Palladium(II)-Catalyzed Oxidation Reactions in Natural Product Synthesis: Efforts toward Bielschowskysin and Phalarine Citation Meyer, Michael Elliott (2011) Palladium(II)-Catalyzed Oxidation Reactions in Natural Product Synthesis: Efforts toward Bielschowskysin and Phalarine. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/J3YQ-SP42. https://resolver.caltech.edu/CaltechTHESIS:08042010-151446303 Abstract Two types of oxidative transformations, an oxidative kinetic resolution and an oxidative heterocyclization, have been developed by several laboratories using palladium(II)-catalysis to provide enantioenriched products. The main drawback of these asymmetric transformations is the limited substrate scope for each set of conditions. To address this, the Stoltz laboratory developed a unique platform utilizing palladium(II)-catalysis that provides a highly effective oxidative kinetic resolution of secondary alcohols and an asymmetric oxidative heterocyclization of phenols. Key to this platform is the use of (–)-sparteine as the chiral ligand and O 2 as the stoichiometric oxidant. Both of these methodologies will be featured in this thesis as they were applied toward the total synthesis of complex natural products. Our palladium(II)-catalyzed oxidative kinetic resolution was used to access an enantioenriched intermediate in our efforts toward the synthesis of bielschowskysin, a polycyclic diterpenoid. A key disconnection in our strategy was formation of the cyclobutane core of bielschowskysin from a cyclopropane intermediate. After considerable experimentation, we were able to synthesize a cyclopropane intermediate that could be used for future research. In separate work, we hoped to use two palladium(II)-catalyzed oxidative heterocyclization reactions to provide the core of phalarine, a polycyclic alkaloid. The synthesis of a key intermediate relied on a Stille coupling reaction of a complex 4,5,7-substituted indole and a nitro-arene. Model cyclization studies on an aniline substrate gave inconclusive results, while a model of a phenolic substrate has shown that cyclization onto styrenyl olefins is possible. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: Palladium, Oxidative Cyclization, bielschowskysin, phalarine Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Stoltz, Brian M. Thesis Committee: Grubbs, Robert H. (chair) Bercaw, John E. Reisman, Sarah E. Stoltz, Brian M. Defense Date: 28 June 2010 Record Number: CaltechTHESIS:08042010-151446303 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:08042010-151446303 DOI: 10.7907/J3YQ-SP42 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 5986 Collection: CaltechTHESIS Deposited By: Michael Meyer Deposited On: 23 Dec 2010 19:25 Last Modified: 08 Nov 2023 00:39 Thesis Files PDF (Thesis (full)) - Final Version See Usage Policy. 14MB Preview PDF (Chapter 1) - Final Version See Usage Policy. 690kB Preview PDF (Chapter 2) - Final Version See Usage Policy. 1MB Preview PDF (Chapter 2 Appendices) - Final Version See Usage Policy. 12MB Preview PDF (Chapter 3) - Final Version See Usage Policy. 1MB Preview PDF (Chapter 3 Appendices) - Final Version See Usage Policy. 12MB Repository Staff Only: item control page

1 Chapter 1 – Introduction CHAPTER 1 1.1 An Introduction to Oxidative Kinetic Resolution 1.1.1 Introduction Enantiopure secondary alcohols are invaluable in organic synthesis as they are found in natural products and medicinal drugs. Furthermore, enantiopure secondary alcohols can also lead to carbon-carbon bond formation while transferring the chirality (e.g., allylic alkylation) to afford various types of complex products. One method to access enantioenriched secondary alcohols is via a kinetic resolution, which allows for the isolation of one enantioenriched alcohol from a racemic mixture via a chemical transformation, not the separation of both enantiomers.1 In an oxidative kinetic resolution of secondary alcohols, one enantiomer (e.g., (R)-1) reacts faster with the enantiopure catalyst, at a rate of kfast, to provide oxidized product 2, while the other enantiomer (e.g., (S)-1) reacts much more slowly (k slow) than its counterpart (Figure 1.1.1). Ideally, the reaction is terminated when all or most of the faster-reacting 2 Chapter 1 – Introduction enantiomer has been converted to product 2. The remaining enantioenriched alcohol ((S)-1) and ketone 2 can then be separated by standard techniques. In an efficient oxidative kinetic resolution, the selectivity factor (s), which is determined by measuring the relative rate (krel) of reaction of the two enantiomers (krel = kfast / kslow), will be high (s > 15). In practice, the selectivity factor is usually determined by measuring the total conversion of starting material to product and the enantiomeric excess of the recovered starting material.2 To achieve optimum selectivity, the chiral reagent or catalyst should maintain the same relative enantiomeric preference throughout the reaction; hence, the selectivity factor remains constant. The enantiomeric excess of the starting material will always increase with increasing conversion for any kinetic resolution with a selectivity factor greater than 1 (Figure 1.1.1). Thus, kinetic resolutions have the capacity to provide compounds with high enantioenrichment for even modestly selective processes at higher levels of conversion. Figure 1.1.1 Kinetic Resolution Overview. OH R1 OH R1 O kfast R2 R1 (R)-1 Chiral Catalyst OH kslow R2 2 R2 (±)-1 H3C R2 (S)-1 selectivity factor s = krel = OH R1 R2 (S)-1 kfast kslow = ln[(1-conv)(1-ee) ln[(1-conv)(1+ee) 3 Chapter 1 – Introduction 1.1.2 Nitroxyl Radicals in an Oxidative Kinetic Resolution of Secondary Alcohols The first approach toward a kinetic resolution via alcohol oxidation involved the catalytic use of a nitroxyl radical, which formed an active N-oxoammonium species (3) under the reaction conditions. Rychnovsky reported the oxidative kinetic resolution of secondary alcohol 4 using chiral nitroxyl radical 5 and sodium hypochlorite as the oxidizing agent (Scheme 1.1.1).3 Although modest selectivities were achieved (s = 1.5–7.1), this system represented the first example of a nonenzymatic catalytic enantioselective oxidation of secondary alcohols. Scheme 1.1.1 N-oxonnium 3 OH N O O (±)-4 NaOCl, KBr CH2Cl2/H2O, 0 °C, 30 min Cl OH 87% conversion 98% ee s = 7.1 5 6 N O 3 (+)-4 Even though improvements in enantioselectivity using this approach have been realized,4 this methodology has not been used in the context of total synthesis. 1.1.3 Transition Metals in Oxidative Kinetic Resolutions of Secondary Alcohols The other general approach to the oxidative kinetic resolution of secondary alcohols employs transition metal catalysis. The first report by Ohkubo et al.5 validated the catalytic use of a transition metal in an oxidative kinetic resolution. The reaction proceeded by transfer hydrogenation using a menthol-derived phosphine (7) ligand to 4 Chapter 1 – Introduction provide sec-phenethyl alcohol in 1.2% ee, and a selectivity factor (s) of 1.055 (Scheme 1.1.2). Since then, Noyori and Uemura have developed highly enantioselective variants of a ruthenium-catalyzed kinetic resolution of secondary alcohols. Noyori demonstrated the use of ruthenium-diamine catalyst 9 to resolve secondary alcohols with acetone as the hydrogen acceptor.6 Uemura later reported a similar system using a ruthenium- ferrocenyloxazoline complex (10).7 In both of these cases, a plethora of benzylic secondary alcohols were resolved to high enantiopurity with very high selectivity (s > 100). Furthermore, Ikariya has shown that iridium and rhodium are viable metal catalysts for the oxidative kinetic resolution of secondary alcohols. Using O2 as the stoichiometric oxidant and Noyori’s diamine ligand motif, Ikariya was able to access highly enantioenriched secondary benzylic alcohols with good selectivity factors (s > 10).8 Scheme 1.1.2 Ohkubo: PPh2 7 OH O OH RuCl2(PPh3)3 37% conv 1.221% ee s = 1.055 O (±)-4 6 (–)-4 8 180 °C, 5 h Noyori: Ts N Ru N H Ph OH Ph O OH 9 50% conv 92% ee s > 80 acetone, 28 °C, 26 h (±)-4 6 Uemura: (+)-4 O OH Fe Ph N PPh3 Ru Cl P Cl Ph2 O OH 47% conv 97% ee s = 183 10 (±)-4 NaOi-Pr, acetone 50 °C, 30 min 6 (+)-4 5 Chapter 1 – Introduction More recently, Xia initially reported an oxidative kinetic resolution of benzylic alcohols using a manganese-salen catalyst (11) and iodobenzene diacetate as the stoichiometric oxidant (Scheme 1.1.3).9 It was later reported by Xia that changes in solvent and catalyst allowed for better selectivities for some substrates.7b In addition, Toste has described a vanadium catalyst using chiral salicylaldimine ligand 13 for the asymmetric oxidation of α-hydroxy esters.10,11 High selectivities for an array of α hydroxy esters were realized, although less-activated alcohols, such as benzylic alcohols, reacted poorly when exposed to this system.12 Scheme 1.1.3 Xia: PF6– t-Bu OH N N Mn+ O O t-Bu t-Bu O t-Bu OH 52% conv 85% ee s = 23.7 11 Bu4NBr, PhI(OAc)2, H2O, 23 °C, 1 h (±)-4 6 (+)-4 t-Bu Toste: N t-Bu OEt (±)-12 OH 13 OH O OH t-Bu VO(Oi-Pr)3 O OH OEt O acetone, O2, 23 °C 14 OEt O 51% conv 99% ee s > 50 (–)-12 In addition, Sigman published a system using (–)-sparteine (17) as the chiral ligand with Pd(OAc)2 or PdCl2,13 and O2 as the stoichiometric oxidant (Scheme 1.1.4). This system was optimized to use either dichloroethane (DCE) or t-butanol (t-BuOH) as solvent to obtain modest selectivities (generally s = 5–15) for a wide range of secondary alcohols.14 Sigman has also shown that at lower catalyst loadings of (–)-sparteine (17), the rate-determining step is deprotonation of the alcohol. However, when 20 mol% of 6 Chapter 1 – Introduction (–)-sparteine is used in the optimized conditions (Scheme 1.1.4), the rate-determining step is β-hydride elimination.9c Since β -hydride elimination is directly involved in enantioselectivity, slowing this step enhances the selectivity. Scheme 1.1.4 Sigman: OH OH 5 mol% Pd[(–)-sparteine]Cl2 20 mol% (–)-sparteine DCE 65% conv 99% ee s = 15.9 O N N 65 °C, DCE or t-BuOH, O2, 20 h (±)-15 t-BuOH 61.5% conv 99% ee s = 21.9 16 (+)-15 (–)-sparteine (17) In general, the oxidation of secondary alcohols to ketones by palladium(II) most likely involves associative alcohol substitution at the palladium(II) center (18), followed by deprotonation of the resulting palladium alcohol complex (19) by base to form palladium alkoxide 20 (Figure 1.1.2). At this stage, β-hydride elimination (20→22) and subsequent dissociation from palladium provides product 23. Figure 1.1.2 Proposed Mechanism for Alcohol Oxidation by Palladium. R OH R L X Pd L L X X Pd L O H 18 X R L R X BH L Pd L O +X R 22 L H R R L O –X R Pd Pd L O 21 O L X L H R R 20 19 H Pd R R 23 1.1.4 A Pd(II)-catalyzed Oxidative Kinetic Resolution Developed by the Stoltz Laboratory In 2001, based on early work by Uemura,15 the Stoltz laboratory developed a palladium(II)-catalyzed oxidative kinetic resolution utilizing (–)-sparteine as the chiral ligand and O2 as the stoichiometric oxidant. 7 Chapter 1 – Introduction Since the initial development of the palladium(II)-catalyzed oxidative kinetic resolution of secondary alcohols using (–)-sparteine (17),16 several improvements and further optimization to the catalytic system were accomplished. The palladium(II)catalyzed oxidative kinetic resolutions can now be performed on a number of activated secondary alcohols to efficiently provide optically enriched secondary alcohols (Table 1.1.1). Table 1.1.1 Oxidative Kinetic Resolution of Secondary Alcohols. OH Ar Pd(nbd)Cl2a (–)-sparteine MS3Å OH Ar O N N Ar (–)-sparteine (17) Original b Rate Accelerated c Chloroform/O2 d Chloroform/Air e O2, PhMe 80 °C O2, PhMe, 60 °C Cs2CO3, t-BuOH O2, CHCl3, 23 °C Cs2CO3 Air, CHCl3, 23 °C Cs2CO3 96 h 67% conv 98% ee s = 12 9.5 h 67% conv 99.5% ee s = 15 48 h 63% conv 99.9% ee s = 27 24 h 62% conv 99.8% ee s = 25 40 h 69% conv 98% ee s = 16 12 h 62% conv 99% ee s = 21 24 h 58% conv 98% ee s = 28 16 h 60% conv 99.6% ee s = 28 120 h 70% conv 92% ee s = 6.6 12 h 65% conv 88% ee s = 7.5 48 h 63% conv 98.7% ee s = 18 44 h 65% conv 98.9% ee s = 16 OH MeO 24 OH 25 OH 26 a nbd = norbornadiene, s = selectivity factor, 500 mg, 3ÅMS/mmol substrate were used for all four sets of conditions. b 5 mol% palladium catalyst, 0.20 equiv (–)-sparteine (17), 0.10 M in PhMe. c 5 mol% palladium catalyst, 0.20 equiv (–)-sparteine (17), 0.50 equiv Cs2CO3, 1.5 equiv t-BuOH, 0.25 M in PhMe. d 5 mol% palladium catalyst, 0.12 equiv (–)-sparteine (17), 0.40 equiv Cs2CO3, 0.25 M in CHCl3. Reactions were run open to air through a short drying tube of Drierite. A model for selectivity in the palladium(II)-catalyzed oxidative kinetic resolution of secondary alcohols was developed by Dr. Raissa Trend, in collaboration with the Goddard laboratory, and is thoroughly discussed within her thesis.17 The key conclusions from Trend’s results are that (–)-sparteine is not behaving as a pseudo C 2 symmetric ligand; rather, it acts as a C 1 ligand allowing for selective displacement of a single 8 Chapter 1 – Introduction chloride from palladium. Furthermore, her results show that the displaced chloride ion, which has been calculated to be closely associated with palladium in an apical position under the square plane,18 affects selectivity by clashing with one of the enantiomers of the substrate bound to palladium (Figure 1.1.3). It is thought that this is the main interaction that inhibits β-hydride elimination of one of the enantiomers. Figure 1.1.3 Proposed β -Hydride Elimination Transition State for Each Enantiomer. ‡ ‡ RL RS N O Pd N N vs O H RS Cl– Pd H Cl– RL fast-reacting enantiomer N slow-reacting enantiomer To demonstrate the utility of this methodology, the Stoltz laboratory has completed the syntheses of (–)-amurensinine (27), (–)-aurantioclavine (28), (–)-lobeline (29), and (–)-sedamine (30) (Figure 1.1.4).19 Each synthesis relied upon a palladium(II)catalyzed oxidative kinetic resolution to establish a benzylic stereocenter in high enantioselectivity. Figure 1.1.4 Natural Products Synthesized via Palladium(II)-catalyzed OKR. OMe O O H N OH O OH OMe N N Me Me N Me N H (+)-amurensinine (27) (–)-aurantioclavine (28) (–)-lobeline (29) (–)-sedamine (30) The scope of secondary alcohols used in the palladium(II)-catalyzed oxidative kinetic resolution currently includes activated alcohols bearing benzylic, allylic, or cyclopropyl substituents. One class of exceptional substrates for the palladium(II)catalyzed oxidative kinetic resolution are 2-aryl cyclopentenols (Figure 1.1.5). Exposure 9 Chapter 1 – Introduction of these racemic alcohols to the original conditions (cf. Table 1.1.1) in the palladium(II)catalyzed oxidative kinetic resolution provides cyclopentenols 31–35 with excellent enantioselectivity and selectivity factors (s).20 Figure 1.1.5 Enantioenriched 2-Aryl Cyclopentenols using the Original Conditions. OH OH CF3 O OH OH OH O O 31 32 33 34 35 10 h 59.2% conv 99.0% ee s = 26 24 h 54.1% conv 99.0% ee s = 59 49 h 54% conv 87.3% ee s = 19 10 h 58.6% conv 99.0% ee s = 28 7h 57% conv 99.7% ee s = 44 These substrates led us to examine several natural products bearing an allylic secondary alcohol for the application of this methodology toward further total syntheses. One such molecule was bielschowskysin (36) (Figure 1.1.6). We envisioned using the palladium(II)-catalyzed oxidative kinetic resolution to access a key alcohol intermediate (37) in high enantioselectivity. Figure 1.1.6 Substrate for the Palladium(II)-catalyzed Ox. Kinetic Resolution. OH H H HO O O OAc OH O O H OH H bielschowskysin (36) O TBSO 37 CO2Me 10 Chapter 1 – Introduction 1.2 Introduction to Palladium(II)-Catalyzed Oxidative Heterocyclizations 1.2.1 Racemic and Enantioselective Pd(II)-catalyzed Oxidative Heterocyclizations In the well-known Wacker process, PdCl2 in the presence of O2 and a copper cocatalyst oxidizes ethylene to acetaldehyde.21 Although the Wacker process has been studied extensively, various aspects of its mechanism, such as the role of the chloride ion, are still disputed.22 For over several decades now, it has been known that using palladium(II) complexes along with a variety of oxidants can catalyze simple Wackertype cyclizations to provide racemic mixtures of products. Larock, Bäckvall, and others have demonstrated that palladium(II)-catalyzed oxidative heterocyclizations of olefinappended nucleophiles provided racemic products using O2 as the stoichiometric oxidant and DMSO as the solvent (Scheme 1.2.1).23 Scheme 1.2.1 Larock: 5 mol% Pd(dba)2 or Pd(OAc)2 KHCO2, DMSO/H2O, air 80% yield OH O 38 39 O 5 mol% Pd(OAc), O2 NaOAc, DMSO O OH O 91% yield 40 41 Bäckvall: OH 5 mol% Pd(OAc)2 O2, DMSO O 91% yield 42 43 10 mol% Pd(OAc)2 O2, DMSO NHTs 44 N Ts 93% yield 45 11 Chapter 1 – Introduction Furthermore, palladium(II)-catalyzed cyclizations have also been developed that use copper/O2 and benzoquinone as the stoichiometric oxidants. In an early example, Hosokawa showed that stoichiometric palladium(II) could be used to cyclize olefinappended phenols (Scheme 1.2.2), and that this methodology could be made catalytic in the presence of copper and O2.24 Other substrates, such as alcohols and amides, have been cyclized under similar conditions as demonstrated by Murahashi, Hegedus, and others.25 Scheme 1.2.2 PdCl2(PhCN)2 NaOMe, PhH or Hosokawa: OH 46 Murahashi: cat. Pd(OAc)2 Cu(OAc)2•H2O O2, MeOH/H2O O 47 10 mol% Pd(OAc)2 Cu(OAc)2•H2O, O2 Ph OH 48 Hegedus: MeOH/H2O (40% yield) single diastereomer Ph O 49 10 mol% PdCl2(MeCN)2 benzoquinone, LiCl NHMe 50 THF (89% yield) N Me 51 More recent examples by Yang and Gouverneur highlight recent advances in palladium(II)-catalyzed oxidative heterocyclizations. Yang has reported an oxidative cascade cyclization using N-acyl anilines (52) to afford spirocycles (53) in high diastereoselectivity and good yield (Scheme 1.2.3).26 In addition, Gouverneur has developed a palladium(II)-catalyzed oxidative cyclization of secondary alcohols (54) onto α,β-unsaturated olefins to provide 2,3-dihydro-4H-pyran-4-ones (55) in good yield.27 12 Chapter 1 – Introduction Scheme 1.2.3 Yang: O O 10 mol% Pd(OAc)2 40 mol% isoquinoline NH 12 examples 33-81% yields N O2, PhMe, 70 °C, 28 h 52 H 53 (81% yield) >24:1 diastereoselectivity Gouverneur: OH Ph O O2, DME, 4h, 50 °C 54 O 10 mol% PdCl2 10 mol% CuCl 10 mol% Na2HPO4 (79% yield) Ph O 8 examples 43-86% yields 55 Although all of these examples constitute significant advances in palladium(II)catalyzed oxidative cyclization reactions, the conditions vary for different substrate types, and many do not meet the ideal conditions for asymmetric reactions. For example, the use of additives and co-oxidants such as Cu(OAc)2 can create complex reaction conditions making optimization difficult. Furthermore, the use of highly coordinating solvents such as DMSO inhibits coordination of chiral ligands and thereby prevents the formation of any chiral palladium species necessary for an asymmetric process. Despite these obstacles, several examples of asymmetric palladium(II)-catalyzed oxidative heterocyclizations have been reported (Scheme 1.2.4). In 1981, Hosokawa described an asymmetric oxidative cyclization with a pinene-derived palladium(II) complex (57).28 More recently, Hayashi and Sasai have employed novel ligand frameworks (ligands 60 and 63, respectively) and benzoquinone (BQ) as an oxidant to obtain cyclized products with high enantioselectivity.29,30 In a proof-of-principle experiment by Bäckvall, a chiral benzoquinone generated in situ from arene 66 acted as a ligand in the enantioselective dialkoxylation of diene 65.31 13 Chapter 1 – Introduction Scheme 1.2.4 10 mol% Hosokawa: O O Pd O Pd O 57 Cu(OAc)2, O2, MeOH, 35 °C OH O 56 77% yield 18% ee H 58 Hayashi: 10 mol% Pd(TFA)2, BQ 72% yield 97% ee OH O i-Pr 59 O N 61 N i-Pr O i-pr boxax (60) Sasai: 20 mol% Pd(TFA)2, BQ OH OBz i-Pr 62 H H H i-Pr i-Pr N O N O 65% yield 95% ee OBz O 64 i-Pr 63 Bäckvall: Fe(II)(Pc): Iron(II) phthalocyanine 10 mol% Pd(OAc)2 20 mol% MeSO3H 3 mol% Fe(II)(Pc) EtO EtOH/CH2Cl2 (1:4), O2 Ph OH 65 OH N H H N i-Pr Ph i-Pr O O OEt 67 45% yield 54% ee N N N Fe N N OH N N N OH 66 These examples established the potential for enantioselective palladium(II)catalyzed oxidative heterocyclizations and dialkoxylations using benzoquinone oxidation systems. While these examples are limited in substrate scope, the examples by Sasai and Hayashi represent significant advances toward a general palladium(II)-catalyzed oxidative heterocyclization system. 14 Chapter 1 – Introduction 1.2.2 Possible Mechanisms for the Pd(II)-catalyzed Oxidative Heterocyclization Palladium(II)-catalyzed nucleophilic attack onto an olefin by a heteroatom can proceed by a variety of mechanisms. One key distinction to be made among them is whether attack occurs with the metal and nucleophile on the same face (syn, internal), or on opposite faces (anti, external) of the olefin. Another subtlety is whether π-allyl palladium(II) species are involved. This section will discuss some of the evidence that has been obtained for each mechanism. A commonly employed mechanism for palladium(II)-catalyzed oxidative heterocyclization initiates with activation of olefin 68 by palladium, followed by antinucleophilic attack (e.g., anti oxypalladation, Figure 1.2.1). The resulting palladium(II) alkyl intermediate (69) then undergoes β-hydride elimination to provide product 70. Figure 1.2.1 A Generic Heteroatom anti Palladation. Nuc H anti [Pd] Nuc 68 β-H elim. H [Pd] [Pd] 69 Nuc H Nuc [Pd] 70 A second possible mechanism is heteroatom syn palladation (e.g., syn oxypalladation), which initially involves a nucleophile bound directly to palladium (71, Figure 1.2.2). The bond formed between nucleophile and olefin occurs internally via a migratory insertion, as well as on the same olefin face as the newly formed alkylpalladium bond (72). At this stage, β-hydride elimination and ligand dissociation provides product 70. 15 Chapter 1 – Introduction Figure 1.2.2 A Generic Heteroatom syn Palladation. Nuc syn [Pd] Nuc H H [Pd] [Pd] 71 Nuc H β-H elim. Nuc [Pd] 72 70 For evidence of syn oxypalladation, Hayashi and coworkers described the reaction of a stereospecifically deuterium-labeled phenol substrate (73) under their enantioselective conditions.32 As shown in Scheme 1.2.5, after the oxypalladation step, the newly formed C-O bond, palladium, and deuterium are all syn to each other (74). Subsequent syn β-deuterium elimination (74→ 75) led to the initial product 76. Compound 77 and olefin isomer 78 are also formed in the reaction as a result of olefin isomerization of product 76. Nevertheless, all three products are consistent with syn oxypalladation. Interestingly, in the presence of excess chloride ion, anti oxypalladation predominated, which suggests that subtle changes in reaction conditions can have dramatic effects on the mechanism. Scheme 1.2.5 D 10 mol% Pd(MeCN)4(BF4)2 (S,S)-i-pr-boxax (63) BQ, MeOH, 40 °C OH 73 O O 76 16% 77 46% D O D 78 29% – [Pd]D D O 74 [Pd] reinsertion, β-H elim. β-D elim. [Pd] D O 75 Further evidence of syn oxypalladation by Wolfe and coworkers shows that both oxygen and nitrogen nucleophiles can operate under this mechanism.33 Another potential reaction pathway for palladium-olefin cyclizations entails allylic C–H activation by palladium(II) to form an intermediate π-allyl species that would 16 Chapter 1 – Introduction then undergo reductive elimination with a heteroatom nucleophile. Trost has shown that Pd(TFA)2 will form π-allyl complexes by C-H activation of olefins in acetone.34 Experimental evidence for this pathway was shown in an intermolecular oxidative acetylation reaction of deuterium-labeled cyclohexene 79 (Scheme 1.2.6).35 Bäckvall reported that the reaction yielded a 1:1 mixture of products 81 and 82. This supports the intermediacy of π-allyl complex 80, whereas anti oxypalladation would produce compound 81 and 83. Scheme 1.2.6 H D Pd(OAc)2, BQ H D H OAc OAc PdOAc D HOAc, 60 °C 79 D 80 D D D OAc D 81 anti oxypalladation D not observed D OAc 81 82 1:1 H D OAc 83 1.2.3 A Pd(II)-catalyzed Oxidative Heterocyclization Developed by the Stoltz Laboratory The Stoltz laboratory has developed an enantioselective palladium(II)-catalyzed oxidative phenol cyclization using palladium(II) catalysis with (–)-sparteine as the chiral ligand, to provide electron-rich dihydrobenzofurans in modest yield and good enantioselectivity (Table 1.2.1).17c Unfortunately, other substrates examined such as amines, anilines, and acids cyclize with only moderate enantioselectivity. 