulting residue was dissolved in EtOAc (2 mL) and washed with 1 N Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 213 NaOH (2 mL). The aqueous phase was extracted with EtOAc (3 x 2 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (50 to 55% acetone in hexanes) to provide 1,3-syn-diol 240 (2.7 mg, 11 µmol, 29% yield) and anti-1,3-diol 244 (6.2 mg, 26 µmol, 67% yield). Spectroscopic data for 1,3-anti-diol 244: 1 H NMR (400 MHz, CDCl3): δ 5.89 (dd, J = 9.3, 7.4 Hz, 1H), 5.53 (ddd, J = 9.3, 3.8, 1.5 Hz, 1H), 4.20 (s, 1H), 4.00 (t, J = 3.3 Hz, 1H), 3.94 (ddd, J = 9.5, 6.4, 2.9 Hz, 1H), 3.91 (d, J = 7.1 Hz, 1H), 3.75 – 3.66 (m, 1H), 2.69 (d, J = 7.3 Hz, 1H), 2.58 (br s, 3H), 2.50 (d, J = 7.7 Hz, 1H), 2.04 (ddd, J = 14.6, 8.2, 1.7 Hz, 1H), 1.80 (dd, J = 14.7, 7.2 Hz, 1H), 1.64 (dt, J = 14.5, 9.0 Hz, 1H), 1.47 (ddd, J = 14.5, 4.3, 2.6 Hz, 1H), 1.17 (d, J = 6.3 Hz, 3H), 1.15 (d, J = 6.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 132.1, 127.7, 81.0, 74.5, 74.3, 74.1, 67.2, 49.1, 47.3, 45.8, 33.5, 24.0, 19.9. Preparation of siliconide 245: Me Me Me OH t-Bu2Si(OTf)2 2,6-lutidine O Me OH O CH2Cl2, –78 °C OH 240 OH (91% yield) O Si O 245 t-Bu t-Bu A 500-mL, round-bottomed flask was charged with triol 240 (6.1 g, 25 mmol, 1.0 equiv), 2,6-lutidine (7.0 mL, 60 mmol, 2.4 equiv), and CH2Cl2 (250 mL), and then cooled to –78 °C. To this solution was added t-Bu2Si(OTf)2 (9.8 mL, 30 mmol, 1.2 equiv), and Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 214 the reaction was stirred for 1 h. The reaction was quenched with sat. NaHCO3 (100 mL) and H2O (100 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 250 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (25% EtOAc in hexanes) to afford siliconide 245 (8.75 g, 22.9 mmol, 91% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 5.83 (ddd, J = 9.5, 4.4, 1.6 Hz, 1H), 5.74 (ddd, J = 9.6, 6.3, 1.2 Hz, 1H), 4.59 (t, J = 4.8 Hz, 1H), 4.04 – 3.91 (m, 2H), 3.80 – 3.70 (m, 2H), 3.39 (s, 1H), 2.78 (dd, J = 6.3, 4.1 Hz, 1H), 2.77 – 2.67 (m, 1H), 1.82 (ddd, J = 15.2, 7.5, 1.3 Hz, 1H), 1.71 (dd, J = 15.0, 7.9 Hz, 1H), 1.60 (dt, J = 14.5, 9.2 Hz, 1H), 1.52 (ddd, J = 14.5, 4.0, 2.6 Hz, 1H), 1.16 (d, J = 6.2 Hz, 3H), 1.12 (d, J = 6.0 Hz, 3H), 1.05 (s, 9H), 0.96 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 129.8, 129.1, 76.4, 74.7, 73.7, 71.0, 67.6, 46.4, 45.9, 38.6, 33.0, 28.7, 28.2, 23.6, 21.2, 20.7, 20.0. FTIR (NaCl, thin film): 3436, 3032, 2968, 2934, 2900, 2859, 1476, 1388, 1364, 1326, 1196, 1174, 1058, 1036, 1019, 998, 826 cm-1. HRMS: (FAB) calc’d for C21H39O4Si [M + H]+ 383.2618, found 383.2630. [!]!" ! = +59° (c = 0.90, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 215 Preparation of ketone 246: Me Me OH Me O Me O O DMP, NaHCO 3 CH2Cl2, rt 245 O Si O t-Bu (99% yield) t-Bu 246 O Si O t-Bu t-Bu A 500-mL, round-bottomed flask was charged with alcohol 245 (8.5 g, 22 mmol, 1.0 equiv), NaHCO3 (5.60 g, 66.6 mmol, 3.0 equiv), and CH2Cl2 (225 mL). Dess–Martin periodinane (12.2 g, 28.9 mmol, 1.3 equiv) was added, and the reaction was stirred for 17 h, after which the reaction was filtered through a plug of silica (eluting with 50% EtOAc in hexanes). The filtrate was concentrated in vacuo, and then diluted in CH2Cl2 (100 mL), washed with sat. NaHCO3 (2 x 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide ketone 246 (8.5 g, 22 mmol, 99% yield) as a light yellow oil. 1 H NMR (400 MHz, CDCl3): δ 5.81 (ddd, J = 9.5, 4.4, 1.6 Hz, 1H), 5.73 (ddd, J = 9.5, 6.2, 1.2 Hz, 1H), 4.55 (t, J = 4.8 Hz, 1H), 3.99 (td, J = 4.0, 0.8 Hz, 1H), 3.92 (h, J = 6.1 Hz, 1H), 3.65 (d, J = 7.1 Hz, 1H), 2.74 – 2.64 (m, 3H), 2.42 (dd, J = 16.0, 5.9 Hz, 1H), 2.16 (s, 3H), 1.76 (ddd, J = 14.9, 7.0, 1.4 Hz, 1H), 1.67 (ddt, J = 14.8, 7.7, 1.3 Hz, 1H), 1.11 (d, J = 6.1 Hz, 3H), 1.05 (s, 9H), 0.96 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 207.2, 129.5, 129.4, 76.9, 73.8, 71.1, 70.2, 51.0, 46.7, 38.5, 32.7, 31.2, 28.7, 28.2, 21.2, 20.7, 20.0. FTIR (NaCl, thin film): 3012, 2970, 2934, 2888, 2859, 1719, 1476, 1388, 1364, 1327, 1176, 1087, 1046, 1018, 999, 826 cm-1. HRMS: (FAB) calc’d for C21H37O4Si [M + H]+ 381.2461, found 381.2465. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 216 [!]!" ! = +67° (c = 1.6, CHCl3). Preparation of alcohol 247: Me Me HO O O KHMDS THF, –78 °C 246 O Si O t-Bu t-Bu (89% yield) O Si O t-Bu t-Bu 247 A 500-mL, round-bottomed flask was charged with ketone 246 (8.5 g, 22 mmol, 1.0 equiv) and THF (225 mL), and cooled to –78 °C. KHMDS (58 mL, 0.5 M in toluene, 29 mmol, 1.3 equiv) was added, and the resulting solution was warmed to 0 °C and stirred for 2.5 h. The reaction was then quenched with sat. NH4Cl (100 mL) and H2O (100 mL) and extracted with CH2Cl2 (3 x 300 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (20% EtOAc in hexanes) to provide alcohol 247 (5.9 g, 20 mmol, 90% yield) as a white solid. 1 H NMR (400 MHz, CDCl3):
5.82 (ddd, J = 9.4, 4.3, 1.6 Hz, 1H), 5.77 (ddd, J = 9.5, 6.1, 1.2 Hz, 1H), 4.78 (dd, J = 5.5, 4.1 Hz, 1H), 4.06 (dd, J = 6.6, 1.6 Hz, 1H), 4.01 (t, J = 3.9 Hz, 1H), 2.81 – 2.72 (m, 1H), 2.63 (ddd, J = 6.0, 4.3, 1.2 Hz, 1H), 1.81 (dd, J = 14.8, 6.8 Hz, 1H), 1.71 (ddt, J = 15.0, 7.9, 1.2 Hz, 1H), 1.07 (s, 9H), 0.98 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 129.6, 129.0, 73.6, 71.8, 71.0, 50.4, 38.7, 34.1, 28.7, 28.2, 21.2, 20.7. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 217 FTIR (NaCl, thin film): 3401, 3033, 2968, 2935, 2896, 2860, 1476, 1442, 1388, 1364, 1321, 1280, 1224, 1175, 1032, 998, 920, 825 cm-1. HRMS: (FAB) calc’d for C16H27O3Si [M + H – H2]+ 295.1747, found 295.1730. [!]!" ! = +89° (c = 1.3, CHCl3). Preparation of ketone 248: O HO DMP, NaHCO 3 O Si O t-Bu t-Bu 247 CH2Cl2, rt (91% yield) O Si O t-Bu t-Bu 248 A 500-mL, round-bottomed flask was charged with alcohol 247 (6.0 g, 20 mmol, 1.0 equiv), NaHCO3 (5.1 g, 60 mmol, 3.0 equiv), and CH2Cl2 (200 mL). Dess–Martin periodinane (10.3 g, 24.3 mmol, 1.2 equiv) was added, and the reaction was stirred for 4 h, after which the reaction was filtered through a plug of silica (eluting with 67% EtOAc in hexanes). The filtrate was concentrated in vacuo, and then diluted in CH2Cl2 (100 mL), washed with sat. NaHCO3 (2 x 100 mL), dried over Na2SO4, filtered, and concentrated in vacuo to provide ketone 248 (5.40 g, 18.3 mmol, 91% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 6.08 (ddd, J = 9.3, 4.6, 1.6 Hz, 1H), 5.76 (ddd, J = 9.2, 6.9, 1.4 Hz, 1H), 4.59 (ddt, J = 5.6, 4.1, 1.1 Hz, 1H), 4.27 (ddd, J = 4.5, 3.4, 0.9 Hz, 1H), 3.14 (dddd, J = 6.8, 4.2, 1.4, 0.7 Hz, 1H), 3.02 (dddq, J = 6.8, 5.0, 3.3, 1.6 Hz, 1H), 2.37 – 2.31 (m, 1H), 2.28 (dd, J = 19.4, 6.4 Hz, 1H), 1.09 (s, 9H), 0.99 (s, 9H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 218 C NMR (101 MHz, CDCl3): δ 206.7, 131.3, 124.8, 71.7, 69.8, 55.1, 38.5, 37.6, 28.6, 28.2, 21.1, 20.8. FTIR (NaCl, thin film): 3036, 2968, 2935, 2859, 1743, 1629, 1476, 1404, 1387, 1365, 1298, 1221, 1187, 1145, 1115, 997, 790 cm-1. HRMS: (FAB) calc’d for C16H27O3Si [M + H]+ 295.1730, found 295.1731. [!]!" ! = +510° (c = 1.1, CHCl3). Preparation of vinyl triflate 249: TfO O KHMDS PhNTf 2 THF, –78 °C O Si O t-Bu t-Bu 248 (95% yield) O Si O t-Bu t-Bu 249 A 250-mL, round-bottomed flask was charged with ketone 248 (3.00 g, 10.2 mmol, 1.0 equiv), which was subsequently dissolved in THF (60 mL) and cooled to –78 °C. KHMDS (22.4 mL, 0.5 M in toluene, 11.2 mmol, 1.1 equiv) was added, and the reaction was stirred for 15 minutes. In a separate flask, a solution of PhNTf2 (4.00 g, 11.2 mmol, 1.1 equiv) in THF (40 mL) was prepared and cannulated into the first reaction flask. The resulting mixture was stirred for an additional hour, and then quenched with sat. NH4Cl (50 mL) and H2O (50 mL). This mixture was extracted with CH2Cl2 (3 x 100 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (9% EtOAc in hexanes) afforded vinyl triflate 249 (4.13 g, 9.68 mmol, 95% yield) as a white solid. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 219 H NMR (400 MHz, CDCl3): δ 6.21 (ddd, J = 9.6, 6.0, 1.1 Hz, 1H), 5.84 (dddd, J = 9.6, 4.5, 2.0, 0.8 Hz, 1H), 5.49 (dd, J = 4.1, 0.8 Hz, 1H), 4.69 (tt, J = 4.8, 1.0 Hz, 1H), 4.28 (ddd, J = 4.0, 2.9, 0.8 Hz, 1H), 3.13 (ddddd, J = 4.8, 3.9, 2.8, 1.9, 0.9 Hz, 1H), 2.91 (ddq, J = 5.6, 4.7, 0.9 Hz, 1H), 1.08 (s, 9H), 1.01 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 163.3, 131.7, 130.8, 113.2, 75.7, 65.0, 45.2, 44.2, 28.8, 28.2, 21.1, 20.7. FTIR (NaCl, thin film): 3042, 2976, 2938, 2906, 2852, 1640, 1478, 1429, 1380, 1365, 1258, 1249, 1214, 1141, 1123, 1074, 1001, 926, 901 cm-1. HRMS: (FAB) calc’d for C17H26F3SSiO5 [M + H]+ 427.1222, found 427.1205. [!]!" ! = +20° (c = 1.2, CHCl3). Preparation of vinyl iodide 251 from ketone 248: I O NH 2NH 2, Et 3N EtOH, 55 °C O Si O t-Bu t-Bu then t-BuNC(NMe2)2 I 2, THF, then 90 °C (39% yield) 248 O Si O t-Bu t-Bu 251 To a 1-dram vial containing ketone 248 (10.0 mg, 34.0 µmol, 1.0 equiv) was added hydrazine hydrate (16 µL, 0.340 mmol, 10 equiv), Et3N (47 µL, 0.340 mmol, 10 equiv), and absolute ethanol (0.34 mL). The reaction was heated to 55 °C for 90 minutes, then concentrated in vacuo, azeotroping with benzene (3 x 1 mL). The crude hydrazone was dissolved in THF (0.4 mL) and used in the next step In separate vial, 2-tert-butyl-1,1,3,3-tetramethylguanidine (47 µL, 0.238 mmol, 7.0 equiv) was added to a solution of I2 (18.1 mg, 71.3 µmol, 2.1 equiv) in THF (0.4 mL). To this solution was added the prepared hydrazone solution in a dropwise fashion, and 220 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine the reaction turns from brown to colorless. After stirring for 20 minutes, the solution was concentrated in vacuo, and the resulting crude residue was heated to 90 °C for 5 h. After cooling to room temperature, purification by silica gel chromatography (25 to 30% CH2Cl2 in hexanes) afforded vinyl iodide 251 (5.3 mg, 13 µmol, 39% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 6.23 (ddd, J = 9.6, 6.0, 1.1 Hz, 1H), 6.21 (d, J = 3.9 Hz, 1H), 4.63 (tt, J = 4.7, 1.0 Hz, 1H), 4.21 (ddd, J = 4.4, 3.0, 0.8 Hz, 1H), 2.98 (ddddd, J = 4.8, 3.7, 2.8, 1.9, 0.7 Hz, 1H), 2.87 (ddq, J = 5.9, 4.5, 0.7 Hz, 1H), 1.07 (s, 9H), 1.00 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 137.3, 133.0, 130.2, 106.7, 76.8, 65.2, 54.5, 48.5, 28.8, 28.2, 21.2, 20.7. FTIR (NaCl, thin film): 3043, 2971, 2931, 2888, 2856, 1578, 1476, 1382, 1364, 1314, 1286, 1248, 1200, 1119, 1082, 1001, 809 cm-1. HRMS: (FAB) calc’d for C16H26IO2Si [M + H]+ 405.0747, found 405.0747. [!]!" ! = +21° (c = 0.96, CHCl3). Preparation of vinyl iodide 251 from vinyl triflate 249: Me 3Sn TfO Me 6Sn2, LiCl Pd(PPh 3)4 THF, 70 °C O Si O t-Bu t-Bu 249 I I2 O Si O t-Bu t-Bu 253 CH2Cl2 (80% yield, 2 steps) O Si O t-Bu t-Bu 251 In an N2-filled glovebox, LiCl (635 mg, 15.0 mmol, 3.0 equiv) and Pd(PPh3)4 (230 mg, 0.200 mmol, 0.04 equiv) were a 250-mL Schlenk tube containing vinyl triflate Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 221 249 (2.13 g, 4.99 mmol, 1.0 equiv). The contents were dissolved in THF (25 mL), and then Me6Sn2 (1.04 mL, 4.99 mmol, 1.0 equiv) was added. The walls of the tube were rinsed with THF (25 mL), and then the tube was sealed and brought out of the glovebox. The reaction was heated to 70 °C with vigorous stirring for 15 h, then cooled to room temperature, diluted with hexanes (ca. 100 mL), and quenched with H2O (50 mL). The solution was extracted with hexanes (3 x 100 mL), and then the combined organic extracts were washed with H2O (50 mL), 10% NH4OH (50 mL), and H2O (50 mL) again. After drying over Na2SO4 and filtration, the filtrate was concentrated in vacuo to afford crude vinyl stannane 253. A small sample was purified by silica gel chromatography (1% EtOAc in hexanes) to afford an analytically pure sample: 1 H NMR (300 MHz, CDCl3): δ 6.07 (ddd, J = 9.5, 6.1, 1.1 Hz, 1H), 5.97 (d, J = 3.5 Hz, 1H), 5.59 (ddd, J = 9.5, 4.5, 1.9 Hz, 1H), 4.47 (t, J = 4.7 Hz, 1H), 4.23 (ddd, J = 4.3, 3.0, 0.6 Hz, 1H), 3.04 – 2.93 (m, 1H), 2.89 (dd, J = 6.2, 4.3 Hz, 1H), 1.08 (s, 9H), 1.01 (s, 9H), 0.14 (s, 9H). The crude vinyl stannane 253 was dissolved in CH2Cl2 (20 mL) and cooled to –20 °C. To this solution was cannulated a solution of I2 (1.25 g, 4.92 mmol, 1.05 equiv) in CH2Cl2 (30 mL). After stirring for 1 h, the reaction was quenched with sat. Na2S2O3 (50 mL), and diluted with H2O (25 mL) and CH2Cl2 (25 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 100 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification of the Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 222 crude residue by silica gel chromatography (25 to 30% CH2Cl2 in hexanes) provided vinyl iodide 251 (1.522 g, 3.76 mmol, 80% yield) as a white solid. Preparation of epoxy alcohol 262: I MeO 2C MeO 2C H 185 O O t-BuLi THF, –78 °C + O Si O t-Bu t-Bu 251 MeO 2C MeO 2C H O OH then 185 THF, –94 °C (72% yield) 262 O Si O t-Bu t-Bu In a 250-mL, round-bottomed flask, vinyl iodide 251 (1.62 g, 4.01 mmol, 1.0 equiv) was dissolved in THF (40 mL) and cooled to –78 °C. To this solution was added t-BuLi (4.7 mL, 1.7 M in pentane, 8.01 mmol, 2.0 equiv) slowly down the side of the flask over 5 minutes, and the resulting mixture was stirred for an additional 15 minutes at –78 °C. This solution was then cannulated over 10 minutes into a pre-cooled solution of epoxyketone 185 (1.40 g, 5.21 mmol, 1.3 equiv) in THF (40 mL) at –94 °C (acetone/liquid N2 bath). The reaction was stirred for an additional 2 h while allowing the acetone/liquid N2 bath to expire, and then quenched with sat. NaHCO3 (100 mL). This was extracted with CH2Cl2 (3 x 100 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (10 to 12% acetone in hexanes) to afford epoxy alcohol 262 (1.58 g, 2.89 mmol, 72% yield) as a white solid. A small sample was recrystallized in hexanes/diethyl ether to obtain crystals suitable for X-ray crystallography. 