17 Chapter 1 – Introduction Table 1.2.1 Enantioselective Cyclization of Olefin-Appended Phenols.a product substrate entry MeO 1. time yieldb eec 24 h 60 h @ 55 °C 64% 57% 88% 90% 36 h 47% 83% 36 h 47% 86% 24 h 60% 20% MeO O OH 84 85 t-Bu t-Bu 2. OH O 86 87 3. OH O 88 89 O O 4. O OH 90 91 a 10 mol% (sp)Pd(TFA)2, 100 mol% (–)-sparteine (17), 2.0 equiv Ca(OH)2, 500 mg 3ÅMS/mmol substrate, 1 atm O2, PhMe (0.10 M), 80 °C. b Isolated yield. c Measured by GC. Accordingly, using a Pd(TFA)2/pyridine/O2 catalyst system, 3ÅMS in toluene at 80 °C, along with an exogenous base such as Na2CO3, a variety of heteroatom substrates cyclize to provide the desired products (92-96) in good yield (Figure 1.2.3). For some substrates, it was found that omitting Na2CO3 allowed for better conversion, probably due to variations of substrate pKa. Figure 1.2.3 Heterocycles Accessed via a Pd(II)-catalyzed Oxidative Heterocyclization. O O NTs O O 92 95% yielda 93 85% yielda 94 62% yieldc 95 88% yieldb Ts N 96 90% yieldb a mol% Pd(TFA)2, 20 mol% pyridine, 2 equiv Na2CO3, 3ÅMS, 1 atm O2, 0.10 M in PhMe, 80 °C. b 5 mol% Pd(TFA)2, 20 mol% pyridine, 3ÅMS, 1 atm O2, 0.10 M in PhMe, 80 °C. c 10 mol% Pd(TFA)2, 40 mol% pyridine, 3ÅMS, 1 atm O2, 0.10 M in PhMe, 80 °C. In addition, further studies found that the mechanism for the palladium(II)catalyzed oxidative heterocyclization changes between syn and anti heteroatom palladation depending on the substrate. Using deuterium-labeled substrates, it was found 18 Chapter 1 – Introduction that alcohol 97 reacted via syn oxypalladation to provide tetrahydrofurans 98 and 99 in a 4:1 ratio, whereas acid 100 cyclized via anti oxypalladation to provide γ-lactone 101 (Scheme 1.2.7).36 These changes in mechanism might be attributed to differences in the pKa of the two substrates (97 and 100); however, the exact reasons for the switch in mechanism has not been fully elucidated.37 Scheme 1.2.7 OH CO2Et CO2Et D PhMe, O2, 80 °C, 4.5 h O CO2H CO2Et CO2Et CO2Et CO2Et D 100 98 (30% yield) CO2Et CO2Et D 4:1 99 O 10 mol% (py)Pd(TFA)2 20 mol% pyridine Na2CO3 (2 equiv) PhMe, O2, 80 °C, 4.5 h O syn oxypalladation (91% yield) 97 D 10 mol% (py)Pd(TFA)2 30 mol% pyridine Na2CO3 (2 equiv) O CO2Et CO2Et H 101 SM anti oxypalladation (recovered 34% yield) To demonstrate the application of this methodology in natural product synthesis, the Stoltz laboratory has completed the formal total synthesis of both enantiomers of cephalotaxine (104), as well as the asymmetric total synthesis of (–)-drupacine (105). All three were derived from intermediate 103, which was accessed in excellent yield via a palladium(II)-catalyzed oxidative heterocyclization to form the spirocyclic amine moiety in intermediate 102 (Figure 1.2.4).38 19 Chapter 1 – Introduction Figure 1.2.4 Natural Products Synthesized via a Pd(II)-catalyzed Oxidative Heterocyclization. via Pd(II)-catalyzed Oxidative Amino Cyclization TsN 99% yield 102 OH N O O O O N O Br separable diastereomers (103) H HO O N O H HO OMe OMe (+) and (–)-Cephalotaxine (104) (–)-Drupacine (105) The Stoltz laboratory is always searching for biologically active natural products that could be efficiently synthesized using developed group methodologies. For one such molecule, phalarine (106), we envisioned using two palladium(II)-catalyzed oxidative heterocyclizations to form the dihydrofuran (red) and dihydropyrrole (blue) rings respectively (Figure 1.2.5). Figure 1.2.5 Structure of (–)-Phalarine. Me OMe N O NH N H via two palladium(II)-catalyzed oxidative heterocyclizations NMe2 Phalarine (106) This thesis will describe efforts toward an enantioselective total synthesis of bielschowskysin using a palladium(II)-catalyzed oxidative kinetic resolution to provide an enantioenriched early intermediate. Moreover, attempts toward the synthesis of phalarine using two palladium(II)-catalyzed oxidative heterocyclizations to construct the core of the natural product will also be discussed. Chapter 1 – Introduction 20 1.3 Notes and References 1 Ten Brink, G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Adv. Synth. Catal. 2002, 344, 355–369. 2 a) Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry; Eliel, E. L., Ed.; Wiley & Sons: New York, 1988; Vol. 18, pp. 249–330. b) Stahl, S. S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am. Chem. Soc. 2001, 123, 7188–7189. 3 Rychnovsky, S. D.; McLernon, T. L.; Rajapakse, J. J. Org. Chem. 1996, 61, 1194–1195. 4 a) Kashiwagi, Y.; Kurashima, F.; Kikuchi, C.; Anzai, J.; Osa, T.; Bobbitt, J. M. Tetrahedron Lett. 1999, 40, 6469–6472. b) Kuroboshi, M.; Yoshihisa, H.; Cortona, M. N.; Kawakami, Y.; Gao, Z.; Tanaka, H. Tetrahedron Lett. 2000, 41, 8131–8135. c) Kashiwagi, Y.; Yanagisawa, Y.; Kurashima, F.; Anzai, J.; Osa, T.; Bobbitt, J. M. Chem. Commun. 1996, 2745–2746. 5 Ohkubo, K.; Hirata, K.; Yoshinaga, K.; Okada, M. Chem. Lett. 1976, 183–184. 6 Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew. Chem. Int. Ed. 1997, 36, 288–290. 7 a) Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai, M Organometallics 1999, 18, 2291–2293. b) Nishibayashi, Y.; Yamauchi, A.; Onodera, G.; Uemura, S. J. Org. Chem. 2003, 68, 5875–5880. 8 a) Arita, S.; Koike, T.; Kayaki, Y.; Ikariya, T. Angew. Chem. 2008, 120, 2481–2483. b) Wills, M. Angew. Chem. Int. Ed. 2008, 47, 4264–4267. Chapter 1 – Introduction 9 21 a) Sun, W.; Wang, H.; Xia, C. G.; Li, J.; Zhao, P. Angew. Chem. Int. Ed. 2003, 42, 1042–1044. b) Li, Z.; Tang, Z. H.; Hu, X. X.; Xia, C. G. Chem. Eur. J. 2005, 11, 1210–1216. 10 Radosevich, A. T.; Musich, C.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 1090–1091. 11 For a related vanadium system, see: a) Pawar, V. D.; Bettigeri, S.; Weng, S.-S., Kao, J.-Q.; Chen, C.-T. J. Am. Chem. Soc. 2006, 128, 6308–6309. b) Weng, S.-S.; Shen, M.-W.; Kao, J.-Q.; Munot, Y. S.; Chen, C.-T. Proc. Natl. Acad. Sic. U.S.A. 2006, 103, 3522–3527. c) Chen, C.-T.; Bettigeri, S.; Weng, S.-S.; Pawar, V. D.; Lin, Y.-H.; Liu, C.-Y.; Lee, W.-Z. J. Org. Chem. 2007, 72, 8175–8185. 12 Alcohols that cannot undergo two-point binding give poor selectivities. 13 Initially Sigman consistently used Pd(OAc)2; however, after publications from the Stoltz laboratory, Sigman switched to PdCl2 due to overall higher selectivities. 14 a) Mandal, S. K.; Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Org. Chem. 2003, 68, 4600–4603. b) Jensen, D. R.; Sigman, M. S. Org. Lett. 2003, 5, 63–65. c) Mueller, J. A.; Jensen, D. R.; Sigman, M. S. J. Am. Chem. Soc. 2002, 124, 8202–8203. 15 Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64, 6750–6755. 16 Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725–7726. 17 a) Trend, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 4482–4483. b) Trend, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 15957–15966. c) Trend, R. M. Concerning the Mechanism and Selectivity of Palladium(II)-catalyzed Aerobic Oxidation Reactions. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, 2006. Chapter 1 – Introduction 18 22 Nielson, R. J.; Keith, J. M.; Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc. 2004, 126, 7967–7974. 19 a) Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752–11753. b) Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C.; Ramtohul, Y. K.: Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745–13754. 20 Ebner, D. C. Development and Applications of the Palladium-catalyzed Enantioselective Oxidation of Secondary Alcohols. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, 2009. 21 a) Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, S.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80–88. b) Moiseev, I. I.; Vargaftik, M. N.; Syrkin, Ya. K. Dokl. Akad. Nauk. SSSR 1963, 153, 140. c) Henry, P. M. J. Am. Chem. Soc. 1964, 86, 32463250. d) Jira, R.; Sedlmeier, J.; Smidt, J. Ann. Chem. 1966 , 693, 99. e) Phillips, F. C. Am. Chem. J. 1984, 16, 255–277. 22 For instance, [Cl-] has large effects on the mechanism, see: a) Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. b) Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem. Soc. 1979, 101, 2411–2416. c) Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681–682. d) Gregor, N.; Zaw, K.; Henry, P. M. Organometallics, 1984, 3, 1251–1256. e) Hamed, O.; Henry P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745–7750. 23 For examples of phenol cyclizations, see: a) Larock, R. C.; Wei, L.; Hightower, T. Synlett 1998, 522–524. b) For examples of alcohol cyclizations, see, Rönn, M.; Bäckvall, J.-E.; Andersson, P. G. Tetrahedron Lett. 1995, 36, 7749–7752. c) For 23 Chapter 1 – Introduction examples of acid cyclizations, see: Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298–5300. d) For examples of tosylamide cyclizations, see: Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584–3585, and references therein. 24 Hosokawa, T.; Ohkata, H.; Moritani, I. Bull. Chem. Soc. Japan 1975, 48, 1533–1536. 25 a) For examples of racemic alcohol cyclizations that employ the copper/O2 system, see: Hosokawa, T.; Hirata, M.; Murahashi, S.-I.: Sonoda, A. Tetrahedron Lett. 1976, 21, 1821–1824. b) For examples of racemic systems that employ benzoquinone, see: Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800–5807. c) For oxidative carbon-carbon bond forming aryl/olefin cyclizations, see: Zhang, H.; Ferreira, E. M.; Stoltz B. M. Angew. Chem. Int. Ed. 2004, 43, 6144–6148. 26 Yip, K.-T.; Zhu, N.-Y.; Yang, D. Org. Lett. 2009, 11, 1911–1914. 27 Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91–94. 28 a) Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S. J. Am. Chem. Soc. 1981, 103, 2318–2323. b) Hosokawa, T.; Okuda, C.; Murahashi, S. J. Org. Chem. 1985, 50, 1282–1287. 29 a) Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997, 119, 5063–5064. b) Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071–5075. c) Uozumi, Y.; Kyota, H. Ogasawara, M; Hayashi, T. J. Org. Chem. 1999, 64, 1620–1625. 30 Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907–2908. Chapter 1 – Introduction 31 24 a) Thorarensen, A.; Palmgren, A.; Itami, K.; Bäckvall, J.-E. Tetrahedron Lett. 1997, 38, 8541–8544. b) Itami, K.; Palmgren, A.; Thorarensen, A.; Bäckvall, J.-E. J. Org. Chem. 1998, 63, 6466–6471. c) Cotton, H. K.; Verboom, R. C.; Johansson, L.; Plietker, B. J.; Bäckvall, J.-E. Organometallics 2002, 21, 3367–3375. 32 Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036–3037. 33 For systems containing oxygen nucleophiles, see: Hay, M. B.; Hardin, A. R.; Wolfe, J. P. J. Org. Chem. 2005, 70, 3099–3107. For systems containing nitrogen nucleophiles, see: a) Ney, J. E.; Wolfe, J. P. Angew. Chem. Int. Ed. 2004, 43, 3605–3608. b) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644–8657. 34 Trost, B. M.; Metzner, P. J. J. Am. Chem. Soc. 1980, 102, 3572–3577. 35 Grennberg, H.; Simon, V.; Bäckvall, J.-E. Chem. Eur. J. 1998, 4, 1083–1089. 36 For further details, see: a) ref. 29. b) Ferreira, E. M. The Design and Development of Palladium-catalyzed Aerobic Oxidative Transformations. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, 2005. 37 It was also shown that anilines can react via syn or anti aminopalladation depending on the ligand used. In one case, use of a bisoxazoline ligand resulted in product formation via syn aminopalladation, while use of pyridine as the ligand led to a 1:1 product mixture resulting from both syn and anti aminopalladation. See ref. 33b for further details. 38 Liu, Q.; Ferreira, E. M.; Stoltz, B. M. J. Org. Chem. 2007, 72, 7352–7358.  Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 25 CHAPTER 2 Synthetic Efforts Toward Bielschowskysin Using a Palladium(II)-catalyzed Oxidative Kinetic Resolution 2.1 Introduction and Biosynthesis In 2003, several novel natural products were isolated from the Caribbean gorgonian octocoral Pseudopterogorgia kallos. The structure of one of these compounds, bielschowskysin (36), eluded characterization until an X-ray crystal structure was obtained approximately one year later.1 Bielschowskysin belongs to a sub-class of molecules called pseudopteranes, and is one of several structurally and biosynthetically related diterpenes (Figure 2.1.1).2 Furthermore, bielschowskysin has been identified as a potent inhibitor of EKVX lung cancer cells (GI50 = 10 nM). 26 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Figure 2.1.1 Bielschowskysin and Related Natural Products. O O H O OH H OH H H HO O OAc H O OH O O OH H O O H O O H H H H O O O H O OH O H H H O O O bielschowskysin verrillin ineleganolide scabrolide A 36 107 108 109 A characteristic feature of these molecules is a cis-fused [5,5] oxa-bicycle, as well as a dihydrofuran unit that is sometimes disguised as a 1,4 diketone moiety.3 Bielschowskysin is arguably the most structurally complex member of this group due to its polycyclic ring system bearing eleven stereocenters, one of which is a quaternary stereocenter contained in a tetrasubstituted cyclobutane ring that is also fused to a substituted oxocane ring, resulting in a highly strained cage-like structure.4 Although the biosynthetic pathway of bielschowskysin has not been confirmed, Trauner has hypothesized that bielschowskysin is obtained from bipinnatin J (110) via a stereo- and chemoselective epoxidation of the Δ7,8 olefin (110), followed by the addition of water furan 111, and subsequent [2+2] cycloaddition of intermediate 112 provides the cyclobutane core (113) (Scheme 2.1.1).5 Scheme 2.1.1 OH OH OH OH H HO 7 O 8 [O] O O O + H2O O O HO OH [2+2] O O O O O bipinnatin J (110) 111 112 O H OH O 113 Along with all of the molecules in Figure 2.1.1, bipinnatin J is also a member of the larger cembranoid class of natural products, which are biosynthesized by intramolecular SN1 attack of geranylgeranyldiphosphate (114) and quenching of the Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 27 resultant tertiary carbocation to form the cembrane core (115) (Scheme 2.1.2). The cembrane core can undergo various enzymatic oxidations and transformations to provide an array of natural products.6 Scheme 2.1.2 -OPP SN1 H PPO geranylgeranyl diphosphate (114) cembrane core 115 2.2 Outside Efforts Toward the Total Synthesis of Bielschowskysin Although there are no reported total syntheses of bielschowskysin, there are two reported partial syntheses of the cyclobutane core found in the natural product. First, Doroh and Sulikowski subject alcohol 116 to a [2+2] photocycloaddition providing cyclobutane 117 in 50% yield with a 3.6:1 diastereomeric ratio (Scheme 2.2.1).7 It is thought that this reaction occurs through an unobserved diradical intermediate 118, which then proceeds to form cyclobutane 117. The diastereoselectivity of this reaction is notable in consideration of the observed isomerization of alcohol 116 to isomer 119 under the reaction conditions. Additionally, possible σ-bond rotation of diradical intermediate 118 to its diasterotopic isomer 120, which could also be formed from allylic alcohol 119, could lead to the undesired diastereomer 121.8 28 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.2.1 OH H HO O O O O hν O O H Me2CO H O (50% yield) 3.6:1 dr 116 O 117 OH O OH hν O O O O O 116 O H HO O 119 O O H HO O O H H O O O H HO O 120 118 H H HO O O O O H H O H O O 117 O 121 A second approach, reported by Lear and coworkers, uses a similar method to form the core cyclobutane via photocylcoaddition of allene 123 (Scheme 2.2.2).9 The synthesis of allene 123 is accomplished in twelve steps beginning with commercially available L-malic acid (122). Treatment of allene 123 with UV light in a nonpolar cosolvent provides the desired exo-cyclobutene 124 in 70% yield. Scheme 2.2.2 H H TMSO OH TMSO O • 12 steps HO hν H hexane/CH2Cl2 23 °C, 12 h O OH O L-malic acid (122) O 123 O (70% yield) 6 H O 124 Although these partial syntheses provide access to the strained cyclobutane found in bielschowskysin, they do not address the formation of either the critical C(6) Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 29 quaternary stereocenter or the pendant oxocane ring. As such, a [2+2] cycloaddition to form the quaternary stereocenter on a larger system bearing these components would not be without significant challenges. While a well-organized transition state might be feasible via an enzymatic pathway, practical synthetic limitations encouraged us to envision forming bielschowskysin by other methods such as an aldol condensation or Michael addition. 2.3 Retrosynthesis: Use of a Cyclopropane to Access the Cyclobutane Core While planning an initial synthetic route to bielschowskysin (36), a suitable model system was designed to investigate the key formation of the cyclobutane core and the quaternary stereocenter. Hence, our first synthetic target was cyclobutane 125 (Figure 2.3.1). Unlike the previous partial syntheses, this model system includes the quaternary stereocenter found in the natural product. Figure 2.3.1 Model System for Studies Toward Bielshowskysin's Cyclobutane Core. OH H H HO O H O O OAc O OH H bielschowskysin (36) OH CO2Me H O O H O O O 125 Thus, we predicated our synthetic strategy upon the formation of cyclobutane 125 via a Lewis acid–mediated cyclopropane fragmentation of ketone 126, followed by a 1,4 Michael addition (Scheme 2.3.1). We envisioned cyclopropane 126 arising from αdiazo-β-ketoester 127 by a cyclopropanation reaction using either a copper or rhodium 30 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR catalyst. In turn, α-diazo-β-ketoester 127 can be obtained from allylic alcohol 128 via esterification and diazotization. The latter compound, alcohol 128, can be prepared via Suzuki coupling between iodide 129 and boronic acid 130. Moreover, we postulated that allylic alcohol 128 could lead to a suitable substrate for a palladium(II)-catalyzed oxidative kinetic resolution to provide a secondary alcohol in high enantioselectivity, thus, providing access to an enantioselective synthesis of bielschowskysin. Scheme 2.3.1 O OH CO2Me H O O H O O O CO2Me O H O cyclopropane O fragmentation/ Michael addition O cyclopropanation O O 125 O O O 126 127 O O O HO CO2Me esterification N2 dizaotization I CO2Me (HO)2B O CO2Me TBSO 128 Suzuki coupling 129 130 The proposed key step in our synthesis of cyclobutane 125 is a Lewis acid–mediated cyclopropane fragmentation resulting in an enolate and an enone. We envision that these species will react via a Michael addition to provide the cyclobutane moiety (Figure 2.3.2). Complexation of the Lewis acid to the β-ketoester in compound 126 will lead to weakening of the bridging σ-bond of the cyclopropane ring shown in intermediate 131. Lone pair donation by the furan will result in fragmentation to form a stabilized enolate 132. The latter bond cleavage is preferred for two reasons: first, fragmentation of the most strained bond will relieve ring strain and lower the overall energy of the molecule; second, the π * orbitals of the β-ketoester moiety have good overlap with the breaking C–C σ-bond, leading to favorable enolate generation. Following fragmentation, 1,4-addition produces cyclobutane 133, which can undergo 31 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR rapid tautomerization to provide charged species 134, followed by the addition of water to furnish dihydrofuran 125.10 Figure 2.3.2 Proposed Mechanism for the Formation of Cyclobutane 125. L.A. O L.A. O CO2Me O O Lewis acid H O O O L M O O L L 131 L.A. O O O tautomerization O O 133 1,4 addition M O L 132 O CO2Me H CO2Me O O O 126 H fragmentation H O O CO2Me H O H O O CO2Me O O 134 H2O OH CO2Me H O H O O O 125 2.4 Initial Synthetic Efforts The synthesis began with furan 135, 11 which underwent magnesium-halogen exchange using conditions developed by Knochel,12 followed by a sequential quench of trimethyl borate and 1 M HCl to furnish boronic acid 130 in 85% yield (Scheme 2.4.1). Coupling of enone 129 with boronic acid 130 under similar conditions reported by Johnson provided compound 136 in excellent yield.13,14 At this stage, cleavage of the TBS group under acidic conditions provided allylic alcohol 128 in 98% yield. Exposure of allylic alcohol 118 to diketene and a catalytic amount of 4-(N ,Ndimethylamino)pyridine (DMAP) afforded unstable β-ketoester 137. Unfortunately, immediate treatment of β-ketoester 137 with p-ABSA and Et3N did not yield the desired diazo product; instead, a complex mixture of byproducts was obtained. This mixture of byproducts is the likely result of a Michael addition by the β-ketoester moiety, as well as 32 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR subsequent deprotonation at C(α) followed by β-elimination of the carboxylate functionality. Scheme 2.4.1 O I 1. i-PrMgCl, -35 °C, 1h 2. B(OMe)3, –35 °C → 23 °C Br O CO2Me 3. 1 M HCl, 0 °C, THF TBSO (HO)2B 135 O CO2Me 129 O Ag2O, 8 mol% AsPh3 5 mol% PdCl2(PhCN)2 THF:H2O (500:1) TBSO 130 CO2Me O 136 (85% yield over 2 steps) O O AcCl O MeOH, 0 °C (98% yield) HO 128 CO2Me diketene 5 mol% DMAP α THF, 0 °C O (75% yield) O O CO2Me p-ABSA, Et3N MeCN, 23 °C O complex mixture 137 To circumvent this problem, we postulated that the diazotization of β-ketoester 137 should be examined under neutral conditions. Moreover, we realized that the previous step, the synthesis of β-ketoester 137, is accomplished in a neutral environment. These observations led us to consider 2-diazoacetoacetic acid as an amenable partner in a DCC coupling reaction with allylic alcohol 128.15 The synthesis of 2-diazoacetoacetic acid (139) was carried out from α diazobenzylacetoacetate (138)16 by facile hydrogenolysis of the benzyl group, which provided the desired product along with a minor amount of acetoacetic acid in >95% conversion and purity.17 To our delight, the planned DCC coupling reaction between 2diazoacetoacetic acid (139) and alcohol 128 occurred in a straightforward manner to furnish targeted enone 127 in 75% yield (Scheme 2.4.2). 33 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.4.2 O O O 10% Pd/C (7% w/w) H2 balloon BnO O O HO N2 THF, 40-60 min, 23 °C O N2 HO 138 (>95% conversion) 139 128 CO2Me O acid 139, DCC 10 mol% DMAP O CH2Cl2, 23 °C (75% yield) O CO2Me N2 O O 127 The generation and coupling of 2-diazoacetoacetic acid (139) with allylic alcohol 128 was crucial for the synthesis of enone 127, as these conditions minimized the risk of side reactions, and simplified the standard two-step procedure. With this more efficient route to enone 127, we next investigated the esterification of 2-diazoacetoacetic acid (139) with a number of heteroatom nucleophiles to test the generality of this reaction and compare it with the two-step standard method. Gratifyingly, esterification of 2-diazoacetoacetic acid occurs efficiently for a variety of alcohols (Table 2.4.1). Primary and secondary alcohols couple with acid 139 in good to excellent yields (entries 1-6). Allylic alcohols are also competent substrates, and lead to their respective α-diazo-β-ketoesters in good yields (entries 7-10).18 As shown in entry 11, phenols are also viable substrates in the coupling reaction. Furthermore, the coupling of acid 139 with phenethylamine (162) to produce the α-diazoβ-ketoamide 163 in 95% yield illustrates that amines are also tolerated under these conditions (entry 12).19 34 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Table 2.4.1 Esterification of 2-diazoacetoacetic acid (139) with Heteroatom Nucleophiles. Entry Substratea Product OH O Yieldb O 1 140 O2 N O 141 O2 N O OH 2 142 O 143 O 85 N2 O Me 3 8 OH 92 N2 Me 144 8 O O 145 80 147 77 149 81 N2 O 4d OH 146 O O N2 O OH 5d O O 148 N2 H 3 H H 6d H 3 H 150 H H 151 O H OH O 87 O N2 O OH 7 O O 152 153 82 N2 O O 154 8 OH O R 10 O OH 160 O O O 77 R=H 157 R = NO2 159 95 77 N2 O 11d N2 O R R=H 156 R = NO2 OH 158 9c,d 155 O O O 161 O 75 N2 O 12 NH2 162 N H O 163 95 N2 a Standard conditions: 0.50 mmol substrate, 2-diazoacetic acid (139, 2.2 equiv), DCC (2.0 equiv), DMAP (0.10 equiv), 3.30 mL CH2Cl2, 23 °C, 60–90 min. b Isolated yield. c 0.30 mmol substrate. d Reaction at 40 °C, 60–90 min. With our study of 2-diazoacetoacetic acid couplings complete, our attention returned to enone 1 2 7 , and we began to investigate its ability to undergo Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 35 cyclopropanation. We initiated our studies with Cu(TBSal)2 as the catalyst because it has proven to be a robust catalyst system for cyclopropanation in similar systems.20 Unfortunately, when enone 127 was treated with a variety of rhodium and copper catalysts, including Cu(TBSal)2, cyclopropane 126 was never observed (Scheme 2.4.3).21 In searching the literature, no examples of an α-diazo-β-ketoester undergoing cyclopropanation with an enone were found. Therefore, we hypothesized that the enone functionality contributed to a withdrawal of electron density from the olefin, and thus inhibited cyclopropanation. Scheme 2.4.3 O O O O N2 CO2Me PhMe, 110 °C, O O 2 mol% Cu(TBSal)2 or other Rh and Cu catalysts H O O O 127 CO2Me Cu(TBSal)2: NOT OBSERVED N O Cu O N O 126 Following these initial cyclopropanation studies, we elected to modify the synthesis by reducing the ketone functionality in compound 136 (Scheme 2.4.1). We hypothesized that this would increase the electron density and the corresponding nucleophilicity of the olefin to facilitate cyclopropanation. Furthermore, 1,2-reduction of the enone functionality in compound 136 would provide the necessary substrate (37) with which to explore the palladium(II)-catalyzed oxidative kinetic resolution. The synthesis of alcohol 37 is accomplished from enone 136 via a Luche reduction in high yield and excellent diastereoselectivity (Scheme 2.4.4).22 The observed diastereoselectivity in this reduction is attributed to the bulky siloxy moiety at C(4), that likely prevents the approach of the hydride species from the β-face.23 36 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.4.4 O OH CeCl3•7H2O NaBH4 O CO2Me TBSO MeOH;CH2Cl2, (1:1) –25 °C CO2Me TBSO (95% yield) 10:1 dr (syn:anti) 136 O 4 37 2.5 The Palladium(II)-catalyzed Oxidative Kinetic Resolution As stated previously, we envisioned using the palladium(II)-catalyzed oxidative kinetic resolution as a method to establish the absolute stereochemistry of the C(4) stereocenter that is present in alcohol 37. Thus, with allylic alcohol 37 in hand, we examined the palladium(II)-catalyzed oxidative kinetic resolution. To our delight, treatment of racemic alcohol 37 under the original conditions developed for the palladium(II)-catalyzed oxidative kinetic resolution furnished ketone 136 in 57% conversion, and more importantly, afforded enantioenriched alcohol 37 in ≥ 95% ee and high selectivity for the overall process (s = 23, Scheme 2.5.1).24 Scheme 2.5.1 OH OH 5 mol% Pd(nbd)Cl2 20 mol% (–)-sparteine O CO2Me O MS3Å, O2 (1 atm), PhMe, 80 °C, 24 h TBSO O CO2Me TBSO (57% conversion) single diastereomer CO2Me TBSO ≥ 95% ee (±)-37 O (4S)-136 (1R,4R)-37 s = 23 enantiomers (1S,4S)-37 CeCl3•7H2O, NaBH4 MeOH, -20 °C Furthermore, the opposite enantiomer of alcohol can be obtained by treating (4S)enone 136 under the previously optimized Luche conditions to provide (1S, 4S)-alcohol 37 (Scheme 2.5.1).25 Since the absolute configuration of bielschowskysin is unknown, accessing both enantiomers of alcohol 37 in this fashion is important as it provides a route to potentially synthesize either enantiomer of the natural product. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 37 2.6 Further Investigations into the Model System Given the success of the critical palladium(II)-catalyzed oxidative kinetic resolution, our efforts were now solely focused on the synthesis of intermediate 126 and subsequent investigation into the formation of cyclobutane 127 (Scheme 2.6.1). Scheme 2.6.1 O O H O CO2Me OH CO2Me H Lewis acid O H O O O O O O 126 125 Beginning with furan 37, acetate protection of the alcohol and subsequent cleavage of the silyl ether unveiled allylic alcohol 164 in 85% overall yield (Scheme 2.6.2). The latter compound underwent esterification with diketene and subsequent diazotization to furnish α-diazo-β-ketoester 165 in good overall yield. Although the synthesis of compound 165 could be accomplished by coupling of alcohol 37 with 2diazoacetoacetic acid (139), the traditional two-step procedure ultimately proceeded in overall higher yield in this case. Initially, attempts to form the cyclopropane ring using rhodium catalysts, such as Rh2(oct)4, did not provide any of the desired product. Furthermore, the use of various copper sources, such as copper bronze or Cu(acac)2, led only to trace amounts of the desired product. Gratifyingly, formation of the cyclopropane was accomplished using 2 mol% Cu(TBSal)2 in either refluxing toluene or heating in a microwave using 1,2-dichloroethane as solvent to provide cyclopropane 166 in 55% yield. In general, the microwave conditions furnished cleaner reactions and more consistent yields during the scale-up process. In obtaining cyclopropane 166, we verified Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 38 our hypothesis that the olefin in enone 136 was simply too electron deficient to undergo cyclopropanation. Scheme 2.6.2 O O OH CO2Me O TBSO OAc 1. Ac2O, 10 mol% DMAP CH2Cl2 1. 5 mol% DMAP, THF, 0 °C 37 CO2Me O 2. TBAF, THF, 0 °C (85% yield over 2 steps) HO 2. MsN3, Et3N, MeCN, 0 °C 164 OAc O O O (55% yield) 165 OAc 2 mol% Cu(TBSal)2 PhMe, 110 °C or 10 mol% Cu(TBSal)2 µwave, DCE, Δ N2 O CO2Me (65% yield over 2 steps) O CO2Me H O O O 166 Although the synthesis of cyclopropane 166 was a significant accomplishment, this intermediate still needed to be elaborated to ketone 126. Initially, it was thought that cyclopropane 166 would undergo acetate cleavage to provide alcohol 167, followed by Dess-Martin periodinane oxidation to arrive at ketone 126 (Scheme 2.6.3).26 Gratifyingly, when cyclopropane 166 was subjected to these conditions, the desired ketone (126) appeared to be obtained in high overall yield. We next investigated the Lewis acid–mediated cyclopropane fragmentation and subsequent Michael addition en route to cyclobutane 125. Initial screening with several lanthanide Lewis acids found that treatment of ketone 126 with La(OTf)3 in methanol at 55 °C provided one product (168) as a single diastereomer in a 55% yield (unoptimized). Unfortunately, we were unable to confirm the structure of compound 168 by NMR; thus, we chose to esterify compound 168 to yield compound 169 in 79% yield. This enabled us to grow crystals of compound 169 suitable for analysis by X-ray crystallography. To our dismay, the X-ray data showed the structure of an unexpected product, β-ketoester 168. 39 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.6.3 O OAc OH O H O K2CO3, MeOH, 0 °C O CO2Me H (80% yield) O O 166 I OAc AcO OAc O 1 4 O (55% yield) H O O 126 167 La(OTf)3 O O O p-BrBzCl, Et3N CO2Me O 168 O Br O O O CO2Me O (97% yield) OH MeOH, 55 °C 1-2 h O CH2Cl2, 23 °C O O O O CO2Me CH2Cl2, 0 °C → 23 °C O H O O O CO2Me O (70% yield) O 169 Br X-ray structure obtained Upon examination of the connectivity of β-ketoester 169, we noticed that the oxidation states of C(1) and C(4) were opposite to those of desired ketone 126. This is the likely result of an undesired trans-esterification reaction that occurs when cyclopropane 166 undergoes acetate cleavage (Scheme 2.6.4). Treatment of cyclopropane 166 with K2CO3 in methanol presumably provided alkoxide 170. This alkoxide could potentially undergo a trans-esterification reaction and protonation to form alcohol 171. Finally, treatment of alcohol 171 with Dess-Martin periodinane provided αcyclopropyl ketone 172, which was originally misassigned as ketone 126. 40 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.6.4 OAc O O O K2CO3 HA CO2Me O O workup esterification O 166 O trans- HA MeOH, 0 °C O O O O CO2Me O O CO2Me HA O 170 O O O O O O I OAc AcO OAc O 1 O 4 CO2Me O CH2Cl2, 23 °C HA HO O CO2Me HA O 171 172 To confirm this undesired rearrangement, we partially incorporated deuterium at C(1), allowing us to follow the chemical shifts of the protons on both C(1) and C(4) during the course of acetate removal (Scheme 2.6.5). As hypothesized, the C(1) proton of intermediate 166 underwent a downfield shift in the 1H NMR, while the C(4) proton exhibited a slight upfield shift. Furthermore, cyclopropyl proton HA exhibits a 0.50 ppm shift that we have attributed to conformational changes that result from transesterification.27 These results confirmed that the trans-lactonization reaction did in fact occur during acetate removal. Scheme 2.6.5 O O (D)H OAc 1 4 O HA CO2Me K2CO3 O (D)H MeOH, 0 °C O O O 166 Δδ for HA = 0.5 ppm 1 O 4 HO CO2Me HA 171 In an effort to circumvent the trans-lactonization reaction, we synthesized a variety of compounds similar to cyclopropane 166 that differed only in the hydroxyl protecting group at C(1) (Figure 2.6.2).28 We postulated that these protecting groups may be removed under conditions that suppress the formation of alcohol 171. Unfortunately, 41 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR all attempts to deprotect compounds 173–177 in Figure 2.7.2 led solely to undesired alcohol 171. This result led us to conclude that the undesired lactone (171) is likely the thermodynamic product.29 Figure 2.6.2 Various Cyclopropane Derivatives. OBOM 1 OMOM O CO2Me O H O OSEM O 173 OTBS O H O O CO2Me O O 174 O H O OMEM CO2Me O 175 O H O O CO2Me CO2Me H O O O 176 O O 177 Other interesting observations can be made from the Lewis acid–mediated fragmentation reaction of cyclopropyl ketone 172 to provide unexpected alcohol 168 (Scheme 2.6.3). Beginning with ketone 172 in Scheme 2.6.6, we believe that Lewis acidic activation weakens the cyclopropane ring to allow the furan ring to assist in fragmentation to form an enolate and extended oxocarbenium ion in intermediate 178, both of which are quenched respectively by the overall addition of methanol to provide ketone 179.30 Thus, fragmentation of the cyclopropane ring occurred as anticipated; however, the addition of methanol preserved the aromaticity in the furan ring rather than undergoing a 1,2-addition into the oxocarbenium ion. We hypothesized that the driving force for the observed chemoselectivity in the methanol addition is due to rearomatization. Furthermore, under these conditions, an additional molecule of methanol can add into ketone 179 from the less-hindered α-face to form a hemiketal at C(4), which in turn, can undergo trans-esterification to produce alcohol 168. Notably, formation of the hemiketal at C(4) can occur at any point in the reaction; however, transesterification to generate the fused lactone is not favorable until the cyclopropane ring undergoes fragmentation. Another possible reason for the trans-esterification in Scheme Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 42 2.6.6 is the increased steric interaction that the bridged lactone in compound 179 would sustain with the furan moiety, compared to the fused lactone in alcohol 168. Scheme 2.6.6 L.A. O O L.A. O O O O O O O O CO2Me O O + MeOH CO2Me 4 O 172 + MeOH CO2Me O 178 179 O O OH O O transO HO O O O CO2Me esterification O H O CO2Me O O 180 O O 168 To examine our hypothesis of trans-esterification, we subjected compound 171 to identical Lewis acidic conditions that resulted in the formation of alcohol 181 in 65% yield as a single diastereomer (Scheme 2.6.7). Alcohol 181 can undergo subsequent functionalization to provide compound 182, allowing for suitable X-ray analysis (Figure 2.6.3). We initially believed that the hemiketal in intermediate 180 might force the alcohol into a pseudo-axial position and promote trans-esterification. However, by forming alcohol 181 without the ability for ketalization, we have shown that transesterification is facile once the cyclopropane ring has fragmented, regardless of the C(4) oxidation state. 43 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.6.7 O O OH OH O O O p-BrBzCl, Et3N La(OTf)3 O 4 CO2Me MeOH, 55 °C 1-2 h HO 171 (65% yield) H O CO2Me O O O CH2Cl2, 0 °C → 23 °C (79% yield) H O O O CO2Me O O 181 Br 182 X-ray crystal obtained 2.7 Future Directions Since the formation of alcohol 171 could not be averted, we decided to evaluate an alternative synthetic strategy focusing on initial construction of a macrocyclic intermediate.31 By beginning with macrocycle 188 (Scheme 2.8.1), we can reinforce chemo- and diastereoselectivity later in the synthesis. We believe there are at least two possible routes that could provide the cyclobutane core and the substituted oxocane ring found in bielschowskysin. The first route relies on a Michael addition and subsequent aldol reaction to provide the cyclobutane core, while the second route employs a reduction of an intermediate cyclopropane ring followed by a similar aldol addition to arrive at the highly strained core.32 We believe that ester 183 in Scheme 2.7.1 would serve as an excellent starting point since the enantio- and diastereoselective syntheses of similar compounds has been disclosed previously. Conversion of ester 183 to furan 185 could be accomplished in Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 44 three transformations: LiAlH4 reduction of the ester to the primary alcohol, Dess-Martin periodinane oxidation, followed by Grignard addition of reagent 184 into the newly formed aldehyde. With furan 185 in hand, deoxygenation of the secondary alcohol followed by acidic hydrolysis of the ketal will provide aldehyde 186. At this stage, removal of the MEM protecting group, followed by formation of the α-diazoacetate moiety would provide intermediate 187. It is thought that exposure of compound 187 to SnCl2 would effect the key intramolecular Roskamp reaction to provide macrocycle 188.33 Once formed, treating macrocycle 188 with monomagnesium peroxyphthalate (MMPP),34 a mild oxidizing agent, would oxidize the furan to provide enedione 189. This compound is now ready to undergo critical, sequential enolate additions to furnish the cyclobutane core. Hence, treatment of enedione 189 with DBU would first deprotonate the β-ketoester moiety resulting in a 1,4 Michael addition to form lactone 190. It is thought that protonation of the resulting enolate from the Michael addition will occur from the less-hindered α-face to provide the desired diastereomer needed for the Aldol addition. Once lactone 190 has formed, another equivalent of DBU could again deprotonate the β-ketoester moiety to promote an aldol addition and subsequent hemiketalization to afford cyclobutane 191. 45 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.7.1 OPMB O CO2Me OPMB 1. LiAlH4, THF 2. DMP, CH2Cl2 OH O 3. THF, Mg MEMO 183 O O 3. 1M HCl:THF 0 °C MEMO 184 O OPMB 1. NaH, CS2, MeI 2. AIBN, Bu3SnH MEMO O Br 185 H O O H 186 OPMB 1. ZnBr2, CH2Cl2 OPMB O 2. ClCOCNNHTs, Et3N, CH2Cl2 O CH2Cl2 N2 MMPP O O O O O O O 187 188 OPMB H DBU Michael addition O CH2Cl2 H O O OPMB SnCl2 HO O O O 190 189 OH PMBO O H DBU Aldol addition O O H O O O 191 A second approach, although not as rapid as above, utilizes our knowledge of the cyclopropane system to build the γ-lactone moiety and subsequently set the relative stereochemistry at C(2) by reduction of the cyclopropane ring. Starting with macrocycle 192 (Scheme 2.7.1), standard diazotization of the β-ketoester moiety followed by copper catalyzed cyclopropanation would afford cyclopropane 193. At this stage, removal of the TBS group followed by a Dess-Martin periodinane oxidation would provide ketone 194. Treating this product with La(OTf)3 and NaBH4 is expected to reduce the cyclopropane ring at C(2) as well as the C(7) ketone to provide alcohol 195 in high diastereoselectivity. We believe that the desired diastereoselectivity in the cyclopropane reduction is favored as a result of the observed selectivity that methanol showed in the model system in Scheme 2.6.6. Furthermore, with the macrocycle in place, hydride addition into the C(7) ketone should occur from the accessible α-face to provide the correct diastereomer. Protection of the alcohol in compound 195 as a MEM ether preserves the C(7)-oxygen’s 46 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR ability to direct. Hence, treating this compound with mCPBA should result in a regioand diastereoselective epoxidation of the furan to produce epoxide 196. At this stage, electron donation by the furan should be facile and lead to epoxide opening and the formation of oxocarbenium ion 197. This intermediate is in equilibrium with enol 198, which could undergo an aldol addition into the oxocarbenium ion followed by epimerization of the hemiketal to provide cyclobutane 199. Scheme 2.7.2 OPMB OPMB 1. p-ABSA, Et3N, MeCN O OTBS O O H 2. 2 mol% Cu(TBSal)2 µwave, 1,2-DCE, Δ O 194 O O 1. MEMCl, Et3N, CH2Cl2 OH 2. mCPBA, CH2Cl2 O H O O OMEM H OH PMBO O O OMEM aldol addition H O H OMEM and epimerization O 197 epoxide opening O OPMB H O OMEM 196 OPMB H O furan assisted O O 195 O O OPMB H O O 7 O O OPMB H H O O 193 NaBH4, Ln(OTf)3 O H 2. DMP, CH2Cl2 O O 192 H 2 1. TBAF, THF OTBS O O THF, –20 °C OPMB O OH 198 O O O 199 Both routes discussed above use similar macrocycles as key intermediates in the synthesis of compounds 191 and 199 respectively. The macrocycle is vital in both of these routes as it controls the diastereoselectivity at several stereocenters. Thus, future studies toward bielschowskysin should focus on the formation of either macrocycle 188 or macrocycle 192 prior to any investigations into the cyclobutane core. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 47 2.8 Concluding Remarks Although the cyclopropane route did not achieve its ultimate goal in synthesizing the cyclobutane ring, several successful aspects of our research can be extracted. Foremost, we have successfully implemented the palladium(II)-catalyzed oxidative kinetic resolution early in the synthesis to provide alcohol 37 in ≥95% ee and 43% yield. Moreover, this methodology could allow for rapid access to either enantiomer of allylic alcohol 37, an important intermediate in synthesizing advanced compounds within our synthetic efforts. Secondly, we have effectively developed a general method for obtaining α-diazo-β-ketoesters using 2-diazoacetoacetic acid (139). The latter reagent is readily generated, and has been synthesized on reasonable scale (ca. 5.0 mmol) in a straightforward manner from commercially available starting materials. The coupling of 2-diazoacetoacetic acid (139) using DCC under neutral conditions provided the desired products in high yields and tolerated a variety of alcohols. In addition, amines can be used as substrates for the amidation with 2-diazoacetoacetic acid, thus providing access to α-diazo-β-ketamides. Although our synthetic endeavors did not yield the cyclobutane core found in bielschowskysin, we did discover an important trans-esterification process that was later observed during synthetic efforts toward ineleganolide (108, Figure 2.1.1).35 Finally, an understanding of the reactivity of these molecules has been gained, thus allowing for efficient synthetic revisions and paving the way for further research. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 48 2.9 Experimental Procedures 2.9.1 Materials and Methods Unless otherwise stated, reactions were performed at ambient temperature (typically 20–22 ºC) in flame-dried glassware under an argon or nitrogen atmosphere using dry solvents. Solvents were dried by passage through an activated alumina column under argon. Et3N, iPr2NH, iPr2NEt, and pyridine were freshly distilled from CaH2. Trifluoroacetic acid (99%) was purchased from Aldrich. Tf2O was freshly distilled from P2O5. All other commercially obtained reagents were used as received. Reaction temperatures were controlled by an IKAmag temperature modulator. Thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, anisaldehyde, KMnO4, or CAM staining. ICN silica gel (particle size 0.032–0.063 mm) was used for flash chromatography. Optical rotations were measured with a Jasco P-1010 polarimeter at 589 nm. 1H and 13C NMR spectra were recorded on a Varian Mercury 300 (at 300 MHz and 75 MHz respectively), or a Varian Inova 500 (at 500 MHz and 125 MHz respectively) and are reported relative to solvent for 1H NMR (CHCl3 = 7.27 ppm, C6H6 = 7.16 ppm, CH2Cl2 = 5.30 ppm, DMSO = 2.51 ppm) and 13C NMR (CDCl3 = 77.0 ppm, C6D6 = 128.4 ppm). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicitiy, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, dt = doublet of triplets, td = triplet of doublets, dd = doublet of doublets, m = multiplet, comp. m = complex multiplet, app. = apparent, bs = broad singlet. IR spectra were recorded on a Perkin Elmer BX-11 FT-IR spectrometer and are reported in frequency of absorption (cm-1). High resolution mass 49 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR spectra were obtained from the California Institute of Technology Mass Spectral Facility. Crystallographic analyses were performed at the California Institute of Technology Beckman Institute X-Ray Crystallography Laboratory. Crystallographic data have been deposited at the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK and copies can be obtained on request, free of charge, from the CCDC by quoting the publication citation and the deposition number (see Appendix 3 for deposition numbers). 2.9.2 Preparation of Compounds O I 1. i-PrMgCl, -35 °C, 1h 2. B(OMe)3, –35 °C → 23 °C Br O 135 CO2Me 3. 1 M HCl, 0 °C, THF TBSO (HO)2B O 130 CO2Me 129 Ag2O, 8 mol% AsPh3 5 mol% PdCl2(PhCN)2 THF:H2O (500:1) TBSO O O CO2Me 136 (85% yield over 2 steps) Enone 136. To a solution of furan 135 (609 mg, 2.78 mmol, 1.00 equiv) in THF (15 mL) at –35 °C, was added a 1.84 M solution (THF) of iPrMgCl (1.96 mL, 3.61 mmol, 1.30 equiv) to the reaction. The reaction stirred for 45 minutes and the temperature was maintained between -40 and -30 °C. At this stage, trimethylborate (1.24 mL, 11.1 mmol, 4.00 equiv) was added rapidly at -30 °C, and the reaction was allowed to warm to ambient temperature and stir overnight. The reaction was cooled to 0 °C, 1 M HCl was added, and the mixture stirred for 30 minutes. The reaction was diluted with EtOAc and H2O, and the layers were separated. The aqueous layer was then washed 2x with EtOAc. The organic layers were combined, and washed with saturated K2CO3 (aq.) until the aqueous layer was basic. The basic aqueous layer was then acidified using 1 M HCl, and then washed 5x with EtOAc. The latter batch of EtOAc was washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to afford boronic acid 130 (375 mg, Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 50 73%) as a light-brown solid. This compound was used directly in the following Suzuki coupling reaction. To a solution of vinyl iodide 129 (87.0 mg, 0.260 mmol, 1.00 equiv), boronic acid 130 (71.0 mg, 0.390 mmol, 1.50 equiv), Ag2O (180 mg, 0.770 mmol, 3.00 equiv), and Ph3As (8.00 mg, 0.0260 mmol, 0.100 equiv) in THF (1.30 mL) was added PdCl2(PhCN)2 (5.00 mg, 0.0130 mmol, 0.0500 equiv) and H2O (50.0 µL). The reaction was stirred until consumption of vinyl iodide 129 as indicated by TLC (ca. 1.5 h) and filtered through a pad of celite. The solvent was concentrated in vacuo, and the residue was purified by flash chromatography using 3:97→5:95 EtOAc:hexanes to afford furan 136 as a white solid (74 mg, 80%). RF 0.15 (90:10 hexanes:EtOAc, UV); 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 2.7 Hz, 1H), 7.03 (s, 1H), 5.03 (m, 1H), 3.90 (s, 3H), 2.88 (dd, J = 5.9, 18.3 Hz, 1H), 2.42 (dd, J = 2.2, 18.6 Hz, 1H), 2.34 (s, 3H), 0.91 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 201.8, 160.1, 156.0, 147.4, 140.0, 133.7, 132.6, 116.1, 68.9, 51.8, 45.9, 25.8, 18.3, 11.5, -4.8; IR (film) 3133, 2949, 2928, 2891, 2857, 1721, 1703, 1594, 1509, 1448 cm-1; HRMS (FAB+) calc’d for [C18H26SiO5]+: m/z 350.1550, found 350.1542. O O O TBSO 136 CO2Me AcCl O MeOH, 0 °C (98% yield) HO CO2Me 128 Alcohol 128. To a solution of acetyl chloride (50.5 µL, 0.710 mmol, 5.00 equiv) in MeOH (570 µL) at 0 °C, was added enone 136 (52.5 mg, 0.150 mmol, 1.00 equiv) in one portion. Enone 136 dissolved slowly over 20–30 minutes at 0 °C, and once completely in solution, the reaction stirred for 45 minutes at 0 °C. The reaction was then diluted with Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 51 brine and EtOAc. These layers were separated, and the aqueous layer was washed 2x with EtOAc. The organic layers were combined, washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. This semi-solid was diluted with toluene, and then reconcentrated under vacuum (repeated 3x). Upon final concentration in vacuo, alcohol 128 was obtained as a white solid (35.3 mg, 99%). 