223 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 H NMR (400 MHz, CDCl3): δ 6.10 (ddd, J = 9.6, 6.1, 1.1 Hz, 1H), 5.70 (ddd, J = 9.4, 4.3, 1.6 Hz, 1H), 5.65 (d, J = 3.8 Hz, 1H), 4.48 (t, J = 4.7 Hz, 1H), 4.25 (ddd, J = 4.0, 3.0, 0.8 Hz, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.32 (d, J = 3.6 Hz, 1H), 3.05 – 3.01 (m, 1H), 2.83 (ddd, J = 6.1, 4.4, 0.8 Hz, 1H), 2.71 (dd, J = 10.7, 7.5 Hz, 1H), 2.53 – 2.42 (m, 1H), 2.47 (s, 1H), 2.42 – 2.29 (m, 2H), 2.10 – 1.98 (m, 2H), 1.97 – 1.86 (m, 2H), 1.61 – 1.47 (m, 1H), 1.08 (s, 9H), 1.02 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 171.7, 170.2, 161.6, 134.5, 129.2, 123.4, 77.7, 75.3, 71.2, 66.1, 56.5, 55.0, 52.9, 52.2, 45.6, 45.2, 44.4, 37.3, 29.3, 28.9, 28.3, 23.3, 21.6, 21.2, 20.7. FTIR (NaCl, thin film): 3496, 3032, 2950, 2860, 1732, 1476, 1458, 1434, 1383, 1364, 1306, 1244, 1176, 1108, 991 cm-1. HRMS: (PPM) calc’d for C29H43O8Si [M + H]+ 547.2722, found 547.2713. [!]!" ! = –5.1° (c = 0.30, CHCl3). Preparation of silyl ether 263: MeO 2C MeO 2C H O OH TMSOTf, Et 3N MeO 2C MeO 2C H O OTMS CH2Cl2, –10 °C 262 O Si O t-Bu t-Bu (97% yield) 263 O Si O t-Bu t-Bu In a 100-mL, round-bottomed flask, epoxy alcohol 262 (1.06 g, 1.94 mmol, 1.0 equiv) was dissolved in CH2Cl2 (20 mL) and cooled to –10 °C. Et3N (0.81 mL, 5.82 mmol, 3.0 equiv) was added, followed by TMSOTf (0.42 mL, 2.33 mmol, 1.2 equiv). The reaction was stirred for 15 minutes, then quenched by addition of sat. NaHCO3 (20 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 224 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (10 to 12% EtOAc in hexanes) to afford silyl ether 263 (1.17 g, 1.89 mmol, 97% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 6.03 (ddd, J = 9.6, 6.1, 1.1 Hz, 1H), 5.68 (dddd, J = 9.7, 4.5, 1.9, 0.7 Hz, 1H), 5.57 (d, J = 3.7 Hz, 1H), 4.48 (t, J = 4.7 Hz, 1H), 4.26 (ddd, J = 4.1, 3.0, 0.7 Hz, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.30 (d, J = 3.5 Hz, 1H), 3.08 – 3.03 (m, 1H), 2.90 (ddd, J = 6.3, 4.3, 0.9 Hz, 1H), 2.74 (dd, J = 9.8, 8.8 Hz, 1H), 2.61 (dddd, J = 12.9, 11.0, 8.9, 3.9 Hz, 1H), 2.43 – 2.25 (m, 2H), 2.12 (ddd, J = 12.7, 8.7, 3.9 Hz, 1H), 2.08 – 2.01 (m, 1H), 1.96 (ddd, J = 15.1, 8.2, 3.7 Hz, 1H), 1.89 – 1.77 (m, 1H), 1.45 (ddd, J = 13.3, 10.1, 8.4 Hz, 1H), 1.09 (s, 9H), 1.02 (s, 9H), 0.05 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 172.0, 170.4, 163.2, 135.1, 129.0, 122.5, 77.7, 77.6, 70.1, 66.1, 55.0, 54.0, 52.8, 52.1, 45.8, 44.9, 41.4, 34.5, 29.7, 28.9, 28.3, 22.2, 21.6, 21.2, 20.7, 2.2. FTIR (NaCl, thin film): 3028, 2952, 2904, 2860, 1732, 1477, 1462, 1434, 1364, 1250, 1175, 1110, 1058, 992, 881, 842 cm-1. HRMS: (PPM) calc’d for C32H51O8Si2 [M + H]+ 619.3117, found 619.3106. [!]!" ! = +36° (c = 0.35, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 225 Preparation of ketone 264: MeO 2C MeO 2C H O OTMS TMSNTf2 2,6-t-Bu2-4-MePy OTMS CO2Me O MeO 2C CH2Cl2, –70 °C 263 O Si O t-Bu t-Bu (97% yield) O Si O t-Bu t-Bu 264 A 100-mL, round-bottomed flask was charged with silyl ether 263 (1.168 g, 1.89 mmol, 1.0 equiv) and CH2Cl2 (40 mL), and the solution was cooled to –70 °C in a dry ice/acetone bath. In an N2-filled glovebox, a 100-mL microsyringe was filled with TMSNTf2 (67 mg, 0.189 mmol, 0.10 equiv), plugged with a rubber stopper, and removed from the glovebox. The TMSNTf2 was immediately added in one portion to the reaction mixture. After stirring for an additional 15 minutes at –70 °C, the reaction was quenched with sat. NaHCO3 (30 mL), and the layers were separated. The aqueous phase was extracted with CH2Cl2 (3 x 30 mL), and the organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The resulting crude residue was purified by silica gel chromatography (10% EtOAc in hexanes) to afford ketone 264 (1.13 g, 1.83 mmol, 97% yield) as a white solid. Note: If the starting material is not rigorously dry, the reaction may not reach full conversion. It is possible that trace amounts of water can quench TMSNTf2 and result in early termination. In this case, the crude product can simply be resubjected to the reaction conditions. In order to ensure the starting material is sufficiently free of water, it can be azeotroped with toluene or benzene (1–3x) prior to the reaction. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 226 H NMR (500 MHz, CDCl3): δ 5.88 (ddd, J = 9.5, 6.1, 1.1 Hz, 1H), 5.65 (ddd, J = 9.5, 4.3, 1.9 Hz, 1H), 5.40 (d, J = 3.8 Hz, 1H), 4.66 (t, J = 4.7 Hz, 1H), 4.31 (br s, 1H), 4.23 (appar t, J = 3.0 Hz, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.40 (dd, J = 11.7, 7.3 Hz, 1H), 3.03 – 2.94 (m, 2H), 2.48 (td, J = 14.1, 3.4 Hz, 1H), 2.38 – 2.26 (m, 1H), 2.17 – 2.05 (m, 3H), 1.80 – 1.71 (m, 1H), 1.65 – 1.60 (m, 1H), 1.52 (tdd, J = 14.3, 2.9, 1.9 Hz, 1H), 1.08 (s, 9H), 1.00 (s, 9H), 0.05 (s, 9H). 13 C NMR (126 MHz, CDCl3): δ 215.9, 170.7, 170.6, 158.9, 134.8, 128.2, 124.4, 76.7, 69.9, 66.2, 58.0, 56.2, 52.8, 52.6, 46.2, 46.1, 41.8, 38.8, 28.9, 28.3, 27.4, 23.7, 21.2, 20.7, 19.3, 0.0. FTIR (NaCl, thin film): 3032, 2952, 2896, 2859, 1741, 1477, 1462, 1443, 1384, 1363, 1252, 1170, 1097, 991, 840 cm-1. HRMS: (PMM) calc’d for C32H51O8Si2 [M + H]+ 619.3117, found 619.3105. [!]!" ! = +92° (c = 0.73, CHCl3). Preparation of α-bromoketone 268: OTMS CO2Me O MeO 2C OTMS CO2Me O MeO 2C LHMDS, NBS Br THF, –78 °C O Si O t-Bu t-Bu 264 (82% yield) O Si O t-Bu t-Bu 268 A 5-mL, round-bottomed flask was charged with ketone 264 (31.6 mg, 51.1 µmol, 1.0 equiv) and THF (0.8 mL), and cooled to –78 °C. LiHMDS (61.0 µL, 61.0 µmol, 1.2 equiv) was added, and the reaction was stirred for 25 minutes, after which a solution of NBS (11.8 mg, 66.4 µmol, 1.3 equiv) in THF (0.5 mL) was prepared and added. The Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 227 reaction was stirred at –78 °C for an additional 40 minutes, and then quenched by addition of sat. Na2S2O3 (2 mL) and H2O (2 mL). The resulting mixture was extracted with CH2Cl2 (3 x 1 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (9% EtOAc in hexanes) to afford a-bromoketone 268 (29.3 mg, 42.0 µmol, 82% yield) as a white solid. 1 H NMR (400 MHz, CDCl3):
6.09 (ddd, J = 9.6, 6.1, 1.1 Hz, 1H), 5.68 (ddd, J = 9.5, 4.3, 1.8 Hz, 1H), 5.41 (d, J = 3.8 Hz, 1H), 4.71 (ddt, J = 5.3, 4.4, 1.0 Hz, 1H), 4.34 (br s, 1H), 4.25 – 4.21 (m, 2H), 3.80 (dd, J = 13.5, 6.3 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 3.13 (dd, J = 6.1, 4.4 Hz, 1H), 3.05 – 2.96 (m, 1H), 2.77 (ddd, J = 14.1, 13.0, 6.6 Hz, 1H), 2.41 (td, J = 14.0, 3.6 Hz, 1H), 2.15 (d, J = 14.8 Hz, 1H), 1.93 (dd, J = 14.1, 6.7 Hz, 1H), 1.69 – 1.48 (m, 2H), 1.08 (s, 9H), 1.00 (s, 9H), 0.03 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 208.1, 170.3, 170.2, 158.2, 135.5, 128.0, 125.5, 76.6, 70.1, 65.8, 58.0, 55.6, 53.0, 52.9, 47.0, 46.4, 46.2, 39.1, 35.0, 28.9, 28.3, 27.0, 21.3, 20.7, 19.4, -0.0. FTIR (NaCl, thin film): 2952, 2941, 2896, 2859, 1755, 1741, 1476, 1460, 1434, 1254, 1230, 1175, 1104, 1054, 994, 894 cm-1. HRMS: (ESI) calc’d for C29H41BrO7Si [M – OSiMe3]+ 607.1721, found 607.1731. [!]!" ! = +127° (c = 0.45, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 228 Preparation of diol 272: OTMS CO2Me O MeO 2C OTMS CO2Me O MeO 2C HF•Py MeCN O Si O t-Bu (98% yield) t-Bu 264 OH OH 272 A 125-mL Teflon Erlenmeyer flask was charged with silylene 264 (714 mg, 1.15 mmol, 1.0 equiv) and MeCN (55 mL) and cooled to 0 °C with an ice bath. A solution of HF•Py (pyridine ~30%, HF ~70%, 570 mg) in MeCN (3 mL) was added, and the ice bath was removed to allow the reaction to reach ambient temperature. After stirring for 1.5 h, the solution was filtered through a plug of silica (eluting with EtOAc) and concentrated in vacuo to provide pure diol 272 (540 mg, 1.13 mmol, 98% yield) as a white solid. 1 H NMR (400 MHz, CDCl3): δ 5.83 – 5.75 (m, 2H), 5.47 (d, J = 3.6 Hz, 1H), 4.61 (q, J = 5.2 Hz, 1H), 4.28 (br s, 1H), 3.94 (appar d, J = 8.0 Hz, 1H), 3.74 (s, 3H), 3.67 (s, 3H), 3.38 (dd, J = 12.1, 7.3 Hz, 1H), 2.91 (t, J = 4.5 Hz, 1H), 2.88 – 2.70 (m, 2H), 2.69 – 2.65 (m, 1H), 2.48 (td, J = 14.3, 3.6 Hz, 1H), 2.36 – 2.24 (m, 1H), 2.19 – 2.02 (m, 3H), 1.80 – 1.56 (m, 2H), 1.48 (tdd, J = 14.1, 2.8, 2.0 Hz, 1H), 0.03 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 215.9, 170.7, 170.6, 157.0, 130.9, 129.5, 124.8, 74.3, 69.7, 65.7, 57.8, 56.3, 52.9, 52.7, 47.5, 44.3, 41.8, 38.9, 27.4, 23.6, 19.3, -0.0. FTIR (NaCl, thin film): 3401, 3025, 2954, 1738, 1434, 1404, 1336, 1313, 1252, 1194, 1171, 1074, 1058, 1020, 980, 892, 862, 842 cm-1. HRMS: (PMM) calc’d for C24H33O7Si [M – OH]+ 461.1990, found 461.1980. [!]!" ! = +92° (c = 1.3, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 229 Preparation of enone 273: OTMS CO2Me O MeO 2C OTMS Cu(MeCN) 4OTf, ABNO, NMI, MeObpy CO2Me O MeO 2C MeCN (84–98% yield) OH OH O HO 272 273 To a 100 mL, round-bottomed flask was added diol 272 (540.0 mg, 1.13 mmol, 1.0 equiv), Cu(MeCN)4OTf (21.0 mg, 56.4 µmol, 0.05 equiv), 4,4’-dimethoxy-2,2’bipyridine (MeObpy, 12.2 mg, 56.4 µmol, 0.05 equiv), N-methylimidazole (9.0 µL, 0.113 mmol, 0.10 equiv), and MeCN (25 mL). Lastly, ABNO (7.9 mg, 56.4 µmol, 0.05 equiv) was added, and the clear brownish reaction mixture was stirred until slightly yellowgreen (ca. 80 min), at which point the solution was filtered through a short plug of silica and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (60 to 70% EtOAc in hexanes) afforded enone 273 (454.0 mg, 0.953 mmol, 84% yield) as a white solid. Note: On a 62 mg scale of diol 272, this same procedure provided enone 273 (60.9 mg) in 98% yield. On larger scale, over-oxidation to the 1,3-diketone occurs to a larger extent and provides diminished yields (lowest of 84% on 540 mg scale). 1 H NMR (400 MHz, CDCl3): δ 6.87 (ddd, J = 9.7, 6.4, 1.6 Hz, 1H), 5.89 (ddd, J = 9.7, 2.0, 1.2 Hz, 1H), 5.62 (d, J = 3.9 Hz, 1H), 5.06 – 4.96 (m, 1H), 4.23 (br s, 1H), 3.75 (s, 3H), 3.66 (s, 3H), 3.41 (dd, J = 12.2, 7.3 Hz, 1H), 3.27 (t, J = 5.5 Hz, 1H), 3.26 – 3.18 (br Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 230 m, 1H), 2.62 – 2.41 (m, 2H), 2.38 – 2.25 (m, 1H), 2.23 – 2.07 (m, 3H), 1.82 – 1.59 (m, 2H), 1.48 (tdd, J = 14.3, 3.5, 1.9 Hz, 1H), 0.02 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 215.7, 195.3, 170.8, 170.4, 156.0, 148.7, 127.5, 124.5, 84.3, 69.6, 61.4, 57.9, 56.2, 53.0, 52.8, 47.1, 41.7, 38.8, 27.5, 23.5, 19.3, -0.1. FTIR (NaCl, thin film): 3467, 3009, 3955, 1738, 1674, 1435, 1376, 1314, 1253, 1230, 1172, 1076, 1060, 1021, 981, 843 cm-1. HRMS: (PMM) calc’d for C24H33O8Si [M + H]+ 477.1939, found 477.1952. [!]!" ! = +281° (c = 1.1, CHCl3). Preparation of MOM-ether 274: OTMS CO2Me O MeO 2C MOMCl, n-Bu4NI i-Pr2NEt OTMS CO2Me O MeO 2C DMF, 55 °C O HO 273 (84% yield) O MOMO 274 A 50-mL, round-bottomed flask was charged with alcohol 273 (454 mg, 0.953 mmol, 1.0 equiv), n-Bu4NI (70.0 mg, 0.191 mmol, 0.20 equiv), i-Pr2NEt (1.0 mL, 5.72 mmol, 6.0 equiv), and DMF (10 mL), followed lastly by MOMCl (0.36 mL, 4.76 mmol, 5.0 equiv). The reaction mixture was heated to 55 °C with stirring for 15 h, then cooled to room temperature and diluted with H2O (10 mL) and Et2O (10 mL). The layers thoroughly mixed, separated, and then the aqueous phase was extracted with Et2O (2 x 10 mL). The combined organic extracts were washed with water (3 x 10 mL) and brine (10 mL), dried over MgSO4, filtered, and concentrated in vacuo. Purification of the crude residue by silica gel chromatography (30 to 33% EtOAc in hexanes) afforded methoxymethyl ether 274 (417.5 mg, 0.802 mmol, 84% yield) as a white solid. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 231 H NMR (400 MHz, CDCl3): δ 6.82 (ddd, J = 9.8, 6.3, 1.6 Hz, 1H), 5.82 (d, J = 10.1 Hz, 1H), 5.64 (d, J = 3.8 Hz, 1H), 4.75 (td, J = 4.6, 1.6 Hz, 1H), 4.71 (s, 2H), 4.25 (br s, 1H), 3.75 (s, 3H), 3.67 (s, 3H), 3.43 (dd, J = 12.3, 7.3 Hz, 1H), 3.38 – 3.27 (m, 2H), 3.32 (s, 3H), 2.52 (td, J = 14.2, 3.3 Hz, 1H), 2.39 – 2.26 (m, 1H), 2.23 – 2.08 (m, 3H), 1.81 – 1.59 (m, 2H), 1.48 (tdd, J = 14.3, 3.3, 1.9 Hz, 1H), 0.03 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 215.5, 195.7, 170.7, 170.4, 155.9, 148.5, 126.7, 124.4, 96.6, 90.5, 69.7, 60.2, 57.8, 56.2, 56.1, 52.9, 52.8, 45.7, 41.7, 38.8, 27.5, 23.5, 19.3, -0.1. FTIR (NaCl, thin film): 3009, 2954, 1738, 1681, 1462, 1435, 1253, 1230, 1172, 1059, 1040, 981 cm-1. HRMS: (PMM) calc’d for C26H37O9Si [M + H]+ 521.2201, found 521.2207. [!]!" ! = +258° (c = 1.3, CHCl3). Preparation of pentacycle 275: OTMS CO2Me O MeO 2C OTMS CO2Me O MeO 2C KOt-Bu THF, –78 °C O MOMO 274 (quantitative) O MOMO 275 A 50-mL, round-bottomed flask was charged with enone 274 (417.5 mg, 0.802 mmol, 1.0 equiv), followed by THF (8 mL), and this solution was cooled to –78 °C. KOt-Bu (1.04 mL, 1.0 M in THF, 1.04 mmol, 1.3 equiv) was added to the reaction, which was allowed to stir for 70 minutes. The reaction was quenched by addition of sat. NaHCO3 (20 mL) and extracted with CH2Cl2 (3 x 20 mL). The combined organic Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 232 extracts were dried over Na2SO4, filtered, and concentrated in vacuo to provide pentacycle 275 (417.3 mg, 0.801 mmol, quantitative yield) as a white solid. This was used in following reactions without further purification. Note: Purification of Michael addition product 275 led to slightly diminished yields. Crude material was deemed pure by NMR and used in following reactions without further purification for practical purposes. 1 H NMR (400 MHz, CDCl3): δ 5.54 (d, J = 2.6 Hz, 1H), 4.68 (s, 2H), 4.59 (t, J = 5.5 Hz, 1H), 4.31 (dd, J = 6.5, 3.8 Hz, 1H), 3.76 (s, 3H), 3.65 (s, 3H), 3.36 (s, 3H), 3.32 (dd, J = 5.0, 2.6 Hz, 1H), 3.06 (t, J = 5.5 Hz, 1H), 2.91 (dd, J = 10.2, 5.5 Hz, 1H), 2.61 (dd, J = 19.4, 8.7 Hz, 1H), 2.51 – 2.44 (m, 1H), 2.36 – 2.23 (m, 4H), 2.20 (ddd, J = 13.3, 7.5, 5.6 Hz, 1H), 1.88 – 1.79 (m, 1H), 1.72 – 1.54 (m, 2H), 0.10 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 203.7, 202.7, 173.0, 170.5, 146.8, 122.6, 96.3, 78.6, 66.4, 60.5, 59.0, 56.6, 56.1, 53.1, 51.9, 51.2, 42.4, 41.4, 37.9, 36.0, 27.1, 26.1, 25.1, 0.3. FTIR (NaCl, thin film): 3017, 2954, 2904, 2828, 1747, 1732, 1714, 1589, 1461, 1434, 1406, 1361, 1251, 1215, 1152, 1111, 1043, 866 cm-1. HRMS: (PMM) calc’d for C26H37O9Si [M + H]+ 521.2201, found 521.2186. [!]!" ! = +168° (c = 1.2, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 233 Preparation of lactone 278: MeO 2C OTMS CO2Me O O MeO 2C TFA O O CH2Cl2 O MOMO 275 MOMO O 278 In a 50-mL, round-bottomed flask, diester 275 (417.3 mg, 0.802 mmol, 1.0 equiv) was dissolved in wet CH2Cl2 (8.0 mL). To this solution was added TFA (0.31 mL, 4.05 mmol, 5.0 equiv). The reaction was stirred for 21 h, and then quenched with sat. NaHCO3 (20 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 20 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo to afford crude lactone 278 (<350 mg) as a white foam. This crude material was deemed pure by NMR and used in the next step without further purification. 1 H NMR (400 MHz, CDCl3):