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 2.9 Hz, 1H), 7.02 (s, 1H), 5.21 (br, 1H), 3.90 (s, 3H), 2.96 (dd, J = 6.1, 18.8 Hz, 1H), 2.71 (d, J = 5.40 Hz, 1H), 2.49 (dd, J = 2.2, 18.8 Hz, 1H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 201.8, 160.0, 154.9, 147.1, 139.9, 134.1, 132.4, 116.1, 68.3, 51.7, 45.2, 11.6; IR (film) 3447, 2920, 2850, 1716, 1506, 1440, 1405, 1295, 1167, 1102 cm-1; HRMS (FAB+) calc’d for [C12H13O5]+: m/z 237.0763, found 237.0763. O O O 10% Pd/C (7% w/w) H2 balloon BnO O HO N2 138 THF, 40-60 min, 23 °C (>95% conversion) N2 139 Acid 139. 10% Pd/C (17.5 mg, 7% w/w) was added to a solution of benzyl ester 138 (250 mg, 1.15 mmol, 1.00 equiv) in THF (11.5 mL) at 23 °C. The N2 atmosphere was evacuated and backfilled with H2 (balloon), this was repeated three additional times. The reaction was complete within 40–60 minutes as monitored by TLC (4:6 EtOAc:Hexanes). Once finished, the reaction mixture was passed through a short pad of celite (Et2O eluent), and the solvent was concentrated in vacuo to obtain 2-diazoacetoacetic acid (139) as a pale-yellow solid that was used directly in the esterification step. Compound 139 was ca. 95% pure by 1H NMR. Note: A pure (98%) sample of acid 139 was obtained by crystallization using Et2O/Heptane and cooling at -20 °C. 1H NMR (300 MHz, CDCl3) δ Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 52 2.46 (s, 3H); IR (film) 2932, 2150, 1722, 1601, 1302 cm-1; HRMS (EI+) calc’d for [C4H4N2O3]+: m/z 128.0222; found, 128.0227. O O HO CO2Me O CH2Cl2, 23 °C (75% yield) 128 O acid 139, DCC 10 mol% DMAP O CO2Me N2 O O 127 Enone 127. To a solution of alcohol 128 (71.0 mg, 0.300 mmol, 1.00 equiv), acid 139 (92.1 mg, 0.720 mmol, 2.40 equiv), and DMAP (3.67 mg, 0.0300 mmol, 0.100 equiv) in CH2Cl2 (2.00 mL) at 23 °C, was added DCC (206 mg, 1.00 mmol, 2.0 equiv) in one portion. After the addition of DCC, the reaction was heated to 40 °C for 90 minutes. The reaction was allowed to cool to ambient temperature, filtered through a plug of celite (Et2O eluent), and the resulting filtrate was partitioned between H2O and Et2O. The aqueous layer was extracted 2x with Et2O. The organic extracts were combined, washed once with H2O, and then once with brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography using 25:75 EtOAc:Hexanes to afford compound 127 as a light-yellow solid (78 mg, 75% yield). 1H NMR (500 MHz, C6D6) δ 7.30 (s, 1H), 7.23 (s, 1H), 5.24 (m, 1H), 3.46 (s, 3H), 2.33 (dd, J = 6.6, 18.6 Hz, 1H), 2.24 (s, 3H), 2.18 (s, 3H), 1.90 (d, J = 18.6 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 199.3, 188.6, 160.8, 159.9, 149.1, 147.3, 141.4, 136.4, 132.7, 117.5, 71.2, 51.5, 42.0, 28.4, 11.8; IR (film) 2954, 2145, 1715, 1660, 1366, 1312, 1155, 1062; HRMS (FAB+) calc’d for [C16H14N2O7]+: m/z 346.0801; found, 346.0817. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR O O O DCC, RXH 10 mol% DMAP HO 53 O RX CH2Cl2, 23 °C, 60-90 min N2 N2 X = O, NH 139 General Procedure for the Esterification of Acid 139 (Table 2.4.1). To a solution of substrate (0.500 mmol, 1 equiv), acid 139 (1.20 mmol, 2.4 equiv), and DMAP (0.0500 mmol, 0.10 equiv) in CH2Cl2 (3.30 mL) at 23 °C, was added DCC (1.00 mmol, 2.0 equiv) in one portion. Note: For 1° alcohols, the reaction remained at 23 °C. However, for 2° alcohols, the reaction was heated to 40 °C after the addition of DCC. The reaction was monitored by TLC, and the reaction was complete in 60–90 minutes. The reaction was filtered through a plug of celite (Et2O eluent), and the resulting filtrate was partitioned between H2O and Et2O. The aqueous layer was extracted 2x with Et2O. The organic extracts were combined, washed with NaHCO3 (saturated), and then with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The products were purified by flash chromatography. O O O O2 N 141 N2 Substrate 141.36 See General Procedure for the Esterification of Acid 139 (92% yield). Product was purified by flash chromatography (20:80 EtOAc:Hexanes). RF = 0.40 (30:70 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 5.35 (s, 2H), 2.47 (s, 2H); IR (film) 2148, 1711, 1344 cm-1. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR O 54 O 143 O N2 Substrate 143. See General Procedure for the Esterification of Acid 139 (85% yield). Product was purified by flash chromatography (17:83 EtOAc:Hexanes). RF = 0.45 (30:70 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 2H), 7.23-7.16 (m, 2H), 4.27 (t, J = 6.3 Hz, 2H), 2.71 (t, J = 7.2 Hz, 2H), 2.47 (s, 3H), 2.08-2.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 190.0, 161.2, 140.6, 128.4, 128.2, 126.1, 64.6, 32.0, 30.0, 28.1; IR (film) 2141, 1716, 1660, 1314 cm-1; HRMS (EI+) calc'd for [C13H15N2O3]+: m / z 247.1083; found, 247.1089. O Me 8 O 145 O N2 Substrate 145. See General Procedure for the Esterification of Acid 139 (80% yield). Product was purified by flash chromatography (5:95 EtOAc:Hexanes). RF = 0.50 (20:80 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 4.24 (t, J = 6.6 Hz, 2H), 2.49 (s, 3H), 1.71-1.66 (m, 2H), 1.33-1.27 (m, 14H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 190.2, 161.5, 65.5, 31.8, 29.4, 29.4, 29.2, 29.1, 28.6, 28.2, 25.7, 22.6, 14.1; IR (film) 2927, 2856, 2138, 1721, 1663, 1313 cm-1; HRMS (EI+) calc'd for [C14H25N2O3]+: m/z 269.1865; found, 269.1864. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR O 55 O 147 O N2 Substrate 147. See General Procedure for the Esterification of Acid 139 (77% yield). Product was purified by flash chromatography (10:90 EtOAc:Hexanes). All spectroscopic data is identical to that reported by Doyle.37 O O O 149 N2 Substrate 149. See General Procedure for the Esterification of Acid 139 (81% yield). Product was purified by flash chromatography (10:90 EtOAc:Hexanes). RF = 0.20 (10:90 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 7.90-7.83 (m, 4H), 7.55-7.50 (m, 3H), 6.21 (q, J = 6.6 Hz, 1H), 2.49 (s, 3H), 1.72 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 190.0, 160.7, 138.0, 133.1, 133.0, 128.6, 128.0, 127.6, 126.4, 126.3, 125.2, 123.6, 73.8, 28.2, 22.1; IR (film) 2140, 1715, 1658, 1305 cm-1; HRMS (FAB+) calc'd for [C16H15N2O3]+: m/z 283.1083; found, 283.1079. H 3 H H 151 O H O O N2 Substrate 151. See General Procedure for the Esterification of Acid 139 (87% yield). Product was purified by flash chromatography (5:95 EtOAc:Hexanes). 1H NMR (CDCl3) is identical to that reported by Doyle.38 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR O 56 O O 153 N2 Substrate 153. See General Procedure for the Esterification of Acid 139 (82% yield). Product was purified by flash chromatography (15:85 EtOAc:Hexanes). RF = 0.50 (20:80 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 7.44-7.28 (m, 5H), 6.70 (d, J = 15.6 Hz, 1H), 6.31 (dt, J = 6.6, 15.6 Hz, 1H), 4.90 (dd, J = 1.5, 6.6 Hz, 2H), 2.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 190.0, 161.1, 135.7, 135.3, 128.6, 128.3, 126.6, 122.2, 65.8, 28.2; IR (film) 2140, 1716, 1659, 1316 cm-1; HRMS (EI+) calc'd for [C13H12N2O3]+: m/z 244.0848; found, 244.0839. O O 155 O N2 Substrate 155. See General Procedure for the Esterification of Acid 139 (77% yield). Product was purified by flash chromatography (10:90 EtOAc:Hexanes). RF = 0.50 (20:80 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 5.37 (dt, J = 1.2, 3.6 Hz, 1H), 5.10-5.04 (m, 1H), 4.75 (d, J = 7.2 Hz, 2H), 2.49 (s, 3H), 2.13-2.05 (m, 4H), 1.74 (s, 3H), 1.68 (s, 3H), 1.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 190.1, 161.4, 143.4, 131.9, 123.5, 117.6, 62.1, 39.4, 28.1, 26.1, 25.6, 17.6, 16.4; IR (film) 2138, 1717, 1662, 1309 cm-1; HRMS (FAB+) calc'd for [C14H21N2O3]+, m/z 265.1552; found, 265.1548. O O O 157 O N2 Substrate 157.39 See General Procedure for the Esterification of Acid 139 (95% yield). Product was purified by flash chromatography (15:85 EtOAc:Hexanes). RF = 0.40 (30:70 57 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 7.76-7.73 (m, 2H), 7.68 (d, J = 2.7 Hz, 1H), 7.42-7.40 (m, 2H), 6.05 (dt, J = 2.4, 6.6 Hz, 1H), 3.10 (dd, J = 6.6, 18.6 Hz, 1H), 2.66 (dd, J = 1.8, 18.6 Hz, 1H), 2.50 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 202.0, 189.6, 160.9, 150.8, 146.3, 129.7, 129.6, 128.5, 127.6, 70.7, 42.4, 28.3; IR (film) 2144, 1716, 1654, 1313 cm-1; HRMS (FAB+) calc'd for [C15H13N2O4]+: m / z 285.0875; found, 285.0869. O I O O2N B O TBSO 129 1. Ag2O, 10 mol% AsPh3, 5.8 mol% PdCl2(PhCN)2, THF:H2O (19:1), 23 °C O O2N 2. AcCl, MeOH, 0 °C OH 158 Hydroxy Enone 158. A flask containing 4-(tert-butyldimethylsilyloxy)-2-iodocyclopent2-enone40 (400 mg, 1.60 mmol, 1.40 equiv) was charged with p-nitrophenyl pinacolato borate (388 mg, 1.15 mmol, 1.00 equiv),41 silver(I) oxide (800 mg, 3.45 mmol, 3.00 equiv), and Ph3As (35.2 mg, 0.120 mmol, 0.100 equiv) at 23 °C. THF (5.5 mL) and H2O (290 µL) were added, followed by addition of PdCl2(PhCN)2 (22.1 mg, 0.0580 mmol). The reaction mixture was stirred for 15 minutes at 23 °C, at which point TLC (5:95 EtOAc:Hexanes) indicated the reaction was complete. The reaction was passed through a pad of celite (EtOAc eluent), and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (7:93 EtOAc:Hexanes) to afford the Suzuki product as an oil (405 mg, 95% yield). This product (125 mg, 0.370 mmol, 1.00 equiv) was then added to a solution of AcCl (130 µL, 1.90 mmol, 5.10 equiv) in MeOH (7.5 mL) at 0 °C. The reaction was allowed to stir for 20 minutes, upon which TLC (40:60 EtOAc:Hexanes) showed consumption of the Suzuki product. The reaction was diluted with brine and EtOAc. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 58 The layers were separated, and the aqueous layer was washed 2x with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. TBSOH was removed azeotropically with toluene to afford alcohol 158 (80 mg, 99% yield). RF = 0.20 (50:50 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 8.25-8.20 (m, 2H), 7.91-7.87 (m, 2H), 7.82 (d, J = 2.4 Hz, 1H), 5.15 (m, 1H), 3.05 (dd, J = 6.6, 18.9 Hz, 1H), 2.60 (dd, J = 2.1, 18.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 203.2, 159.3, 147.8, 142.1, 136.7, 128.4, 123.7, 67.7, 45.7; IR (film) 3415, 1711, 1516, 1348 cm-1; HRMS (EI+): calc’d for [C11H9NO4]+: m/z 219.0532; found, 219.0506. O2N O O O 159 O N2 Substrate 159. See General Procedure for the Esterification of Acid 139 (77% yield). Product was purified by flash chromatography (50:50 EtOAc:Hexanes). RF = 0.30 (30:70 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3): δ 8.28 (m, 2H), 7.97-7.93 (m, 2H), 7.87 (d, J = 2.7 Hz, 1H), 6.09 (dt, J = 2.7, 6.6 Hz, 1H), 3.18 (dd, J = 6.6, 18.9 Hz, 1H), 2.70 (dd, J = 2.1, 18.9 Hz, 1H), 2.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 201.0, 189.4, 160.9, 153.8, 148.3, 144.4, 135.9, 128.6, 124.0, 70.4, 42.3, 28.3; IR (film) 2145, 1717, 1519, 1350, 1317 cm-1; HRMS (EI+) calc'd for [C15H11N3O6]+: m/z 329.0648; found, 329.0647. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR O O 59 O 161 O N2 Substrate 161. See General Procedure for the Esterification of Acid 139 (75% yield). Product was purified by flash chromatography (15:85 EtOAc:Hexanes). RF = 0.20 (20:80 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 7.28-7.23 (m, 2H), 7.13-7.08 (m, 2H), 4.00 (s, 3H), 2.71 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 189.9, 160.4, 157.6, 143.0, 122.3, 114.5, 55.6, 28.3; IR (film) 2142, 1732, 1507, 1324, 1191 cm-1; HRMS (FAB+) calc'd for [C11H11N2O4]+: m/z 235.0179; found, 235.0174. O N H O 163 N2 Substrate 163. See General Procedure for the Esterification of Acid 139 (95% yield). Product was purified by flash chromatography (40:60 EtOAc:Hexanes). RF = 0.25 (40:60 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 8.21 (br, 1H), 7.32-7.19 (m, 5H), 3.60 (q, J = 6.9 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.29 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 189.8, 160.5, 138.9, 129.0, 128.8, 126.8, 41.4, 36.1, 26.9; IR (film) 3309, 2124, 1667, 1538, 1312 cm-1; HRMS (EI+) calc'd for [C12H13N3O2]+: m/z 231.1008; found, 231.1007. O OH CeCl3•7H2O NaBH4 O TBSO 136 CO2Me MeOH;CH2Cl2, (1:1) –25 °C (95% yield) 10:1 dr (syn:anti) O CO2Me TBSO 37 Alcohol 37. To a solution of furan 136 (100 mg, 0.290 mmol, 1.00 equiv) and CeCl3•7H2O (430 mg, 1.10 mmol, 4.00 equiv) in MeOH:CH2Cl2 (4.90 mL, 1:1) at -25 °C, was added sodium borohydride (43.0 mg, 1.10 mmol, 4.00 equiv) portionwise while Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 60 maintaining the reaction between -25 and -20 °C. Upon consumption of the ketone as visualized by TLC (ca. 30 min.), the reaction was diluted with EtOAc and H2O. The solution was allowed to warm to ambient temperature and the layers were separated. The aqueous layer was extracted 3x with EtOAc, and the organic layers were combined and washed with brine. The EtOAc layer was dried with Na2SO4, filtered, and concentrated in vacuo to provide allylic alcohol 137 as a yellow oil (96 mg, 95%). RF = 0.20 (20:80 EtOAc:hexanes, UV); 1H NMR (500 MHz, CDCl3) δ 6.58 (s, 1H), 6.39 (s, 1H), 4.84 (m, 1H), 4.79 (m, 1H), 3.91 (s, 3H), 2.76 (dt, J = 6.9, 14.2 Hz, 1H), 2.36 (s, 3H), 1.98 (d, J = 9.3 Hz, 1H), 1.77 (d, J = 14.2 Hz, 1H), 0.92 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 160.0, 151.7, 139.5, 136.2, 133.0, 132.6, 113.7, 74.8, 74.2, 51.5, 44.7, 25.8, 18.1, 11.6, -4.6, 4.7; IR (film) 3420, 2954, 2930, 2857, 1711, 1440, 1298, 1101 cm-1; HRMS (FAB+) calc'd for [C18H27O5Si]+: m/z 351.1628; found 351.1632. OH O CO2Me O MS3Å, O2 (1 atm), PhMe, 80 °C, 24 h TBSO OH 5 mol% Pd(nbd)Cl2 20 mol% (–)-sparteine CO2Me TBSO ≥ 95% ee (±)-37 (57% conversion) (1R,4R)-37 s ≈ 23 (1R,4R)-Alcohol 37. A 10 mL Schlenk tube equipped with a magnetic stir bar was charged with powdered molecular sieves (3ÅMS, 150 mg) and flame-dried under vacuum. After cooling under dry N2, Pd(nbd)Cl2 (0.380 mg, 1.42 µmol, 0.0500 equiv) was added, followed by toluene (285 µL). To this yellow suspension was added (–)sparteine (1.33 mg, 5.67 µmol, 0.200 equiv), and the top of the Schlenk tube was then fitted with an O2 balloon. The reaction was purged under vacuum and replaced with O2, and this process was repeated 4x's. The light yellow suspension was stirred at ambient Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 61 temperature for 10 minutes, then heated to 80 °C for an additional 10 minutes. The reaction mixture darkened to an orange suspension. Upon completion of the 10 minutes, racemic alcohol 37 (10.0 mg, 28.4 µmol, 1.00 equiv, in 100µL of PhMe) was added to the reaction mixture. The suspension was then heated to 80 °C for 24 hours. The reaction was allowed to cool to ambient temperature, and was then filtered through a small pad of celite using toluene as eluent. The filtrate was concentrated in vacuo, and the 1H NMR of this material indicated a 43% yield of (1R,4R)-alcohol 37 (4.3 mg, 43% yield, 95% ee). [α]D24.98 +26.4 (c = 0.15, EtOAc).42 OH O TBSO 37 CO2Me OAc 1. Ac2O, 10 mol% DMAP CH2Cl2 O 2. TBAF, THF, 0 °C (85% yield over 2 steps) HO CO2Me 164 Allylic Alcohol 164. To a solution of alcohol 37 (96.0 mg, 0.270 mmol, 1.00 equiv) in pyridine (2.70 mL, 0.100 M) was added acetic anhydride (0.270 mL, 2.50 mmol, 9.00 equiv) and DMAP (3.30 mg, 0.0270, 0.100 equiv) at ambient temperature. The reaction was stirred until consumption of allylic alcohol 37 as monitored by TLC (ca. 30 min). The solution was cooled to 0 °C and diluted with EtOAc:brine (1:1). The aqueous solution was extracted 2x with EtOAc. The combined organic layer was successively washed with sat. CuSO4 (aq.), H2O, sat. NaHCO3 (aq.), and brine. The organic layer was then dried with Na2SO4, filtered, and concentrated in vacuo to yield an allylic acetate (101 mg, 95%). 1H NMR (300 MHz, CDCl3) δ 6.49 (dd, J = 0.9, 2.1 Hz, 1H), 6.26 (s, 1H), 5.85 (dd, J = 4.2, 7.5 Hz, 1H), 4.84 (m, 1H), 3.90 (s, 3H), 2.96 (dt, J = 7.5, 14.4 Hz, 1H), 2.33 (s, 3H), 2.10 (s, 3H), 1.73 (m, 1H), 0.91 (s, 9H), 0.11 (s, 3H), 0.11 (s, 3H). Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 62 A solution of TBAF (0.290 mL of 1M solution in THF, 0.289 mmol, 1.20 equiv) was added to the crude silyl ether (95 mg, 0.241 mmol, 1.00 equiv) in THF (4.8 mL) at 0 °C and under N2. The reaction was allowed to warm to ambient temperature and monitored by TLC. Once complete, the reaction was diluted with H2O, and the reaction was extracted 3x with EtOAc. The combined organic extracts were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude solid was purified by flash chromatography (50:50, EtOAc:hexanes) to provide allylic alcohol 164 as a white solid (64 mg, 85% from alcohol 37).: RF 0.2 (40:60, EtOAc:hexanes, UV); 1H NMR (500 MHz, CDCl3) δ 6.60 (d, J = 2.4 Hz, 1H), 6.29 (s, 1H), 5.88 (dd, J = 2.9, 7.3 Hz, 1H), 4.83 (m, 1H), 3.88 (s, ,3H), 2.88 (app dt, J = 14.7, 7.1, 1H), 2.32 (s, 3H), 2.07 (s, 3H), 1.81 (app dt, J = 12.2, 2.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 170.8, 160.0, 150.6, 140.1, 134.6, 133.6, 132.6, 113.8, 75.7, 74.4, 51.7, 41.5, 21.3, 11.7; IR (film) 3424, 2953, 1712, 1598, 1511, 1440, 1374, 1297, 1240, 1197, 1104, 1035 cm-1; HRMS (EI+) calc’d for [C14H16O6]+: m/z 280.2804, found 280.2800. O O OAc OAc 1. 5 mol% DMAP THF, 0 °C O HO 164 CO2Me 2. MsN3, Et3N MeCN, 0 °C (65% yield) O O CO2Me N2 O O 165 Ester 165. A solution of allylic alcohol 164 (15.0 mg, 0.0540 mmol, 1.00 equiv) and diketene (8.00 µL, 0.110 mmol, 2.00 equiv) in THF (1.10 mL) was cooled to 0 °C, and DMAP (0.350 mg, 0.00270 mmol, 0.0500 equiv) was added. The reaction was stirred at 0 °C for 10 minutes, and was then allowed to warm to ambient temperature. Once Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 63 complete by TLC (ca. 30 min), the reaction was concentrated in vacuo and carried on directly. 1H NMR (300 MHz, CDCl3) δ 6.59 (d, J = 1.8 Hz, 1H), 6.34 (s, 1H), 5.99 (dd, J = 2.7, 7.2 Hz, 1H), 5.73 (m, 1H), 3.90 (s, 3H), 3.48 (s, 2H), 3.00 (dt, J = 7.8, 15.6 Hz, 1H), 2.34 (s, 3H), 2.10 (s, 3H), 1.94 (dt, J = 7.8, 15.6 Hz, 1H). The crude β-ketoester (380 mg, 1.0 mmol, 1.0 equiv) was dissolved in MeCN (10.4 mL), and MsN3 (630 mg, 5.20 mmol, 5.00 equiv) followed by Et3N (0.870 mL, 6.20 mmol, 6.00 equiv) was added to the reaction. The resulting solution was stirred at ambient temperature until complete by TLC (ca. 6 h). The reaction was concentrated in vacuo, and the resulting crude oil was purified by silica gel chromatography (80:20→75:25, hexanes:EtOAc) to yield ester 165 as a light-yellow solid (338 mg, 65% average). 1H NMR (500 MHz, CDCl3) δ 6.60 (d, J = 2.2 Hz, 1H), 6.30 (s, 1H), 6.19 (m, 1H), 6.07 (m, 1H), 3.88 (s, 3H), 2.47 (s, 3H), 2.44 (m, 2H), 2.33 (s, 3H), 2.08 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 190.0, 170.8, 161.2, 159.8, 149.9, 140.5, 136.2, 132.5, 130.5, 114.7, 79.0, 76.2, 51.8, 39.1, 28.4, 21.2, 11.7; IR (film) 2142, 1713, 1657, 1295, 1237 cm-1; HRMS (EI+) calc’d for [C18H18N2O8]+: m/z 390.1063, found 390.1061. OAc O O CO2Me 10 mol% Cu(TBSal)2 µwave, DCE, Δ N2 O (55% yield) O 165 OAc 2 mol% Cu(TBSal)2 PhMe, 110 °C or O CO2Me H O O O 166 Cyclopropane 166. µwave conditions: The microwave is pre-warmed by undergoing an actual run with just DCE in the reaction tube. A solution of compound 165 (45.0 mg, 0.120 mmol, 1.00 equiv) and Cu(TBSal)2 (5.00 mg, 0.0120 mmol, 0.100 equiv) in DCE (3.00 mL) was heated for 20 min at 105 °C in the microwave. The following parameters Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 64 for the µwave are as follows: Power = 150 W, Temperature = 105 °C, Pressure = 200 atm, Ramp = 1 minute, Run Time = 20 minutes. The reaction was concentrated in vacuo, and the resulting crude oil was purified by silica gel chromatography (40:60 EtOAc:hexanes) to yield cyclopropane 166 as a white solid (21 mg, 55%). 1H NMR (500 MHz, C6D6) δ 6.20 (s, 1H), 5.47 (dd, J = 1.7, 7.3 Hz, 1H), 4.01 (m, 1H), 3.53 (d, J = 4.6 Hz, 1H), 3.39 (s, 3H), 2.39 (s, 3H), 2.13 (s, 3H), 1.73 (d, J = 14.4 Hz, 1H), 1.71 (s, 3H), 1.29 (ddd, J = 3.4, 7.6, 14.6 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 195.7, 170.8, 170.5, 160.0, 150.8, 141.5, 132.8, 116.2, 81.6, 78.4, 52.8, 51.9, 50.4, 46.0, 45.8, 29.7, 20.8, 12.0; IR (film) 2954, 1770, 1747, 1714, 1230 cm-1; HRMS (EI+) calc’d for [C18H19O8]+: m/z 363.1080, found 363.1085. Thermal conditions: A solution of Cu(TBSal)2 (1.30 mg, 0.00300 mmol, 0.0200 equiv) in toluene (2.40 mL) was heated, under Ar, to 108 °C. A warm solution of diazo 165 (62.0 mg, 0.150 mmol, 1.00 equiv) in toluene (0.400 mL) was added dropwise over 6 minutes. The reaction was heated to 112 °C, and monitored by TLC (40:60 EtOAc:hexanes). After 100 minutes, the reaction was complete, and allowed to cool to ambient temperature. The solvent was removed in vacuo, and the dark residue was purified by flash chromatography (40:60 EtOAc:hexanes) to provide cyclopropane 166 (35 mg, 56%). Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR OAc 65 O O O CO2Me K2CO3, MeOH, 0 °C H O O O (80% yield) O O CO2Me H HO 171 166 Alcohol 171. K2CO3 (32.0 mg, 0.240 mmol, 2.00 equiv) was added to a solution of cyclopropane 166 (43.0 mg, 0.120 mmol, 1.00 equiv) in MeOH (2.30 mL) at 0 °C. The reaction was stirred at 0 °C and monitored by TLC. Once complete, the reaction was diluted with saturated NH4Cl (aq.) and EtOAc, the layers were then separated, and the aqueous layer was further extracted 2x with EtOAc. The organic layers were combined, washed with H2O and brine, dried with Na2SO4, filtered, and concentrated in vacuo to afford a crude oil. The latter was purified by silica gel chromatography (50:50 EtOAc:Hexanes) to provide alcohol 171 as a glue (30 mg, 80%). 1H NMR (500 MHz, C6D6) δ 5.66 (s, 1H), 4.69 (m, 1H), 4.03 (app. q, J = 1.7, 5.6 Hz, 1H), 3.42 (s, 3H), 3.34 (d, J = 5.6 Hz, 1H), 2.28 (s, 3H), 2.12 (s, 3H), 1.53 (d, J = 14.4 Hz, 1H), 1.13 (ddd, J = 3.4, 7.3, 14.4 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 209.4, 196.2, 171.1, 159.6, 148.7, 141.6, 132.3, 114.6, 84.0, 71.5, 58.4, 51.4, 46.8, 45.9, 29.8, 11.8; IR (film) 3469, 1770, 1706, 1299, 1081 cm-1; HRMS (EI+) calc’d for [C16H16O7Na]+: m/z 343.0794, found 343.0811. O O O OAc AcO OAc O HO O O O I O CO2Me O CH2Cl2, 23 °C H (97% yield) 171 O O CO2Me H 172 Ketone 172. To a solution of alcohol 171 (62.0 mg, 0.190 mmol, 1.00 equiv) in CH2Cl2 (3.90 mL) was added Dess-Martin periodinane (160 mg, 0.390 mmol, 2.00 equiv), and Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 66 the resulting slurry stirred until consumption of starting material (ca. 1 h). The reaction was diluted with EtOAc and a 1:1 ratio of saturated Na2S2O4 (aq.) to saturated NaHCO3(aq.), and stirred vigorously for 5 minutes. The layers were separated and the organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to yield crude ketone 172 as a colorless oil (60 mg, 97%). The ketone was carried on crude as attempts toward further purification resulted in decomposition. 1H NMR (500 MHz, C6D6) δ 5.53 (s, 1H), 4.59 (dd, J = 1.2, 4.4 Hz, 1H), 3.49 (d, J = 1.2 Hz, 1H), 3.43 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H), 1.90 (d, J = 17.6 Hz, 1H), 1.66 (dd, J = 4.6, 17.6 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 202.0, 193.2, 168.7, 159.6, 146.2, 140.0, 142.4, 132.3, 115.9, 78.4, 54.4, 52.6, 51.6, 49.9, 45.3, 29.5, 11.8; IR (film) 2924, 2854, 1180, 1750, 1715, 1559, 1438, 1294, 1102 cm-1; HRMS (EI+) calc’d for [C16H14O7]+: m/z 318.0740, found 318.0732. OH O O O La(OTf)3 O O O O H CO2Me MeOH, 55 °C 1-2 h (55% yield) 172 O CO2Me O O O 168 Alcohol 168. Crude ketone 172 (11.0 mg, 0.0340 mmol, 1.00 equiv) and La(OTf)3 (20.0 mg, 0.0340 mmol, 1.00 equiv) were dissolved in MeOH (0.670 mL) at ambient temperature, then heated to 55 °C and stirred until the majority of starting material appeared consumed by TLC. The reaction was diluted with EtOAc and H2O and the aqueous layer was extracted 3x with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using 66:34 EtOAc:Hexanes to afford alcohol 168 as an oil (8.0 mg, 55%).; 1H NMR (500 MHz, C6D6) δ 5.90 (s, 1H), 4.26 (dd, J = 1.7, 5.6 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 67 Hz, 1H), 4.24 (m, 1H), 4.04 (d, J = 5.8 Hz, 1H), 3.38 (s, 3H), 3.20 (s, 3H), 2.80 (s, 3H), 2.56 (dd, J = 4.2, 14.2 Hz, 1H), 2.26 (s, 3H), 2.20 (d, J = 14.2 Hz, 1H), 2.15 (s, 3H), 1.84 (d, J = 2.7 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 199.3, 170.6, 159.8, 154.1, 140.9, 132.0, 119.4, 115.9, 87.4, 76.9, 60.5, 52.0, 51.5, 51.4, 48.0, 43.7, 29.5, 11.8; IR (film) 3465, 2955, 1771, 1722, 1441, 1297, 1197, 1102 cm-1; HRMS (EI+) calc’d for [C18H22O9]+: m/z 382.1264, found 382.1259. O OH 1 4 O O O p-BrBzCl, Et3N CO2Me O O O 168 O Br O CH2Cl2, 0 °C → 23 °C O H O O O CO2Me O (70% yield) O 169 Br X-ray structure obtained Furan 169. Triethylamine (19.0 mL, 0.140 mmol, 2.40 equiv) was added at ambient temperature to a solution of alcohol 168 (22.0 mg, 0.0580 mmol, 1.00 equiv) in CH2Cl2 (310 mL). DMAP (0.700 mg, 0.00580 mmol, 0.100 equiv) and p-bromobenzoyl bromide (28.0 mg, 0.130 mmol, 2.20 equiv) were then added, and the reaction stirred for 1 hour at ambient temperature. The reaction was diluted with EtOAc and H2O, the layers were separated, and the aqueous layer was washed once with EtOAc. The EtOAc layers were combined, washed with saturated NaHCO3 (aq.), washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. Crystals suitable for X-ray analysis were obtained by crystallization of crude furan 169 (30 mg, yield 70%) from EtOAc:heptane. 1H NMR (500 MHz, C6D6) δ 7.97 (m, 2H), 7.39 (m, 2H), 7.25 (m, 2H), 7.10 (m, 2H), 5.99 (s, 1H), 5.73 (m, 1H), 3.93 (s, 1H), 3.24 (s, 3H), 3.13 (s, 3H), 2.88 (s, 3H), 2.54 (s, 3H), 2.49 (m, 2H), 2.15 (s, 3H); 13C NMR (125 MHz, C6D6) δ 168.1, 164.6, 161.9, 161.6, 159.2, 152.9, Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 68 141.0, 132.1, 132.0, 132.0, 131.8, 131.4, 129.3, 128.8, 128.6, 127.7, 114.9, 114.7, 114.2, 87.4, 78.1, 55.5, 52.3, 51.6, 50.1, 39.3, 17.4, 11.4; IR (film) 2948, 1762, 1725, 1589, 1227, 1101, 1070, 1010 cm-1; HRMS (FAB+) calc’d for [C32H30O11Br81Br]+: m/z 750.0135, found 750.0159. mp = 175-177 °C (heptane/EtOAc). OBOM O CO2Me H O O O 173 Cyclopropane 173. Cyclopropane 173 was obtained from allylic alcohol 37 using the same route employed to obtain cyclopropane 1 6 6 (Scheme 2.6.2). For the cyclopropanation reaction, cyclopropane 173 was obtained as an oil (3.5 mg, 74 %). 1H NMR (500 MHz, C6D6) δ 7.30 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 7.6 Hz, 1H), 7.06 (t, J = 7.3 Hz, 2H), 5.93 (s, 1H), 4.93 (d, J = 7.1 Hz, 1H), 4.63 (d, J = 7.1 Hz, 1H), 4.60 (s, 2H), 4.11 (m, 1H), 3.42 (d, J = 4.6 Hz, 1H), 3.39 (s, 3H), 2.42 (s, 3H), 2.12 (s, 3H), 1.86 (d, J = 14.2 Hz, 1H), 1.20 (dd, J = 3.2, 14.2 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 195.0, 169.4, 158.9, 150.4, 140.4, 138.0, 131.4, 128.2, 114.2, 93.3, 80.7, 69.7, 51.4, 50.6, 50.3, 44.8, 28.6, 11.1; IR (film) 2952, 1769, 1713, 1297, 1102, 1037 cm-1; HRMS (EI+) calc’d for [C24H23DO8]+: m/z 441.1534, found 441.1523. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 69 OMOM O CO2Me H O O O 174 Cyclopropane 174. Cyclopropane 174 was obtained from allylic alcohol 37 using the same route employed to obtain cyclopropane 1 6 6 (Scheme 2.6.2). For the cyclopropanation reaction, cyclopropane 174 was obtained as an oil (2.3 mg, 62%). 1H NMR (500 MHz, C6D6) δ 5.95 (s, 1H), 4.78 (d, J = 7.1 Hz, 1H), 4.48 (d, J = 7.1 Hz), 4.09 (m, 1H), 3.43 (d, J = 4.9, 1H), 3.39 (s, 3H), 3.23 (s, 3H), 2.43 (s, 3H), 2.13 (s, 3H), 1.82 (d, J = 14.2, 1H), 1.20 (dd, J = 3.4, 14.2 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 196.0, 170.3, 159.8, 151.3, 141.2, 132.3, 115.0, 96.1, 81.5, 56.3, 52.3, 51.5, 51.1, 45.8, 45.7, 29.4, 12.0; IR (film) 2926, 1767, 1711, 1402, 1297, 1100 cm-1; HRMS (EI+) calc’d for [C18H19DO8]+: m/z 365.1221, found 365.1216. OSEM O CO2Me H O O O 175 Cyclopropane 175. Cyclopropane 175 was obtained from allylic alcohol 37 using the same route employed to obtain cyclopropane 1 6 6 (Scheme 2.6.2). For the cyclopropanation reaction, cyclopropane 175 was obtained as an oil (2.9 mg, 62%). 1H NMR (500 MHz, C6D6) δ 6.02 (s, 1H), 4.94 (d, J = 7.1Hz, 1H), 4.65 (d, J = 7.1 Hz, 1H), 4.13-4.11 (m, 1H), 3.78-3.73 (m, 1H), 3.46 (d, J = 4.6Hz, 1H), 3.42 (s, 3H), 2.44 (s, 3H), 2.15 (s, 3H), 1.93 (d, J = 14.2 Hz, 1H), 1.27 (dd, J = 3.2, 13.9 Hz, 1H), 0.94-0.90 (m), 0.01 (s, 9H); 13C NMR (125 MHz, C6D6) δ 196.0, 170.3, 159.8, 151.5, 141.2, 132.4, Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 70 115.2, 94.3, 81.6, 66.5, 56.2, 51.6, 51.1, 45.9, 46.0, 29.5, 18.6, 12.0, -0.80; IR (film) 2953, 1770, 1713, 1440, 1297 cm-1; HRMS (FAB+) calc’d for [C22H29DO8SiNa]+: m/z 474.1773, found 474.1675. OTBS O CO2Me H O O O 176 Cyclopropane 176. Cyclopropane 176 was obtained from allylic alcohol 37 using the same route employed to obtain cyclopropane 1 6 6 (Scheme 2.6.2). For the cyclopropanation reaction, cyclopropane 176 was obtained as an oil (6.5 mg, 71%). 1H NMR (500 MHz, C6D6) δ 5.71 (s, 1H), 4.15-4.13 (m, 1H), 3.42 (s, 3H), 3.33 (d, J = 4.6 Hz, 1H), 2.45 (s, 3H), 2.13 (s, 3H), 1.63 (d, J = 13.7 Hz, 1H), 1.21 (dd, J = 3.4, 13.7 Hz, 1H), 1.09 (s, 9H), 0.29 (s, 3H), 0.10 (s, 3H); 13C NMR (125 MHz, C6D6) δ 196.3, 170.2, 159.7, 151.2, 141.4, 132.0, 114.4, 81.6, 53.6, 52.6, 51.4, 48.2, 45.3, 29.4, 26.3, 18.8, 11.9, -4.5, -4.6; IR (film) 2953, 2930, 2857, 1770, 1714, 1297, 1113 cm-1; HRMS (FAB+) calc’d for [C22H29DO7SiNa]+: m/z 459.1800, found 458.1749. OMEM O CO2Me H O O O 177 Cyclopropane 177. Cyclopropane 177 was obtained from allylic alcohol 37 using the same route employed to obtain cyclopropane 1 6 6 (Scheme 2.6.2). For the cyclopropanation reaction, thermal conditions were used, and cyclopropane 177 was Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 71 obtained as an oil (9.1 mg, 42%). 1H NMR (500 MHz, CDCl3) δ 6.23 (s, 1H), 5.11 (m, 1H), 5.02 (d, J = 7.1 Hz, 1H), 4.92 (d, J = 7.1 Hz, 1H), 3.99 (d, J = 4.9 Hz, 1H), 3.86 (s, 3H), 3.83 (q, J = 4.4 Hz, 2H), 3.58 (t, J = 4.4 Hz, 2H), 3.39 (s, 3H), 2.46 (s, 3H), 2.34 (d, J = 14.2 Hz, 1H), 2.29 (s, 3H), 2.20 (dd, J = 3.2, 14.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 196.2, 170.1, 159.4, 149.8, 140.2, 131.9, 114.7, 94.3, 81.5, 71.6, 67.4, 59.0, 51.6, 51.4, 50.9, 45.4, 45.2, 29.1, 11.6; IR (film) 2925, 1767, 1711, 1613, 1548, 1440, 1297, 1198, 1099, 1037 cm-1; HRMS (EI+) calc'd for [C20H23DNaO9]+: m/z 432.1381, found 432.1365. O O OH O O La(OTf)3 O CO2Me MeOH, 55 °C 1-2 h HO 171 (65% yield) HO CO2Me O O O 181 Alcohol 181. Furan 171 (49.0 mg, 0.153 mmol, 1.00 equiv) and La(OTf)3 (89.5 mg, 0.153 mmol, 1.00 equiv) were dissolved in MeOH (3.00 mL) at ambient temperature, and then heated to 55 °C and stirred for 1–2 hours. The reaction was diluted with EtOAc and H2O and the aqueous layer was extracted 3x with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using 60:40 EtOAc:Hexanes to afford alcohol 181 as an oil (35 mg, 65%). 1H NMR (300 MHz, CDCl3) δ 6.34 (s, 1H), 5.30 (br, 1H), 5.17 (t, J = 7.3 Hz, 1H), 4.64 (d, J = 3.8 Hz, 1H), 4.10 (t, J = 6.7 Hz, 1H), 3.91 (d, J = 5.5 Hz, 1H), 3.89 (s, 3H), 3.03 (s, 3H) 2.50 (ddd, J = 4.1, 7.1, 15.4 Hz, 1H), 2.43 (s, 3H), 2.47 (s, 3H), 2.20 (d, J = 15.4 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 200.0, 172.4, 159.9, 154.3, 140.9, 132.1, 116.2, 88.5, 83.5, 77.0, 58.6, 51.4, 51.4, 45.9, 40.0, 29.6, Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 72 11.8; IR (film) 3474, 2952, 1769, 1717, 1297, 1195, 1098 cm-1; HRMS (EI+) calc'd for [C17H21O8Na]+: m/z 353.1236, found 353.1246. OH OH O O p-BrBzCl, Et3N H O CO2Me O O O CH2Cl2, 0 °C → 23 °C (79% yield) CO2Me Br O H O O O O 181 182 Furan 182. Triethylamine (43.0 µL , 306 µmol, 4.00 equiv) was added at 0 °C and under N2, to a solution of alcohol 181 (27.0 mg, 76.6 µmol, 1.00 equiv) in CH2Cl2 (955 µL). After 1 minute, p-bromobenzoyl bromide (42.0 mg, 192 µmol, 2.50 equiv) was added, and the reaction was stirred for 30 minutes at 0 °C. The reaction was allowed to warm to ambient temperature and stir for an additional 1 hour. The reaction was then diluted with Et2O and H2O, the layers were separated, and the aqueous layer was washed once with Et2O. The Et2O layers were combined, washed with saturated NaHCO3 (aq.), washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. Crystals suitable for X-ray analysis were obtained by crystallization of crude furan 182 (54 mg, 98% yield) from EtOAc:heptane. 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 6.38 (s, 1H)5.06 (t, J = 6.4 Hz, 1H), 4.46 (q, J = 7.2, 3.5 Hz, 1H), 3.80 (m, 4H), 3.18 (s, 3H), 2.45 (s, 3H), 2.37 (m, 1H), 2.33 (s, 3H), 2.28 (d, J = 3.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 169.5, 162.0, 159.9, 153.5, 139.9, 132.0, 131.9, 131.6, 129.2, 129.0, 127.6, 115.8, 115.3, 88.7, 79.8, 52.6, 52.3, 51.5, 38.5, 17.1, 11.6; IR (film) 3445, 2950, 1749, 1705, 1589, 1439, 1399, 1300, 1231, 1070, 1010 cm-1; HRMS (EI+) calc'd for [C24H23BrO9]+: m/z 557.0423, found 557.0427. mp = 158-159 °C (EtOAc:Heptane). Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 73 2.10 Notes and References 1 Marrero, J.; Rodriguez, A. D.; Baran, P.; Raptis, R. G.; Sanchez, J. A.; Ortega-Barria, E.; Capson, T. L. Org. Lett. 2004, 6, 1661–1664. 2 For verrillin, see: Rodriguez, A. D.; Shi, Y. P. J. Org. Chem. 2000, 65, 5839–5842.; For ineleganolide, see: Duh, C. Y.; Wang, S. K.; Chiang, M. Y. Tetrahedron Lett. 1999, 40, 6033–6035.; For scabrolide A, see; Sheu, J. H.; Ahmed, A. F.; Shiue, R. T.; Dai, C. F.; Kuo Y. H. J. Nat. Prod. 2002, 65, 1904–1908. 3 The dihydrofuran unit actually disguises a 1,4 enedione moiety. However, as in ineleganolide (108) and scabrolide A (109), the olefin may further undergo various reactions such as 1,4-hetero-Michael addition or an olefin migration, respectively. 4 An oxocane is an 8-membered ethereal ring that is fully saturated. 5 (a) Roethle, P. A.; Trauner, D. Org. Lett. 2006, 8, 345–347. (b) Roethle, P. A.; Hernandez, P. T.; Trauner, D. Org. Lett. 2006, 8, 5901–5904. 6 For example, bipinnatin A can undergo two different cycloisomerization reactions to provide two known natural products. For examples, see: (a) Rodriguez, A. D.; Shi, J.G. J. Org. Chem. 1998, 63, 420–421. (b) Rodriguez, A. D.; Shi, J.-G.; Huang, S. D. J. Org. Chem. 1998, 63, 4425–4432. 7 Doroh, B.; Sulikowski, G. A. Org. Lett. 2006, 8, 903–906. 8 Although this is possible, it is also feasible that the undesired diradical intermediate 120 is higher in energy and undergoes σ-bond rotation to the desired diradical intermediate 118. Since neither diradical intermediate 118 or 120 has been observed, Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 74 one can only speculate as to how prevalent σ-bond rotation is, as well as its impact on the diastereoselectivity. 9 Miao, R.; Subramanian, G. G.; Lear, M. L. Tetrahedron Lett. 2009, 50, 1731–1733. 10 Although the addition of water into the oxocarbenium ion is shown as the last step of the mechanism, it is possible that this may occur at any point after cyclopropane fragmentation. 11 Khatuya, J. Tetrahedron Lett. 2001, 42, 2643–2644. 12 (a) Knochel, P.; Cahiez, G.; Rottlander, M.; Boymond, L. Angew. Chem., Int. Ed. Engl. 1998, 37, 1701–1703. (b) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. Engl. 2004, 43, 3333–3336. 13 Myers, A.; Dragovich, P. S. J. Am. Chem. Soc. 1993, 115, 7021–7022. 14 Johnson, C. R.; Braun, M. P.; Ruel, F. S. Org. Synth. 1996, 75, 69–72. 15 For a related system that provides nonsymmetrical α-diazomalonates, see: Kido, F.; Yamaji, K.; Abiko, T.; Kato, M. J. Chem. Res. 1993, 18–19. 16 Prepared using standard diazotization conditions (see S.I.). 17 Although the crude product could be crystallized to higher purity using 95% EtOH at –20 °C overnight, the crude solid was used in the coupling reaction and still provided acceptable yields. 18 Meyer, M. E.; Ferreira, E. M.; Stoltz, B. M. Chem. Commun. 2006, 1316–1318. 19 For examples of α-diazo-β-ketoamides, see: (a) Jeganathan, A.; Richardson, S. K.; Mani, R. S.; Haley, E. B.; Watt, D. S. J. Org. Chem. 1986, 51, 5362–5367. (b) Padwa, Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 75 A.; Zhi, L. J. Am. Chem. Soc. 1990, 112, 2037–2038. (c) Padwa, A.; Dean, D. C.; Fairfax, D. J.; Xu, S. L. J. Org. Chem. 1993, 58, 4646–4655. 20 For examples of Cu(TBSal)2 being used in total synthesis, see: (a) Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559–3562. (b) Corey, E. J.; Wess, G.; Xiang, Y. B.; Singh, A. K. J. Am. Chem. Soc. 1987, 109, 4717–4718. (c) Singh, A. K.; Bakshi, R. K.; Corey, E. J. J. Am. Chem. Soc. 1987, 109, 6187–6189. (d) Fukuyama, T.; Chen, X. J. Am. Chem. Soc. 1994, 116, 3125–3126. (e) Fernandez, M. A.; Barba, L. J. Org. Chem. 1995, 60, 3580–3585. 21 The only isolated product from this reaction other than starting material was an αhydroxy-β-ketoester that resulted from the overall addition of water to the "carbene". 22 Germal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454–5459. 23 For a study of reduction conditions for a similar enone, see: Curran, T. T.; Hay, D. A.; Koegel, C. P. Tetrahedron 1997, 53, 1983–2004. 24 Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725–7726. 25 In a separate run, ketone 136 was obtained in 40% yield and 93% ee after 18 hours. 26 Dess, D. B.; Martin, J. C. J. Org. Chem. 1991, 113, 7277–7287. 27 Deuterium labeling may not be needed if the 1H NMR spectra of cyclopropane 166, alcohol 171, and ketone 172, are attained in C6D6, and each spectrum is analyzed and compared. The spectra, in C6D6, for these three compounds are in Appendix 2.2 (Spectra of Compounds Relevant to Chapter 2). 28 All compounds in Figure 2.6.2 had partial deuterium incorporation at C(1) similar to cyclopropane 166 in Scheme 2.6.5. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 29 76 Spartan calculations (semi-empirical, AM1) show that undesired alcohol 171 is 4.3 kcal lower in energy than desired alcohol 167. 30 For examples of nucleophilic addition into a cyclopropane ring, see: (a) Danishefsky, S.; Dynak, J. J. Org. Chem. 1974, 39, 1979–1980. (b) Isobe, M.; Lio, H.; Kawai, T.; Goto, T. J. Am. Chem. Soc. 1978, 100, 1940–1942. (c) Callant, P.; Wilde, H. D.; Vaderwalle, M. Tetrahedron 1981, 37, 2079–2084. 31 32 See Appendix 2.1 for our attempts to form a macrocycle. For an example of a domino Michael addition followed by an aldol addition to provide a fused cyclobutane ring, see: (a) Ihara, M.; Toyota, M.; Fukumoto, K. J. Chem. Soc. Perkin Trans. I 1986, 2151–2161. (b) Ihara, M.; Ohnishi, M.; Takano, M. J. Am. Chem. Soc. 1992, 114, 4408–4410. (c) Ihara, M.; Taniguchi, T.; Makita, K.; Takano, M.; Ohnishi, M.; Taniguchi, N.; Fukumoto, K.; Kabuto, C. J. Am. Chem. Soc. 1993, 115, 8107–8115. (d) Takasu, K.; Misawa, K.; Ihara, M. Tetrahedron Lett. 2001, 42, 8489–8491. (e) Stelmakh, A.; Stellfeld, T.; Kalesse, M. Org. Lett. 2006, 8, 3485–3488. 33 (a) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258–3260. (b) Holmquist, C. R.; Roskamp, E. J. Tetrahedron Lett. 1992, 33, 1131–1134. (c) Kanemasa, S.; Kanai, T.; Araki, T.; Wada, E. Tetrahedron Lett. 1999, 40, 5055–5058. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 34 77 Furan 200 can be treated with MMPP to provide enedione 202 in an unoptomized 63% yield: OTBS Furan Oxidation O Decomposition CO2Me MMPP: O TESO O 1. DIBAL 2. TBSCl imid. DMF OTBS OTBS O TESO 35 O 200 O Mg OH HO O O O O OTBS MMPP OTBS O (63% yield) 201 TESO O 202 Roizen, J. L.; Progress Toward an Enantioselective Total Synthesis of Ineleganolide. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, 2009. 36 Ueda, Y.; Roberge, G.; Vinet, V. Can. J. Chem. 1984, 62, 2936–2939. 37 Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115, 958–964. 38 Doyle, M. P.; Davies, S. B.; May, E. J. J. Org. Chem. 2001, 66, 8112–8119. 39 This starting alcohol (156) was prepared in the same manner as compound 158, using phenyl boronic acid as the coupling partner. It was also made via a known route, see: D’Auria, M. Heterocycles 2000, 52, 185–194. 40 Reul, F. S.; Braun, M. P.; Johnson, C. R. Org. Synth. 1996, 75, 69–72. 41 Zhu, L.; Duquette, J.; Zhang, M. J. Org. Chem. 2003, 68, 3729–3732. 42 For a separate sample, alcohol 37 at 70% ee, gave an [α]D24.9 +16.9.  78 Ch. 2 Appendices Appendix 2.1 Failed Synthetic Approaches Toward a Macrocyclic Intermediate (All Characterization Data Obtained for Compounds i–xx in Appendix 2.1 can be found in “JHP Characterized Compounds” binder) 79 Ch. 2 Appendices Scheme A2.1.1 Stille coupling route: formation of vinyl halide and vinyl stannane. O OPMB 1. NaBH4, CeCl3·7H2O THF:CH2Cl2 (1:1) I 2. PMB-TCA, 20 mol% La(OTf)3 MeCN, 23 °C TESO i OPMB 10 mol% Pd(PPh3)4 (Bu3Sn)2 I SnBu3 NaHCO3, PhMe, Δ TESO ii (69% yield over 2 steps) TESO iii (50% yield) OPMB SnBu3 1. TBAF, THF O 2. O NNHTs Cl DMA, CH2CH2, then Et3N O N2 (71% yield over 2 steps) iv 1. Mg0, THF, 0 °C CO2Me O N Br 2. Br2, MeCN O O Br OMe Br O O 2. 2M HCl:THF (1:1) O (60% yield over 2 steps) v H O 1. HCl·NHMe(OMe) iPrMgCl, THF, -10 °C O (86% yield over 2 steps) vi vii Scheme A2.1.2 Stille coupling route: Attempts at macrocyclization. OPMB OPMB SnBu3 H Br O O N2 iv O O CH2Cl2, 23 °C O O vii O O OPMB O viii N N O ix (32% yield) (32% yield) Br O O O O O viii Various Stille Conditions O O Br OPMB SnBu3 O SnBu3 Br SnCl2 O O OPMB SnBu3 O O O O NOT OBSERVED x O Sampling of conditions tried: Pd(PPh3)4, LiCl, CuCl, DMSO, 60 °C Pd2(dba)3, iPr2NEt, DMF CuTC, NMP Pd2(dba)3, AsPh3, NMP Pd2(dba)3, TFP, NMP Pd2(dba)3, P(o-tol)3, NMP 80 Ch. 2 Appendices Scheme A2.1.3 Intramolecular esterification route. O CO2Me O OH 1. NaBH4, CeCl3·7H2O THF:CH2Cl2 (1:1), -30 °C 1. Cs2CO3, NaI, DMF CO2H O 2. KOTMS, THF, 0 °C TBSO TBSO (88% yield over 2 steps) xi O xii O Br O 2. Ac2O, DMAP, pyridine (45% yield over 2 steps) OAc OAc O O O O TBAF O TBSO O 3ÅMS O HO THF PhMe (10-4 M), Δ O (81% yield) O O O O xiii xiii OAc OAc O O intramolecular O HO O esterification O O NOT OBSERVED O • O O xiii O xiv OAc OAc O over time O -CO2 O O O trace H2O O HO HO O O O OH xv xvi Scheme A2.1.4 Ring closing metathesis route. OPMB OPMB Ag2O, 8 mol% AsPh3 5 mol% PdCl2(PhCN)2 I Br O CO2Me TESO xvii O THF:H2O (500:1) XX CO2Me 2. Mg0, 4-Br-1-butene, THF, 23 °C TESO xviii (90% yield) OPMB 1. HCl·NHMe(OMe) iPrMgCl, THF, -10 °C (76% yield over 2 steps) OPMB O O 1. AcCl, MeOH, 0 °C O 2. cinnamoyl chloride, NEt3, CH2Cl2, 23 °C TESO PhH or CH2Cl2 or 1,2-DCE O Ph G = Grubbs GH = Grubbs-Hoveyda O (75% yield over 2 steps) xix G-2, GH-2, G-3, GH-3 O xx OPMB OPMB O O O O O Ph O O O ONLY ISOLABLE PRODUCT TRACE AMOUNTS NOT OBSERVED xxi xxii O 81 Ch. 2 Appendices Appendix 2.2 Spectra of Compounds Relevant to Chapter Two TBSO O 136 O CO2Me Figure A2.2.1 1H NMR (500 MHz, CDCl3) of compound 136 Ch. 2 Appendices 82 83 Ch. 2 Appendices Figure A2.2.2 Infrared spectrum (film/NaCl) of compound 136 Figure A2.2.3 13C NMR (125 MHz, CDCl3) of compound 136 HO O 128 O CO2Me Figure A2.2.4 1H NMR (500 MHz, CDCl3) of compound 128 Ch. 2 Appendices 84 85 Ch. 2 Appendices Figure A2.2.5 Infrared spectrum (film/NaCl) of compound 128 Figure A2.2.6 13C NMR (125 MHz, CDCl3) of compound 128 HO O 139 N2 O Figure A2.2.7 1H NMR (300 MHz, CDCl3) of compound 139 Ch. 2 Appendices 86 87 Ch. 2 Appendices Figure A2.2.8 Infrared spectrum (film/NaCl) of compound 139 O O O O N2 127 O CO2Me Figure A2.2.9 1H NMR (500 MHz, C6D6) of compound 127 Ch. 2 Appendices 88 89 Ch. 2 Appendices Figure A2.2.10 Infrared spectrum (film/NaCl) of compound 127 Figure A2.2.11 13C NMR (125 MHz, C6D6) of compound 127 O2N 141 O O N2 O Figure A2.2.12 1H NMR (300 MHz, CDCl3) of compound 141 Ch. 2 Appendices 90 Ch. 2 Appendices Figure A2.2.13 Infrared spectrum (film/NaCl) of compound 141 91 143 O O N2 O Figure A2.2.14 1H NMR (300 MHz, CDCl3) of compound 143 Ch. 2 Appendices 92 93 Ch. 2 Appendices Figure A2.2.15 Infrared spectrum (film/NaCl) of compound 143 Figure A2.2.16 13C NMR (75 MHz, CDCl3) of compound 143 Me 8 145 O O N2 O Figure A2.2.17 1H NMR (300 MHz, CDCl3) of compound 145 Ch. 2 Appendices 94 95 Ch. 2 Appendices Figure A2.2.18 Infrared spectrum (film/NaCl) of compound 145 Figure A2.2.19 13C NMR (75 MHz, CDCl3) of compound 145 147 O O N2 O Figure A2.2.20 1H NMR (300 MHz, CDCl3) of compound 147 Ch. 2 Appendices 96 97 Ch. 2 Appendices Figure A2.2.21 Infrared spectrum (film/NaCl) of compound 147 Figure A2.2.22 13C NMR (75 MHz, CDCl3) of compound 147 149 O O N2 O Figure A2.2.23 1H NMR (300 MHz, CDCl3) of compound 149 Ch. 2 Appendices 98 99 Ch. 2 Appendices Figure A2.2.24 Infrared spectrum (film/NaCl) of compound 149 Figure A2.2.25 13C NMR (75 MHz, CDCl3) of compound 149 H 3 H H H 151 O O N2 O Figure A2.2.26 1H NMR (300 MHz, CDCl3) of compound 151 Ch. 2 Appendices 100 Ch. 2 Appendices Figure A2.2.27 Infrared spectrum (film/NaCl) of compound 151 101 153 O O N2 O Figure A2.2.28 1H NMR (300 MHz, CDCl3) of compound 153 Ch. 2 Appendices 102 103 Ch. 2 Appendices Figure A2.2.29 Infrared spectrum (film/NaCl) of compound 153 Figure A2.2.30 13C NMR (75 MHz, CDCl3) of compound 153 155 O O O N2 Figure A2.2.31 1H NMR (300 MHz, CDCl3) of compound 155 Ch. 2 Appendices 104 105 Ch. 2 Appendices Figure A2.2.32 Infrared spectrum (film/NaCl) of compound 155 Figure A2.2.33 13C NMR (75 MHz, CDCl3) of compound 155 157 O O O N2 O Figure A2.2.34 1H NMR (300 MHz, CDCl3) of compound 157 Ch. 2 Appendices 106 107 Ch. 2 Appendices Figure A2.2.35 13C NMR (125 MHz, CDCl3) of compound 157 158 O OH Figure A2.2.36 1H NMR (300 MHz, CDCl3) of compound 158 O2N Ch. 2 Appendices 108 109 Ch. 2 Appendices Figure A2.2.37 Infrared spectrum (film/NaCl) of compound 158 Figure A2.2.38 13C NMR (75 MHz, CDCl3) of compound 158 O2N 159 O O O N2 O Figure A2.2.39 1H NMR (300 MHz, CDCl3) of compound 159 Ch. 2 Appendices 110 111 Ch. 2 Appendices Figure A2.2.40 Infrared spectrum (film/NaCl) of compound 159 Figure A2.2.41 13C NMR (75 MHz, CDCl3) of compound 159 O 161 O O N2 O Figure A2.2.42 1H NMR (300 MHz, CDCl3) of compound 161 Ch. 2 Appendices 112 113 Ch. 2 Appendices Figure A2.2.43 Infrared spectrum (film/NaCl) of compound 161 Figure A2.2.44 13C NMR (125 MHz, CDCl3) of compound 161 163 N H O N2 O Figure A2.2.45 1H NMR (300 MHz, CDCl3) of compound 163 Ch. 2 Appendices 114 115 Ch. 2 Appendices Figure A2.2.46 Infrared spectrum (film/NaCl) of compound 163 Figure A2.2.47 13C NMR (75 MHz, CDCl3) of compound 163 TBSO OH 37 O CO2Me Figure A2.2.48 1H NMR (500 MHz, CDCl3) of compound 37 Ch. 2 Appendices 116 117 Ch. 2 Appendices Figure A2.2.49 Infrared spectrum (film/NaCl) of compound 37 Figure A2.2.50 13C NMR (125 MHz, CDCl3) of compound 37 HO OAc 164 O CO2Me Figure A2.2.51 1H NMR (500 MHz, CDCl3) of compound 164 Ch. 2 Appendices 118 119 Ch. 2 Appendices Figure A2.2.52 Infrared spectrum (film/NaCl) of compound 164 Figure A2.2.53 13C NMR (125 MHz, CDCl3) of compound 164 O O O N2 OAc 165 O CO2Me Figure A2.2.54 1H NMR (500 MHz, CDCl3) of compound 165 Ch. 2 Appendices 120 121 Ch. 2 Appendices Figure A2.2.55 Infrared spectrum (film/NaCl) of compound 164 Figure A2.2.56 13C NMR (125 MHz, CDCl3) of compound 164 O O OAc 166 O H O CO2Me Figure A2.2.57 1H NMR (500 MHz, C6D6) of compound 166 Ch. 2 Appendices 122 123 Ch. 2 Appendices Figure A2.2.58 Infrared spectrum (film/NaCl) of compound 166 Figure A2.2.59 13C NMR (125 MHz, C6D6) of compound 166 HO O H O O 171 O CO2Me Figure A2.2.60 1H NMR (500 MHz, C6D6) of compound 171 Ch. 2 Appendices 124 125 Ch. 2 Appendices Figure A2.2.61 Infrared spectrum (film/NaCl) of compound 171 Figure A2.2.62 13C NMR (125 MHz, C6D6) of compound 171 O O H O O 172 O CO2Me Figure A2.2.63 1H NMR (500 MHz, C6D6) of compound 172 Ch. 2 Appendices 126 127 Ch. 2 Appendices Figure A2.2.64 Infrared spectrum (film/NaCl) of compound 172 Figure A2.2.65 13C NMR (125 MHz, C6D6) of compound 172 O O O OH O 168 O O CO2Me Figure A2.2.66 1H NMR (500 MHz, C6D6) of compound 168 Ch. 2 Appendices 128 129 Ch. 2 Appendices Figure A2.2.67 Infrared spectrum (film/NaCl) of compound 168 Figure A2.2.68 13C NMR (125 MHz, CDCl3) of compound 168 Br O O O O 169 O O H O O CO2Me Br O Figure A2.2.69 1H NMR (500 MHz, C6D6) of compound 169 Ch. 2 Appendices 130 131 Ch. 2 Appendices Figure A2.2.70 Infrared spectrum (film/NaCl) of compound 169 Figure A2.2.71 13C NMR (125 MHz, C6D6) of compound 169 O O O 173 O H OBOM CO2Me Figure A2.2.72 1H NMR (500 MHz, C6D6) of compound 173 Ch. 2 Appendices 132 133 Ch. 2 Appendices Figure A2.2.73 Infrared spectrum (film/NaCl) of compound 173 Figure