5.35 (d, J = 2.6 Hz, 1H), 5.20 (dd, J = 4.7, 0.8 Hz, 1H), 4.71 (d, J = 6.9 Hz, 1H), 4.69 (d, J = 6.9 Hz, 1H), 4.63 (t, J = 5.5 Hz, 1H), 3.82 (s, 3H), 3.38 (dd, J = 4.9, 2.6 Hz, 1H), 3.36 (s, 3H), 3.11 (t, J = 5.7 Hz, 1H), 2.99 (dd, J = 9.6, 7.2 Hz, 1H), 2.73 (dd, J = 19.3, 9.1 Hz, 1H), 2.64 (dtd, J = 9.0, 4.5, 1.8 Hz, 1H), 2.47 – 2.22 (m, 5H), 2.10 – 1.99 (m, 2H), 1.82 (dddd, J = 13.8, 11.3, 5.0, 1.0 Hz, 1H), 4.66 – 4.59 (m, 1H). 13 C NMR (101 MHz, CDCl3): δ 203.8, 200.6, 169.2, 169.1, 143.3, 121.9, 96.6, 78.3, 72.0, 62.2, 60.8, 56.2, 52.8, 52.8, 51.3, 43.7, 43.0, 38.8, 36.0, 28.5, 28.0, 21.2. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 234 FTIR (NaCl, thin film): 3009, 2954, 1749, 1711, 1444, 1367, 1298, 1264, 1220, 1153, 1108, 1068, 1047, 997 cm-1. HRMS: (ESI) calc’d for C22H24KO8 [M + K]+ 455.1103, found 455.1096. [!]!" ! = +183° (c = 0.67, CHCl3). Preparation of carbocycle 279: O MeO 2C O O H 2 (1 atm) Pd/C O MeO 2C H O O EtOH/EtOAc MOMO 278 O (96% yield, 3 steps) MOMO O 279 To a 50-mL, round-bottomed flask containing crude lactone 278 (<350 mg) under N2 was added Pd/C (10 wt%, 333 mg), followed by absolute EtOH (6 mL) and EtOAc (6 mL). The reaction vessel was purged with H2 for 5 minutes via a double-walled balloon, and stirred for another 22 h under H2 (1 atm). The H2 balloon was then removed, and the flask was purged with N2 for 15 minutes. The suspension was filtered through a plug of silica (eluting with EtOAc), and the resulting solution was concentrated in vacuo to provide carbocycle 279 (322.6 mg, 0.771 mmol, 96% yield over 3 steps from enone 274) as a white foam. 1 H NMR (400 MHz, CDCl3): δ 4.77 (dd, J = 4.5, 1.2 Hz, 1H), 4.63 (d, J = 6.9 Hz, 1H), 4.61 (d, J = 6.9 Hz, 1H), 4.19 (t, J = 4.6 Hz, 1H), 3.82 (s, 3H), 3.34 (s, 3H), 2.88 – 2.73 (m, 5H), 2.65 – 2.53 (m, 1H), 2.47 (dd, J = 14.9, 9.7 Hz, 1H), 2.39 (ddd, J = 13.5, 11.8, Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 235 4.8 Hz, 1H), 2.34 (d, J = 18.1 Hz, 1H), 2.23 – 2.09 (m, 2H), 2.05 – 1.86 (m, 3H), 1.80 (dddd, J = 14.1, 11.1, 4.2, 1.2 Hz, 1H), 1.46 (ddd, J = 14.8, 6.6, 0.9 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 213.9, 210.2, 169.3, 169.1, 96.3, 79.2, 74.1, 56.1, 55.9, 53.1, 52.8, 52.8, 51.5, 49.6, 45.3, 39.9, 39.0, 37.6, 28.2, 27.9, 24.2, 19.8. FTIR (NaCl, thin film): 2953, 2915, 2854, 1740, 1711, 1458, 1449, 1377, 1298, 1262, 1151, 1103, 1048, 992, 753 cm-1. HRMS: (ESI) calc’d for C22H28NO8 [M + NH4]+ 436.1966, found 436.1963. [!]!" ! = +32° (c = 1.0, CHCl3). Preparation of α-selenide 276: MeO 2C OTMS CO2Me O MeO 2C LiHMDS, PhSeCl OTMS CO2Me O THF, –78 °C O MOMO 275 (80% yield) SePh O MOMO 276 In a 1-dram vial, pentacycle 275 (15.0 mg, 28.8 µmol, 1.0 equiv) was dissolved in THF (0.3 mL) and cooled to – 78°C. LiHMDS (35 µL, 1.0 M in THF, 34.6 µmol, 1.2 equiv) was added, and the resulting solution was stirred for 15 minutes. In a separate 1dram vial, a solution of PhSeCl (7.2 mg, 37.5 µmol, 1.3 equiv) in THF (0.3 mL) was prepared, and added to the reaction mixture at –78 °C. After stirring for an additional 2 h, the reaction was quenched with sat. NaHCO3 (1 mL), extracted with CH2Cl2 (3 x 1 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 236 (30% EtOAc in hexanes) to afford α-selenide 276 (15.6 mg, 23.1 µmol, 80% yield) as a yellow foam. 1 H NMR (400 MHz, CDCl3): δ 7.74 – 7.67 (m, 2H), 7.30 – 7.25 (m, 3H), 5.59 (d, J = 2.6 Hz, 1H), 4.58 (s, 2H), 4.53 (t, J = 5.5 Hz, 1H), 4.29 (dd, J = 6.7, 4.1 Hz, 1H), 3.76 (s, 3H), 3.68 (d, J = 4.1 Hz, 1H), 3.64 (s, 3H), 3.50 (dd, J = 5.1, 2.6 Hz, 1H), 3.36 (s, 3H), 3.05 (t, J = 5.5 Hz, 1H), 2.92 (dd, J = 10.2, 5.5 Hz, 1H), 2.69 (q, J = 4.7 Hz, 1H), 2.43 (dd, J = 7.3, 4.7 Hz, 1H), 2.31 – 2.09 (m, 3H), 1.90 – 1.77 (m, 1H), 1.68 – 1.53 (m, 2H), 0.09 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 203.7, 201.6, 172.9, 170.4, 145.9, 135.2, 129.7, 129.0, 127.9, 122.9, 96.0, 78.5, 66.6, 60.8, 59.1, 56.6, 56.3, 53.1, 52.0, 50.1, 48.1, 46.7, 43.4, 41.4, 27.1, 26.0, 25.0, 0.3. FTIR (NaCl, thin film): 3051, 2953, 2896, 1740, 1730, 1579, 1436, 1360, 1250, 1216, 1108, 1039, 931, 869, 841, 753 cm-1. HRMS: (PMM) calc’d for C32H41O9SeSi [M + H]+ 677.1680, found 677.1696. [!]!" ! = +89° (c = 1.1, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 237 Preparation of β-hydroxyketone 277: MeO 2C OTMS CO2Me O SePh O MOMO MeO 2C n-Bu4NIO 4 OTMS CO2Me O CH2Cl2 (44% yield) 276 MOMO HO O 277 To a 1-dram vial containing α-selenide 276 (15.0 mg, 22.2 µmol, 1.0 equiv) was added n-Bu4NIO4 (38.0 mg, 0.0888 µmol, 4.0 equiv) and wet CH2Cl2 (0.44 mL). The reaction was sealed and stirred for 25 h, then diluted with CH2Cl2 (1 mL) and quenched with sat. NaHCO3 (0.5 mL) and sat. Na2S2O3 (1 mL). The layers were separated, and the aqueous phase was extracted with CH2Cl2 (3 x 1 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative thin-layer chromatography (50% acetone in hexanes) to afford 3°alcohol 277 (5.2 mg, 9.69 µmol, 44% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3): δ 5.62 (d, J = 2.7 Hz, 1H), 4.76 – 4.69 (m, 3H), 4.34 (dd, J = 7.0, 4.6 Hz, 1H), 3.77 (s, 3H), 3.67 (s, 3H), 3.52 (dd, J = 4.9, 2.7 Hz, 1H), 3.50 (br s, 1H), 3.38 (s, 3H), 3.07 – 2.95 (m, 3H), 2.67 (d, J = 20.0 Hz, 1H), 2.36 (d, J = 7.1 Hz, 1H), 2.32 – 2.13 (m, 3H), 2.03 (dt, J = 14.5, 6.4 Hz, 1H), 1.87 (dddd, J = 13.7, 8.6, 6.9, 1.8 Hz, 1H), 1.71 – 1.59 (m, 1H), 0.10 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 201.6, 200.9, 172.9, 170.4, 144.1, 125.4, 96.6, 79.8, 73.5, 66.5, 60.5, 58.0, 57.6, 56.7, 56.3, 53.2, 52.1, 49.0, 49.0, 41.4, 27.2, 24.9, 23.2, 0.3. FTIR (NaCl, thin film): 3524, 2954, 2919, 2854, 1734, 1458, 1434, 1362, 1251, 1211, 1110, 1040, 841, 754 cm-1. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 238 HRMS: (ESI) calc’d for C26H37O10Si [M + H]+ 537.2151, found 537.2167. [!]!" ! = +166° (c = 0.37, CHCl3). Preparation of α-selenide 280: O MeO 2C H O O O MeO 2C LiHMDS, PhSeCl O O THF, –78 °C MOMO 279 O (88% yield) SePh O MOMO 280 A 50-mL, round-bottomed flask was charged with diketone 279 (168 mg, 0.401 mmol, 1.0 equiv), which was dissolved in THF (4 mL) and cooled to –78 °C. In a separate flask, a solution of PhSeCl (123 mg, 0.642 mmol, 1.6 equiv) in THF (4 mL) was prepared. LiHMDS (0.60 mL, 1.0 M in THF, 0.60 mmol, 1.5 equiv) was added to the solution of diketone 279, and the resulting mixture was stirred for 30 minutes at –78 °C. The THF solution of PhSeCl was then added, and the mixture was stirred for another 2 hours. The reaction was quenched with sat NaHCO3 (10 mL), and extracted with CH2Cl2 (3 x 10 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (90% ethyl acetate in hexanes) to afford α-selenide 280 as a yellow foam (201.5 mg, 0.351 mmol, 88% yield). 1 H NMR (500 MHz, CDCl3): δ 7.72 – 7.68 (m, 2H), 7.31 – 7.27 (m, 3H), 4.75 (dd, J = 4.4, 1.0 Hz, 1H), 4.58 (d, J = 6.9 Hz, 1H), 4.56 (d, J = 6.9 Hz, 1H), 4.22 (t, J = 5.0 Hz, 1H), 3.81 (s, 1H), 3.76 (d, J = 4.5 Hz, 1H), 3.38 (s, 3H), 3.11 (dtd, J = 6.8, 4.4, 2.2 Hz, Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 239 1H), 3.05 (dd, J = 8.4, 5.4 Hz, 1H), 2.85 (q, J = 5.3 Hz, 1H), 2.72 (dd, J = 9.8, 7.3 Hz, 1H), 2.59 – 2.53 (m, 1H), 2.41 (dd, J = 15.1, 9.8 Hz, 1H), 2.40 – 2.33 (m, 1H), 2.21 (dd, J = 6.7, 4.1 Hz, 1H), 2.16 (ddt, J = 14.3, 11.8, 4.5 Hz, 1H), 2.02 – 1.91 (m, 3H), 1.78 (ddd, J = 14.7, 11.4, 4.1 Hz, 1H), 1.50 (dd, J = 15.2, 7.2 Hz, 1H). 13 C NMR (126 MHz, CDCl3): δ 214.0, 207.8, 169.2, 168.9, 134.9, 130.1, 129.1, 128.2, 96.0, 78.7, 73.9, 56.3, 56.2, 53.2, 53.0, 52.8, 51.6, 50.3, 49.2, 47.8, 45.4, 39.5, 28.3, 27.5, 24.4, 19.7. FTIR (NaCl, thin film): 3017, 2952, 2896, 2854, 1755, 1739, 1713, 1477, 1464, 1438, 1377, 1298, 1262, 1103, 1052, 989 cm-1. HRMS: (ESI) calc’d for C28H34NO8Se [M + NH4]+ 592.1444, found 592.1424. [!]!" ! = +13° (c = 0.60, CHCl3). Preparation of β-hydroxyketone 281: O MeO 2C NaIO 4 O SePh O MOMO 280 O MeO 2C O O O THF/H2O (51% yield) MOMO HO O 281 To a 1-dram vial was added α-selenide 280 (10.4 mg, 18.1 µmol, 1.0 equiv), NaIO4 (19.4 mg, 90.7 µmol, 5.0 equiv), THF (0.3 mL), and H2O (60 µL). The reaction was allowed to stir for 10 h, and then quenched by addition of sat. NaHCO3 (1 mL). The aqueous phase was extracted with EtOAc (3 x 1 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. Purification by silica gel Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 240 chromatography (40% acetone in hexanes) afforded β-hydroxyketone 281 (4.0 mg, 9.2 µmol, 51% yield) as a colorless oil. 1 H NMR (400 MHz, CDCl3):
4.78 (dd, J = 4.3, 0.9 Hz, 1H), 4.70 (d, J = 6.6 Hz, 1H), 4.65 (d, J = 6.6 Hz, 1H), 4.37 (t, J = 4.9 Hz, 1H), 3.83 (s, 3H), 3.39 – 3.35 (m, 1 H), 3.36 (s, 3H), 2.99 (d, J = 20.1 Hz, 1H), 2.92 (dd, J = 8.2, 5.0 Hz, 1H), 2.85 (dd, J = 15.1, 9.9 Hz, 1H), 2.75 (d, J = 5.6 Hz, 1H), 2.74 (d, J = 19.9 Hz, 1H), 2.66 (dd, J = 9.9, 7.4 Hz, 1H), 2.48 – 2.37 (m, 2H), 2.35 (d, J = 6.5 Hz, 1H), 2.24 – 2.15 (m, 1H), 2.02 – 1.84 (m, 3H), 1.79 (dddd, J = 14.3, 11.2, 4.3, 1.2 Hz, 1H), 1.41 (dd, J = 15.0, 6.8 Hz, 1H). 13 C NMR (101 MHz, CDCl3):
210.7, 207.7, 169.1, 168.9, 96.6, 79.7, 76.7, 73.8, 57.8, 56.5, 56.2, 53.0, 52.8, 52.2, 50.8, 47.6, 45.5, 43.9, 28.3, 24.3, 23.8, 20.1. FTIR (NaCl, thin film): 3468, 2960, 2915, 2851, 1745, 1717, 1464, 1445, 1379, 1298, 1272, 1104, 1051 cm-1. HRMS: (FAB) calc’d for C22H27O9 [M + H]+ 435.1655, found 435.1639. [!]!" ! = +16° (c = 0.21, CHCl3). Preparation of β-methoxyketone 282: O MeO 2C O3 MeOH, –78 °C O O SePh O MOMO 280 O MeO 2C O O then pyridine –78 °C to rt (88% yield) MOMO MeO O 282 A 25-mL, round-bottomed flask was charged with α-selenide 280 (90.6 mg, 0.158 mmol, 1.0 equiv), CH2Cl2 (4 mL), and methanol (4 mL). The flask was cooled to –78 °C, Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 241 at which time ozone (as a mixture with O2) was gently bubbled through the solution (O2 flow rate = 1/4 L/min, 2 setting on ozone generator) for 20 min. The solution was then sparged with Ar for 15 minutes, and pyridine (64 µL, 0.790 mmol, 5 equiv) was added. The reaction was allowed to warm to ambient temperature, and stirred for a further 48 h. The methanol solvent and pyridine were then removed by concentration in vacuo, and the crude residue was purified by silica gel chromatography (44% acetone in hexane) to afford β-methoxyketone 282 as a white solid (62.3 mg, 0.139 mmol, 88% yield) with a small amount of inseperable arene impurity (<10%). 1 H NMR (400 MHz, CDCl3): δ 4.78 (d, J = 6.9 Hz, 1H), 4.75 (d, J = 4.0 Hz, 1H), 4.56 (d, J = 6.9 Hz, 1H), 4.23 (t, J = 4.6 Hz, 1H), 3.81 (s, 3H), 3.32 (s, 3H), 3.11 (s, 3H), 2.98 (d, J = 17.9 Hz, 1H), 2.79 (dd, J = 7.4, 4.5 Hz, 1H), 2.72 (q, J = 6.0 Hz, 1H), 2.69 – 2.58 (m, 3H), 2.55 (d, J = 6.7 Hz, 1H), 2.45 (dt, J = 11.2, 6.5 Hz, 1H), 2.42 – 2.34 (m, 1H), 2.23 – 2.09 (m, 1H), 2.03 – 1.70 (m, 4H), 1.39 (ddd, J = 14.9, 6.1, 2.8 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 211.5, 208.3, 169.1, 169.1, 95.7, 81.0, 76.9, 74.1, 56.6, 55.8, 53.8, 53.0, 52.8, 52.6, 48.9, 45.8, 45.0, 44.6, 44.5, 28.0, 24.2, 24.2, 20.1. FTIR (NaCl, thin film): 2954, 2915, 2832, 1746, 1711, 1462, 1443, 1375, 1298, 1262, 1221, 1152, 1103, 1049, 916, 753 cm-1. HRMS: (FAB) calc’d for C23H29O9 [M + H]+ 449.1811, found 449.1801. [!]