A2.2.74 13C NMR (125 MHz, C6D6) of compound 173 O O O 174 O H OMOM CO2Me Figure A2.2.75 1H NMR (500 MHz, C6D6) of compound 174 Ch. 2 Appendices 134 135 Ch. 2 Appendices Figure A2.2.76 Infrared spectrum (film/NaCl) of compound 174 Figure A2.2.77 13C NMR (125 MHz, CDCl3) of compound 174 O O O 175 O H OSEM CO2Me Figure A2.2.78 1H NMR (500 MHz, C6D6) of compound 175 Ch. 2 Appendices 136 137 Ch. 2 Appendices Figure A2.2.79 Infrared spectrum (film/NaCl) of compound 175 Figure A2.2.80 13C NMR (125 MHz, C6D6) of compound 175 O O O 176 O H OTBS CO2Me Figure A2.2.81 1H NMR (500 MHz, C6D6) of compound 176 Ch. 2 Appendices 138 139 Ch. 2 Appendices Figure A2.2.82 Infrared spectrum (film/NaCl) of compound 176 Figure A2.2.83 13C NMR (125 MHz, C6D6) of compound 176 O O O 177 O H OMEM CO2Me Figure A2.2.84 1H NMR (500 MHz, C6D6) of compound 177 Ch. 2 Appendices 140 141 Ch. 2 Appendices Figure A2.2.85 Infrared spectrum (film/NaCl) of compound 177 Figure A2.2.86 13C NMR (125 MHz, CDCl3) of compound 177 O O OH 181 O H O O CO2Me Figure A2.2.87 1H NMR (300 MHz, CDCl3) of compound 181 Ch. 2 Appendices 142 143 Ch. 2 Appendices Figure A2.2.88 Infrared spectrum (film/NaCl) of compound 181 Figure A2.2.89 13C NMR (125 MHz, CDCl3) of compound 181 O O OH O O O 182 H CO2Me Br O Figure A2.2.90 1H NMR (500 MHz, CDCl3) of compound 182 Ch. 2 Appendices 144 145 Ch. 2 Appendices Figure A2.2.91 Infrared spectrum (film/NaCl) of compound 182 Figure A2.2.92 13C NMR (125 MHz, CDCl3) of compound 182 146 Ch. 2 Appendices Appendix 2.3 X-Ray Crystallographic Data Relevant to Chapter Two 147 Ch. 2 Appendices CALIFORNIA INSTITUTE OF TECHNOLOGY BECKMAN INSTITUTE X-RAY CRYSTALLOGRAPHY LABORATORY Crystal Structure Analysis of: Alcohol 182 (CCDC 606989) Contents Table 1.Crystal data Table 2.Atomic Coordinates Table 3.Full bond distances and angles Table 4.Anisotropic displacement parameters Table 5.Hydrogen atomic coordinates Table 6.Hydrogen bond distances and angles Figure A2.3.1 Representation of alcohol 182. Br O O O O H O MeO2C 182 O OH 148 Ch. 2 Appendices Table 1. Crystal data and structure refinement for alcohol 182 (CCDC 606989). Empirical formula C24H23O9Br Formula weight 535.33 Crystallization Solvent Ethyl acetate/hexanes Crystal Habit Fragment Crystal size 0.34 x 0.26 x 0.18 mm3 Crystal color Colorless Data Collection Type of diffractometer Bruker SMART 1000 Wavelength 0.71073 Å MoKα Data Collection Temperature 100(2) K θ range for 20114 reflections used in lattice determination 2.43 to 41.82° Unit cell dimensions a = 11.1074(2) Å b = 13.5443(3) Å c = 16.7177(4) Å α= 106.8590(10)° β= 104.9520(10)° γ = 98.6060(10)° Volume 2255.89(8) Å3 Z 4 Crystal system Triclinic Space group P-1 Density (calculated) 1.576 Mg/m3 F(000) 1096 Data collection program Bruker SMART v5.630 θ range for data collection 1.71 to 42.84° Completeness to θ = 42.84° 87.4 % Index ranges -21 ≤ h ≤ 21, -24 ≤ k ≤ 25, -31 ≤ l ≤ 31 Data collection scan type ω scans at 8 φ settings Data reduction program Bruker SAINT v6.45A Reflections collected 68261 Independent reflections 28932 [Rint= 0.0502] Absorption coefficient 1.876 mm-1 Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.000000 and 0.820201 149 Ch. 2 Appendices Table 1 (cont.) Structure solution and Refinement Structure solution program Bruker XS v6.12 Primary solution method Direct methods Secondary solution method Difference Fourier map Hydrogen placement Difference Fourier map Structure refinement program Bruker XL v6.12 Refinement method Full matrix least-squares on F2 Data / restraints / parameters 28932 / 0 / 797 Treatment of hydrogen atoms Unrestrained Goodness-of-fit on F2 1.189 Final R indices [I>2σ(I), 18290 reflections] R1 = 0.0407, wR2 = 0.0734 R indices (all data) R1 = 0.0831, wR2 = 0.0812 Type of weighting scheme used Sigma Weighting scheme used w=1/σ2(Fo2) Max shift/error 0.007 Average shift/error 0.000 Largest diff. peak and hole 0.844 and -0.543 e.Å-3 Special Refinement Details Refinement of F2 against ALL reflections. The weighted R-factor (wR) and goodness of fit (S) are based on F2, conventional R-factors (R) are based on F, with F set to zero for negative F2. The threshold expression of F2 > 2σ( F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. 150 Ch. 2 Appendices Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for alcohol 182 (CCDC 606989). U(eq) is defined as the trace of the orthogonalized Uij tensor. ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1) 11019(1) 1482(1) 10581(1) 19(1) O(1A) 4709(1) 873(1) 8210(1) 34(1) O(2A) 5774(1) 1287(1) 7327(1) 20(1) O(3A) 2091(1) 777(1) 5288(1) 36(1) O(4A) 2261(1) 2445(1) 6087(1) 25(1) O(5A) 5897(1) 4595(1) 7735(1) 19(1) O(6A) 4432(1) 3010(1) 5395(1) 20(1) O(7A) 7570(1) 3438(1) 7662(1) 16(1) O(8A) 10665(1) 2911(1) 8096(1) 26(1) O(9A) 9571(1) 3647(1) 8987(1) 18(1) C(1A) 9361(1) 1314(1) 9804(1) 16(1) C(2A) 9229(1) 1148(1) 8922(1) 20(1) C(3A) 8037(1) 1072(1) 8348(1) 18(1) C(4A) 6990(1) 1154(1) 8661(1) 15(1) C(5A) 7140(1) 1289(1) 9543(1) 18(1) C(6A) 8330(1) 1375(1) 10125(1) 18(1) C(7A) 5707(1) 1080(1) 8070(1) 18(1) C(8A) 4599(1) 1014(1) 6651(1) 22(1) C(9A) 4200(2) -138(1) 6108(1) 34(1) C(10A) 4018(1) 1783(1) 6549(1) 19(1) C(11A) 2731(1) 1566(1) 5895(1) 24(1) C(12A) 3206(1) 3353(1) 6785(1) 22(1) C(13A) 4414(1) 2941(1) 7101(1) 17(1) C(14A) 5506(1) 3668(1) 6955(1) 15(1) C(15A) 4787(1) 3946(1) 6159(1) 17(1) C(16A) 3600(1) 4196(1) 6402(1) 21(1) C(17A) 6832(1) 5468(1) 7761(1) 25(1) C(18A) 6643(1) 3217(1) 6874(1) 14(1) C(19A) 6986(1) 2623(1) 6200(1) 16(1) C(20A) 8221(1) 2463(1) 6582(1) 16(1) C(21A) 8535(1) 2986(1) 7470(1) 16(1) C(22A) 8979(1) 1840(1) 6099(1) 22(1) C(23A) 9698(1) 3171(1) 8201(1) 17(1) C(24A) 10696(1) 3849(1) 9740(1) 20(1) Br(2) O(1B) O(2B) O(3B) O(4B) O(5B) O(6B) O(7B) O(8B) O(9B) C(1B) C(2B) 3493(1) 9806(1) 8714(1) 12418(1) 12534(1) 9146(1) 10420(1) 7219(1) 4007(1) 5099(1) 5143(1) 5228(1) 3385(1) 4309(1) 3943(1) 4788(1) 3196(1) 747(1) 2346(1) 1646(1) 1961(1) 1226(1) 3643(1) 3750(1) -883(1) 1640(1) 2530(1) 4624(1) 3826(1) 2103(1) 4444(1) 2160(1) 1733(1) 841(1) -75(1) 794(1) 18(1) 28(1) 19(1) 30(1) 23(1) 20(1) 19(1) 16(1) 21(1) 18(1) 15(1) 17(1) Ch. 2 Appendices C(3B) 6417(1) 3885(1) 1395(1) 17(1) C(4B) 7512(1) 3913(1) 1131(1) 14(1) C(5B) 7415(1) 3819(1) 261(1) 17(1) C(6B) 6229(1) 3685(1) -347(1) 17(1) C(7B) 8798(1) 4077(1) 1764(1) 17(1) C(8B) 9866(1) 4308(1) 3237(1) 19(1) C(9B) 10039(1) 5424(1) 3807(1) 28(1) C(10B) 10611(1) 3636(1) 3334(1) 18(1) C(11B) 11900(1) 3974(1) 4011(1) 21(1) C(12B) 11713(1) 2235(1) 3104(1) 22(1) C(13B) 10398(1) 2503(1) 2764(1) 17(1) C(14B) 9408(1) 1648(1) 2882(1) 16(1) C(15B) 10213(1) 1430(1) 3687(1) 18(1) C(16B) 11459(1) 1343(1) 3466(1) 22(1) C(17B) 8407(1) -225(1) 2091(1) 25(1) C(18B) 8174(1) 1940(1) 2947(1) 14(1) C(19B) 7771(1) 2456(1) 3621(1) 15(1) C(20B) 6467(1) 2480(1) 3241(1) 14(1) C(21B) 6179(1) 1972(1) 2353(1) 15(1) C(22B) 5613(1) 2941(1) 3728(1) 20(1) C(23B) 4983(1) 1725(1) 1626(1) 15(1) C(24B) 3965(1) 998(1) 90(1) 20(1) ________________________________________________________________________________ 151 Ch. 2 Appendices Table 3. Bond lengths [Å] and angles [°] for alcohol 182 (CCDC 606989). _______________________________________________________________________________ Br(1)-C(1A) 1.8967(11) C(20A)-C(21A) 1.3699(16) O(1A)-C(7A) 1.2006(15) C(20A)-C(22A) 1.4966(15) O(2A)-C(7A) 1.3673(15) C(21A)-C(23A) 1.4612(15) O(2A)-C(8A) 1.4031(14) C(22A)-H(22A) 0.86(2) O(3A)-C(11A) 1.2030(18) C(22A)-H(22B) 0.89(2) O(4A)-C(11A) 1.3573(18) C(22A)-H(22C) 0.91(2) O(4A)-C(12A) 1.4575(16) C(24A)-H(24A) 0.945(19) O(5A)-C(17A) 1.4344(17) C(24A)-H(24B) 0.950(18) O(5A)-C(14A) 1.4363(14) C(24A)-H(24C) 0.921(17) O(6A)-C(15A) 1.4308(15) Br(2)-C(1B) 1.8886(10) O(6A)-H(6A) 0.76(2) O(1B)-C(7B) 1.2031(14) O(7A)-C(18A) 1.3641(13) O(2B)-C(7B) 1.3679(14) O(7A)-C(21A) 1.3745(12) O(2B)-C(8B) 1.4040(13) O(8A)-C(23A) 1.2169(13) O(3B)-C(11B) 1.2033(17) O(9A)-C(23A) 1.3406(14) O(4B)-C(11B) 1.3588(17) O(9A)-C(24A) 1.4513(14) O(4B)-C(12B) 1.4660(16) C(1A)-C(6A) 1.3878(15) O(5B)-C(17B) 1.4358(18) C(1A)-C(2A) 1.3900(17) O(5B)-C(14B) 1.4305(13) C(2A)-C(3A) 1.3897(16) O(6B)-C(15B) 1.4301(15) C(2A)-H(2A) 0.969(18) O(6B)-H(6B) 0.79(2) C(3A)-C(4A) 1.3984(15) O(7B)-C(18B) 1.3659(13) C(3A)-H(3A) 0.929(18) O(7B)-C(21B) 1.3763(12) C(4A)-C(5A) 1.3950(16) O(8B)-C(23B) 1.2158(13) C(4A)-C(7A) 1.4795(15) O(9B)-C(23B) 1.3397(14) C(5A)-C(6A) 1.3897(16) O(9B)-C(24B) 1.4497(14) C(5A)-H(5A) 0.891(17) C(1B)-C(6B) 1.3940(14) C(6A)-H(6A1) 0.951(16) C(1B)-C(2B) 1.3935(16) C(8A)-C(10A) 1.3341(19) C(2B)-C(3B) 1.3865(16) C(8A)-C(9A) 1.489(2) C(2B)-H(2B) 0.901(16) C(9A)-H(9A1) 0.88(2) C(3B)-C(4B) 1.3958(15) C(9A)-H(9A2) 0.97(2) C(3B)-H(3B) 0.927(18) C(9A)-H(9A3) 0.96(2) C(4B)-C(5B) 1.3976(16) C(10A)-C(11A) 1.4857(15) C(4B)-C(7B) 1.4823(15) C(10A)-C(13A) 1.5001(18) C(5B)-C(6B) 1.3904(15) C(12A)-C(16A) 1.525(2) C(5B)-H(5B) 0.910(18) C(12A)-C(13A) 1.5563(15) C(6B)-H(6B1) 0.944(15) C(12A)-H(12A) 0.902(19) C(8B)-C(10B) 1.3346(18) C(13A)-C(14A) 1.5609(16) C(8B)-C(9B) 1.4872(19) C(13A)-H(13A) 0.941(16) C(9B)-H(9B1) 0.91(2) C(14A)-C(18A) 1.5024(14) C(9B)-H(9B2) 0.99(2) C(14A)-C(15A) 1.5430(16) C(9B)-H(9B3) 0.93(2) C(15A)-C(16A) 1.5315(15) C(10B)-C(11B) 1.4851(15) C(15A)-H(15A) 0.966(16) C(10B)-C(13B) 1.4994(18) C(16A)-H(16A) 0.928(17) C(12B)-C(16B) 1.522(2) C(16A)-H(16B) 0.958(17) C(12B)-C(13B) 1.5604(15) C(17A)-H(17A) 0.95(2) C(12B)-H(12B) 0.921(16) C(17A)-H(17B) 0.95(2) C(13B)-C(14B) 1.5654(17) C(17A)-H(17C) 0.88(2) C(13B)-H(13B) 0.937(16) C(18A)-C(19A) 1.3602(15) C(14B)-C(18B) 1.5037(14) C(19A)-C(20A) 1.4326(15) C(14B)-C(15B) 1.5461(16) C(19A)-H(19A) 0.968(16) C(15B)-C(16B) 1.5338(15) 152 153 Ch. 2 Appendices C(15B)-H(15B) C(16B)-H(16C) C(16B)-H(16D) C(17B)-H(17D) C(17B)-H(17E) C(17B)-H(17F) C(18B)-C(19B) C(19B)-C(20B) C(19B)-H(19B) C(20B)-C(21B) C(20B)-C(22B) C(21B)-C(23B) C(22B)-H(22D) C(22B)-H(22E) C(22B)-H(22F) C(24B)-H(24D) C(24B)-H(24E) C(24B)-H(24F) 0.959(16) 0.941(18) 0.940(19) 0.965(17) 0.967(18) 0.940(19) 1.3621(15) 1.4325(14) 1.020(17) 1.3693(15) 1.4940(14) 1.4673(15) 0.88(2) 0.92(2) 0.95(2) 0.925(17) 0.949(19) 0.96(2) C(7A)-O(2A)-C(8A) C(11A)-O(4A)-C(12A) C(17A)-O(5A)-C(14A) C(15A)-O(6A)-H(6A) C(18A)-O(7A)-C(21A) C(23A)-O(9A)-C(24A) C(6A)-C(1A)-C(2A) C(6A)-C(1A)-Br(1) C(2A)-C(1A)-Br(1) C(3A)-C(2A)-C(1A) C(3A)-C(2A)-H(2A) C(1A)-C(2A)-H(2A) C(2A)-C(3A)-C(4A) C(2A)-C(3A)-H(3A) C(4A)-C(3A)-H(3A) C(3A)-C(4A)-C(5A) C(3A)-C(4A)-C(7A) C(5A)-C(4A)-C(7A) C(6A)-C(5A)-C(4A) C(6A)-C(5A)-H(5A) C(4A)-C(5A)-H(5A) C(1A)-C(6A)-C(5A) C(1A)-C(6A)-H(6A1) C(5A)-C(6A)-H(6A1) O(1A)-C(7A)-O(2A) O(1A)-C(7A)-C(4A) O(2A)-C(7A)-C(4A) C(10A)-C(8A)-O(2A) C(10A)-C(8A)-C(9A) O(2A)-C(8A)-C(9A) C(8A)-C(9A)-H(9A1) C(8A)-C(9A)-H(9A2) H(9A1)-C(9A)-H(9A2) C(8A)-C(9A)-H(9A3) H(9A1)-C(9A)-H(9A3) 115.48(9) 112.39(9) 115.97(9) 108.2(15) 106.33(8) 114.99(9) 121.98(10) 120.04(9) 117.97(8) 119.10(10) 117.5(11) 123.2(11) 119.89(11) 120.5(11) 119.6(11) 119.86(10) 121.46(10) 118.68(10) 120.73(10) 121.7(11) 117.5(11) 118.40(11) 122.4(10) 119.2(10) 122.51(11) 125.43(12) 112.05(10) 118.54(12) 128.62(12) 112.79(12) 110.0(14) 108.7(12) 112.6(18) 107.5(13) 111.6(18) H(9A2)-C(9A)-H(9A3) C(8A)-C(10A)-C(11A) C(8A)-C(10A)-C(13A) C(11A)-C(10A)-C(13A) O(3A)-C(11A)-O(4A) O(3A)-C(11A)-C(10A) O(4A)-C(11A)-C(10A) O(4A)-C(12A)-C(16A) O(4A)-C(12A)-C(13A) C(16A)-C(12A)-C(13A) O(4A)-C(12A)-H(12A) C(16A)-C(12A)-H(12A) C(13A)-C(12A)-H(12A) C(10A)-C(13A)-C(12A) C(10A)-C(13A)-C(14A) C(12A)-C(13A)-C(14A) C(10A)-C(13A)-H(13A) C(12A)-C(13A)-H(13A) C(14A)-C(13A)-H(13A) O(5A)-C(14A)-C(18A) O(5A)-C(14A)-C(15A) C(18A)-C(14A)-C(15A) O(5A)-C(14A)-C(13A) C(18A)-C(14A)-C(13A) C(15A)-C(14A)-C(13A) O(6A)-C(15A)-C(16A) O(6A)-C(15A)-C(14A) C(16A)-C(15A)-C(14A) O(6A)-C(15A)-H(15A) C(16A)-C(15A)-H(15A) C(14A)-C(15A)-H(15A) C(12A)-C(16A)-C(15A) C(12A)-C(16A)-H(16A) C(15A)-C(16A)-H(16A) C(12A)-C(16A)-H(16B) C(15A)-C(16A)-H(16B) H(16A)-C(16A)-H(16B) O(5A)-C(17A)-H(17A) O(5A)-C(17A)-H(17B) H(17A)-C(17A)-H(17B) O(5A)-C(17A)-H(17C) H(17A)-C(17A)-H(17C) H(17B)-C(17A)-H(17C) C(19A)-C(18A)-O(7A) C(19A)-C(18A)-C(14A) O(7A)-C(18A)-C(14A) C(18A)-C(19A)-C(20A) C(18A)-C(19A)-H(19A) C(20A)-C(19A)-H(19A) C(21A)-C(20A)-C(19A) C(21A)-C(20A)-C(22A) C(19A)-C(20A)-C(22A) C(20A)-C(21A)-O(7A) C(20A)-C(21A)-C(23A) 106.3(17) 122.62(12) 128.54(10) 108.45(11) 119.81(12) 131.28(14) 108.86(11) 109.45(10) 106.21(11) 107.12(9) 105.6(12) 114.7(12) 113.4(12) 103.48(9) 117.70(9) 103.81(10) 109.9(10) 113.2(10) 108.6(10) 109.54(9) 109.05(10) 116.10(9) 102.55(8) 115.37(10) 103.20(9) 110.76(10) 107.37(10) 101.58(9) 111.0(9) 115.1(9) 110.4(9) 104.43(10) 110.8(11) 108.7(11) 110.1(10) 113.1(10) 109.6(14) 112.3(12) 106.5(12) 109.6(16) 109.7(15) 110.7(18) 108.0(18) 110.52(9) 135.62(10) 113.85(9) 107.01(10) 126.8(10) 126.2(10) 105.30(9) 128.17(10) 126.52(10) 110.82(9) 131.59(10) 154 Ch. 2 Appendices O(7A)-C(21A)-C(23A) C(20A)-C(22A)-H(22A) C(20A)-C(22A)-H(22B) H(22A)-C(22A)-H(22B) C(20A)-C(22A)-H(22C) H(22A)-C(22A)-H(22C) H(22B)-C(22A)-H(22C) O(8A)-C(23A)-O(9A) O(8A)-C(23A)-C(21A) O(9A)-C(23A)-C(21A) O(9A)-C(24A)-H(24A) O(9A)-C(24A)-H(24B) H(24A)-C(24A)-H(24B) O(9A)-C(24A)-H(24C) H(24A)-C(24A)-H(24C) H(24B)-C(24A)-H(24C) C(7B)-O(2B)-C(8B) C(11B)-O(4B)-C(12B) C(17B)-O(5B)-C(14B) C(15B)-O(6B)-H(6B) C(18B)-O(7B)-C(21B) C(23B)-O(9B)-C(24B) C(6B)-C(1B)-C(2B) C(6B)-C(1B)-Br(2) C(2B)-C(1B)-Br(2) C(3B)-C(2B)-C(1B) C(3B)-C(2B)-H(2B) C(1B)-C(2B)-H(2B) C(2B)-C(3B)-C(4B) C(2B)-C(3B)-H(3B) C(4B)-C(3B)-H(3B) C(3B)-C(4B)-C(5B) C(3B)-C(4B)-C(7B) C(5B)-C(4B)-C(7B) C(6B)-C(5B)-C(4B) C(6B)-C(5B)-H(5B) C(4B)-C(5B)-H(5B) C(1B)-C(6B)-C(5B) C(1B)-C(6B)-H(6B1) C(5B)-C(6B)-H(6B1) O(1B)-C(7B)-O(2B) O(1B)-C(7B)-C(4B) O(2B)-C(7B)-C(4B) C(10B)-C(8B)-O(2B) C(10B)-C(8B)-C(9B) O(2B)-C(8B)-C(9B) C(8B)-C(9B)-H(9B1) C(8B)-C(9B)-H(9B2) H(9B1)-C(9B)-H(9B2) C(8B)-C(9B)-H(9B3) H(9B1)-C(9B)-H(9B3) H(9B2)-C(9B)-H(9B3) C(8B)-C(10B)-C(11B) C(8B)-C(10B)-C(13B) 117.52(9) 109.5(13) 109.0(13) 113.7(18) 113.4(14) 107.2(18) 104.0(18) 124.47(11) 123.07(11) 112.46(9) 109.4(11) 104.7(11) 114.6(15) 110.5(10) 110.9(15) 106.6(14) 115.66(9) 112.32(9) 115.45(10) 106.6(16) 106.33(8) 115.07(8) 121.43(10) 120.97(8) 117.56(8) 119.09(10) 118.7(10) 122.2(10) 120.33(10) 118.2(11) 121.5(11) 119.95(10) 121.41(10) 118.61(9) 120.25(10) 119.5(11) 120.2(11) 118.94(10) 119.9(9) 121.2(9) 122.88(10) 125.44(11) 111.68(9) 118.62(11) 129.16(11) 112.17(11) 108.9(13) 108.8(11) 111.2(17) 110.2(13) 109.1(17) 108.6(16) 122.54(12) 128.24(10) C(11B)-C(10B)-C(13B) O(3B)-C(11B)-O(4B) O(3B)-C(11B)-C(10B) O(4B)-C(11B)-C(10B) O(4B)-C(12B)-C(16B) O(4B)-C(12B)-C(13B) C(16B)-C(12B)-C(13B) O(4B)-C(12B)-H(12B) C(16B)-C(12B)-H(12B) C(13B)-C(12B)-H(12B) C(10B)-C(13B)-C(12B) C(10B)-C(13B)-C(14B) C(12B)-C(13B)-C(14B) C(10B)-C(13B)-H(13B) C(12B)-C(13B)-H(13B) C(14B)-C(13B)-H(13B) O(5B)-C(14B)-C(18B) O(5B)-C(14B)-C(15B) C(18B)-C(14B)-C(15B) O(5B)-C(14B)-C(13B) C(18B)-C(14B)-C(13B) C(15B)-C(14B)-C(13B) O(6B)-C(15B)-C(16B) O(6B)-C(15B)-C(14B) C(16B)-C(15B)-C(14B) O(6B)-C(15B)-H(15B) C(16B)-C(15B)-H(15B) C(14B)-C(15B)-H(15B) C(12B)-C(16B)-C(15B) C(12B)-C(16B)-H(16C) C(15B)-C(16B)-H(16C) C(12B)-C(16B)-H(16D) C(15B)-C(16B)-H(16D) H(16C)-C(16B)-H(16D) O(5B)-C(17B)-H(17D) O(5B)-C(17B)-H(17E) H(17D)-C(17B)-H(17E) O(5B)-C(17B)-H(17F) H(17D)-C(17B)-H(17F) H(17E)-C(17B)-H(17F) C(19B)-C(18B)-O(7B) C(19B)-C(18B)-C(14B) O(7B)-C(18B)-C(14B) C(18B)-C(19B)-C(20B) C(18B)-C(19B)-H(19B) C(20B)-C(19B)-H(19B) C(21B)-C(20B)-C(19B) C(21B)-C(20B)-C(22B) C(19B)-C(20B)-C(22B) C(20B)-C(21B)-O(7B) C(20B)-C(21B)-C(23B) O(7B)-C(21B)-C(23B) C(20B)-C(22B)-H(22D) C(20B)-C(22B)-H(22E) 108.95(10) 120.34(11) 130.84(13) 108.76(11) 109.34(10) 106.11(10) 107.02(9) 103.6(10) 115.6(10) 114.6(10) 103.30(9) 117.00(9) 103.80(10) 112.2(10) 111.4(10) 108.7(10) 109.68(8) 109.46(10) 115.52(9) 102.99(9) 115.51(10) 102.78(9) 111.39(10) 106.82(10) 101.42(9) 111.5(9) 114.3(9) 110.7(9) 104.35(10) 112.9(11) 111.9(11) 111.3(12) 108.7(12) 107.6(15) 111.8(10) 105.7(11) 107.5(14) 111.6(11) 109.7(15) 110.4(15) 110.36(9) 134.82(10) 114.81(9) 107.13(9) 129.1(10) 123.7(10) 105.29(9) 128.21(10) 126.48(10) 110.88(9) 130.75(9) 118.37(9) 112.6(13) 111.6(13) 155 Ch. 2 Appendices H(22D)-C(22B)-H(22E) C(20B)-C(22B)-H(22F) H(22D)-C(22B)-H(22F) H(22E)-C(22B)-H(22F) O(8B)-C(23B)-O(9B) O(8B)-C(23B)-C(21B) O(9B)-C(23B)-C(21B) O(9B)-C(24B)-H(24D) O(9B)-C(24B)-H(24E) H(24D)-C(24B)-H(24E) O(9B)-C(24B)-H(24F) H(24D)-C(24B)-H(24F) H(24E)-C(24B)-H(24F) 110.7(18) 107.9(13) 108.0(18) 105.6(18) 124.50(10) 123.17(10) 112.32(9) 111.4(10) 107.6(11) 107.5(14) 109.6(11) 109.1(15) 111.6(15) 156 Ch. 2 Appendices Table 4. Anisotropic displacement parameters (Å2x 104 ) for alcohol 182 (CCDC 606989). The anisotropic displacement factor exponent takes the form: -2π2 [ h2 a*2U 11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ Br(1) 146(1) 261(1) 176(1) 80(1) 24(1) 90(1) O(1A) 132(4) 651(8) 255(5) 227(5) 30(3) 27(4) O(2A) 141(3) 272(5) 191(4) 141(3) 1(3) 29(3) O(3A) 266(5) 363(6) 294(6) 129(5) -109(4) -32(4) O(4A) 120(3) 405(6) 231(4) 158(4) -4(3) 56(3) O(5A) 164(3) 229(4) 146(4) 15(3) 41(3) 60(3) O(6A) 186(3) 296(5) 108(4) 66(3) 31(3) 101(3) O(7A) 113(3) 235(4) 120(3) 52(3) 32(3) 71(3) O(8A) 138(3) 413(6) 195(4) 45(4) 41(3) 119(4) O(9A) 129(3) 280(4) 136(4) 62(3) 27(3) 68(3) C(1A) 139(4) 167(5) 153(5) 58(4) 20(3) 59(4) C(2A) 169(4) 287(6) 186(5) 88(5) 69(4) 112(4) C(3A) 170(4) 245(6) 148(5) 81(4) 47(4) 82(4) C(4A) 140(4) 165(5) 161(5) 75(4) 32(3) 32(4) C(5A) 129(4) 256(6) 171(5) 88(4) 50(4) 40(4) C(6A) 152(4) 226(6) 152(5) 73(4) 36(4) 42(4) C(7A) 151(4) 212(5) 186(5) 97(4) 26(4) 31(4) C(8A) 157(4) 274(6) 187(5) 120(5) -6(4) -10(4) C(9A) 345(7) 232(7) 320(8) 102(6) -71(6) 0(6) C(10A) 132(4) 275(6) 146(5) 108(4) 7(3) 21(4) C(11A) 154(4) 342(7) 211(6) 158(5) -20(4) 11(4) C(12A) 135(4) 384(7) 144(5) 92(5) 46(4) 110(4) C(13A) 115(4) 285(6) 117(4) 83(4) 30(3) 65(4) C(14A) 124(4) 208(5) 123(4) 46(4) 37(3) 64(4) C(15A) 169(4) 226(5) 144(5) 77(4) 52(4) 87(4) C(16A) 190(5) 311(7) 157(5) 77(5) 47(4) 143(4) C(17A) 214(5) 221(6) 275(7) 41(5) 46(5) 56(5) C(18A) 112(4) 194(5) 124(4) 61(4) 31(3) 50(3) C(19A) 132(4) 214(5) 130(5) 53(4) 38(3) 54(4) C(20A) 132(4) 188(5) 163(5) 67(4) 59(3) 57(4) C(21A) 113(4) 210(5) 161(5) 74(4) 49(3) 61(3) C(22A) 174(5) 281(6) 196(6) 42(5) 74(4) 101(4) C(23A) 131(4) 214(5) 163(5) 66(4) 37(4) 49(4) C(24A) 139(4) 276(6) 168(5) 68(4) 18(4) 43(4) Br(2) O(1B) O(2B) O(3B) O(4B) O(5B) O(6B) O(7B) O(8B) O(9B) 116(1) 129(3) 126(3) 251(4) 104(3) 137(3) 161(3) 97(3) 131(3) 120(3) 277(1) 509(6) 287(5) 294(5) 370(5) 262(4) 297(5) 248(4) 308(5) 273(4) 151(1) 203(4) 155(4) 232(5) 184(4) 155(4) 114(4) 115(3) 183(4) 128(4) 84(1) 165(4) 117(3) 88(4) 100(4) 1(3) 66(3) 45(3) 55(3) 50(3) 26(1) 39(3) 11(3) -79(4) -9(3) 29(3) 14(3) 21(2) 41(3) 18(3) 65(1) 30(4) 22(3) -27(4) 25(3) 61(3) 82(3) 59(3) 89(3) 60(3) Ch. 2 Appendices C(1B) 116(4) 195(5) 132(4) 60(4) 22(3) 39(3) C(2B) 138(4) 241(6) 150(5) 71(4) 58(4) 58(4) C(3B) 149(4) 226(6) 130(5) 71(4) 42(3) 49(4) C(4B) 120(4) 170(5) 140(4) 62(4) 30(3) 30(3) C(5B) 128(4) 237(6) 164(5) 81(4) 48(4) 39(4) C(6B) 139(4) 250(6) 130(5) 79(4) 42(3) 46(4) C(7B) 137(4) 217(5) 141(5) 78(4) 31(3) 37(4) C(8B) 143(4) 259(6) 144(5) 88(4) 11(4) 2(4) C(9B) 261(6) 229(6) 276(7) 70(5) -1(5) 26(5) C(10B) 121(4) 283(6) 110(4) 75(4) 8(3) 2(4) C(11B) 146(4) 313(7) 150(5) 110(5) -6(4) -2(4) C(12B) 107(4) 382(7) 132(5) 51(5) 20(3) 67(4) C(13B) 100(4) 294(6) 110(4) 62(4) 14(3) 50(4) C(14B) 107(4) 233(5) 109(4) 31(4) 15(3) 56(4) C(15B) 134(4) 240(6) 153(5) 64(4) 19(3) 69(4) C(16B) 136(4) 309(7) 189(5) 51(5) 19(4) 103(4) C(17B) 158(5) 254(6) 273(7) 15(5) 36(4) 52(4) C(18B) 99(4) 213(5) 109(4) 50(4) 18(3) 42(3) C(19B) 127(4) 204(5) 117(4) 61(4) 33(3) 50(3) C(20B) 127(4) 174(5) 141(4) 66(4) 53(3) 51(3) C(21B) 105(4) 209(5) 135(4) 65(4) 41(3) 51(3) C(22B) 167(4) 261(6) 174(5) 54(4) 78(4) 90(4) C(23B) 118(4) 194(5) 148(5) 70(4) 37(3) 44(3) C(24B) 137(4) 256(6) 154(5) 51(4) 7(4) 40(4) ______________________________________________________________________________ 157 Ch. 2 Appendices 158 Table 5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for alcohol 182 (CCDC 606989). ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(6A) 4022(19) 3125(16) 5005(13) 34(5) H(2A) 9944(17) 1133(14) 8691(12) 29(5) H(3A) 7926(17) 956(14) 7756(12) 29(5) H(5A) 6455(17) 1346(14) 9721(11) 25(4) H(6A1) 8415(15) 1494(12) 10728(10) 16(4) H(9A1) 3480(20) -272(16) 5676(14) 44(6) H(9A2) 4130(20) -548(16) 6491(14) 43(6) H(9A3) 4890(20) -310(17) 5886(14) 45(6) H(12A) 2831(18) 3565(15) 7202(12) 33(5) H(13A) 4643(15) 3019(12) 7703(10) 16(4) H(15A) 5328(15) 4527(12) 6094(10) 15(4) H(16A) 3834(16) 4872(13) 6823(11) 22(4) H(16B) 2907(16) 4157(13) 5905(11) 20(4) H(17A) 7453(19) 5236(15) 7498(13) 36(5) H(17B) 7248(19) 5884(16) 8368(14) 39(5) H(17C) 6440(20) 5868(18) 7502(15) 53(7) H(19A) 6485(16) 2343(13) 5581(11) 20(4) H(22A) 9760(20) 1990(16) 6439(13) 39(5) H(22B) 8910(20) 1969(17) 5596(14) 42(6) H(22C) 8670(20) 1125(18) 5922(14) 50(6) H(24A) 10882(17) 3196(15) 9758(12) 29(5) H(24B) 10482(17) 4239(14) 10234(12) 28(5) H(24C) 11386(16) 4291(13) 9709(10) 19(4) H(6B) 10850(20) 2237(17) 4856(14) 45(6) H(2B) 4532(16) 3722(13) 977(11) 20(4) H(3B) 6458(17) 3951(14) 1970(12) 27(4) H(5B) 8127(17) 3839(14) 87(11) 26(4) H(6B1) 6152(15) 3634(12) -935(10) 15(4) H(9B1) 9470(20) 5439(16) 4110(14) 43(6) H(9B2) 9907(19) 5870(16) 3429(13) 38(5) H(9B3) 10870(20) 5685(16) 4206(13) 42(6) H(12B) 12161(15) 2122(12) 2706(10) 17(4) H(13B) 10187(16) 2419(13) 2165(11) 21(4) H(15B) 9775(15) 799(13) 3743(10) 18(4) H(16C) 12138(17) 1399(14) 3962(12) 27(4) H(16D) 11321(18) 673(15) 3039(12) 33(5) H(17D) 8936(16) -580(13) 2410(11) 19(4) H(17E) 8073(17) -680(14) 1479(12) 29(5) H(17F) 7731(18) -109(14) 2320(12) 30(5) H(19B) 8272(17) 2803(14) 4277(12) 28(5) H(22D) 4980(20) 3105(15) 3392(13) 37(5) H(22E) 6070(20) 3520(17) 4226(14) 45(6) H(22F) 5250(20) 2420(18) 3935(14) 50(6) H(24D) 3248(16) 632(13) 160(11) 20(4) H(24E) 4109(18) 552(15) -413(12) 31(5) H(24F) 3812(18) 1649(15) 20(12) 32(5) ________________________________________________________________________________ Ch. 2 Appendices Table 6. Hydrogen bonds for alcohol 182 (CCDC 606989) [Å and °]. ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ O(6A)-H(6A)...O(4B)#1 0.76(2) 2.26(2) 3.0125(12) 169(2) O(6B)-H(6B)...O(4A)#2 0.79(2) 2.16(2) 2.9238(12) 163(2) ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 x-1,y,z #2 x+1,y,z 159 160 Ch. 2 Appendices CALIFORNIA INSTITUTE OF TECHNOLOGY BECKMAN INSTITUTE X-RAY CRYSTALLOGRAPHY LABORATORY Crystal Structure Analysis of: Furan 169 (CCDC 602164) Contents Table 1.Crystal data Table 2.Atomic Coordinates Table 3.Full bond distances and angles Table 4.Anisotropic displacement parameters Figure A2.3.2 Representation of Furan 169. Br O O O O O O H O O MeO2C O 169 Br 161 Ch. 2 Appendices Table 1. Crystal data and structure refinement for furan 169 (CCDC 602164). Empirical formula C32H28O11Br2 Formula weight 748.36 Crystallization Solvent Ethylacetate/n-heptane Crystal Habit Blade Crystal size 0.31 x 0.24 x 0.11 mm3 Crystal color Colorless Data Collection Type of diffractometer Bruker SMART 1000 Wavelength 0.71073 Å MoKα Data Collection Temperature 100(2) K θ range for 10496 reflections used in lattice determination 2.30 to 28.23° Unit cell dimensions a = 17.2333(11) Å b = 10.2395(7) Å c = 18.3237(12) Å β= 104.5150(10)° Volume 3130.2(4) Å3 Z 4 Crystal system Monoclinic Space group P21/c Density (calculated) 1.588 Mg/m3 F(000) 1512 Data collection program Bruker SMART v5.630 θ range for data collection 1.22 to 28.58° Completeness to θ = 28.58° 93.7 % Index ranges -22 ≤ h ≤ 22, -13 ≤ k ≤ 13, -23 ≤ l ≤ 23 Data collection scan type ω scans at 5 φ settings Data reduction program Bruker SAINT v6.45A Reflections collected 49507 Independent reflections 49509 [Rint= 0.0820] Absorption coefficient 2.651 mm-1 Absorption correction TWINABS Max. and min. transmission 1.0000 and 0.6884 162 Ch. 2 Appendices Table 1 (cont.) Structure solution and Refinement Structure solution program Bruker XS v6.12 Primary solution method Direct methods Secondary solution method Difference Fourier map Hydrogen placement Geometric positions Structure refinement program Bruker XL v6.12 Refinement method Full matrix least-squares on F2 Data / restraints / parameters 49509 / 0 / 412 Treatment of hydrogen atoms Riding Goodness-of-fit on F2 1.273 Final R indices [I>2σ(I), 35818 reflections] R1 = 0.0465, wR2 = 0.0991 R indices (all data) R1 = 0.0708, wR2 = 0.1032 Type of weighting scheme used Sigma Weighting scheme used w=1/σ2(Fo2) Max shift/error 0.002 Average shift/error 0.000 Largest diff. peak and hole 1.202 and -0.725 e.Å-3 Special Refinement Details The crystal is twinned. CELL_NOW was used to define the two domains and produce a matrix for the twin law as follows; 751 reflections within 0.100 of an integer index assigned to domain 1, 751 of them exclusively; 248 reflections not yet assigned to a domain Rotated from first domain by 179.7 degrees about reciprocal axis 1.000 0.002 0.000 and real axis 1.000 -0.003 0.237 474 reflections within 0.100 of an integer index assigned to domain 2, 233 of them exclusively; 14 reflections not yet assigned to a domain Twin Law: Transforms h1 -> h2 1.00010 -0.00089 0.47107 0.00022 -0.99985 0.00031 -0.00044 -0.00057 -1.00002 The data was integrated with SAINT then TWINABS was used to write the file used for refinement. From TWINABS; 13830 data ( 3969 unique ) involve component 1 only, mean I/sigma 7.8 13557 data ( 3916 unique ) involve component 2 only, mean I/sigma 5.4 23827 data ( 6687 unique ) involve 2 components, mean I/sigma 7.3 36 data ( 36 unique ) involve 3 components, mean I/sigma 4.0 Refinement using an HKLF 5 type file produced a final set of atomic parameters and a scale factor between the two domains, BASF=0.33261 Refinement of F2 against ALL reflections. The weighted R-factor (wR) and goodness of fit (S) are based 2 on F , conventional R-factors (R) are based on F, with F set to zero for negative F2. The threshold expression of F2 > Ch. 2 Appendices 163 2σ( F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger. Ch. 2 Appendices 164 Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for furan 169 (CCDC 602164). U(eq) is defined as the trace of the orthogonalized Uij tensor. ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1) 1046(1) 2805(1) -1563(1) 22(1) Br(2) 6652(1) 13142(1) 1456(1) 27(1) O(1) 1187(1) 9543(1) -1711(1) 35(1) O(2) 2058(1) 9038(1) -609(1) 20(1) O(3) 3071(1) 12918(1) 41(1) 21(1) O(4) 2149(1) 12868(1) 709(1) 19(1) O(5) 786(1) 12476(1) 499(1) 23(1) O(6) 1221(1) 9189(1) 1375(1) 22(1) O(7) 4613(1) 6506(1) 716(1) 22(1) O(8) 4502(1) 8654(1) 420(1) 23(1) O(9) 3103(1) 8783(1) 845(1) 16(1) O(10) 3048(1) 10949(1) 1772(1) 17(1) O(11) 3322(1) 12169(1) 2836(1) 25(1) C(1) 1757(1) 6474(2) -736(1) 18(1) C(2) 1655(1) 5142(2) -808(1) 21(1) C(3) 1145(1) 4653(2) -1455(1) 16(1) C(4) 728(1) 5454(2) -2020(1) 20(1) C(5) 839(1) 6796(2) -1941(1) 21(1) C(6) 1362(1) 7304(2) -1303(1) 17(1) C(7) 1500(1) 8738(2) -1257(1) 20(1) C(8) 2396(1) 10292(2) -517(1) 17(1) C(9) 2936(1) 10604(2) -1014(1) 25(1) C(10) 2250(1) 10981(2) 45(1) 14(1) C(11) 2562(1) 12316(2) 235(1) 17(1) C(12) 1542(1) 11995(2) 853(1) 18(1) C(13) 607(1) 13733(2) 765(1) 32(1) C(14) 1668(1) 10657(2) 502(1) 14(1) C(15) 1918(1) 9702(2) 1191(1) 17(1) C(16) 684(1) 8458(2) 792(1) 30(1) C(17) 2263(1) 10637(2) 1858(1) 17(1) C(18) 1709(1) 11803(2) 1706(1) 19(1) C(19) 2474(1) 8589(2) 1155(1) 15(1) C(20) 2489(1) 7352(2) 1426(1) 19(1) C(21) 3171(1) 6719(2) 1281(1) 18(1) C(22) 3450(1) 5356(2) 1519(1) 28(1) C(23) 3523(1) 7618(2) 921(1) 15(1) C(24) 4257(1) 7678(2) 656(1) 17(1) C(25) 5373(1) 6476(2) 504(1) 26(1) C(26) 3520(1) 11758(2) 2291(1) 19(1) C(27) 4283(1) 12027(2) 2093(1) 16(1) C(28) 4504(1) 11392(2) 1500(1) 17(1) C(29) 5210(1) 11697(2) 1320(1) 17(1) C(30) 5693(1) 12672(2) 1724(1) 19(1) C(31) 5490(1) 13312(2) 2315(1) 19(1) C(32) 4787(1) 12986(2) 2499(1) 18(1) ________________________________________________________________________________ Ch. 2 Appendices Table 3. Bond lengths [Å] and angles [°] for furan 169 (CCDC 602164). _______________________________________________________________________________ Br(1)-C(3) 1.9056(18) C(11)-O(4)-C(12) 111.90(14) Br(2)-C(30) 1.900(2) C(12)-O(5)-C(13) 114.44(15) O(1)-C(7) 1.198(2) C(15)-O(6)-C(16) 116.16(14) O(2)-C(7) 1.363(2) C(24)-O(7)-C(25) 114.82(15) O(2)-C(8) 1.402(2) C(19)-O(9)-C(23) 106.47(14) O(3)-C(11) 1.196(2) C(26)-O(10)-C(17) 118.12(15) O(4)-C(11) 1.376(2) C(2)-C(1)-C(6) 120.62(18) O(4)-C(12) 1.450(2) C(1)-C(2)-C(3) 118.70(18) O(5)-C(12) 1.392(2) C(4)-C(3)-C(2) 122.03(18) O(5)-C(13) 1.438(2) C(4)-C(3)-Br(1) 119.91(15) O(6)-C(15) 1.425(2) C(2)-C(3)-Br(1) 118.05(14) O(6)-C(16) 1.437(2) C(3)-C(4)-C(5) 118.68(18) O(7)-C(24) 1.340(2) C(6)-C(5)-C(4) 120.12(18) O(7)-C(25) 1.458(2) C(1)-C(6)-C(5) 119.81(18) O(8)-C(24) 1.206(2) C(1)-C(6)-C(7) 121.52(18) O(9)-C(19) 1.357(2) C(5)-C(6)-C(7) 118.65(17) O(9)-C(23) 1.385(2) O(1)-C(7)-O(2) 123.04(19) O(10)-C(26) 1.366(2) O(1)-C(7)-C(6) 127.05(19) O(10)-C(17) 1.436(2) O(2)-C(7)-C(6) 109.91(17) O(11)-C(26) 1.209(2) C(10)-C(8)-O(2) 115.29(18) C(1)-C(2) 1.377(2) C(10)-C(8)-C(9) 129.09(19) C(1)-C(6) 1.383(2) O(2)-C(8)-C(9) 115.29(16) C(2)-C(3) 1.381(2) C(8)-C(10)-C(11) 123.14(18) C(3)-C(4) 1.374(2) C(8)-C(10)-C(14) 127.04(18) C(4)-C(5) 1.390(2) C(11)-C(10)-C(14) 109.23(16) C(5)-C(6) 1.386(2) O(3)-C(11)-O(4) 120.67(18) C(6)-C(7) 1.486(3) O(3)-C(11)-C(10) 131.11(19) C(8)-C(10) 1.324(2) O(4)-C(11)-C(10) 108.22(17) C(8)-C(9) 1.489(2) O(5)-C(12)-O(4) 109.29(15) C(10)-C(11) 1.478(2) O(5)-C(12)-C(18) 115.84(17) C(10)-C(14) 1.495(2) O(4)-C(12)-C(18) 107.84(16) C(12)-C(18) 1.529(2) O(5)-C(12)-C(14) 109.33(16) C(12)-C(14) 1.552(2) O(4)-C(12)-C(14) 106.62(15) C(14)-C(15) 1.570(2) C(18)-C(12)-C(14) 107.52(15) C(15)-C(19) 1.502(3) C(10)-C(14)-C(12) 102.71(15) C(15)-C(17) 1.548(2) C(10)-C(14)-C(15) 120.16(16) C(17)-C(18) 1.511(2) C(12)-C(14)-C(15) 104.72(14) C(19)-C(20) 1.359(2) O(6)-C(15)-C(19) 108.41(15) C(20)-C(21) 1.423(3) O(6)-C(15)-C(17) 102.80(15) C(21)-C(23) 1.361(2) C(19)-C(15)-C(17) 112.34(16) C(21)-C(22) 1.504(2) O(6)-C(15)-C(14) 110.07(16) C(23)-C(24) 1.467(3) C(19)-C(15)-C(14) 119.06(16) C(26)-C(27) 1.475(3) C(17)-C(15)-C(14) 102.90(15) C(27)-C(32) 1.397(3) O(10)-C(17)-C(18) 111.90(16) C(27)-C(28) 1.398(2) O(10)-C(17)-C(15) 103.75(15) C(28)-C(29) 1.374(3) C(18)-C(17)-C(15) 104.04(15) C(29)-C(30) 1.388(2) C(17)-C(18)-C(12) 103.76(15) C(30)-C(31) 1.384(2) O(9)-C(19)-C(20) 110.22(17) C(31)-C(32) 1.377(3) O(9)-C(19)-C(15) 119.53(17) C(20)-C(19)-C(15) 130.16(19) C(7)-O(2)-C(8) 119.53(15) C(19)-C(20)-C(21) 107.29(18) 165 166 Ch. 2 Appendices C(23)-C(21)-C(20) C(23)-C(21)-C(22) C(20)-C(21)-C(22) C(21)-C(23)-O(9) C(21)-C(23)-C(24) O(9)-C(23)-C(24) O(8)-C(24)-O(7) O(8)-C(24)-C(23) O(7)-C(24)-C(23) O(11)-C(26)-O(10) O(11)-C(26)-C(27) O(10)-C(26)-C(27) C(32)-C(27)-C(28) C(32)-C(27)-C(26) C(28)-C(27)-C(26) C(29)-C(28)-C(27) C(28)-C(29)-C(30) C(31)-C(30)-C(29) C(31)-C(30)-Br(2) C(29)-C(30)-Br(2) C(32)-C(31)-C(30) C(31)-C(32)-C(27) 105.73(17) 128.2(2) 125.96(18) 110.29(17) 135.72(19) 113.77(16) 125.31(19) 124.23(19) 110.46(17) 123.0(2) 126.35(19) 110.68(17) 119.08(19) 118.29(17) 122.59(19) 120.74(19) 118.97(18) 121.5(2) 119.30(16) 119.23(15) 119.16(19) 120.55(18) 167 Table 4. Anisotropic displacement parameters (Å2x 104 ) for furan 169 (CCDC 602164). The anisotropic displacement factor exponent takes the form: -2π2 [ h2 a*2U 11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ Br(1) 259(1) 175(1) 232(1) -2(1) 60(1) -29(1) Br(2) 217(1) 295(1) 321(1) -33(1) 84(1) -52(1) O(1) 409(12) 190(8) 336(9) 75(7) -96(8) 28(8) O(2) 278(10) 146(8) 156(8) -5(6) 22(7) -13(7) O(3) 187(9) 183(8) 266(8) 10(7) 98(7) -23(7) O(4) 202(9) 162(8) 232(8) -2(6) 101(7) 6(7) O(5) 163(9) 238(9) 276(8) 6(6) 50(7) 74(7) O(6) 161(9) 270(9) 240(8) 29(6) 98(7) -26(7) O(7) 190(9) 174(8) 288(8) -13(6) 64(7) 32(7) O(8) 256(10) 190(8) 273(8) 27(7) 119(7) 14(7) O(9) 163(9) 151(7) 180(7) 25(6) 57(7) 5(6) O(10) 149(9) 199(8) 161(7) -36(6) 39(7) -12(7) O(11) 250(9) 324(9) 186(8) -78(7) 87(7) 4(8) C(1) 176(13) 181(12) 158(11) -17(9) 2(10) -4(10) C(2) 213(14) 201(12) 191(12) 42(9) 30(11) -11(10) C(3) 184(13) 135(11) 176(11) -18(9) 72(10) 6(10) C(4) 208(13) 229(12) 150(11) -37(9) 22(10) -9(10) C(5) 231(14) 200(12) 178(11) 35(9) 14(10) 33(10) C(6) 201(13) 150(11) 168(11) 1(9) 72(9) 21(10) C(7) 183(14) 225(12) 189(12) -11(10) 50(10) 12(11) C(8) 207(14) 113(11) 174(11) 51(9) 5(10) 19(10) C(9) 322(15) 188(12) 250(12) -10(10) 115(11) 16(11) C(10) 132(12) 131(11) 153(11) 47(9) 15(10) 18(9) C(11) 165(13) 184(12) 134(11) 34(9) 7(10) 42(10) C(12) 144(13) 179(12) 208(11) 3(9) 56(10) 35(10) C(13) 287(15) 274(13) 411(15) 14(11) 101(12) 117(12) C(14) 125(12) 159(11) 144(11) 9(9) 21(9) 12(9) C(15) 135(13) 194(12) 188(12) 26(9) 72(10) -18(10) C(16) 183(14) 335(14) 345(14) 41(11) 18(11) -110(11) C(17) 138(13) 236(12) 145(11) 18(9) 59(10) 11(10) C(18) 153(13) 230(12) 198(11) 4(9) 87(10) 35(10) C(19) 110(12) 199(12) 125(11) 2(9) 17(9) -8(10) C(20) 174(13) 191(12) 190(11) -3(10) 44(10) -45(10) C(21) 182(14) 187(11) 147(11) -20(9) -24(10) -6(10) C(22) 338(16) 166(12) 330(14) 39(10) 67(12) -22(11) C(23) 172(13) 119(11) 142(11) -10(9) 9(9) 36(9) C(24) 147(13) 197(12) 136(11) -28(9) -20(9) -4(10) C(25) 201(14) 243(13) 332(13) -28(10) 62(11) 77(11) C(26) 203(14) 134(11) 193(11) 43(9) -5(10) 24(10) C(27) 180(13) 143(11) 128(10) 24(9) 14(9) 44(10) C(28) 213(14) 120(11) 152(11) -15(9) 11(10) 7(10) C(29) 181(13) 163(11) 171(11) -23(9) 48(10) 41(10) C(30) 184(13) 177(11) 214(11) 34(10) 44(10) 39(10) C(31) 208(14) 135(11) 199(12) -13(9) -12(10) 24(10) C(32) 218(14) 159(12) 137(11) -11(9) -3(10) 48(10) ___________________________________________________________________  Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 168 CHAPTER 3 Synthetic Efforts Toward (–)-Phalarine Using Palladium(II)-catalyzed Oxidative Heterocyclizations 3.1 Introduction and Biosynthesis In 1999, (–)-phalarine (106) was isolated from Phalaris coerulescens and displayed a [4.3.3.0] fused tricyclic core structure including a novel furanobisindole ring system (Figure 3.1.1).1,2 In addition, the natural product contains vicinal stereocenters that are contained within the propellar-like core. Although (–)-phalarine (106) is not reported to be biologically active, the properties of this molecule still warrants medicinal evaluation since many alkaloids isolated from the genus Phalaris have proven to be poisonous to livestock when the native plant was ingested (e.g., canary grass, P . arundinacea). 169 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations Figure 3.1.1 (–)-Phalarine (106) in Two and Three Dimensions. Me OMe N O NH N H Hydrogens omitted for clarity NMe2 (–)-Phalarine (106) Although the biosynthesis of (–)-phalarine (106) has not been fully elucidated, it is proposed by the isolation chemists that (–)-phalarine (106) is obtained via an oxidative coupling of known tetrahydro-β-carboline 203 with a functionalized indole akin to phenol 204 (Scheme 3.1.1).3 It is hypothesized that indole 204 is oxidized to an intermediate similar to arene 205. This activated intermediate undergoes addition by tetrahydro-β-carboline 203 to provide cationic species 206, which will undergo rapid tautomerization to provide enol 207. Formation of the natural product (106) is accomplished by the addition of the phenol in intermediate 207 onto the benzylic cation. Scheme 3.1.1 Me OMe N O HO N H NMe2 NMe OMe 203 N H [O] and NH N H cyclization NMe2 204 Phalarine (106) NMe2 Proposed Mechanism: X N H O O NMe2 C–C bond NMe OMe 203 206 Me NMe2 OMe N O phenol cyclization HO NH N H OMe NMe N H 205 tautomerization NH formation N H OMe NMe 207 NH N H NMe2 Phalarine (106) 170 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations Initial synthetic efforts by the Danishefsky laboratory to access the skeletal framework of the natural product using a biosynthetic approach proved unsuccessful. Their first attempt began with oxidation of phenol 208 to generate intermediate 209 (Scheme 3.1.2). Treatment of this intermediate with tetrahydro-β-carboline 210 provided polycycle 211 exclusively; however, the reaction occurred with undesired regioselectivity in the formation of the bridging dihydobenzofuran functionality.4 A second generation approach employed oxidation of tetrahydro-β-carboline 210 with t-butyl hypochlorite to yield α-chloroimine 212. Unfortunately, exposing imine 212 to phenol 208 in the presence of a catalytic amount of camphorsulfonic acid (CSA) in refluxing benzene afforded indole 213 as the sole product.5 Scheme 3.1.2 MeO OMe PIFA: HO OMe OMe PIFA X O OMe MeCN OMe 208 TFA 3 N H 209 2 NCO2Me N H 210 210 CH2Cl2 208 cat. CSA N 212 NCO2Me TFA phenol t-BuOCl NCO2Me 2 211 Cl N H I O 3 NCO2Me N H NCO2Me OH PhH, 85 °C MeO OMe 213 In the end, Danishefsky's efforts to synthesize the core of (–)-phalarine using a biomimetic strategy failed due to the lack of regio-control in the oxidative coupling step. These results infer that the proposed biosynthesis of (–)-phalarine (106) are likely catalyzed in a chiral environment that effects the key oxidative coupling reaction to provide the correct regiochemistry. Despite these synthetic challenges, Danishefsky's laboratory persisted, and in 2007 accomplished a total synthesis of racemic phalarine. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 171 More recently, Danishefsky’s laboratory completed an asymmetric synthesis of (–)phalarine using a C(2)-functionalized tryptophan. The results of their work will be discussed in the next section. 3.2 Previous Efforts Toward the Total Synthesis of Phalarine The only total syntheses of phalarine were reported by the Danishefsky laboratory in 2007 and 2010.6 The synthesis of racemic phalarine was accomplished using a key retro-Mannich reaction followed by a Pictet-Spengler cyclization to provide the core of the natural product (Scheme 3.2.1). The key steps of the synthesis began with addition of lithiated arene 215 into oxindole 214 to provide ketone 216 in excellent yield. Exposing ketone 216 to two sequential organic acids first cleaved the MOM group, and then facilitated the condensation of the aniline onto the pendant ketone to provide iminium 217. This activated species underwent a retro-Mannich reaction to generate intermediate 218, which cyclized in a Pictet-Spengler fashion to form cationic intermediate 219. Finally, cyclization of the phenol moiety furnished the core of phalarine (220) in 72% yield from ketone 216. 172 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations Scheme 3.2.1 NMe TsHN NMe O OMOM 1. TFA, CH2Cl2, 0 °C n-BuLi Br O OMOM THF, –78 °C N Ts MeO 214 2. CSA, PhMe, 130 °C (96% yield) (72% yield) OMe 215 NMe HO N Ts 216 N retro-Mannich N Ts HO OMe 217 NMe OH Pictet-Spengler N Ts OMe OMe 218 cyclization Me N O 219 Me OMe N O OMe 6 steps NH N H N Ts NMe2 220 (±)-Phalarine (106) Although an alternate mechanism invoking a Wagner-Meerwein ring-expansion is plausible (Scheme 3.2.2), Danishefsky found that treatment of enantioenriched ketone 217 under the same conditions provided product 220 as a racemic mixture.7 This result indicates the formation of an achiral intermediate, such as iminium 218, prior to product formation. Scheme 3.2.2 NMe HO NMe OH Wagner-Meerwein N Ts OMe 217 shift N Ts 219 cyclization Me O N OMe N Ts OMe 220 With a rapid synthesis of pentacycle 220 complete, Danishefsky sought to complete the molecule by synthesizing the indole unit and appending the gramine side chain (Scheme 3.2.3).8 Although the synthesis of pentacycle 220 is rapid, the completion of phalarine required an additional six steps to synthesize the gramine moiety of the natural product. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 173 Scheme 3.2.3 Me N O Me OMe N O OMe 6 steps NH N H N Ts 220 NMe2 (±)-Phalarine (106) Danishefsky’s synthesis of racemic phalarine (106) required nine synthetic steps starting from oxindole 2149 and provided the core of the natural product via a retroMannich reaction/Pictet-Spengler addition cascade sequence. Unfortunately, this reaction sequence occurred through an achiral intermediate, thus initially negating an asymmetric synthesis. However, Danishefsky recently published an asymmetric synthesis of (–)phalarine utilizing a chiral variant of iminium 218 (cf. Scheme 3.2.1). In an ingenuous attempt, Danishefsky began with L-tryptophan methyl ester (221) to synthesize indole 222 in nine steps (Scheme 3.2.4). Exposing indole 222 to formalin under acidic conditions provided iminium 223. This species underwent a Pictet-Spengler cyclization with either C(2) or C(3) of the indole moiety to provide intermediates 224 and 225, respectively. Although it is unclear which mechanism is operative,10 the desired pentacycle (226) is obtained as a single diastereomer in 91% yield beginning from indole 222. At this stage, an additional ten synthetic operations provided the desired natural product. 174 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations Scheme 3.2.4 CO2Me CO2Me NHBn NHBn 9 steps formalin, CSA, 4ÅMS OMe (20% yield over 9 steps) N H N Ts 221 PhMe, 125 °C HO (91% yield) 222 CO2Me NBn C(3) cyclize OMe a N Ts CO2Me N Bn a Bn O N 224 b N Ts MeO2C HO Ar CO2Me 223 C(2) cyclize b N Ts NBn 226 OH single diastereomer N Ts 225 OMe OMe 3.3 Retrosynthetic Analysis of Phalarine Our retrosynthetic analysis of phalarine (106) began with late-stage formation of the bridging piperidine ring via a double reductive amination of bis-aldehyde 227 and methylamine (Scheme 3.3.1). We envisioned unveiling the two aldehyde units by an ozonolysis of a terminal olefin and hydrolysis of a PMB vinyl ether, which led us to intermediate 228. We anticipated the formation of pentacycle 228 via a double palladium(II)-catalyzed oxidative heterocyclization beginning from diene 229. At this stage, we planned to synthesize diene 229 from a Stille coupling between vinyl iodide 230 and vinyl stannane 231. The synthesis of vinyl iodide 230 was seen to arise from known compound 232 by a Sonogashira coupling. However, we anticipated that the synthesis of vinyl stannane 231 would be difficult since fully differentiated 4,5,7substituted indoles lack an efficient synthetic route that is compatible with many common 175 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations functional groups. Instead of addressing this problem prior to indole formation, we sought out indole 233 as a suitable starting point to effect differentiation between C(5) and C(7), and allow for selective C(4) functionalization. Scheme 3.3.1 double reductive amination Me N O PdII catalyzed ox. cyclization O OMe NH N H NMe2 N Ts nucleophilic addition PMBO OMe O NBoc NBoc N Ts O PdII catalyzed ox. cyclization ozonolysis 227 Phalarine (106) OMe O 228 NO2 NO2 I reduction/protection I PMBO NHTs 230 Sonogashira coupling PMBO HO Stille coupling 232 Bu3Sn N Boc Negishi coupling TBSO 229 OMe N Boc OMe 231 4 MeO 5 7 N H OMe 233 3.4 Model System Studies There are very few examples of palladium(II)-catalyzed oxidative heterocyclizations onto styrenyl or conjugated olefins.11 Thus, we decided to investigate the palladium(II)-catalyzed oxidative phenol cyclization using a model system. We envisioned phenol 237 (Scheme 3.4.1) as a suitable substrate to test the palladium(II)-catalyzed oxidative cyclization since it possessed a trisubstituted styrenyl olefin that is similar to diene 229 (cf. Scheme 3.3.1). The synthesis of phenol 237 began with a radical bromination of arene 234 to provide benzyl bromide 235 in excellent yield.12 From here, Stille coupling using known vinyl stannane 236 provided the desired product, which then underwent silyl cleavage to arrive at phenol 237 in 50% yield.13 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 176 Scheme 3.4.1 1. hν NBS OTBS OH Ph Bu3Sn Br CCl4 (85% yield) 234 236 OTBS 235 10 mol% Pd(PPh3)4 30 mol% AsPh3 DME, 80 °C 237 2. TBAF, THF, 23 °C (50% yield over two steps) With the model substrate in hand, phenol 237 was subjected to the DMSO/O2 conditions as well as conditions for the palladium(II)-catalyzed oxidative cyclization previously developed in our group.14,15 As shown in Table 3.4.1, using the DMSO/O2 conditions without NaOAc allowed for an 80% yield of dihydrobenzofuran 238 in only 4 hours.16 Under our optimized conditions (Entry 3), the formation of dihydrobenzofuran 238 was significantly slower than the DMSO/O2 conditions. Nevertheless, all entries in Table 3.4.1 provided dihydrobenzofuran 238 as the only observable product, with the remaining mass recovered as unreacted starting material. Table 3.4.1 Attempts at the Pd(II)-catalyzed Oxidative Cyclization of Phenol 237. Pd(II)-catalyzed oxidative cyclization OH Ph O 237 238 Entry 1. 2. a Ph Conditions 5 mol% Pd(TFA)2 20 mol% pyridine 3ÅMS, Na2CO3, O2 PhMe, 80 °C Time (h) Yield (%)a 3 30 18 60 3. 10 mol% Pd(OAc)2 40 mol% pyridine 3ÅMS, O2 PhMe, 80 °C 2 25 4. 10 mol% Pd(OAc)2, O2 DMSO, 60 °C 4 80 5. 5 mol% Pd(OAc)2, NaOAc (2 equiv), O2 DMSO, 60 °C 3 20 Isolated yield. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 177 3.5 Initial Synthetic Efforts Our initial synthetic efforts focused on the synthesis of diene 229, which could be used to test both the phenol and aniline palladium(II)-catalyzed oxidative heterocyclizations. Thus, beginning with 2-nitro iodobenzene (232), Sonogashira coupling of alkyne 239 provided arene 240 in high yield (Scheme 3.5.1). Regioselective hydrostannylation of alkyne 240 using conditions developed by Alami, provided vinyl stannane 241 in 65% yield.17 Subsequent exposure of this intermediate to I2 in acetonitrile provided vinyl iodide 242 in 76% yield.18 Scheme 3.5.1 OTBS 239 NO2 2 mol% PdCl2(PPh3)2 6 mol% CuI I i-Pr2NH, 23 °C 232 2 mol% PdCl2(PPh3)2 Bu3SnH NO2 OTBS (95% yield) (89% yield) 240 NO2 SnBu3 NO2 I2 MeCN, 23 °C TBSO THF (0.75 M), 23 °C I TBSO (76% yield) 241 242 Although we were confident that the TBS moiety in vinyl iodide 242 would be stable in upcoming transformations, we decided to synthesize vinyl stannanes 246 and 248. We hypothesized that the TIPS group would provide greater bulk and stability, while the PMB moiety was an orthogonal functional group that would allow for a silyl protecting group on indole fragment 231 (Scheme 3.5.2). Accordingly, exposure of alcohol 24319 to 20 mol% La(OTf)3 and trichloroacetimidate 24420 provided alkyne 245 in 86% yield. Hydrostannylation of this product provided vinyl stannane 246 in 63% yield. The analogous TIPS protected intermediate was obtained via the aforementioned strategy. Silylation of alcohol 243 with TIPSCl proceeded in 83% yield, affording nitro- 178 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations arene 247. As expected, hydrostannylation of alkyne 247 proceeded regioselectively to furnish vinyl stannane 248 in 74% yield. Scheme 3.5.2 NH Cl3C NO2 OH 244 OPMB NO2 20 mol% La(OTf)3 2 mol% PdCl2(PPh3)2 Bu3SnH PhMe, 23 °C THF, 23 °C OPMB NO2 SnBu3 PMBO 243 (86% yield) 245 (63% yield) 246 NO2 TIPSCl imidazole NO2 1 mol% PdCl2(PPh3)2 Bu3SnH NO2 OH DMF, 23 °C (83% yield) 243 SnBu3 THF, 23 °C OTIPS TIPSO (74% yield) 247 248 The second coupling partner needed for the Stille coupling, substituted indole 231, was obtained from 5,7-dimethoxy indole (233).21,22 The synthesis of this indole is shown below in Scheme 3.5.3. Initial exposure of commercially available 3,5-dimethoxy benzaldehyde (249) to nitromethane under acidic conditions effected a Henry reaction to provide arene 250 in 72% yield.23 Subsequent nitration using copper(II)nitrate in acetic anhydride provided nitro-arene 251 in 98% yield. At this stage, reductive cyclization afforded indole 233, which underwent protection of the indole nitrogen as an amide, providing N-acyl indole 252 in 88% yield. Scheme 3.5.3 MeO CHO MeO MeNO2, NH4OAc NO2 glacial AcOH, 120 °C Cu(NO3)2•5/2H2O MeO Ac2O, 45 °C OMe NO2 OMe (72% yield) 249 Fe powder 250 OMe (98% yield) powdered KOH DMSO, 23 °C MeO 80% AcOH (aq), 80 °C (54% yield) NO2 N H OMe 233 251 MeO N Ac then Ac2O, 23 °C (88% yield) OMe 252 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 179 With the synthesis of indole 252 complete, we attempted to demethylate the two methoxy substituents on the indole core. Dimethoxy indole 252 proved surprisingly difficult to demethylate and all attempts were unsuccessful.24 Hence, we elected to use this dimethylated system to probe the feasibility of the palladium(II)-catalyzed oxidative aniline cyclization. To this end, we needed to first functionalize, and then transform, C(4) of indole 252 to the appropriate vinyl stannane for the Stille coupling. Black has shown that formylation of 5,7-dimethoxyindoles occurs exclusively at C(4), rather than at C(3), when an acyl group (e.g., Ac, Piv, or Boc) is protecting the indole nitrogen.25 Hence, selective C(4) functionalization commenced with iodination of indole 252 using NIS to provide intermediate 253 in excellent yield (Scheme 3.5.4). At this stage, it was found that the acetyl moiety was not stable toward further functionalization at C(4) via a Negishi coupling. To address this chemoselectivity issue, we sought a more robust protecting group. Thus, cleavage of the acyl amide provided indole 254 in nearly quantitative yield. Reprotection of the indole nitrogen in arene 254 as a sulfonamide afforded indole 255 in 75% yield. Further elaboration at C(4) occurred smoothly via a Negishi coupling providing alkyne 256 in excellent yield. Completion of the Stille coupling partner (257) was accomplished in 65% yield using a regioselective palladiumcatalyzed hydrostannylation reaction.10 180 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations Scheme 3.5.4 I MeO 4 NIS N Ac I MeO THF: 10% NaOH (aq) N Ac CHCl3, 23 °C OMe N H (1:1), 23 °C OMe (90% yield) 252 powdered KOH 15 mol% Bu4NBr TsCl MeO (98% yield) 253 THF, 0 → 23 °C OMe (75% yield) 254 Bu3Sn I 5 mol% Pd(PPh3)4 THF, 23 °C MeO N Ts 1 mol% PdCl2(PPh3)2 Bu3SnH MeO N Ts OMe then propynyl-MgBr ZnCl2, THF, 0→60 °C OMe 255 (89% yield) 256 MeO N Ts THF (0.75 M), 23 °C OMe (60% yield) 257 With both Stille coupling fragments in hand, we attempted the carbon-carbon bond-forming reaction. In the event, coupling of arene 242 with indole 257 provided intermediate 258 in good yield using conditions developed by Han, Stoltz, and Corey (Scheme 3.5.5).26 At this stage, reduction of the nitro functionality was accomplished under pH-neutral conditions, followed by formation of a sulfonamide to afford diene 259 in 55% yield over the two steps.27 Scheme 3.5.5 Bu3Sn MeO N Ts OMe LiCl, CuCl 10 mol% Pd(PPh3)4 257 NO2 I TBSO 242 DMSO, 60 °C, 20 h NHTs NO2 1. NiCl2•6H2O, NaBH4 MeOH, 23 °C TBSO MeO N Ts (78% yield) TBSO MeO 2. TsCl, pyridine CH2Cl2, 23 °C OMe 258 (60% yield over two steps) N Ts OMe 259 We then subjected tosyl aniline 259 to our conditions developed for the palladium(II)-catalyzed oxidative cyclization conditions (Scheme 3.5.6). Unfortunately, these conditions afforded an intractable mixture of products. We also tried DMSO/O2, although the same mixture of products was formed.28 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 181 Scheme 3.5.6 NHTs TBSO 5 mol% Pd(TFA)2 20 mol% pyridine 3ÅMS, Na2CO3 O2 balloon PhMe, 80 °C AND MeO N Ts OMe 5 mol% Pd(OAc)2 O2 balloon DMSO, 80 °C intractable mixture of products 259 Since our phenolic model system was successful, we reconcentrated our efforts toward accessing the C(5) phenol contained on the indole fragment. 