!" ! = –14° (c = 0.24, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 242 Preparation of alcohol 283: O MeO 2C O O NaBH 4 O MeO 2C OH O EtOH/THF, 0 °C MOMO MeO O (66% yield) MOMO 282 MeO O 283 A solution of 282 (17.0 mg, 37.9 µmol, 1.0 equiv) in absolute EtOH (0.28 mL) and THF (0.28 mL) was cooled to 0 °C in a 5-mL round-bottomed flask. NaBH4 (3.6 mg, 94.8 µmol, 2.5 equiv) was added, and three more equal portions of NaBH4 were added each successive hour. An hour after the fourth portion was added, the reaction was quenched with sat. NaHCO3 (2 mL) and extracted with CH2Cl2 (3 x 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (3% MeOH in CH2Cl2) to afford alcohol 283 as a clear oil (11.2 mg, 24.9 µmol, 66% yield). Note: Extended reaction time leads to over-reduction of the methyl ester. Remarkably, the methyl ester undergoes facile reduction, while the C16 ketone remains inert. 1 H NMR (400 MHz, CDCl3): δ 4.82 (d, J = 6.8 Hz, 1H), 4.73 (d, J = 4.2 Hz, 1H), 4.61 (d, J = 6.8 Hz, 1H), 4.20 (td, J = 4.9, 1.6 Hz, 1H), 4.16 (dd, J = 4.8, 3.9 Hz, 1H), 3.78 (s, 3H), 3.35 (s, 3H), 3.15 (s, 3H), 2.93 (d, J = 16.9 Hz, 1H), 2.77 (ddd, J = 7.3, 4.0, 1.3 Hz, 1H), 2.71 (d, J = 16.9 Hz, 1H), 2.64 – 2.60 (m, 1H), 2.45 (ddd, J = 6.4, 4.9, 1.3 Hz, 1H), 2.39 (t, J = 5.5 Hz, 1H), 2.35 – 2.23 (m, 3H), 2.22 – 2.10 (m, 2H), 2.06 (dd, J = 9.7, 7.5 Hz, 1H), 1.97 – 1.86 (m, 2H), 1.71 – 1.63 (m, 1H), 1.56 (ddd, J = 14.5, 7.5, 5.9 Hz, 1H). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 243 C NMR (101 MHz, CDCl3): δ 212.6, 171.2, 169.4, 95.8, 78.1, 76.0, 74.4, 72.0, 55.7, 53.5, 53.0, 52.6, 48.5, 48.4, 47.7, 47.5, 43.9, 43.3, 40.6, 28.6, 26.6, 25.4, 20.5. FTIR (NaCl, thin film): 3436, 2951, 2854, 2832, 1738, 1730, 1713, 1468, 1449, 1375, 1330, 1287, 1251, 1115, 1050 cm-1. HRMS: (ESI) calc’d for C22H25O8 [M – OMe]+ 419.1700, found 419.1709. [!]!" ! = –10° (c = 0.53, CHCl3). Preparation of amide 287: O MeO 2C O O OH O NHEt O MeO 2C EtNH 2 THF MOMO MeO O (69% yield) 282 MOMO MeO O 287 To a 1-dram vial containing lactone 282 (4.6 mg, 10.3 µmol, 1.0 equiv) was added ethylamine (0.30 mL, 2.0 M in THF, 0.60 mmol). The resulting solution was stirred for 72 h at room temperature, then concentrated in vacuo. The crude residue was purified by silica gel chromatography (50% acetone in hexanes) to afford amide 287 as a colorless oil (3.5 mg, 7.1 µmol, 69% yield). 1 H NMR (400 MHz, CDCl3): δ 6.66 (t, J = 5.5 Hz, 1H), 4.82 (d, J = 6.9 Hz, 1H), 4.56 (d, J = 6.9 Hz, 1H), 4.29 (t, J = 4.8 Hz, 1H), 4.12 (d, J = 9.6 Hz, 1H), 3.82 (s, 3H), 3.61 (td, J = 9.9, 6.0 Hz, 1H), 3.34 (s, 3H), 3.32 – 3.16 (m, 2H), 3.06 (s, 3H), 2.88 – 2.61 (m, 6H), 2.44 – 2.30 (m, 2H), 2.19 (ddd, J = 15.8, 11.3, 8.0 Hz, 1H), 2.03 (ddd, J = 13.8, 6.1, 4.6 Hz, 1H), 1.98 – 1.87 (m, 2H), 1.84 – 1.63 (m, 3H), 1.10 (t, J = 7.3 Hz, 3H). 244 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 13 C NMR (101 MHz, CDCl3): δ 216.1, 209.1, 174.6, 169.0, 95.5, 81.9, 77.3, 73.6, 58.3, 55.8, 53.6, 53.3, 52.7, 52.6, 51.3, 48.9, 44.1, 43.2, 42.2, 34.7, 30.3, 29.0, 26.3, 24.8, 14.7. FTIR (NaCl, thin film): 3370, 2952, 2900, 2824, 1720, 1657, 1529, 1452, 1236, 1152, 1046, 753 cm-1. HRMS: (ESI) calc’d for C25H36NO9 [M + H]+ 494.2385, found 494.2381. [!]!" ! = –30° (c = 0.47, CHCl3). One-pot preparation amide 287: O MeO 2C O3 MeOH, –78 °C O O SePh O O then pyridine –78 °C to rt O MOMO O MeO 2C 280 OH O NHEt O MeO 2C EtNH 2 THF MOMO MeO 282 O (87% yield) MOMO MeO O 287 A 25-mL, round-bottomed flask was charged with α-selenide 280 (30.0 mg, 52.3 µmol, 1.0 equiv) and methanol (3 mL). The flask was cooled to –78 °C, at which time ozone (as a mixture with O2) was gently bubbled through the solution (O2 flow rate = 1/4 L/min, 2 setting on ozone generator) for 10 min. The solution was sparged with Ar for 10 minutes, and then pyridine (85 µL, 1.05 mmol, 20 equiv) was added. The reaction was allowed to warm to ambient temperature, and stirred for a further 17 h. The methanol solvent and pyridine were then removed by concentration in vacuo, and ethylamine (3 mL, 2.0 M in THF) was added. After stirring for 72 h, the reaction mixture was concentrated in vacuo, and the resulting crude residue was purified by silica gel chromatography (50% acetone in hexanes) to provide amide 287 as a white solid (22.4 mg, 45.4 µmol, 87% yield). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 245 Preparation of diol amide 288: OH O NHEt O MeO 2C OH O NHEt OH MeO 2C NaBH 4 EtOH/THF 0 °C MOMO MeO O 287 (65% yield) MOMO MeO O 288 A 25-mL, round-bottomed flask was charged with ketone 287 (20.0 mg, 40.5 µmol, 1.0 equiv), absolute EtOH (1 mL), and THF (1 mL). The resulting solution was cooled to 0 °C, and three portions of NaBH4 (8 mg, 0.211 mmol, 5 equiv) were added over one hour (one portion every 20 minutes, total of 24 mg added). The reaction was then quenched with sat. NaHCO3 (5 mL) and stirred for an additional 15 minutes. The biphasic mixture was concentrated in vacuo to remove ethanol and THF. The aqueous layer was extracted with CH2Cl2 (3 x 5 mL), and the combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by silica gel chromatography (4% MeOH in CH2Cl2) to afford diol amide 288 as a white solid (13.1 mg, 26.4 µmol, 65% yield). Note: Extended reaction time leads to over-reduction of the methyl ester. Remarkably, the methyl ester undergoes facile reduction, while the C16 ketone remains inert. 1 H NMR (400 MHz, CDCl3):
6.62 (t, J = 5.4 Hz, 1H), 4.86 (d, J = 6.8 Hz, 1H), 4.62 (d, J = 6.8 Hz, 1H), 4.43 (d, J = 5.2 Hz, 1H), 4.16 (t, J = 4.4 Hz, 1H), 3.84 (q, J = 6.3 Hz, 1H), 3.77 (s, 3H), 3.48 (br s, 1H), 3.36 (s, 3H), 3.26 (qdd, J = 7.3, 5.4, 2.9 Hz, 2H), 3.12 (s, 3H), 2.86 (d, J = 17.0 Hz, 1H), 2.80 – 2.73 (m, 1H), 2.73 (d, J = 17.1 Hz, 1H), 2.60 – Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 246 2.52 (m, 2H), 2.53 – 2.42 (m, 3H), 2.26 – 1.84 (m, 6H), 1.83 – 1.71 (m, 1H), 1.32 (ddd, J = 14.2, 8.2, 6.4 Hz, 1H), 1.12 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 213.0, 175.8, 169.6, 95.7, 78.1, 74.8, 74.5, 70.7, 55.8, 55.7, 53.5, 53.3, 48.3, 47.7, 46.1, 45.9, 45.3, 43.4, 43.0, 34.9, 29.4, 27.1, 23.2, 22.1, 14.5. FTIR (NaCl, thin film): 3369, 2934, 2896, 2847, 2824, 1726, 1708, 1660, 1640, 1545, 1530, 1464, 1449, 1221, 1166, 1115, 1044 cm-1. HRMS: (ESI) calc’d for C25H38NO9 [M + H]+ 496.2541, found 496.2540. [!]!" ! = –96° (c = 0.23, CHCl3). Preparation of mesyl acetal 291: O MeO 2C OH O n-BuLi, MsCl O MeO 2C O THF, –78 °C to rt MOMO MeO O (15% yield) 283 MeO MOMO H O OMs 291 In a 1-dram vial, n-BuLi (3.2 µL, 2.5 M solution in hexane, 8.06 µmol, 1.1 equiv) was added to a solution of alcohol 283 (3.3 mg, 7.33 µmol, 1.0 equiv) in THF (0.30 mL) at –78 °C. After stirring for 20 minutes, MsCl (3.0 µL, 38.7 µmol, 5.3 equiv) was added. The reaction was allowed to warm to room temperature overnight, and then quenched with sat. NaHCO3 (1 mL) and extracted with CH2Cl2 (3 x 1 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative thin-layer chromatography (5% MeOH in CH2Cl2) to afford mesyl acetal 291 (0.6 mg, 1 µmol, 15% yield). 247 Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 H NMR (400 MHz, CDCl3): δ 4.87 (d, J = 4.2 Hz, 1H), 4.74 (d, J = 6.5 Hz, 1H), 4.71 (d, J = 6.8 Hz, 1H), 4.66 (d, J = 6.8 Hz, 1H), 3.86 (dd, J = 4.0, 2.3 Hz, 1H), 3.79 (s, 3H), 3.40 (s, 3H), 3.27 (d, J = 11.2 Hz, 1H), 3.22 (s, 3H), 3.12 (s, 3H), 2.88 (br s, 1H), 2.50 (t, J = 5.9 Hz, 1H), 2.44 – 2.24 (m, 4H), 2.22 – 2.05 (m, 3H), 1.95 (d, J = 12.6 Hz, 1H), 1.91 – 1.84 (m, 2H), 1.43 – 1.30 (m, 2H). 13 C NMR (101 MHz, CDCl3): δ 170.5, 169.3, 113.3, 96.2, 81.1, 81.0, 77.4, 75.8, 55.8, 53.1, 52.7, 52.0, 49.5, 49.2, 47.7, 44.9, 42.8, 42.3, 42.2, 38.6, 27.3, 24.7, 24.6, 20.6. Preparation of mesylate 293: O MeO 2C OH O KHMDS Ms 2O O MeO 2C MeO O 283 (32% yield, 46% brsm) MOMO MeO 293 O OH O + THF, –78 °C MOMO O MeO 2C OMs O MOMO MeO OMs S7 In a flame-dried 5-mL, round-bottomed flask, alcohol 283 (24.2 mg, 53.6 µmol, 1.0 equiv) was dissolved in THF (0.8 mL) and cooled to –78 °C. KHMDS (130 µL, 0.5 M in PhMe, 65.0 mmol, 1.2 equiv) was added, and the resulting solution was stirred for 10 minutes. In a separate 1-dram vial, Ms2O (20.5 mg, 0.118 mmol, 2.2 equiv) was dissolved in THF (0.2 mL) and added to the alkoxide solution. After stirring for an additional 40 minutes, the reaction was quenched with sat. NaHCO3 (2 mL) and extracted with CH2Cl2 (3 x 2 mL). The combined extracts were dried over Na2SO4, filtered, and concentrated in vacuo. The crude residue was purified by preparative thin-layer chromatography (5% MeOH in CH2Cl2) to afford mesylate 293 (9.0 mg, 17 µmol, 32% Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 248 yield) as a colorless oil, mesyl enol ether S7 (5.3 mg, 10 µmol, 19% yield) as a colorless oil, and starting material 283 (7.4 mg, 16 µmol, 30% recovery). Data for mesylate 293: 1 H NMR (400 MHz, CDCl3): δ 4.97 (dd, J = 5.2, 1.6 Hz, 1H), 4.84 (d, J = 6.9 Hz, 1H), 4.71 (d, J = 4.3 Hz, 1H), 4.61 (d, J = 6.8 Hz, 1H), 4.20 (t, J = 4.4 Hz, 1H), 3.80 (s, 3H), 3.36 (s, 3H), 3.16 (s, 3H), 3.08 (s, 3H), 3.02 (d, J = 17.2 Hz, 1H), 2.84 (ddd, J = 7.0, 4.0, 1.3 Hz, 1H), 2.71 (d, J = 17.3 Hz, 1H), 2.66 (t, J = 5.6 Hz, 1H), 2.51 (ddd, J = 6.5, 5.0, 1.3 Hz, 1H), 2.41 (dd, J = 14.7, 9.9 Hz, 1H), 2.38 – 2.32 (m, 1H), 2.28 – 2.12 (m, 3H), 1.99 – 1.88 (m, 3H), 1.78 (ddd, J = 14.3, 12.1, 7.5 Hz, 1H), 1.70 (ddd, J = 14.6, 7.8, 5.9 Hz, 1H). 13 C NMR (101 MHz, CDCl3): δ 211.0, 169.5, 169.0, 95.7, 75.6, 74.9, 73.9, 55.8, 53.4, 52.8, 52.8, 48.7, 47.8, 47.3, 46.7, 43.7, 41.9, 40.5, 38.2, 28.3, 25.9, 25.1, 20.4. FTIR (NaCl, thin film): 3017, 2952, 2839 1756, 1736, 1709, 1466, 1450, 1335, 1287, 1256, 1218, 1177, 1112, 1085, 959, 839 cm-1. HRMS: (PMM) calc’d for C24H36NO11S [M + NH4]+ 546.2004, found 546.2011. [!]!" ! = +61° (c = 0.70, CHCl3). Data for mesyl enol ether S7: 1 H NMR (400 MHz, CDCl3): δ 5.95 (t, J = 1.4 Hz, 1H), 4.77 (d, J = 6.9 Hz, 1H), 4.72 (d, J = 4.1 Hz, 1H), 4.62 (d, J = 6.9 Hz, 1H), 4.04 (t, J = 3.6 Hz, 1H), 3.96 (t, J = 4.4 Hz, 1H), 3.78 (s, 3H), 3.38 (s, 3H), 3.22 (s, 3H), 3.17 (s, 3H), 2.78 (dd, J = 6.2, 4.6 Hz, 1H), Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 249 2.64 (dd, J = 13.3, 5.5 Hz, 1H), 2.47 (t, J = 5.4 Hz, 1H), 2.35 – 2.17 (m, 4H), 2.12 – 2.00 (m, 3H), 2.00 – 1.88 (m, 2H), 1.74 (ddd, J = 13.3, 11.4, 6.4 Hz, 1H), 1.69 – 1.60 (m, 1H). 13 C NMR (101 MHz, CDCl3): δ 171.0, 169.4, 150.5, 115.1, 95.6, 77.4, 76.0, 74.0, 72.2, 55.7, 53.0, 52.6, 49.2, 47.4, 47.1, 44.0, 43.8, 42.9, 39.9, 38.1, 28.9, 28.9, 25.0, 20.4. FTIR (NaCl, thin film): 2952, 2930, 2851, 2828, 1738, 1730, 1668, 1466, 1451, 1360, 1301, 1180, 1151, 1054, 971 cm-1. HRMS: (ESI) calc’d for C23H29O10S [M – OMe]+ 497.1476, found 497.1462. [!]!" ! = –2.6° (c = 0.40, CHCl3). Preparation of mesylate amide 294: O MeO 2C OMs O H 2NEt OH O NHEt OMs MeO 2C neat MOMO MeO 293 O (88% yield) MOMO MeO O 294 To a 1-dram vial containing lactone 293 (7.0 mg, 13.2 µmol, 1.0 equiv) was added neat ethylamine (~0.3 mL, distilled from a 70% solution in water and stored over KOH). The vial was sealed with a Teflon cap and allowed to stir for 72 h at room temperature. The reaction was then opened to the atmosphere to allow evaporation of ethylamine. The resulting residue was dissolved in dichloromethane, and further concentrated in vacuo. The crude residue was purified by silica gel chromatography (45% acetone in hexanes) to afford amide 294 as a white solid (6.7 mg, 11.7 µmol, 88% yield). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 1 250 H NMR (400 MHz, CDCl3): δ 6.73 (t, J = 5.3 Hz, 1H), 5.20 (dd, J = 5.4, 1.1 Hz, 1H), 4.87 (d, J = 6.8 Hz, 1H), 4.62 (d, J = 6.8 Hz, 1H), 4.18 (t, J = 4.4 Hz, 1H), 3.78 (s, 3H), 3.72 (td, J = 8.8, 5.7 Hz, 1H), 3.36 (s, 3H), 3.26 (qd, J = 7.3, 5.5 Hz, 2H), 3.12 (s, 3H), 3.09 (s, 3H), 2.99 (d, J = 17.2 Hz, 1H), 2.89 (d, J = 8.9 Hz, 1H), 2.80 (ddd, J = 7.7, 4.2, 1.2 Hz, 1H), 2.74 – 2.59 (m, 4H), 2.31 – 2.20 (m, 3H), 2.19 – 2.06 (m, 2H), 2.06 – 1.90 (m, 2H), 1.85 (dtd, J = 14.1, 9.0, 1.7 Hz, 1H), 1.43 (ddd, J = 14.3, 7.9, 6.3 Hz, 1H), 1.13 (t, J = 7.3 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 211.9, 175.3, 169.0, 95.7, 77.4, 77.4, 74.0, 69.8, 56.2, 55.7, 53.4, 53.3, 48.5, 47.8, 45.6, 44.9, 44.7, 43.0, 42.6, 38.4, 34.9, 28.5, 26.1, 22.4, 21.9, 14.5. FTIR (NaCl, thin film): 3387, 2940, 2900, 2851, 2832, 1710, 1660, 1647, 1529, 1464, 1331, 1220, 1172, 1044, 948, 852 cm-1. HRMS: (ESI) calc’d for C26H40NO11S [M + H]+ 574.2317, found 574.2302. [!]!" ! = –14° (c = 0.45, CHCl3). Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 3.9 251 NOTES AND REFERENCES (1) Cherney, E. C.; Baran, P. S. Isr. J. Chem. 2011, 51, 391. (2) (a) Masamune, S. J. Am. Chem. Soc. 1964, 86, 290. (b) Nagata, W.; Narisada, M.; Wakabayashi, T.; Sugasawa, T. J. Am. Chem. Soc. 1967, 89, 1499. (c) Valenta, Z.; Wiesner, K.; Wong, C. M. Tetrahedron Lett. 1964, 5, 2437. (d) Wiesner, K.; Uyeo, S.; Phillip, A.; Valenta, Z. Tetrahedron Lett. 1968, 9, 6279. (3) (a) Masamune, S. J. Am. Chem. Soc. 1964, 86, 291. (b) Guthrie, R. W.; Valenta, Z.; Wiesner, K. Tetrahedron Lett. 1966, 7, 4645. (c) Nagata, W.; Sugasawa, T.; Narisada, M.; Wakabayashi, T.; Hayase, Y. J. Am. Chem. Soc. 1967, 89, 1483. (d) Ihara, M.; Suzuki, M.; Fukumoto, K.; Kabuto, C. J. Am. Chem. Soc. 1990, 112, 1164. (e) Cherney, E. C.; Lopchuk, J. M.; Green, J. C.; Baran, P. S. J. Am. Chem. Soc. 2014, 136, 12592. (f) Cheng, H.; Zeng, F.-H.; Yang, X.; Meng, Y.-J.; Xu, L.; Wang, F.-P. Angew. Chem. Int. Ed. 2016, 55, 392. (4) (a) Wiesner, K.; Tsai, T. Y. R.; Huber, K.; Bolton, S. E.; Vlahov, R. J. Am. Chem. Soc. 1974, 96, 4990. (b) Wiesner, K. Pure Appl. Chem. 1975, 41, 93. (c) Lee, S.F.; Sathe, G. M.; Sy, W. W.; Ho, P.-T.; Wiesner, K. Can. J. Chem. 1976, 54, 1039. (d) Tsai, T. Y. R.; Tsai, C. S. J.; Sy, W. W.; Shanbhag, M. N.; Liu, W. C.; Lee, S. F.; Wisner, K. Heterocycles 1977, 7, 217. (e) Wiesner, K.; Tsai, T. Y. R.; Nambiar, K. P. Can. J. Chem. 1978, 56, 1451. (f) Wiesner, K. Pure Appl. Chem. 1979, 51, 689. (g) Wiesner, K. Tetrahedron, 1985, 41, 485. (5) (a) Peese, K. M.; Gin, D. Y. Org. Lett. 2005, 7, 3323. (b) Gin, D. Y.; Peese, K. M. J. Am. Chem. Soc. 2006, 128, 8734. (c) Peese, K. M.; Gin, D. Y. Chem. Eur. J. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 252 2008, 14, 1654. (d) Hamlin, A. M.; Cortez, J. J.; Lapointe, D.; Sarpong, R. Angew. Chem. Int. Ed. 2013, 52, 4854. (e) Hamlin, A. M.; Lapointe, D.; Owens, K.; Sarpong, R. J. Org. Chem. 2014, 79, 6783. (f) Hamlin, A. M.; Kisunzu, J. K.; Sarpong, R. Org. Biomol. Chem. 2014, 12, 1846. (6) (a) Shishido, K.; Hiroya, K.; Fukumoto, K.; Kametani, T. Tetrahedron Lett. 1986, 27, 1167. (b) Kraus, G. A.; Andersh, B.; Su, Q.; Shim J. Tetrahedron Lett. 1993, 34, 1741. (c) Baillie, L. C.; Batsanov, A.; Bearder. J. R.; Whiting. D. A. J. Chem. Soc. Perkin Trans. 1, 1998, 3471. (d) Baillie, L. C.; Bearder, J. R.; Li, W.-S.; Sherringham, J. A.; Whiting, D. A. J. Chem. Soc. Perkin Trans. 1, 1998, 4047. (e) Taber, D. F.; Liang, J.-L.; Chen, B.; Cai, L. J. Org. Chem. 2005, 70, 8739. (f) Kraus, G. A.; Kesavan, S. Tetrahedron Lett. 2005, 46, 1111. (g) Conrad, R. M.; Du Bois, J. Org. Lett. 2007, 9, 5465. (h) Yang, Z.-K.; Chen, Q.-H.; Wang, F.-P. Tetrahedron 2011, 67, 4192. (i) Liu, Z.-G.; Xu, L.; Chen, Q.-H.; Wang, F.-P. Tetrahedron 2012, 68, 159. (j) Goodall, K. J.; Brimble, M. A.; Barker, D. Tetrahedron 2012, 68, 5759. (k) Liu, Z.-G.; Cheng, H.; Ge, M.-J.; Xu, L.; Wang, F.-P. Tetrahedron 2013, 69, 5431. (l) Cheng, H.; Zeng, F.-H.; Ma, D.; Jiang, M.L.; Xu, L.; Wang, F.-P. Org. Lett. 2014, 16, 2299. (m) Tabuchi, T.; Urabe, D.; Inoue, M. J. Org. Chem. 2016, 81, 10204. (n) Minagawa, K.; Urabe, D.; Inoue, M. J. Antibiotics 2017, In Press. DOI: 10.1038/ja.2017.69. (7) Johnston, J. P.; Overton, K. H. J. C. S. Perkin 1 1971, 1490. (8) (a) Wiesner, K.; Ho, P.-T.; Chang, D.; Lam, Y. K.; Pan, C. S. J.; Ren, W. Y. Can. J. Chem. 1973, 51, 3978. (b) Wiesner, K.; Ho, P.-T.; Tsai, C. S. J. Can. J. Chem. 1974, 52, 2353. (c) Wiesner, K.; Ho, P.-T.; Tsai, C. S. J.; Lam, Y.-K. Can. J. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 253 Chem. 1974, 52, 2355. (d) Atwal, K. S.; Marini-Bettolo, R.; Sanchez, I. H.; Tsai, T. Y. R.; Wiesner, K. Can. J. Chem. 1978, 56, 1102. (e) Sethi, S. P.; Atwal, K. S.; Marini-Bettolo, R. M.; Tsai, T. Y. R.; Wiesner, K. Can. J. Chem. 1980, 58, 1889. (9) Shi, Y.; Wilmot, J. T.; Nordstrøm, L. U.; Tan, D. S.; Gin, D. Y. J. Am. Chem. Soc. 2013, 135, 14313. (10) Marth, C. J.; Gallego, G. M.; Lee, J. C.; Lebold, T. P.; Kulyk, S.; Kou, K. G. M.; Qin, J.; Lilien, R.; Sarpong R. Nature 2015, 528, 493. (11) Kou, K. G. M.; Li, B. X.; Lee, J. C.; Gallego, G. M.; Lebold, T. P.; DiPasquale, A. G.; Sarpong, R. J. Am. Chem. Soc. 2016, 138, 10830. (12) Nishiyama, Y.; Han-ya, Y.; Yokoshima, S.; Fukuyama, T. J. Am. Chem. Soc. 2014, 136, 6598. (13) Nishiyama, Y.; Yokoshima, S.; Fukuyama, T. Org. Lett. 2016, 18, 2359. (14) (a) Song, Z.-L.; Fan, C.-A.; Tu, Y.-Q. Chem. Rev. 2011, 111, 7523. (b) Snape, T. J. Chem. Soc. Rev. 2007, 36, 1823. (15) Urankar, D.; Rutar, I.; Modec, B.; Dolenc, D. Eur. J. Org. Chem. 2005, 2349. (16) Rajamannar, T.; Balasubramanian, K. K. Tetrahedron Lett. 1988, 29, 5789. (17) (a) Kim, Y. S.; Matsunaga, S.; Das, J.; Sekine, A.; Ohshima, T.; Shibasaki, M. J. Am. Chem. Soc. 2000, 122, 6506. (b) Takita, R.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett. 2002, 43, 4661. (18) Arai, T.; Yamada, Y. M. A.; Yamamoto, N.; Sasai, H.; Shibasaki, M. Chem. Eur. J. 1996, 11, 1368. (19) Chappell, D.; Russell, A. T. Org. Biomol. Chem. 2006, 4, 4409. (20) Cornelisse, J. Chem. Rev. 1993, 93, 615. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 254 (21) (a) Hagiya, K.; Yamasaki, A.; Okuyama, T.; Sugimura, T. Tetrahedron: Asymmetry 2004, 15, 1409. (b) Sugimura, T.; Yamasaki, A.; Okuyama, T. Tetrahedron: Asymmetry 2005, 16, 675. (22) Fenton, G. A.; Gilbert, A. Tetrahedron 1989, 45, 2979. (23) (a) Avent, A. G.; Byrne, P. W.; Penkett, C. S. Org. Lett. 1999, 1, 2073. (b) Penkett, C. S;, Byrne, P. W.; Theobald, B. J.; Rola, B.; Ozanne, A.; Hitchcock, P. B. Tetrahedron, 2004, 60, 2771. (24) (a) Habata, Y.; Akabori, S.; Sato, M. Bull. Chem. Soc. Jpn. 1985, 58, 3540. (b) Paquette, L. A.; Pierre, F.; Cottrell, C. E. J. Am. Chem. Soc. 1987, 109, 5731. (25) Spaggiari, A.; Vaccari, D.; Davoli, P.; Torre, G.; Prati, F. J. Org. Chem. 2007, 72, 2216. (26) Barton, D. H. R.; Bashiardes, G.; Fourrey, J.-L. Tetrahedron Lett. 1983, 24, 1605. (27) (a) Shen, X.; Hyde, A. M.; Buchwald, S. L. J. Am. Chem. Soc. 2010, 132, 14076. (b) Pan, J.; Wang, X.; Zhang, Y.; Buchwald, S. L. Org. Lett. 2011, 13, 4974. (28) Gilbertson, S. R.; Challener, C. A.; Bos, M. E.; Wulff, W. D. Tetrahedron Lett. 1988, 29, 4795. (29) (a) Scott, W. J.; Stille, J. K. J. Am. Chem. Soc. 1986, 108, 3033. (b) Wulff, W. D.; Peterson, G. A.; Bauta, W. E.; Chan, K.-S.; Faron, K. L.; Gilbertson, S. R.; Kaesler, R. W.; Yang, D. C.; Murray, C. K. J. Org. Chem. 1986, 51, 277. (30) Ren, H.; Krasovskiy, A.; Knochel, P. Chem. Commun. 2005, 543. (31) Mathieu, B.; Ghosez, L. Tetrahedron 2002, 58, 8219. (32) (a) Steves, J. E.; Stahl, S. S. J. Am. Chem. Soc. 2013, 135, 15742. (b) Steves, J. E.; Stahl, S. S. J. Org. Chem. 2015, 80, 11184. Chapter 3 – Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine (33) 255 Tang, P.; Wang, L.; Chen, Q.-F.; Chen, Q.-H.; Jian, X.-X.; Wang, F.-P. Tetrahedron 2012, 68, 6249. (34) (a) Joshi, B. S.; Glinski, J. A.; Chokshi, H. P.; Chen, S.-Y.; Srivastava, S. K.; Pelletier, S. W. Heterocycles 1984, 22, 2037. (b) Pelletier, S. W.; Srivastava, S. K.; Joshi, B. S.; Olsen, J. D. Heterocycles, 1985, 23, 331. (c) See also References 9 and 13. (35) Watanabe, M.; Murata, K.; Ikariya, T. J. Am. Chem. Soc. 2003, 125, 7508. (36) Piers, E.; Lung, G. L.; Ruediger, E. H. Can. J. Chem. 1987, 65, 670. Appendix 2 – Spectra Relevant to Chapter 3 256 Appendix 2 Spectra Relevant to Chapter 3: Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine 208 MeO 2C MeO 2C O O Appendix 2 – Spectra Relevant to Chapter 3 257 MeO 2C MeO 2C O 189 O O Appendix 2 – Spectra Relevant to Chapter 3 258 MeO 2C MeO 2C O 189 O O Appendix 2 – Spectra Relevant to Chapter 3 259 O Br S3 Appendix 2 – Spectra Relevant to Chapter 3 260 HO Br 194 Appendix 2 – Spectra Relevant to Chapter 3 261 262 TMSO Br 196 Appendix 2 – Spectra Relevant to Chapter 3 263 TMSO Br 196 Appendix 2 – Spectra Relevant to Chapter 3 TIPSO Br 195 Appendix 2 – Spectra Relevant to Chapter 3 264 TIPSO Br 195 Appendix 2 – Spectra Relevant to Chapter 3 265 266 MeO 2C MeO 2C H 197 TIPSO O OH Appendix 2 – Spectra Relevant to Chapter 3 267 MeO 2C MeO 2C H 197 TIPSO O OH Appendix 2 – Spectra Relevant to Chapter 3 268 OTIPS 198 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 269 OTIPS 198 CO2Me O MeO 2C OTMS Appendix 2 – Spectra Relevant to Chapter 3 270 OTMS 200 CO2Me O MeO 2C OTMS Appendix 2 – Spectra Relevant to Chapter 3 271 OTMS 200 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 MeO 2C 201 OTMS OH CO2Me O S4 (E = CO2Me) MeO 2C OTMS E OH O Appendix 2 – Spectra Relevant to Chapter 3 272 MeO 2C 201 OTMS OH CO2Me O S4 (E = CO2Me) MeO 2C OTMS E OH O Appendix 2 – Spectra Relevant to Chapter 3 273 274 202 O H CO2Me O MeO 2C OTMS Appendix 2 – Spectra Relevant to Chapter 3 O H 202 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 275 276 OH 203 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 277 OH 203 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 278 OH 203 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 OMOM 204 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 279 OMOM 204 MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 280 OMOM 205 MeO 2C OH CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 281 282 OMOM 205 MeO 2C OH CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 206 OMOM CO2Me O MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 283 206 OMOM CO2Me O MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 284 207 OMOM CO2Me NHEt MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 285 207 OMOM CO2Me NHEt MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 286 287 207 OMOM CO2Me NHEt MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 288 207 OMOM CO2Me NHEt MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 289 OMOM 207 MeO 2C OMe CO2Me NHEt Appendix 2 – Spectra Relevant to Chapter 3 290 207 OMOM CO2Me NHEt MeO 2C OMe Appendix 2 – Spectra Relevant to Chapter 3 291 H MeO 2C MeO 2C 209 O Appendix 2 – Spectra Relevant to Chapter 3 H MeO 2C MeO 2C 210 O O Appendix 2 – Spectra Relevant to Chapter 3 292 H MeO 2C MeO 2C 210 O O Appendix 2 – Spectra Relevant to Chapter 3 293 294 O 211 MeO 2C MeO 2C H O O O Appendix 2 – Spectra Relevant to Chapter 3 295 O 211 MeO 2C MeO 2C H O O O Appendix 2 – Spectra Relevant to Chapter 3 296 190 MeO 2C MeO 2C H O Appendix 2 – Spectra Relevant to Chapter 3 297 190 MeO 2C MeO 2C H O Appendix 2 – Spectra Relevant to Chapter 3 O 192 Br MeO 2C MeO 2C H OH Appendix 2 – Spectra Relevant to Chapter 3 298 O 192 Br MeO 2C MeO 2C H OH Appendix 2 – Spectra Relevant to Chapter 3 299 300 185 MeO 2C MeO 2C H O O Appendix 2 – Spectra Relevant to Chapter 3 185 MeO 2C MeO 2C H O O Appendix 2 – Spectra Relevant to Chapter 3 301 Me OH S5 O Me Appendix 2 – Spectra Relevant to Chapter 3 302 Me O 216 O Me Appendix 2 – Spectra Relevant to Chapter 3 303 Me 218 O H Me O H H Appendix 2 – Spectra Relevant to Chapter 3 304 305 217 O Me H Me O H H Appendix 2 – Spectra Relevant to Chapter 3 306 Me OH 228 O O Me Appendix 2 – Spectra Relevant to Chapter 3 Me OH O O 233 Me Cl Appendix 2 – Spectra Relevant to Chapter 3 307 308 Me OH O O S6 O Me Cl Appendix 2 – Spectra Relevant to Chapter 3 309 Me O O O 234 O Me Cl Appendix 2 – Spectra Relevant to Chapter 3 310 O HO 235 O Cl Appendix 2 – Spectra Relevant to Chapter 3 311 236 O O O Cl Appendix 2 – Spectra Relevant to Chapter 3 236 O O O Cl Appendix 2 – Spectra Relevant to Chapter 3 312 313 Me OH O O Me 239 OH Appendix 2 – Spectra Relevant to Chapter 3 Me OH O O Me 239 OH Appendix 2 – Spectra Relevant to Chapter 3 314 315 Me OH 240 OH O Me OH Appendix 2 – Spectra Relevant to Chapter 3 316 Me OH 240 OH O Me OH Appendix 2 – Spectra Relevant to Chapter 3 317 Me 244 HO OH O Me OH Appendix 2 – Spectra Relevant to Chapter 3 Me 244 HO OH O Me OH Appendix 2 – Spectra Relevant to Chapter 3 318 319 Me 244 HO OH O Me OH Appendix 2 – Spectra Relevant to Chapter 3 320 Me 244 HO OH O Me OH Appendix 2 – Spectra Relevant to Chapter 3 321 Me O Si O 245 t-Bu t-Bu OH O Me Appendix 2 – Spectra Relevant to Chapter 3 322 Me O Si O 245 t-Bu t-Bu OH O Me Appendix 2 – Spectra Relevant to Chapter 3 323 Me O Si O t-Bu t-Bu 246 O O Me Appendix 2 – Spectra Relevant to Chapter 3 324 Me O Si O t-Bu t-Bu 246 O O Me Appendix 2 – Spectra Relevant to Chapter 3 325 247 O Si O t-Bu t-Bu HO Appendix 2 – Spectra Relevant to Chapter 3 326 247 O Si O t-Bu t-Bu HO Appendix 2 – Spectra Relevant to Chapter 3 327 248 O Si O t-Bu t-Bu O Appendix 2 – Spectra Relevant to Chapter 3 328 248 O Si O t-Bu t-Bu O Appendix 2 – Spectra Relevant to Chapter 3 329 249 O Si O t-Bu t-Bu TfO Appendix 2 – Spectra Relevant to Chapter 3 249 O Si O t-Bu t-Bu TfO Appendix 2 – Spectra Relevant to Chapter 3 330 331 251 O Si O t-Bu t-Bu I Appendix 2 – Spectra Relevant to Chapter 3 332 251 O Si O t-Bu t-Bu I Appendix 2 – Spectra Relevant to Chapter 3 253 O Si O t-Bu t-Bu Me 3Sn Appendix 2 – Spectra Relevant to Chapter 3 333 334 O Si O t-Bu t-Bu 262 MeO 2C MeO 2C H O OH Appendix 2 – Spectra Relevant to Chapter 3 O Si O t-Bu t-Bu 262 MeO 2C MeO 2C H O OH Appendix 2 – Spectra Relevant to Chapter 3 335 336 O Si O t-Bu t-Bu 263 MeO 2C MeO 2C H O OTMS Appendix 2 – Spectra Relevant to Chapter 3 337 O Si O t-Bu t-Bu 263 MeO 2C MeO 2C H O OTMS Appendix 2 – Spectra Relevant to Chapter 3 338 264 O Si O t-Bu t-Bu MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 339 264 O Si O t-Bu t-Bu CO2Me O MeO 2C OTMS Appendix 2 – Spectra Relevant to Chapter 3 340 268 Br O Si O t-Bu t-Bu MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 341 268 Br O Si O t-Bu t-Bu MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 342 MeO 2C 272 OH OH OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 343 MeO 2C 272 OH OH OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 344 HO MeO 2C 273 O OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 345 HO MeO 2C 273 O OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 MOMO MeO 2C 274 O OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 346 347 MOMO MeO 2C 274 O OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 348 275 O MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 349 275 O MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 350 278 MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 351 278 MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 352 278 MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 353 278 MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 354 279 MOMO H MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 355 279 MOMO H MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 356 279 MOMO H MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 357 276 O SePh MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 276 O SePh MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 358 359 277 O HO MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 360 277 O HO MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 361 277 O HO MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 362 277 O HO MOMO MeO 2C OTMS CO2Me O Appendix 2 – Spectra Relevant to Chapter 3 363 280 MOMO MeO 2C O O O O SePh Appendix 2 – Spectra Relevant to Chapter 3 364 280 MOMO MeO 2C O O O O SePh Appendix 2 – Spectra Relevant to Chapter 3 365 281 HO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 366 281 HO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 367 281 HO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 368 281 HO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 369 282 MeO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 282 MeO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 370 371 282 MeO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 372 282 MeO MOMO MeO 2C O O O O Appendix 2 – Spectra Relevant to Chapter 3 373 283 MeO MOMO MeO 2C O O O OH Appendix 2 – Spectra Relevant to Chapter 3 283 MeO MOMO MeO 2C O O O OH Appendix 2 – Spectra Relevant to Chapter 3 374 375 283 MeO MOMO MeO 2C O O O OH Appendix 2 – Spectra Relevant to Chapter 3 376 283 MeO MOMO MeO 2C O O O OH Appendix 2 – Spectra Relevant to Chapter 3 377 283 MeO MOMO MeO 2C O O O OH Appendix 2 – Spectra Relevant to Chapter 3 378 287 O MeO MOMO MeO 2C OH O NHEt O Appendix 2 – Spectra Relevant to Chapter 3 379 287 O MeO MOMO MeO 2C OH O NHEt O Appendix 2 – Spectra Relevant to Chapter 3 380 287 O MeO MOMO MeO 2C OH O NHEt O Appendix 2 – Spectra Relevant to Chapter 3 381 288 O MeO MOMO MeO 2C OH O NHEt OH Appendix 2 – Spectra Relevant to Chapter 3 382 288 O MeO MOMO MeO 2C OH O NHEt OH Appendix 2 – Spectra Relevant to Chapter 3 383 288 O MeO MOMO MeO 2C OH O NHEt OH Appendix 2 – Spectra Relevant to Chapter 3 384 288 O MeO MOMO MeO 2C OH O NHEt OH Appendix 2 – Spectra Relevant to Chapter 3 385 288 O MeO MOMO MeO 2C OH O NHEt OH Appendix 2 – Spectra Relevant to Chapter 3 386 291 O OMs MeO MOMO MeO 2C O O H Appendix 2 – Spectra Relevant to Chapter 3 387 291 O OMs MeO MOMO MeO 2C O O H Appendix 2 – Spectra Relevant to Chapter 3 388 291 O OMs MeO MOMO MeO 2C O O H Appendix 2 – Spectra Relevant to Chapter 3 389 291 O OMs MeO MOMO MeO 2C O O H Appendix 2 – Spectra Relevant to Chapter 3 390 293 MeO MOMO MeO 2C O O O OMs Appendix 2 – Spectra Relevant to Chapter 3 391 293 MeO MOMO MeO 2C O O O OMs Appendix 2 – Spectra Relevant to Chapter 3 392 293 MeO MOMO MeO 2C O O O OMs Appendix 2 – Spectra Relevant to Chapter 3 393 293 MeO MOMO MeO 2C O O O OMs Appendix 2 – Spectra Relevant to Chapter 3 394 S7 MeO MOMO MeO 2C O O OMs OH Appendix 2 – Spectra Relevant to Chapter 3 S7 MeO MOMO MeO 2C O O OMs OH Appendix 2 – Spectra Relevant to Chapter 3 395 396 294 O MOMO MeO 2C MeO OH O NHEt OMs Appendix 2 – Spectra Relevant to Chapter 3 294 O MOMO MeO 2C MeO OH O NHEt OMs Appendix 2 – Spectra Relevant to Chapter 3 397 398 294 O MOMO MeO 2C MeO OH O NHEt OMs Appendix 2 – Spectra Relevant to Chapter 3 399 294 O MOMO MeO 2C MeO OH O NHEt OMs Appendix 2 – Spectra Relevant to Chapter 3 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 400 Appendix 3 X-Ray Crystallography Reports Relevant to Chapter 3: Synthetic Studies towards the C19-Diterpenoid Alkaloid Talatisamine† † X-ray crystallographic analysis of 262 was completed by Dr. Michael Takase at the Caltech X-ray crystallography lab and Julie Hofstra, a graduate student in the Reisman lab. Crystals of 262 were obtained by Alice Wong, a graduate student in the Reisman lab. 401 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 A3.1 CRYSTAL STRUCTURE ANALYSIS: EPOXY ALCOHOL 262 Figure A3.1. Epoxy alcohol 262. Table A3.1. Crystal data and structure refinement for epoxy alcohol 262. Identification code ARWIII-253 Empirical formula C29 H42 O8 Si Formula weight 546.71 Temperature 100 K Wavelength 0.71073 Å Crystal system Monoclinic Space group P 1 21 1 Unit cell dimensions a = 8.8034(13) Å α= 90°. b = 24.957(4) Å β= 101.552(5)°. c = 13.429(2) Å γ = 90°. Volume 2890.6(7) Å3 Z 4 Density (calculated) 1.256 Mg/m3 Absorption coefficient 0.129 mm-1 F(000) 1176 Crystal size 0.28 x 0.17 x 0.08 mm3 Theta range for data collection 2.361 to 30.544°. Index ranges -12<=h<=12, -35<=k<=35, -19<=l<=19 Reflections collected 130883 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Independent reflections 17688 [R(int) = 0.0665] Completeness to theta = 26.000° 99.9 % Absorption correction Semi-empirical from equivalents Max. and min. transmission 0.7461 and 0.7071 Refinement method Full-matrix least-squares on F2 Data / restraints / parameters 17688 / 1 / 707 Goodness-of-fit on F2 1.036 Final R indices [I>2sigma(I)] R1 = 0.0394, wR2 = 0.0851 R indices (all data) R1 = 0.0512, wR2 = 0.0896 Absolute structure parameter 0.02(2) Extinction coefficient n/a Largest diff. peak and hole 0.295 and -0.229 e.Å-3 402 X-Ray Structure Determination Low-temperature diffraction data (φ- and ω-scans) were collected on a Bruker AXS D8 VENTURE KAPPA diffractometer coupled to a PHOTON 100 CMOS detector with MoKα radiation (λ = 0.71073 Å) from a IµS HB micro-focus sealed X-ray tube. All diffractometer manipulations, including data collection, integration, and scaling were carried out using the Bruker APEXII software.1 Absorption corrections were applied using SADABS.2 The structure was solved by intrinsic phasing using SHELXT3 and refined against F2 on all data by full-matrix least squares with SHELXL-20143 using established refinement techniques.4 All non-hydrogen atoms were refined anisotropically. The coordinates for the hydrogen atoms bound to O1A and O1B were located in the difference Fourier synthesis and refined using a riding model. All other hydrogen atoms were included into the model at geometrically calculated positions and refined using a riding model. The isotropic displacement parameters of all hydrogen atoms were fixed to 1.2 times the U value of the atoms they are linked to (1.5 times for methyl groups). Compound 262 crystallizes in the monoclinic space group P21 with two molecules in the 403 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 asymmetric unit. Absolute configuration was determined by anomalous dispersion (Flack = 0.03(2)). 5 Graphical representation of the structure with 50% probability thermal ellipsoids was generated using Mercury visualization software.6 Table A3.2. Atomic coordinates (x 104) and equivalent isotropic displacement parameters (Å2 x 103) for epoxy alcohol 262 U(eq) is defined as one third of the trace of the orthogonalized Uij tensor. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ Si(1A) -417(1) 3653(1) 6121(1) 14(1) Si(1B) 3569(1) 3793(1) 10636(1) 15(1) O(6A) 5658(2) 6948(1) 5081(1) 19(1) O(7A) 3572(2) 6865(1) 2890(1) 18(1) O(1B) 3404(2) 5702(1) 7078(1) 17(1) O(5A) 3783(2) 6613(1) 5803(1) 18(1) O(8A) 5721(2) 6371(1) 2976(1) 20(1) O(4A) 390(2) 4186(1) 6751(1) 15(1) O(2B) 6490(2) 5967(1) 7042(1) 15(1) O(3B) 3262(2) 4027(1) 9464(1) 17(1) O(6B) 10631(2) 6672(1) 9865(1) 23(1) O(7B) 8245(2) 6976(1) 7998(1) 18(1) O(1A) -110(2) 5232(1) 2172(1) 20(1) O(3A) -674(2) 3811(1) 4908(1) 16(1) O(8B) 10005(2) 6412(1) 7583(1) 22(1) O(2A) 2891(2) 5682(1) 2430(1) 16(1) O(4B) 4357(2) 4295(1) 11372(1) 18(1) O(5B) 9349(2) 6112(1) 10692(1) 36(1) C(18A) 4510(2) 6609(1) 5133(2) 14(1) C(2A) 5081(3) 5280(1) 3699(2) 19(1) C(18B) 9573(2) 6303(1) 9913(2) 17(1) C(14B) 3066(2) 4580(1) 9215(2) 15(1) C(19A) 4436(2) 6520(1) 3293(2) 15(1) 404 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(4A) 4221(2) 6214(1) 4244(2) 13(1) C(15A) 2132(2) 4509(1) 5681(2) 15(1) C(19B) 8910(2) 6554(1) 8099(2) 15(1) C(12B) 3469(2) 5490(1) 9611(2) 14(1) C(13A) -677(2) 4785(1) 5368(2) 13(1) C(12A) -486(2) 5272(1) 4736(2) 14(1) C(7B) 4352(2) 6396(1) 8394(2) 14(1) C(3B) 9366(2) 5568(1) 8668(2) 18(1) C(4B) 8693(2) 6125(1) 8871(2) 14(1) C(17B) 4403(2) 5810(1) 8028(2) 12(1) C(10B) 4023(2) 5406(1) 8768(2) 13(1) C(2B) 8570(3) 5307(1) 7666(2) 20(1) C(15B) 6076(2) 4701(1) 10377(2) 17(1) C(3A) 5338(2) 5728(1) 4506(2) 17(1) C(8A) 1977(2) 4442(1) 4682(2) 16(1) C(26A) 919(2) 3048(1) 6314(2) 19(1) C(5B) 6994(2) 6027(1) 8938(2) 12(1) C(20A) 5995(3) 7333(1) 5903(2) 23(1) C(1B) 6854(2) 5414(1) 7364(2) 15(1) C(11B) 6113(2) 5773(1) 7980(2) 12(1) C(1A) 3447(2) 5226(1) 3093(2) 16(1) C(13B) 3256(2) 4967(1) 10130(2) 15(1) C(17A) 471(2) 5488(1) 3110(2) 15(1) C(9B) 4345(2) 4804(1) 8693(2) 15(1) C(16B) 4716(2) 4789(1) 10890(2) 16(1) C(24B) 939(3) 3115(1) 10428(2) 28(1) C(6A) 1151(2) 6367(1) 3956(2) 17(1) C(11A) 2227(2) 5577(1) 3314(2) 14(1) C(5A) 2573(2) 5989(1) 4149(2) 13(1) C(8B) 5905(2) 4691(1) 9374(2) 16(1) C(22B) 1653(3) 3618(1) 11001(2) 22(1) C(10A) 83(2) 5132(1) 3927(2) 14(1) C(14A) -860(2) 4347(1) 4536(2) 14(1) C(29B) 5046(3) 2887(1) 11684(2) 26(1) C(6B) 5915(2) 6492(1) 9139(2) 15(1) 405 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(24A) -3098(3) 3016(1) 5953(2) 27(1) C(22A) -2378(2) 3531(1) 6467(2) 20(1) C(27A) 2614(3) 3231(1) 6415(2) 29(1) C(26B) 4954(3) 3207(1) 10695(2) 20(1) C(29A) 811(3) 2734(1) 7286(2) 30(1) C(9A) 421(2) 4529(1) 3979(2) 15(1) C(16A) 768(2) 4642(1) 6167(2) 13(1) C(7A) -104(2) 6070(1) 3179(2) 16(1) C(28A) 530(3) 2675(1) 5398(2) 27(1) C(25B) 1813(3) 3532(1) 12148(2) 35(1) C(23A) -3478(3) 3990(1) 6060(3) 32(1) C(28B) 4473(3) 2837(1) 9771(2) 26(1) C(21A) 5882(3) 6600(1) 2016(2) 30(1) C(21B) 10332(3) 6806(1) 6866(2) 37(1) C(23B) 520(3) 4089(1) 10688(3) 35(1) C(27B) 6602(3) 3410(1) 10686(3) 34(1) C(20B) 11536(3) 6842(1) 10841(2) 32(1) C(25A) -2292(3) 3501(1) 7619(2) 34(1) ________________________________________________________________________________ Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.3. Bond lengths [Å] and angles [°] for epoxy alcohol 262. _____________________________________________________ Si(1A)-O(4A) 1.6588(16) Si(1A)-O(3A) 1.6473(16) Si(1A)-C(26A) 1.899(2) Si(1A)-C(22A) 1.900(2) Si(1B)-O(3B) 1.6483(17) Si(1B)-O(4B) 1.6592(17) Si(1B)-C(22B) 1.900(2) Si(1B)-C(26B) 1.896(2) O(6A)-C(18A) 1.331(3) O(6A)-C(20A) 1.450(3) O(7A)-C(19A) 1.203(3) O(1B)-C(17B) 1.423(3) O(1B)-H(1B) 0.78(4) O(5A)-C(18A) 1.204(3) O(8A)-C(19A) 1.339(3) O(8A)-C(21A) 1.444(3) O(4A)-C(16A) 1.458(2) O(2B)-C(1B) 1.461(3) O(2B)-C(11B) 1.448(2) O(3B)-C(14B) 1.422(2) O(6B)-C(18B) 1.321(3) O(6B)-C(20B) 1.454(3) O(7B)-C(19B) 1.201(3) O(1A)-C(17A) 1.415(3) O(1A)-H(1A) 0.75(4) O(3A)-C(14A) 1.427(3) O(8B)-C(19B) 1.343(2) O(8B)-C(21B) 1.446(3) O(2A)-C(1A) 1.467(3) O(2A)-C(11A) 1.447(2) O(4B)-C(16B) 1.456(3) O(5B)-C(18B) 1.200(3) C(18A)-C(4A) 1.529(3) 406 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(2A)-H(2AA) 0.9900 C(2A)-H(2AB) 0.9900 C(2A)-C(3A) 1.542(3) C(2A)-C(1A) 1.510(3) C(18B)-C(4B) 1.524(3) C(14B)-H(14B) 1.0000 C(14B)-C(13B) 1.546(3) C(14B)-C(9B) 1.545(3) C(19A)-C(4A) 1.531(3) C(4A)-C(3A) 1.556(3) C(4A)-C(5A) 1.537(3) C(15A)-H(15A) 0.9500 C(15A)-C(8A) 1.332(3) C(15A)-C(16A) 1.514(3) C(19B)-C(4B) 1.528(3) C(12B)-H(12B) 0.9500 C(12B)-C(10B) 1.334(3) C(12B)-C(13B) 1.510(3) C(13A)-H(13A) 1.0000 C(13A)-C(12A) 1.511(3) C(13A)-C(14A) 1.547(3) C(13A)-C(16A) 1.532(3) C(12A)-H(12A) 0.9500 C(12A)-C(10A) 1.330(3) C(7B)-H(7BA) 0.9900 C(7B)-H(7BB) 0.9900 C(7B)-C(17B) 1.545(3) C(7B)-C(6B) 1.549(3) C(3B)-H(3BA) 0.9900 C(3B)-H(3BB) 0.9900 C(3B)-C(4B) 1.556(3) C(3B)-C(2B) 1.532(3) C(4B)-C(5B) 1.536(3) C(17B)-C(10B) 1.500(3) C(17B)-C(11B) 1.523(3) 407 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(10B)-C(9B) 1.536(3) C(2B)-H(2BA) 0.9900 C(2B)-H(2BB) 0.9900 C(2B)-C(1B) 1.507(3) C(15B)-H(15B) 0.9500 C(15B)-C(16B) 1.513(3) C(15B)-C(8B) 1.324(3) C(3A)-H(3AA) 0.9900 C(3A)-H(3AB) 0.9900 C(8A)-H(8A) 0.9500 C(8A)-C(9A) 1.516(3) C(26A)-C(27A) 1.541(3) C(26A)-C(29A) 1.542(3) C(26A)-C(28A) 1.528(3) C(5B)-H(5B) 1.0000 C(5B)-C(11B) 1.503(3) C(5B)-C(6B) 1.557(3) C(20A)-H(20A) 0.9800 C(20A)-H(20B) 0.9800 C(20A)-H(20C) 0.9800 C(1B)-H(1BA) 1.0000 C(1B)-C(11B) 1.459(3) C(1A)-H(1AA) 1.0000 C(1A)-C(11A) 1.462(3) C(13B)-H(13B) 1.0000 C(13B)-C(16B) 1.538(3) C(17A)-C(11A) 1.531(3) C(17A)-C(10A) 1.503(3) C(17A)-C(7A) 1.546(3) C(9B)-H(9B) 1.0000 C(9B)-C(8B) 1.517(3) C(16B)-H(16B) 1.0000 C(24B)-H(24D) 0.9800 C(24B)-H(24E) 0.9800 C(24B)-H(24F) 0.9800 408 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(24B)-C(22B) 1.539(3) C(6A)-H(6AA) 0.9900 C(6A)-H(6AB) 0.9900 C(6A)-C(5A) 1.547(3) C(6A)-C(7A) 1.548(3) C(11A)-C(5A) 1.508(3) C(5A)-H(5A) 1.0000 C(8B)-H(8B) 0.9500 C(22B)-C(25B) 1.532(4) C(22B)-C(23B) 1.545(3) C(10A)-C(9A) 1.534(3) C(14A)-H(14A) 1.0000 C(14A)-C(9A) 1.541(3) C(29B)-H(29D) 0.9800 C(29B)-H(29E) 0.9800 C(29B)-H(29F) 0.9800 C(29B)-C(26B) 1.537(3) C(6B)-H(6BA) 0.9900 C(6B)-H(6BB) 0.9900 C(24A)-H(24A) 0.9800 C(24A)-H(24B) 0.9800 C(24A)-H(24C) 0.9800 C(24A)-C(22A) 1.534(3) C(22A)-C(23A) 1.530(3) C(22A)-C(25A) 1.535(4) C(27A)-H(27A) 0.9800 C(27A)-H(27B) 0.9800 C(27A)-H(27C) 0.9800 C(26B)-C(28B) 1.536(4) C(26B)-C(27B) 1.540(3) C(29A)-H(29A) 0.9800 C(29A)-H(29B) 0.9800 C(29A)-H(29C) 0.9800 C(9A)-H(9A) 1.0000 C(16A)-H(16A) 1.0000 409 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(7A)-H(7AA) 0.9900 C(7A)-H(7AB) 0.9900 C(28A)-H(28A) 0.9800 C(28A)-H(28B) 0.9800 C(28A)-H(28C) 0.9800 C(25B)-H(25D) 0.9800 C(25B)-H(25E) 0.9800 C(25B)-H(25F) 0.9800 C(23A)-H(23A) 0.9800 C(23A)-H(23B) 0.9800 C(23A)-H(23C) 0.9800 C(28B)-H(28D) 0.9800 C(28B)-H(28E) 0.9800 C(28B)-H(28F) 0.9800 C(21A)-H(21A) 0.9800 C(21A)-H(21B) 0.9800 C(21A)-H(21C) 0.9800 C(21B)-H(21D) 0.9800 C(21B)-H(21E) 0.9800 C(21B)-H(21F) 0.9800 C(23B)-H(23D) 0.9800 C(23B)-H(23E) 0.9800 C(23B)-H(23F) 0.9800 C(27B)-H(27D) 0.9800 C(27B)-H(27E) 0.9800 C(27B)-H(27F) 0.9800 C(20B)-H(20D) 0.9800 C(20B)-H(20E) 0.9800 C(20B)-H(20F) 0.9800 C(25A)-H(25A) 0.9800 C(25A)-H(25B) 0.9800 C(25A)-H(25C) 0.9800 O(4A)-Si(1A)-C(26A) 112.20(9) O(4A)-Si(1A)-C(22A) 108.76(9) 410 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 O(3A)-Si(1A)-O(4A) 105.86(8) O(3A)-Si(1A)-C(26A) 106.49(9) O(3A)-Si(1A)-C(22A) 109.19(10) C(26A)-Si(1A)-C(22A) 113.97(10) O(3B)-Si(1B)-O(4B) 105.73(8) O(3B)-Si(1B)-C(22B) 110.10(10) O(3B)-Si(1B)-C(26B) 107.11(9) O(4B)-Si(1B)-C(22B) 107.86(9) O(4B)-Si(1B)-C(26B) 111.64(10) C(26B)-Si(1B)-C(22B) 114.08(10) C(18A)-O(6A)-C(20A) 115.06(17) C(17B)-O(1B)-H(1B) 106(3) C(19A)-O(8A)-C(21A) 114.45(18) C(16A)-O(4A)-Si(1A) 118.14(13) C(11B)-O(2B)-C(1B) 60.20(13) C(14B)-O(3B)-Si(1B) 123.88(13) C(18B)-O(6B)-C(20B) 115.11(18) C(17A)-O(1A)-H(1A) 105(3) C(14A)-O(3A)-Si(1A) 123.61(13) C(19B)-O(8B)-C(21B) 115.03(19) C(11A)-O(2A)-C(1A) 60.20(13) C(16B)-O(4B)-Si(1B) 118.41(13) O(6A)-C(18A)-C(4A) 112.17(17) O(5A)-C(18A)-O(6A) 123.8(2) O(5A)-C(18A)-C(4A) 123.99(19) H(2AA)-C(2A)-H(2AB) 107.4 C(3A)-C(2A)-H(2AA) 108.4 C(3A)-C(2A)-H(2AB) 108.4 C(1A)-C(2A)-H(2AA) 108.4 C(1A)-C(2A)-H(2AB) 108.4 C(1A)-C(2A)-C(3A) 115.70(17) O(6B)-C(18B)-C(4B) 113.06(18) O(5B)-C(18B)-O(6B) 124.0(2) O(5B)-C(18B)-C(4B) 122.9(2) O(3B)-C(14B)-H(14B) 109.5 411 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 O(3B)-C(14B)-C(13B) 115.46(17) O(3B)-C(14B)-C(9B) 113.19(16) C(13B)-C(14B)-H(14B) 109.5 C(9B)-C(14B)-H(14B) 109.5 C(9B)-C(14B)-C(13B) 99.29(16) O(7A)-C(19A)-O(8A) 123.59(19) O(7A)-C(19A)-C(4A) 124.09(19) O(8A)-C(19A)-C(4A) 112.29(18) C(18A)-C(4A)-C(19A) 107.48(17) C(18A)-C(4A)-C(3A) 109.07(16) C(18A)-C(4A)-C(5A) 107.81(16) C(19A)-C(4A)-C(3A) 113.54(17) C(19A)-C(4A)-C(5A) 112.63(17) C(5A)-C(4A)-C(3A) 106.15(17) C(8A)-C(15A)-H(15A) 118.9 C(8A)-C(15A)-C(16A) 122.13(19) C(16A)-C(15A)-H(15A) 118.9 O(7B)-C(19B)-O(8B) 123.9(2) O(7B)-C(19B)-C(4B) 124.64(19) O(8B)-C(19B)-C(4B) 111.40(18) C(10B)-C(12B)-H(12B) 124.6 C(10B)-C(12B)-C(13B) 110.84(18) C(13B)-C(12B)-H(12B) 124.6 C(12A)-C(13A)-H(13A) 111.7 C(12A)-C(13A)-C(14A) 99.69(16) C(12A)-C(13A)-C(16A) 114.18(16) C(14A)-C(13A)-H(13A) 111.7 C(16A)-C(13A)-H(13A) 111.7 C(16A)-C(13A)-C(14A) 107.09(16) C(13A)-C(12A)-H(12A) 124.7 C(10A)-C(12A)-C(13A) 110.53(18) C(10A)-C(12A)-H(12A) 124.7 H(7BA)-C(7B)-H(7BB) 108.7 C(17B)-C(7B)-H(7BA) 110.5 C(17B)-C(7B)-H(7BB) 110.5 412 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(17B)-C(7B)-C(6B) 105.93(16) C(6B)-C(7B)-H(7BA) 110.5 C(6B)-C(7B)-H(7BB) 110.5 H(3BA)-C(3B)-H(3BB) 107.6 C(4B)-C(3B)-H(3BA) 108.7 C(4B)-C(3B)-H(3BB) 108.7 C(2B)-C(3B)-H(3BA) 108.7 C(2B)-C(3B)-H(3BB) 108.7 C(2B)-C(3B)-C(4B) 114.22(17) C(18B)-C(4B)-C(19B) 108.01(17) C(18B)-C(4B)-C(3B) 106.28(17) C(18B)-C(4B)-C(5B) 108.28(16) C(19B)-C(4B)-C(3B) 113.80(17) C(19B)-C(4B)-C(5B) 113.97(16) C(5B)-C(4B)-C(3B) 106.13(16) O(1B)-C(17B)-C(7B) 114.45(16) O(1B)-C(17B)-C(10B) 106.65(16) O(1B)-C(17B)-C(11B) 112.85(16) C(10B)-C(17B)-C(7B) 113.59(17) C(10B)-C(17B)-C(11B) 109.95(16) C(11B)-C(17B)-C(7B) 99.36(15) C(12B)-C(10B)-C(17B) 128.58(19) C(12B)-C(10B)-C(9B) 108.26(18) C(17B)-C(10B)-C(9B) 123.03(17) C(3B)-C(2B)-H(2BA) 108.6 C(3B)-C(2B)-H(2BB) 108.6 H(2BA)-C(2B)-H(2BB) 107.6 C(1B)-C(2B)-C(3B) 114.73(17) C(1B)-C(2B)-H(2BA) 108.6 C(1B)-C(2B)-H(2BB) 108.6 C(16B)-C(15B)-H(15B) 119.1 C(8B)-C(15B)-H(15B) 119.1 C(8B)-C(15B)-C(16B) 121.8(2) C(2A)-C(3A)-C(4A) 114.13(17) C(2A)-C(3A)-H(3AA) 108.7 413 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(2A)-C(3A)-H(3AB) 108.7 C(4A)-C(3A)-H(3AA) 108.7 C(4A)-C(3A)-H(3AB) 108.7 H(3AA)-C(3A)-H(3AB) 107.6 C(15A)-C(8A)-H(8A) 119.8 C(15A)-C(8A)-C(9A) 120.46(19) C(9A)-C(8A)-H(8A) 119.8 C(27A)-C(26A)-Si(1A) 109.86(16) C(27A)-C(26A)-C(29A) 107.4(2) C(29A)-C(26A)-Si(1A) 112.31(16) C(28A)-C(26A)-Si(1A) 110.04(16) C(28A)-C(26A)-C(27A) 107.91(19) C(28A)-C(26A)-C(29A) 109.2(2) C(4B)-C(5B)-H(5B) 106.5 C(4B)-C(5B)-C(6B) 121.77(17) C(11B)-C(5B)-C(4B) 110.98(16) C(11B)-C(5B)-H(5B) 106.5 C(11B)-C(5B)-C(6B) 103.55(16) C(6B)-C(5B)-H(5B) 106.5 O(6A)-C(20A)-H(20A) 109.5 O(6A)-C(20A)-H(20B) 109.5 O(6A)-C(20A)-H(20C) 109.5 H(20A)-C(20A)-H(20B) 109.5 H(20A)-C(20A)-H(20C) 109.5 H(20B)-C(20A)-H(20C) 109.5 O(2B)-C(1B)-C(2B) 113.35(18) O(2B)-C(1B)-H(1BA) 117.1 C(2B)-C(1B)-H(1BA) 117.1 C(11B)-C(1B)-O(2B) 59.47(13) C(11B)-C(1B)-C(2B) 119.65(18) C(11B)-C(1B)-H(1BA) 117.1 O(2B)-C(11B)-C(17B) 114.71(16) O(2B)-C(11B)-C(5B) 115.82(16) O(2B)-C(11B)-C(1B) 60.33(13) C(5B)-C(11B)-C(17B) 106.44(16) 414 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(1B)-C(11B)-C(17B) 128.31(18) C(1B)-C(11B)-C(5B) 122.08(17) O(2A)-C(1A)-C(2A) 115.00(18) O(2A)-C(1A)-H(1AA) 116.7 C(2A)-C(1A)-H(1AA) 116.7 C(11A)-C(1A)-O(2A) 59.21(13) C(11A)-C(1A)-C(2A) 119.75(19) C(11A)-C(1A)-H(1AA) 116.7 C(14B)-C(13B)-H(13B) 112.0 C(12B)-C(13B)-C(14B) 100.18(17) C(12B)-C(13B)-H(13B) 112.0 C(12B)-C(13B)-C(16B) 113.05(17) C(16B)-C(13B)-C(14B) 106.88(17) C(16B)-C(13B)-H(13B) 112.0 O(1A)-C(17A)-C(11A) 113.37(17) O(1A)-C(17A)-C(10A) 106.75(17) O(1A)-C(17A)-C(7A) 114.45(17) C(11A)-C(17A)-C(7A) 100.62(16) C(10A)-C(17A)-C(11A) 108.91(17) C(10A)-C(17A)-C(7A) 112.71(17) C(14B)-C(9B)-H(9B) 113.6 C(10B)-C(9B)-C(14B) 99.43(16) C(10B)-C(9B)-H(9B) 113.6 C(8B)-C(9B)-C(14B) 108.23(17) C(8B)-C(9B)-C(10B) 107.41(17) C(8B)-C(9B)-H(9B) 113.6 O(4B)-C(16B)-C(15B) 109.99(17) O(4B)-C(16B)-C(13B) 108.24(16) O(4B)-C(16B)-H(16B) 108.9 C(15B)-C(16B)-C(13B) 111.82(18) C(15B)-C(16B)-H(16B) 108.9 C(13B)-C(16B)-H(16B) 108.9 H(24D)-C(24B)-H(24E) 109.5 H(24D)-C(24B)-H(24F) 109.5 H(24E)-C(24B)-H(24F) 109.5 415 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(22B)-C(24B)-H(24D) 109.5 C(22B)-C(24B)-H(24E) 109.5 C(22B)-C(24B)-H(24F) 109.5 H(6AA)-C(6A)-H(6AB) 108.8 C(5A)-C(6A)-H(6AA) 110.7 C(5A)-C(6A)-H(6AB) 110.7 C(5A)-C(6A)-C(7A) 105.37(16) C(7A)-C(6A)-H(6AA) 110.7 C(7A)-C(6A)-H(6AB) 110.7 O(2A)-C(11A)-C(1A) 60.59(13) O(2A)-C(11A)-C(17A) 116.03(17) O(2A)-C(11A)-C(5A) 115.59(17) C(1A)-C(11A)-C(17A) 129.30(19) C(1A)-C(11A)-C(5A) 120.87(18) C(5A)-C(11A)-C(17A) 106.12(16) C(4A)-C(5A)-C(6A) 120.71(17) C(4A)-C(5A)-H(5A) 106.5 C(6A)-C(5A)-H(5A) 106.5 C(11A)-C(5A)-C(4A) 110.91(16) C(11A)-C(5A)-C(6A) 104.79(16) C(11A)-C(5A)-H(5A) 106.5 C(15B)-C(8B)-C(9B) 120.95(18) C(15B)-C(8B)-H(8B) 119.5 C(9B)-C(8B)-H(8B) 119.5 C(24B)-C(22B)-Si(1B) 110.71(15) C(24B)-C(22B)-C(23B) 107.9(2) C(25B)-C(22B)-Si(1B) 112.58(18) C(25B)-C(22B)-C(24B) 109.5(2) C(25B)-C(22B)-C(23B) 107.7(2) C(23B)-C(22B)-Si(1B) 108.20(16) C(12A)-C(10A)-C(17A) 128.24(19) C(12A)-C(10A)-C(9A) 108.72(18) C(17A)-C(10A)-C(9A) 122.89(18) O(3A)-C(14A)-C(13A) 114.88(17) O(3A)-C(14A)-H(14A) 109.5 416 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 O(3A)-C(14A)-C(9A) 113.71(16) C(13A)-C(14A)-H(14A) 109.5 C(9A)-C(14A)-C(13A) 99.37(16) C(9A)-C(14A)-H(14A) 109.5 H(29D)-C(29B)-H(29E) 109.5 H(29D)-C(29B)-H(29F) 109.5 H(29E)-C(29B)-H(29F) 109.5 C(26B)-C(29B)-H(29D) 109.5 C(26B)-C(29B)-H(29E) 109.5 C(26B)-C(29B)-H(29F) 109.5 C(7B)-C(6B)-C(5B) 105.40(16) C(7B)-C(6B)-H(6BA) 110.7 C(7B)-C(6B)-H(6BB) 110.7 C(5B)-C(6B)-H(6BA) 110.7 C(5B)-C(6B)-H(6BB) 110.7 H(6BA)-C(6B)-H(6BB) 108.8 H(24A)-C(24A)-H(24B) 109.5 H(24A)-C(24A)-H(24C) 109.5 H(24B)-C(24A)-H(24C) 109.5 C(22A)-C(24A)-H(24A) 109.5 C(22A)-C(24A)-H(24B) 109.5 C(22A)-C(24A)-H(24C) 109.5 C(24A)-C(22A)-Si(1A) 109.78(15) C(24A)-C(22A)-C(25A) 110.2(2) C(23A)-C(22A)-Si(1A) 109.42(15) C(23A)-C(22A)-C(24A) 107.0(2) C(23A)-C(22A)-C(25A) 107.3(2) C(25A)-C(22A)-Si(1A) 112.99(17) C(26A)-C(27A)-H(27A) 109.5 C(26A)-C(27A)-H(27B) 109.5 C(26A)-C(27A)-H(27C) 109.5 H(27A)-C(27A)-H(27B) 109.5 H(27A)-C(27A)-H(27C) 109.5 H(27B)-C(27A)-H(27C) 109.5 C(29B)-C(26B)-Si(1B) 111.03(16) 417 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(29B)-C(26B)-C(27B) 106.9(2) C(28B)-C(26B)-Si(1B) 111.06(16) C(28B)-C(26B)-C(29B) 110.13(19) C(28B)-C(26B)-C(27B) 107.4(2) C(27B)-C(26B)-Si(1B) 110.16(16) C(26A)-C(29A)-H(29A) 109.5 C(26A)-C(29A)-H(29B) 109.5 C(26A)-C(29A)-H(29C) 109.5 H(29A)-C(29A)-H(29B) 109.5 H(29A)-C(29A)-H(29C) 109.5 H(29B)-C(29A)-H(29C) 109.5 C(8A)-C(9A)-C(10A) 108.19(17) C(8A)-C(9A)-C(14A) 108.27(17) C(8A)-C(9A)-H(9A) 113.4 C(10A)-C(9A)-C(14A) 99.01(16) C(10A)-C(9A)-H(9A) 113.4 C(14A)-C(9A)-H(9A) 113.4 O(4A)-C(16A)-C(15A) 110.26(16) O(4A)-C(16A)-C(13A) 108.11(16) O(4A)-C(16A)-H(16A) 108.9 C(15A)-C(16A)-C(13A) 111.62(17) C(15A)-C(16A)-H(16A) 108.9 C(13A)-C(16A)-H(16A) 108.9 C(17A)-C(7A)-C(6A) 107.01(17) C(17A)-C(7A)-H(7AA) 110.3 C(17A)-C(7A)-H(7AB) 110.3 C(6A)-C(7A)-H(7AA) 110.3 C(6A)-C(7A)-H(7AB) 110.3 H(7AA)-C(7A)-H(7AB) 108.6 C(26A)-C(28A)-H(28A) 109.5 C(26A)-C(28A)-H(28B) 109.5 C(26A)-C(28A)-H(28C) 109.5 H(28A)-C(28A)-H(28B) 109.5 H(28A)-C(28A)-H(28C) 109.5 H(28B)-C(28A)-H(28C) 109.5 418 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(22B)-C(25B)-H(25D) 109.5 C(22B)-C(25B)-H(25E) 109.5 C(22B)-C(25B)-H(25F) 109.5 H(25D)-C(25B)-H(25E) 109.5 H(25D)-C(25B)-H(25F) 109.5 H(25E)-C(25B)-H(25F) 109.5 C(22A)-C(23A)-H(23A) 109.5 C(22A)-C(23A)-H(23B) 109.5 C(22A)-C(23A)-H(23C) 109.5 H(23A)-C(23A)-H(23B) 109.5 H(23A)-C(23A)-H(23C) 109.5 H(23B)-C(23A)-H(23C) 109.5 C(26B)-C(28B)-H(28D) 109.5 C(26B)-C(28B)-H(28E) 109.5 C(26B)-C(28B)-H(28F) 109.5 H(28D)-C(28B)-H(28E) 109.5 H(28D)-C(28B)-H(28F) 109.5 H(28E)-C(28B)-H(28F) 109.5 O(8A)-C(21A)-H(21A) 109.5 O(8A)-C(21A)-H(21B) 109.5 O(8A)-C(21A)-H(21C) 109.5 H(21A)-C(21A)-H(21B) 109.5 H(21A)-C(21A)-H(21C) 109.5 H(21B)-C(21A)-H(21C) 109.5 O(8B)-C(21B)-H(21D) 109.5 O(8B)-C(21B)-H(21E) 109.5 O(8B)-C(21B)-H(21F) 109.5 H(21D)-C(21B)-H(21E) 109.5 H(21D)-C(21B)-H(21F) 109.5 H(21E)-C(21B)-H(21F) 109.5 C(22B)-C(23B)-H(23D) 109.5 C(22B)-C(23B)-H(23E) 109.5 C(22B)-C(23B)-H(23F) 109.5 H(23D)-C(23B)-H(23E) 109.5 H(23D)-C(23B)-H(23F) 109.5 419 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 H(23E)-C(23B)-H(23F) 109.5 C(26B)-C(27B)-H(27D) 109.5 C(26B)-C(27B)-H(27E) 109.5 C(26B)-C(27B)-H(27F) 109.5 H(27D)-C(27B)-H(27E) 109.5 H(27D)-C(27B)-H(27F) 109.5 H(27E)-C(27B)-H(27F) 109.5 O(6B)-C(20B)-H(20D) 109.5 O(6B)-C(20B)-H(20E) 109.5 O(6B)-C(20B)-H(20F) 109.5 H(20D)-C(20B)-H(20E) 109.5 H(20D)-C(20B)-H(20F) 109.5 H(20E)-C(20B)-H(20F) 109.5 C(22A)-C(25A)-H(25A) 109.5 C(22A)-C(25A)-H(25B) 109.5 C(22A)-C(25A)-H(25C) 109.5 H(25A)-C(25A)-H(25B) 109.5 H(25A)-C(25A)-H(25C) 109.5 H(25B)-C(25A)-H(25C) 109.5 _____________________________________________________________ 420 421 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.4. Anisotropic displacement parameters (Å2 x 103) for epoxy alcohol 262. The anisotropic displacement factor exponent takes the form: -2π2[h2 a*2U11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ Si(1A) 12(1) 12(1) 19(1) -1(1) 5(1) 0(1) Si(1B) 14(1) 12(1) 19(1) 1(1) 6(1) -1(1) O(6A) 19(1) 24(1) 14(1) -3(1) 3(1) -6(1) O(7A) 21(1) 19(1) 15(1) 2(1) 1(1) -1(1) O(1B) 16(1) 18(1) 15(1) 2(1) -2(1) -2(1) O(5A) 21(1) 21(1) 14(1) 0(1) 5(1) 0(1) O(8A) 15(1) 33(1) 13(1) 4(1) 4(1) -1(1) O(4A) 16(1) 14(1) 15(1) 1(1) 4(1) -2(1) O(2B) 18(1) 18(1) 11(1) -1(1) 4(1) 3(1) O(3B) 20(1) 10(1) 20(1) -1(1) 3(1) -1(1) O(6B) 22(1) 31(1) 14(1) 0(1) -2(1) -11(1) O(7B) 19(1) 19(1) 16(1) 5(1) 4(1) 1(1) O(1A) 23(1) 22(1) 13(1) -1(1) 0(1) -3(1) O(3A) 18(1) 11(1) 18(1) -2(1) 3(1) -2(1) O(8B) 19(1) 31(1) 19(1) 6(1) 9(1) 5(1) O(2A) 18(1) 19(1) 13(1) 1(1) 5(1) 2(1) O(4B) 22(1) 14(1) 17(1) 2(1) 5(1) -4(1) O(5B) 43(1) 47(1) 12(1) 7(1) -6(1) -21(1) C(18A) 14(1) 16(1) 12(1) 2(1) -1(1) 3(1) C(2A) 18(1) 20(1) 19(1) 0(1) 5(1) 6(1) C(18B) 15(1) 19(1) 14(1) 1(1) -2(1) 0(1) C(14B) 15(1) 12(1) 17(1) 0(1) 2(1) -1(1) C(19A) 16(1) 19(1) 11(1) -2(1) 1(1) -5(1) C(4A) 12(1) 16(1) 11(1) 0(1) 2(1) 1(1) C(15A) 10(1) 15(1) 21(1) 1(1) 4(1) -1(1) C(19B) 12(1) 22(1) 11(1) 2(1) 0(1) -1(1) C(12B) 12(1) 12(1) 20(1) 0(1) 4(1) 2(1) C(13A) 12(1) 12(1) 16(1) -1(1) 4(1) -1(1) C(12A) 14(1) 12(1) 18(1) 1(1) 3(1) 0(1) 422 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(7B) 14(1) 13(1) 16(1) 1(1) 4(1) 2(1) C(3B) 14(1) 20(1) 18(1) 1(1) 1(1) 5(1) C(4B) 14(1) 16(1) 10(1) 1(1) 0(1) 1(1) C(17B) 12(1) 13(1) 12(1) 1(1) 1(1) 1(1) C(10B) 10(1) 11(1) 16(1) 1(1) 0(1) 1(1) C(2B) 19(1) 20(1) 21(1) -5(1) 6(1) 5(1) C(15B) 13(1) 14(1) 24(1) 4(1) 3(1) -1(1) C(3A) 16(1) 21(1) 13(1) 1(1) 2(1) 4(1) C(8A) 17(1) 13(1) 20(1) 3(1) 6(1) 3(1) C(26A) 16(1) 16(1) 27(1) 3(1) 9(1) 3(1) C(5B) 14(1) 12(1) 9(1) 0(1) 3(1) 0(1) C(20A) 25(1) 26(1) 17(1) -6(1) 1(1) -6(1) C(1B) 17(1) 15(1) 13(1) -3(1) 2(1) 2(1) C(11B) 13(1) 13(1) 9(1) 0(1) 1(1) 1(1) C(1A) 18(1) 16(1) 14(1) 1(1) 5(1) 3(1) C(13B) 16(1) 12(1) 17(1) 0(1) 6(1) 0(1) C(17A) 16(1) 16(1) 12(1) 1(1) 2(1) 2(1) C(9B) 19(1) 12(1) 14(1) -1(1) 5(1) 0(1) C(16B) 18(1) 14(1) 15(1) 0(1) 3(1) -4(1) C(24B) 21(1) 22(1) 44(2) -5(1) 12(1) -5(1) C(6A) 15(1) 14(1) 22(1) -1(1) 4(1) 2(1) C(11A) 14(1) 15(1) 12(1) 1(1) 4(1) 1(1) C(5A) 13(1) 14(1) 13(1) 0(1) 4(1) 2(1) C(8B) 15(1) 12(1) 23(1) 3(1) 7(1) 3(1) C(22B) 18(1) 17(1) 34(1) -2(1) 14(1) -2(1) C(10A) 13(1) 14(1) 16(1) 1(1) 1(1) 1(1) C(14A) 14(1) 12(1) 17(1) -1(1) 1(1) 0(1) C(29B) 29(1) 18(1) 31(1) 6(1) 3(1) -1(1) C(6B) 17(1) 14(1) 14(1) -4(1) 5(1) 1(1) C(24A) 18(1) 18(1) 47(2) -4(1) 11(1) -4(1) C(22A) 16(1) 16(1) 30(1) -1(1) 9(1) -1(1) C(27A) 16(1) 24(1) 48(2) 6(1) 9(1) 4(1) C(26B) 16(1) 16(1) 29(1) 6(1) 9(1) 1(1) C(29A) 28(1) 30(1) 35(2) 14(1) 10(1) 10(1) C(9A) 19(1) 14(1) 14(1) -2(1) 4(1) 1(1) 423 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(16A) 14(1) 12(1) 14(1) -1(1) 5(1) -2(1) C(7A) 16(1) 16(1) 16(1) 2(1) 2(1) 4(1) C(28A) 32(1) 16(1) 37(2) -2(1) 16(1) 3(1) C(25B) 45(2) 27(1) 40(2) -4(1) 30(1) -5(1) C(23A) 17(1) 19(1) 63(2) 6(1) 18(1) 2(1) C(28B) 32(1) 17(1) 34(1) 2(1) 16(1) 6(1) C(21A) 19(1) 55(2) 16(1) 10(1) 5(1) -3(1) C(21B) 37(2) 49(2) 30(2) 17(1) 20(1) 7(1) C(23B) 19(1) 24(1) 67(2) 2(1) 22(1) 3(1) C(27B) 17(1) 22(1) 65(2) 12(1) 16(1) 4(1) C(20B) 27(1) 44(2) 20(1) -5(1) -5(1) -14(1) C(25A) 31(1) 40(2) 36(2) -3(1) 20(1) -2(1) ______________________________________________________________________________ 424 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.5. Hydrogen coordinates (x 104) and isotropic displacement parameters (Å2 x 103) for epoxy alcohol 262. ________________________________________________________________________________ x y z U(eq) ________________________________________________________________________________ H(2AA) 5782 5345 3220 23 H(2AB) 5389 4935 4044 23 H(14B) 2029 4636 8763 18 H(15A) 3130 4471 6103 18 H(12B) 3241 5833 9851 17 H(13A) -1621 4812 5674 16 H(12A) -738 5628 4894 17 H(7BA) 3474 6448 8743 17 H(7BB) 4233 6646 7812 17 H(3BA) 10483 5609 8664 22 H(3BB) 9273 5324 9234 22 H(2BA) 9077 5437 7117 23 H(2BB) 8733 4915 7723 23 H(15B) 7081 4652 10784 21 H(3AA) 6420 5858 4591 20 H(3AB) 5208 5575 5164 20 H(8A) 2848 4339 4408 19 H(5B) 7006 5759 9494 14 H(20A) 6811 7578 5783 35 H(20B) 6345 7144 6547 35 H(20C) 5056 7538 5933 35 H(1BA) 6197 5126 6979 18 H(1AA) 3121 4861 2824 19 H(13B) 2317 4971 10444 18 H(9B) 4264 4675 7979 18 H(16B) 4995 5072 11423 19 H(24D) 908 3160 9700 42 H(24E) -116 3064 10543 42 H(24F) 1571 2801 10678 42 425 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 H(6AA) 1414 6714 3675 20 H(6AB) 783 6435 4594 20 H(5A) 2552 5797 4799 16 H(8B) 6772 4611 9078 19 H(14A) -1895 4385 4072 17 H(29D) 5339 3128 12267 39 H(29E) 5824 2604 11720 39 H(29F) 4033 2727 11694 39 H(6BA) 5773 6485 9851 18 H(6BB) 6359 6843 9006 18 H(24A) -3156 3041 5218 40 H(24B) -4143 2970 6089 40 H(24C) -2454 2708 6223 40 H(27A) 2738 3412 5789 43 H(27B) 3300 2918 6531 43 H(27C) 2884 3479 6989 43 H(29A) 1051 2973 7875 46 H(29B) 1554 2437 7372 46 H(29C) -241 2591 7227 46 H(9A) 343 4359 3296 18 H(16A) 1049 4955 6634 15 H(7AA) -1105 6072 3408 20 H(7AB) -252 6246 2506 20 H(28A) -538 2546 5327 41 H(28B) 1243 2369 5496 41 H(28C) 637 2870 4782 41 H(25D) 2402 3203 12350 52 H(25E) 781 3500 12311 52 H(25F) 2360 3837 12515 52 H(23A) -3070 4327 6385 47 H(23B) -4503 3919 6210 47 H(23C) -3565 4020 5323 47 H(28D) 3444 2687 9772 39 H(28E) 5227 2545 9807 39 H(28F) 4442 3042 9146 39 426 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 H(21A) 5044 6470 1477 44 H(21B) 6884 6496 1864 44 H(21C) 5826 6992 2055 44 H(21D) 9439 6837 6301 55 H(21E) 11246 6695 6605 55 H(21F) 10533 7154 7207 55 H(23D) 893 4405 11099 52 H(23E) -510 3990 10799 52 H(23F) 459 4172 9967 52 H(27D) 6599 3608 10055 51 H(27E) 7311 3104 10728 51 H(27F) 6946 3647 11269 51 H(20D) 12329 7099 10730 47 H(20E) 12038 6530 11210 47 H(20F) 10851 7013 11239 47 H(25A) -1696 3184 7894 51 H(25B) -3343 3476 7755 51 H(25C) -1783 3823 7943 51 H(1B) 3550(40) 5932(15) 6710(30) 51 H(1A) 10(40) 5430(15) 1780(30) 51 ________________________________________________________________________________ Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 Table A3.6. Torsion angles [°] for epoxy alcohol 262. ________________________________________________________________ Si(1A)-O(4A)-C(16A)-C(15A) -71.36(19) Si(1A)-O(4A)-C(16A)-C(13A) 50.91(18) Si(1A)-O(3A)-C(14A)-C(13A) 4.5(2) Si(1A)-O(3A)-C(14A)-C(9A) 118.06(17) Si(1B)-O(3B)-C(14B)-C(13B) 3.5(2) Si(1B)-O(3B)-C(14B)-C(9B) 116.99(17) Si(1B)-O(4B)-C(16B)-C(15B) -71.0(2) Si(1B)-O(4B)-C(16B)-C(13B) 51.4(2) O(6A)-C(18A)-C(4A)-C(19A) -38.0(2) O(6A)-C(18A)-C(4A)-C(3A) 85.5(2) O(6A)-C(18A)-C(4A)-C(5A) -159.66(17) O(7A)-C(19A)-C(4A)-C(18A) -68.7(3) O(7A)-C(19A)-C(4A)-C(3A) 170.5(2) O(7A)-C(19A)-C(4A)-C(5A) 49.9(3) O(1B)-C(17B)-C(10B)-C(12B) -117.6(2) O(1B)-C(17B)-C(10B)-C(9B) 67.1(2) O(1B)-C(17B)-C(11B)-O(2B) 36.7(2) O(1B)-C(17B)-C(11B)-C(5B) 166.21(16) O(1B)-C(17B)-C(11B)-C(1B) -33.9(3) O(5A)-C(18A)-C(4A)-C(19A) 142.1(2) O(5A)-C(18A)-C(4A)-C(3A) -94.5(2) O(5A)-C(18A)-C(4A)-C(5A) 20.4(3) O(8A)-C(19A)-C(4A)-C(18A) 109.53(19) O(8A)-C(19A)-C(4A)-C(3A) -11.2(2) O(8A)-C(19A)-C(4A)-C(5A) -131.87(18) O(4A)-Si(1A)-O(3A)-C(14A) -26.29(16) O(4A)-Si(1A)-C(26A)-C(27A) -34.4(2) O(4A)-Si(1A)-C(26A)-C(29A) 85.08(18) O(4A)-Si(1A)-C(26A)-C(28A) -153.06(14) O(2B)-C(1B)-C(11B)-C(17B) 99.4(2) O(2B)-C(1B)-C(11B)-C(5B) -103.6(2) O(3B)-Si(1B)-O(4B)-C(16B) -4.46(16) O(3B)-Si(1B)-C(22B)-C(24B) 71.23(19) 427 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 O(3B)-Si(1B)-C(22B)-C(25B) -165.81(16) O(3B)-Si(1B)-C(22B)-C(23B) -46.8(2) O(3B)-Si(1B)-C(26B)-C(29B) -167.99(15) O(3B)-Si(1B)-C(26B)-C(28B) -45.10(17) O(3B)-Si(1B)-C(26B)-C(27B) 73.8(2) O(3B)-C(14B)-C(13B)-C(12B) 163.40(16) O(3B)-C(14B)-C(13B)-C(16B) 45.3(2) O(3B)-C(14B)-C(9B)-C(10B) -167.12(17) O(3B)-C(14B)-C(9B)-C(8B) -55.2(2) O(6B)-C(18B)-C(4B)-C(19B) -18.9(2) O(6B)-C(18B)-C(4B)-C(3B) 103.6(2) O(6B)-C(18B)-C(4B)-C(5B) -142.76(18) O(7B)-C(19B)-C(4B)-C(18B) -76.6(3) O(7B)-C(19B)-C(4B)-C(3B) 165.7(2) O(7B)-C(19B)-C(4B)-C(5B) 43.8(3) O(1A)-C(17A)-C(11A)-O(2A) 33.4(2) O(1A)-C(17A)-C(11A)-C(1A) -38.8(3) O(1A)-C(17A)-C(11A)-C(5A) 163.26(17) O(1A)-C(17A)-C(10A)-C(12A) -135.8(2) O(1A)-C(17A)-C(10A)-C(9A) 49.0(2) O(1A)-C(17A)-C(7A)-C(6A) -153.31(18) O(3A)-Si(1A)-O(4A)-C(16A) -3.15(15) O(3A)-Si(1A)-C(26A)-C(27A) 80.99(19) O(3A)-Si(1A)-C(26A)-C(29A) -159.54(17) O(3A)-Si(1A)-C(26A)-C(28A) -37.68(17) O(3A)-C(14A)-C(9A)-C(8A) -54.5(2) O(3A)-C(14A)-C(9A)-C(10A) -167.18(17) O(8B)-C(19B)-C(4B)-C(18B) 99.9(2) O(8B)-C(19B)-C(4B)-C(3B) -17.8(2) O(8B)-C(19B)-C(4B)-C(5B) -139.69(18) O(2A)-C(1A)-C(11A)-C(17A) 100.9(2) O(2A)-C(1A)-C(11A)-C(5A) -103.9(2) O(2A)-C(11A)-C(5A)-C(4A) -36.0(2) O(2A)-C(11A)-C(5A)-C(6A) 95.80(19) O(4B)-Si(1B)-O(3B)-C(14B) -24.72(17) 428 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 O(4B)-Si(1B)-C(22B)-C(24B) -173.86(17) O(4B)-Si(1B)-C(22B)-C(25B) -50.90(19) O(4B)-Si(1B)-C(22B)-C(23B) 68.1(2) O(4B)-Si(1B)-C(26B)-C(29B) 76.71(17) O(4B)-Si(1B)-C(26B)-C(28B) -160.39(14) O(4B)-Si(1B)-C(26B)-C(27B) -41.5(2) O(5B)-C(18B)-C(4B)-C(19B) 163.3(2) O(5B)-C(18B)-C(4B)-C(3B) -74.2(3) O(5B)-C(18B)-C(4B)-C(5B) 39.4(3) C(18A)-C(4A)-C(3A)-C(2A) 175.82(17) C(18A)-C(4A)-C(5A)-C(6A) 59.5(2) C(18A)-C(4A)-C(5A)-C(11A) -177.49(17) C(2A)-C(1A)-C(11A)-O(2A) 103.1(2) C(2A)-C(1A)-C(11A)-C(17A) -156.0(2) C(2A)-C(1A)-C(11A)-C(5A) -0.9(3) C(18B)-C(4B)-C(5B)-C(11B) -171.67(17) C(18B)-C(4B)-C(5B)-C(6B) 66.1(2) C(14B)-C(13B)-C(16B)-O(4B) -73.0(2) C(14B)-C(13B)-C(16B)-C(15B) 48.3(2) C(14B)-C(9B)-C(8B)-C(15B) -34.7(3) C(19A)-C(4A)-C(3A)-C(2A) -64.4(2) C(19A)-C(4A)-C(5A)-C(6A) -58.9(2) C(19A)-C(4A)-C(5A)-C(11A) 64.1(2) C(15A)-C(8A)-C(9A)-C(10A) 71.8(2) C(15A)-C(8A)-C(9A)-C(14A) -34.6(3) C(19B)-C(4B)-C(5B)-C(11B) 68.1(2) C(19B)-C(4B)-C(5B)-C(6B) -54.1(3) C(12B)-C(10B)-C(9B)-C(14B) 31.2(2) C(12B)-C(10B)-C(9B)-C(8B) -81.4(2) C(12B)-C(13B)-C(16B)-O(4B) 177.69(16) C(12B)-C(13B)-C(16B)-C(15B) -61.0(2) C(13A)-C(12A)-C(10A)-C(17A) -179.08(19) C(13A)-C(12A)-C(10A)-C(9A) -3.3(2) C(13A)-C(14A)-C(9A)-C(8A) 68.04(19) C(13A)-C(14A)-C(9A)-C(10A) -44.62(18) 429 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(12A)-C(13A)-C(14A)-O(3A) 164.74(16) C(12A)-C(13A)-C(14A)-C(9A) 43.02(18) C(12A)-C(13A)-C(16A)-O(4A) 176.92(16) C(12A)-C(13A)-C(16A)-C(15A) -61.6(2) C(12A)-C(10A)-C(9A)-C(8A) -81.7(2) C(12A)-C(10A)-C(9A)-C(14A) 31.0(2) C(7B)-C(17B)-C(10B)-C(12B) 9.4(3) C(7B)-C(17B)-C(10B)-C(9B) -165.92(18) C(7B)-C(17B)-C(11B)-O(2B) -84.90(19) C(7B)-C(17B)-C(11B)-C(5B) 44.57(19) C(7B)-C(17B)-C(11B)-C(1B) -155.6(2) C(3B)-C(4B)-C(5B)-C(11B) -57.9(2) C(3B)-C(4B)-C(5B)-C(6B) 179.91(18) C(3B)-C(2B)-C(1B)-O(2B) 71.0(2) C(3B)-C(2B)-C(1B)-C(11B) 4.0(3) C(4B)-C(3B)-C(2B)-C(1B) -34.9(3) C(4B)-C(5B)-C(11B)-O(2B) -38.7(2) C(4B)-C(5B)-C(11B)-C(17B) -167.54(16) C(4B)-C(5B)-C(11B)-C(1B) 31.1(3) C(4B)-C(5B)-C(6B)-C(7B) 136.71(18) C(17B)-C(7B)-C(6B)-C(5B) 16.1(2) C(17B)-C(10B)-C(9B)-C(14B) -152.61(18) C(17B)-C(10B)-C(9B)-C(8B) 94.8(2) C(10B)-C(12B)-C(13B)-C(14B) -24.7(2) C(10B)-C(12B)-C(13B)-C(16B) 88.6(2) C(10B)-C(17B)-C(11B)-O(2B) 155.68(16) C(10B)-C(17B)-C(11B)-C(5B) -74.9(2) C(10B)-C(17B)-C(11B)-C(1B) 85.0(3) C(10B)-C(9B)-C(8B)-C(15B) 71.8(2) C(2B)-C(3B)-C(4B)-C(18B) 177.26(18) C(2B)-C(3B)-C(4B)-C(19B) -64.0(2) C(2B)-C(3B)-C(4B)-C(5B) 62.1(2) C(2B)-C(1B)-C(11B)-O(2B) 101.2(2) C(2B)-C(1B)-C(11B)-C(17B) -159.4(2) C(2B)-C(1B)-C(11B)-C(5B) -2.4(3) 430 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(3A)-C(2A)-C(1A)-O(2A) 65.8(2) C(3A)-C(2A)-C(1A)-C(11A) -1.7(3) C(3A)-C(4A)-C(5A)-C(6A) 176.26(18) C(3A)-C(4A)-C(5A)-C(11A) -60.7(2) C(8A)-C(15A)-C(16A)-O(4A) 110.1(2) C(8A)-C(15A)-C(16A)-C(13A) -10.1(3) C(26A)-Si(1A)-O(4A)-C(16A) 112.62(14) C(26A)-Si(1A)-O(3A)-C(14A) -145.88(15) C(20A)-O(6A)-C(18A)-O(5A) 0.0(3) C(20A)-O(6A)-C(18A)-C(4A) -179.93(18) C(1B)-O(2B)-C(11B)-C(17B) -121.5(2) C(1B)-O(2B)-C(11B)-C(5B) 113.8(2) C(11B)-O(2B)-C(1B)-C(2B) -111.8(2) C(11B)-C(17B)-C(10B)-C(12B) 119.8(2) C(11B)-C(17B)-C(10B)-C(9B) -55.6(2) C(11B)-C(5B)-C(6B)-C(7B) 11.1(2) C(1A)-O(2A)-C(11A)-C(17A) -122.3(2) C(1A)-O(2A)-C(11A)-C(5A) 112.5(2) C(1A)-C(2A)-C(3A)-C(4A) -29.0(3) C(1A)-C(11A)-C(5A)-C(4A) 33.7(3) C(1A)-C(11A)-C(5A)-C(6A) 165.43(18) C(13B)-C(14B)-C(9B)-C(10B) -44.17(18) C(13B)-C(14B)-C(9B)-C(8B) 67.79(19) C(13B)-C(12B)-C(10B)-C(17B) 180.00(19) C(13B)-C(12B)-C(10B)-C(9B) -4.1(2) C(17A)-C(11A)-C(5A)-C(4A) -166.14(17) C(17A)-C(11A)-C(5A)-C(6A) -34.4(2) C(17A)-C(10A)-C(9A)-C(8A) 94.4(2) C(17A)-C(10A)-C(9A)-C(14A) -152.92(19) C(9B)-C(14B)-C(13B)-C(12B) 42.08(18) C(9B)-C(14B)-C(13B)-C(16B) -75.97(19) C(16B)-C(15B)-C(8B)-C(9B) 4.2(3) C(11A)-O(2A)-C(1A)-C(2A) -111.1(2) C(11A)-C(17A)-C(10A)-C(12A) 101.4(2) C(11A)-C(17A)-C(10A)-C(9A) -73.8(2) 431 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(11A)-C(17A)-C(7A)-C(6A) -31.4(2) C(5A)-C(4A)-C(3A)-C(2A) 59.9(2) C(5A)-C(6A)-C(7A)-C(17A) 11.6(2) C(8B)-C(15B)-C(16B)-O(4B) 109.3(2) C(8B)-C(15B)-C(16B)-C(13B) -11.0(3) C(22B)-Si(1B)-O(3B)-C(14B) 91.53(17) C(22B)-Si(1B)-O(4B)-C(16B) -122.23(15) C(22B)-Si(1B)-C(26B)-C(29B) -45.9(2) C(22B)-Si(1B)-C(26B)-C(28B) 77.01(18) C(22B)-Si(1B)-C(26B)-C(27B) -164.13(19) C(10A)-C(17A)-C(11A)-O(2A) 152.03(17) C(10A)-C(17A)-C(11A)-C(1A) 79.9(3) C(10A)-C(17A)-C(11A)-C(5A) -78.1(2) C(10A)-C(17A)-C(7A)-C(6A) 84.5(2) C(14A)-C(13A)-C(12A)-C(10A) -25.7(2) C(14A)-C(13A)-C(16A)-O(4A) -73.74(19) C(14A)-C(13A)-C(16A)-C(15A) 47.7(2) C(6B)-C(7B)-C(17B)-O(1B) -156.67(16) C(6B)-C(7B)-C(17B)-C(10B) 80.5(2) C(6B)-C(7B)-C(17B)-C(11B) -36.19(19) C(6B)-C(5B)-C(11B)-O(2B) 93.54(19) C(6B)-C(5B)-C(11B)-C(17B) -35.28(19) C(6B)-C(5B)-C(11B)-C(1B) 163.32(18) C(22A)-Si(1A)-O(4A)-C(16A) -120.36(15) C(22A)-Si(1A)-O(3A)-C(14A) 90.64(16) C(22A)-Si(1A)-C(26A)-C(27A) -158.56(17) C(22A)-Si(1A)-C(26A)-C(29A) -39.1(2) C(22A)-Si(1A)-C(26A)-C(28A) 82.77(18) C(26B)-Si(1B)-O(3B)-C(14B) -143.91(16) C(26B)-Si(1B)-O(4B)-C(16B) 111.68(15) C(26B)-Si(1B)-C(22B)-C(24B) -49.2(2) C(26B)-Si(1B)-C(22B)-C(25B) 73.7(2) C(26B)-Si(1B)-C(22B)-C(23B) -167.30(18) C(16A)-C(15A)-C(8A)-C(9A) 3.5(3) C(16A)-C(13A)-C(12A)-C(10A) 88.1(2) 432 433 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 C(16A)-C(13A)-C(14A)-O(3A) 45.6(2) C(16A)-C(13A)-C(14A)-C(9A) -76.15(18) C(7A)-C(17A)-C(11A)-O(2A) -89.3(2) C(7A)-C(17A)-C(11A)-C(1A) -161.5(2) C(7A)-C(17A)-C(11A)-C(5A) 40.6(2) C(7A)-C(17A)-C(10A)-C(12A) -9.3(3) C(7A)-C(17A)-C(10A)-C(9A) 175.45(18) C(7A)-C(6A)-C(5A)-C(4A) 139.42(19) C(7A)-C(6A)-C(5A)-C(11A) 13.5(2) C(21A)-O(8A)-C(19A)-O(7A) -8.7(3) C(21A)-O(8A)-C(19A)-C(4A) 173.00(19) C(21B)-O(8B)-C(19B)-O(7B) -0.9(3) C(21B)-O(8B)-C(19B)-C(4B) -177.4(2) C(20B)-O(6B)-C(18B)-O(5B) -0.3(3) C(20B)-O(6B)-C(18B)-C(4B) -178.1(2) ________________________________________________________________ Table A3.7. Hydrogen bonds for epoxy alcohol 262 [Å and °]. ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ O(1B)-H(1B)...O(5A) 0.78(4) 2.13(4) 2.905(2) 174(4) O(1A)-H(1A)...O(5B)#1 0.75(4) 2.24(4) 2.937(3) 155(4) ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 x-1,y,z-1 Appendix 3 – X-Ray Crystallography Reports Relevant to Chapter 2 A3.2 (1) 434 REFERENCES APEX2, Version 2 User Manual, M86-E01078, Bruker Analytical X-ray Systems, Madison, WI, June 2006. (2) Sheldrick, G.M. “SADABS (version 2008/1): Program for Absorption Correction for Data from Area Detector Frames”, University of Göttingen, 2008. (3)## Sheldrick, G. Acta Crystallogr., Sect. A: Found. Crystallogr. 2008, 64, 112. (4) Müller, P. Crystallogr. Rev. 2009, 15, 57. (5) Parsons, S; Flack, H. D; Wagner, T. Acta Crystallogr. 2013, B69, 249. (6) Macrae, C. F.; Edgington, P. R.; McCabe, P.; Pidcock, E.; Shields, G. P.; Taylor, R.; Towler M.; van de Streek, J. J. Appl. Cryst. 2006, 39, 453. 435 ABOUT THE AUTHOR Victor Wei-Dek Mak was born on March 21, 1991 in Oakland, CA, to parents Michael Mak and Cathy Mak. He grew up around the San Francisco Bay Area, and developed an early interest in science through school and television. He later moved to Irvine, CA to pursue undergraduate studies at University of California, Irvine. He developed an interest in organic chemistry, and in the summer of 2010, began working in the laboratory of Professor Kenneth J. Shea, under the supervision of Dr. Leah Cleary. As an undergraduate, Victor conducted research towards the total synthesis of a biologically active alkaloid, stenine, and found his passion for total synthesis. In 2012, he moved to Pasadena, CA to pursue doctoral studies under Professor Sarah Reisman at Caltech. In her laboratory, Victor has focused on the total synthesis of architecturally complex small molecules such as longikaurin E and talatisamine. Upon completion of his Ph.D., Victor will move back to the Bay Area to join a new medicinal chemistry team at Merck in South San Francisco.