3.6 Further Studies Toward the Pd(II)-catalyzed Oxidative Phenol Cyclization As previously stated, attempts to demethylate N-acetyl 5,7-dimethoxyindole (252, cf. Scheme 3.5.3) were unsuccessful. We speculated that the acetyl unit was cleaved when demethylation was attempted using BBr3. Thus, we replaced the acetyl moiety with a pivaloyl group to provide greater stability and steric bulk, as well as to preserve exclusive functionalization at C(4) (Scheme 3.6.1). Beginning with 5,7-dimethoxyindole (233), protection of the indole nitrogen using pivaloyl chloride provided arene 260 in 83% yield. To our delight, demethylation of indole 260 occurred smoothly at –10 °C using BBr3 to provide bis-phenol 261 in good yield.29 At this stage, selective silylation of the C(5) phenol using TBDPSCl under standard conditions, followed by methylation at C(7) and pivaloate removal led to indole 262 in 90% overall yield. Further functionalization of indole 262 was accomplished by a two-step sequence beginning with Boc protection of the indole nitrogen, followed by silyl cleavage to arrive at phenol 263 in 70% overall yield. It was found that the TBDPS group prevented iodination at C(4) of 182 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations the indole, likely because of steric hindrance, and thus, was replaced with a TBS group. With phenol 263 in hand, protection as a TBS silyl ether occurred readily to yield arene 264. Subsequent iodination using NIS provided indole 265 in 80% yield. By accessing indole 265, we have accomplished our goal of synthesizing a differentially substituted 4,5,7-substituted indole from indole 233. Furthermore, indole 265 should provide vinyl stannane 231 in two additional synthetic transformations. Scheme 3.6.1 MeO MeO HO BBr3 NaH, PivCl N H N Piv DMF, 0 → 23 °C OMe CH2Cl2, –10 °C 7 OMe (83% yield) 233 1. TBDPSCl imidazole CH2Cl2, 23 °C 5 N Piv 2. NaOH, Me2SO4 50 mol% Bu4NBr CH2Cl2/H2O (1:1) OH (65-71% yield) 260 261 (90% yield over 2 steps) (Boc)2O 10 mol% DMAP THF, 23 °C TBDPSO N H OMe 262 HO TBSCl imidazole N Boc then TBAF, 23 °C OMe 263 (70% yield) NIS N Boc CH2Cl2, 23 °C OMe 264 (96% yield) I TBSO TBSO 2 steps TBSO N Boc 265 (81% yield) Bu3Sn 4 OMe CHCl3, 23 °C N Boc OMe 231 Although we are now able to access the C(5) phenol, further functionalization at C(4) is required to reach vinyl stannane 231, which is needed for a Stille coupling and subsequent palladium(II)-catalyzed oxidative phenol cyclization. Thus, optimization of our protecting group strategy, as well as the synthesis of vinyl stannane 231 must occur to continue the synthesis. 183 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 3.7 Conclusions and Future Directions The efforts described in this chapter have established an efficient synthesis to advanced intermediates that can be further functionalized and modified en route to phalarine. In general, the synthesis of 4,5,7 differentially substituted indoles can be difficult; nevertheless, we have developed an efficient route that allows for selective functionalization at each position, and thus allows for the possibility of accessing novel indoles that may be bioactive or found in nature. The key aspects of the proposed synthesis of phalarine involved two palladium(II)-catalyzed oxidative heterocyclizations. Due to the efforts in this chapter, the aniline cyclization can be tested immediately. Furthermore, the synthesis of phenol 267, needed for testing the other palladium(II)-catalyzed oxidative cyclization, is only several synthetic operations away from being synthesized (Scheme 3.7.1). Scheme 3.7.1 NHTs Pd(II)-catalyzed Oxidative TBSO NTs TBSO Aniline Cyclization MeO MeO N Ts N Ts OMe OMe 259 266 Bu3Sn TBSO 1. N Boc OMe LiCl, CuCl 10 mol% Pd(PPh3)4 231 NO2 I PMBO 230 DMSO, 60 °C NO2 NO2 PMBO Pd(II)-catalyzed Oxidative HO PMBO O Phenol Cyclization 2. TBAF, THF N Boc OMe 267 N Boc OMe 268 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 184 Once results from the two palladium(II)-catalyzed oxidative heterocyclizations, shown in Scheme 3.7.1, have been obtained, it should become evident as to how to complete the synthesis of phalarine. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 185 3.8 Experimental Procedures 3.8.1 Materials and Methods Unless otherwise stated, reactions were performed at ambient temperature (typically 20–22 ºC) in flame-dried glassware under an argon or nitrogen atmosphere using dry solvents. Solvents were dried by passage through an activated alumina column under argon. Et3N, iPr2NH, iPr2NEt, and pyridine were freshly distilled from CaH2. Trifluoroacetic acid (99%) was purchased from Aldrich. Tf2O was freshly distilled from P2O5. All other commercially obtained reagents were used as received. Reaction temperatures were controlled by an IKAmag temperature modulator. Thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, anisaldehyde, KMnO4, or CAM staining. ICN silica gel (particle size 0.032–0.063 mm) was used for flash chromatography. Optical rotations were measured with a Jasco P-1010 polarimeter at 589 nm. 1H and 13C NMR spectra were recorded on a Varian Mercury 300 (at 300 MHz and 75 MHz respectively), or a Varian Inova 500 (at 500 MHz and 125 MHz respectively) and are reported relative to solvent for 1H NMR (CHCl3 = 7.27 ppm, C6H6 = 7.16 ppm, CH2Cl2 = 5.30 ppm, DMSO = 2.51 ppm) and 13C NMR (CDCl3 = 77.0 ppm, C6D6 = 128.4 ppm). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicitiy, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, hex = hextet, dq = doublet of quartets, dt = doublet of triplets, td = triplet of doublets, dd = doublet of doublets, m = multiplet, comp. m = complex multiplet, app. = apparent, bs = broad singlet. IR spectra were recorded on a Perkin Elmer BX-11 FT-IR spectrometer and are reported in Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 186 frequency of absorption (cm-1). High resolution mass spectra were obtained from the California Institute of Technology Mass Spectral Facility. For reactions involving UV light, a Mercury UV-lamp was used. 3.8.2 Preparation of Compounds OTBS OTBS hν Br CCl4 234 (85% yield) 235 Benzyl Bromide 235. To a solution of arene 23412 (1.00 g, 4.50 mmol, 1.00 equiv) in CCl4 (40 mL) at ambient temperature was added NBS (881 mg, 4.95 mmol, 1.10 equiv). A reflux condenser was fitted onto the reaction (no water) as a precaution. The reaction mixture was then stirred for 2 hours with continuous irradiation using UV light. At this time, TLC (100% Hexanes) showed the reaction was complete. The reaction mixture was filtered with filter paper, washed with minimal CH2Cl2, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography using 100% Hexanes to provide a clear oil (1.15 g, 85%). All spectroscopic data of benzyl bromide 235 matched those reported by Hartwig.12 1. 236 OTBS Bu3Sn Br 235 10 mol% Pd(PPh3)4 30 mol% AsPh3 DME, 80 °C OH Ph 237 2. TBAF, THF, 23 °C (50% yield over two steps) Phenol 237. A round-bottom flask was charged with benzyl bromide 235 (510 mg, 1.69 mmol, 1.00 equiv) and vinyl stannane 23613 (825 mg, 2.03 mmol, 1.20 equiv), followed Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 187 by DME (17 mL). This solution was sparged for 10 minutes with argon, followed by the sequential addition of AsPh3 (155 mg, 0.507 mmol, 0.300 equiv) and Pd(PPh3)4 (195 mg, 0.169 mmol, 0.100 equiv) at ambient temperature, and fitted with a reflux condenser (no water). The reaction mixture was heated to 80 °C, and monitored by TLC (100% Hexanes). After 6–8 hours, the reaction was complete and diluted with Et2O to provide a white precipitate. This suspension was filtered through a small pad of celite, and the Et2O layer was washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide a crude oil. To this oil was added THF (17 mL) at ambient temperature, followed by TBAF (2.03 mL of 1.0 M solution in THF, 2.03 mmol, 1.20 equiv). After 1 hour , TLC (10:90 EtOAc:Hexanes) showed the reaction was complete. The reaction was diluted with Et2O and water, and the layers were separated. The aqueous layer was extracted 2x with Et2O, and the Et2O layers were combined and washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil. This crude oil was purified by flash chromatography using 7:93 EtOAc:Hexanes to provide phenol 237 as a clear oil (189 mg, 50% yield over two steps). RF = 0.40 (15:85 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.32 (t, J = 7.3 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 7.14 (m, 3H), 7.02 (d, J = 6.8 Hz, 1H), 6.82 (t, J = 8.3 Hz, 2H), 5.64 (q, J = 6.8 Hz, 1H), 5.04 (s, 1H), 3.68 (s, 2H), 1.62 (d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 154.5, 140.2, 139.8, 131.1, 128.3, 128.2, 127.9, 126.8, 124.9, 123.4, 120.8, 115.9, 40.5, 14.7; IR (film) 3468, 3030, 2914, 1592, 1489, 1455, 1215 cm-1; HRMS (FAB+) calc’d for [C16H16O]+: m/z 224.1201, found 224.1206. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations OH Ph 10 mol% Pd(OAc)2, O2 O 188 Ph DMSO, 60 °C, 4 h XX (80% yield) XX Dihydrobenzofuran 238. To a 14/20 fitted glass tube (6.00 mL capacity) containing phenol 237 (10.0 mg, 44.6 µmol, 1.00 equiv) was added Pd(OAc)2 (1.00 mg, 4.46 µmol, 0.100 equiv) followed immediately by DMSO (890 µL) at ambient temperature. A 14/20 fitted glass three-way adapter containing an O2 balloon was attached accordingly. The reaction mixture was purged under vacuum and backfilled with O2, and repeated 4x. The reaction mixture was then heated to 60 °C and monitored by TLC (20:80 EtOAc:Hexanes). After 4 hours the reaction was complete. The reaction mixture was allowed to cool to ambient temperature, and the dark solution was transferred to a biphasic system of Et2O:brine (2:1). The layers were separated, and the aqueous layer was extracted 3x with Et2O. The Et2O layers were combined and washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 20:80 EtOAc:Hexanes to provide dihydrobenzofuran 238 as a colorless oil (8.00 mg, 80%). RF = 0.35 (30:70 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.3 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.28 (app. d, J = 7.3 Hz, 1H), 7.16 (m, 2H), 6.94 (d, J = 7.8 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 6.23 (dd, J = 10.5, 17.1 Hz, 1H), 5.30 (dd, J = 0.9, 17.1 Hz, 1H), 5.18 (dd, J = 0.9, 10.5 Hz, 1H), 3.60 (d, J = 15.4 Hz, 1H), 3.56 (d, J = 15.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 158.7, 144.0, 141.0, 128.3, 128.2, 127.3, 125.9, 125.4, 124.9, 120.7, 114.0, 109.5, 90.7, 42.8; IR (film) 3056, 3031, 1598, 1480, 1462, 1241; HRMS (FAB+) calc’d for [C16H14O]+: m/z 222.1045, found 222.1035. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 189 OTBS 239 NO2 2 mol% PdCl2(PPh3)4 6 mol% CuI I i-Pr2NH, 23 °C 232 NO2 OTBS (95% yield) 240 Alkyne 240. To a solution of arene 232 (2.50 g, 10.0 mmol, 1.00 equiv) and alkyne 239 (5.11 g, 30.0 mmol, 3.00 equiv) in N,N-diisopropylamine (33 mL) at ambient temperature, PdCl2(PPh3)2 (140 mg, 0.200 mmol, 0.0200 equiv) and CuI (115 mg, 0.600 mmol, 0.0600 equiv) were added sequentially to the reaction. A slurry formed after several minutes, and the reaction mixture was monitored by TLC (20:80 EtOAc:Hexanes). After 30–60 minutes, the reaction was complete, and diluted with saturated NaHCO3 (aq.). The aqueous layer was extracted 3x with Et2O, and the Et2O layer was then washed 2x with water, once with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 5:95 EtOAc:Hexanes to provide alkyne 2 4 0 as an oil (2.77 g, 95% yield). All spectroscopic data were identical to those reported by Sakamoto.30 OTBS 240 NO2 1 mol% PdCl2(PPh3)4 Bu3SnH NO2 SnBu3 THF (0.75 M), 23 °C TBSO (89% yield) 241 Vinyl Stannane 241. To a solution of alkyne 240 (1.00 g, 3.43 mmol, 1.00 equiv) and PdCl2(PPh3)2 (24.0 mg, 0.0343 mmol, 0.0100 equiv) in THF (4.60 mL) at ambient temperature was added Bu3SnH (1.10 mL, 4.12 mmol, 1.20 equiv) over 30 seconds, and the reaction was monitored by TLC (5:95 EtOAc:Hexanes). After 3 hours, the reaction was complete and was concentrated in vacuo to provide a dark oil that was purified by flash chromatography using 1:99 EtOAc:Hexanes to provide vinyl stannane 241 as a Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 190 yellow oil (1.78 g, 89% yield). RF = 0.35 (5:95 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 8.3 Hz, 1H), 7.54 (dt, J = 0.7, 7.5 Hz, 1H), 7.33 (dt, J = 1.0, 7.3 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 5.94 (t, J = 5.6 Hz, 1H), 4.02 (t, J = 5.8 Hz, 2H), 1.44 (m, 6H), 1.30 (hex, J = 7.3 Hz, 6H), 0.97–0.84 (m, 24H), 0.020 (s, 3H), 0.00 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.0, 143.7, 141.0, 139.9, 133.0, 129.2, 126.0, 124.5, 61.7, 28.8, 27.3, 25.8, 18.2, 13.6, 10.6, –5.2, –5.3; IR (film) 2957, 2929, 2856, 1523, 1464, 1343, 1254, 1102 cm-1; HRMS (FAB+) calc’d for [C27H48SiSnO3N]+: m/z 582.2426, found 582.2451. NO2 SnBu3 NO2 I2 MeCN, 23 °C TBSO I TBSO (76% yield) 241 242 Vinyl Iodide 242. To a solution vinyl stannane 241 (1.10 g, 1.89 mmol, 1.00 equiv) in MeCN (19.0 mL) at ambient temperature was added I2 (528 mg, 2.08 mmol, 1.10 equiv) in several portions, and the reaction was monitored by TLC (5:95 EtOAc:Hexanes). After 1 hour, the reaction was complete, and was quenched with 5% Na2S2O3 (aq.). The reaction mixture was diluted with water and Et2O, and the layers were then separated. The Et2O layer was washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 2:98→5:95 EtOAc:Hexanes to provide vinyl iodide 242 as a pale-yellow oil (600 mg, 76% yield) RF = 0.40 (10:90 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.00 (dd, J = 1.1, 8.2 Hz, 1H), 7.62 (dt, J = 1.2, 7.5 Hz, 1H), 7.48 (dt, J = 1.5, 8.2 Hz, 1H), 7.38 (dd, J = 1.2, 7.6 Hz, 1H), 6.63 (t, J = 6.5 Hz, 1H), 3.88 (dq, J = 6.5, 13.2 Hz, 2H), 0.82 (s, 9H), –0.060 (s, 3H), –0.072 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 147.0, 143.2, 136.3, Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 191 133.3, 130.7, 129.4, 124.7, 88.5, 61.9, 25.8, 18.2, –5.4, –5.5; IR (film) 2954, 2929, 2857, 1529, 1472, 1348, 1257, 1103 cm-1; HRMS (FAB+) calc’d for [C15H23O3NISi]+: m/z 470.0492, found 420.0480. NH Cl3C NO2 244 OPMB NO2 20 mol% La(OTf)3 OH 243 PhMe, 23 °C (86% yield) OPMB 245 Alkyne 245. To a solution of alcohol 243 (448 mg, 2.53 mmol, 1.00 equiv) and reagent 24420a (1.00 g, 3.54 mmol, 1.40 equiv) in PhMe (12.7 mL) at ambient temperature was added La(OTf)3 (296 mg, 0.506 mmol, 0.200 equiv), and the reaction was monitored by TLC (20:80 EtOAc:Hexanes). After 24 hours the reaction was complete by TLC, and quenched with water. The reaction mixture was diluted with Et2O, and the layers are separated. The organic extract was washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide a crude oil that was purified by flash chromatography using 15:85 EtOAc:Hexanes to obtain alkyne 245 as a red-orange semisolid (650 mg, 86% yield). RF = 0.40 (30:70 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 7.8 Hz, 1H), 7.65 (dd, J = 1.0, 7.8 Hz, 1H), 7.59 (dt, J = 1.0, 7.8 Hz, 1H), 7.48 (dt, J = 1.5, 7.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.67 (s, 2H), 4.44 (s, 2H), 3.82 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.5, 149.8, 134.9, 132.8, 130.0, 129.3, 128.8, 124.6, 118.1, 113.9, 93.6, 81.6, 71.3, 57.3, 55.3; IR (film) 2838, 1610, 1525, 1514, 1343, 1248, 1073, 1034 cm-1; HRMS (FAB+) calc’d for [C17H15O4N]+: m/z 297.1001, found 297.1007. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations NO2 NO2 2 mol% PdCl2(PPh3)4 Bu3SnH OPMB 245 THF, 23 °C 192 SnBu3 PMBO 246 (63% yield) Vinyl Stannane 246. To a solution of alkyne 245 (605 mg, 2.03 mmol, 1.00 equiv) and PdCl2(PPh3)2 (28.5 mg, 0.0406 mmol, 0.0200 equiv) in THF (2.70 mL) at ambient temperature was added Bu3SnH (655 µL, 2.44 mmol, 1.20 equiv) over 60 seconds. The reaction was monitored by TLC (20:80 EtOAc:Hexanes), and was complete after 30 minutes. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography using 6:94 EtOAc:Hexanes to provide vinyl stannane 246 as a neon oil (755 mg, 63% yield). RF = 0.35 (20:80 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 1H), 7.48 (dt, J = 1.0, 7.8 Hz, 1H), 7.28 (dt, J = 1.5, 8.3 Hz, 1H), 7.18 (d, J = 8.3 Hz, 2H), 7.04 (dd, J = 1.0, 7.8 Hz, 1H), 6.84 (d, J = 8.3 Hz, 2H), 5.96 (t, J = 5.9 Hz, 1H), 4.32 (d, J = 11.2 Hz, 1H), 4.30 (d, J = 11.2 Hz, 1H), 3.80 (comp. m, 5H), 1.44 (hex, J = 7.3 Hz, 6H), 1.26 (hex., J = 7.3 Hz, 6H), 0.88 (m, 15H); 13C NMR (125 MHz, CDCl3) δ 159.1,147.2, 145.9, 140.9, 136.7, 133.0, 130.3, 129.3, 129.1, 126.1, 124.5, 113.7, 71.8, 67.9, 55.2, 28.8, 27.3, 13.6, 10.7; IR (film) 2956, 2927, 2853, 1613, 1517, 1464, 1342, 1285, 1080, 1038 cm-1; HRMS (FAB+) calc’d for [C25H34SnO4N]+ (–Bu group): m/z 532.1510, found 532.1524. NO2 TIPSCl imidazole OH 243 NO2 DMF, 23 °C (83% yield) OTIPS 247 Alkyne 247. To a solution of alcohol 243 (2.49 g, 14.1 mmol, 1.00 equiv) and imidazole (2.01g, 29.6 mmol, 2.10 equiv) in DMF (56.0 mL) at 0 °C was added TIPSCl (3.04 mL, 14.8 mmol, 1.05 equiv). The reaction mixture was allowed to warm to ambient Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 193 temperature and stir overnight. TLC analysis (30:70 EtOAc:Hexanes) revealed the reaction was complete. The reaction mixture was diluted with water and Et2O, and the layers were separated. The aqueous layer was extracted 3x with Et2O, the Et2O layers were combined, washed 3x with water, once with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 5:95 EtOAc:Hexanes to provide alkyne 247 as a light-yellow oil (3.92 g, 83% yield). RF = 0.30 (10:90 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.10 (dd, J = 1.2, 8.3 Hz, 1H), 7.63 (dd, J = 1.5, 7.8 Hz, 1H), 7.54 (dt, J = 1.2, 7.8 Hz, 1H), 4.69 (s, 2H), 1.20 (comp. m, 21H); 13C NMR (125 MHz, CDCl3) δ 149.4, 134.9, 132.7, 128.6, 124.5, 118.4, 96.2, 79.6, 52.6, 17.9, 12.0; IR (film) 2944, 2866, 1609, 1569, 1530, 1463, 1344, 1261, 1098 cm-1; HRMS (FAB+) calc’d for [C18H28NSiO3]+: m/z 334.1838, found 334.1843. NO2 OTIPS 247 NO2 1 mol% PdCl2(PPh3)4 Bu3SnH SnBu3 THF, 23 °C TIPSO (74% yield) 248 Vinyl Stannane 248. To a solution of alkyne 247 (3.90 g, 11.7 mmol, 1.00 equiv) and PdCl2(PPh3)2 (82.1 mg, 0.117 mmol, 0.0100 equiv) in THF (16.0 mL) at ambient temperature was added Bu3SnH (3.47 mL, 12.9 mmol, 1.10 equiv) over 30–45 seconds. The reaction darkens, and was monitored by TLC (5:95 EtOAc:Hexanes). After stirring overnight, the reaction mixture was concentrated in vacuo to provide a crude oil that was purified by flash chromatography using 2:98 EtOAc:Hexanes to provide vinyl stannane 248 as a neon-yellow liquid (5.44 g, 74% yield). RF = 0.40 (5:95 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.0 (dd, J = 1.2, 8.2 Hz, 1H), 7.50 (dt, J = 1.2, 7.6 Hz, 1H), 7.28 (dt, J = 1.5, 8.3 Hz, 1H), 7.08 (dd, J = 1.5, 7.8 Hz, 1H), 5.93 (t, J = 5.5 Hz, 1H), 4.02 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 194 (m, 2H), 1.44 (hex, J = 7.1 Hz, 6H), 1.25 (hex, J = 7.3 Hz, 6H), 1.00 (s, 18H), 0.86 (m, 18H); 13C NMR (125 MHz, CDCl3) δ 146.1, 143.2, 141.0, 140.3, 133.0, 129.2, 126.0, 124.5, 61.9, 28.8, 27.3, 17.9, 13.6, 12.0, 10.7; IR (film) 2957, 2867, 1524, 1464, 1342, 1105, 1064 cm-1; HRMS (FAB+) calc’d for [C26H46O3NSnSi]+: m/z 568.2269, found 568.2268. MeO CHO MeNO2, NH4OAc MeO NO2 glacial AcOH, 120 °C OMe OMe (72% yield) 249 250 Arene 250. 3,5-dimethoxybenzaldehyde (249) (50.0g, 0.301 mol, 1.00 equiv), nitromethane (50.1 mL, 0.923 mol, 3.07 equiv), and ammonium acetate (76.0 g, 0.998 mol, 1.07 equiv) were dissolved in glacial acetic acid (615 mL) and refluxed for 2 h. The reaction mixture was allowed to cool to ambient temperature, at which time yellow crystals form. The suspension was placed in an ice bath for 30 minutes, and the product was then filtered and washed with cold 95% ethanol to provide compound 250 as yellow needles (45.3 g, 72% yield). All spectroscopic data of arene 250 matched those reported by Black.12 MeO NO2 Cu(NO3)2•5/2H2O MeO NO2 Ac2O, 45 °C OMe 250 NO2 OMe (98% yield) 251 Arene 251. To a flask containing acetic anhydride (380 mL) warmed to 65 °C was added compound 250 (40.0 g, 0.191 mol, 1.00 equiv). This suspension was stirred at 65 °C until all of compound 250 had dissolved. Once homogeneous, the solution was allowed to cool to 45 °C, and Cu(NO3)2•5/2 H2O (30.9 g, 0.105 mol, 0.550 equiv) was added in Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 195 4–5 portions over 1–2 minutes. A slight exotherm occurs, and once brown fumes appeared (ca. 5 min), the reaction was complete and allowed to cool to ambient temperature. The reaction mixture was poured over ice and allowed to stir and warm to ambient temperature overnight. The resulting yellow solid was filtered and washed with water 3x to provide arene 251 (47.6 g, 98% yield). All spectroscopic data of arene 251 matched those reported by Black.12 MeO NO2 NO2 OMe 251 Fe powder MeO 80% AcOH (aq), 80 °C (54% yield) N H OMe 233 Indole 233. Iron powder (32.0 g, 576 mmol, 38.5 equiv) was added to a solution of arene 251 (4.00 g, 15.7 mmol, 1 equiv) in 80% acetic acid (130 mL) and the suspension was stirred mechanically. After an exotherm that lasts approximately 30 minutes, 40 mL of water was added and the suspension was heated to 80 °C for 1 hour. The reaction mixture was then allowed to cool to ambient temperature. Upon cooling, the reaction mixture hardens to become a single solid. This solid was partially dissolved by adding CH2Cl2 and 10% HCl (aq.), followed by manual irritation using a sturdy spatula until stirring with a mechanical stirrer became possible. This suspension stirred for an additional hour, and was then filtered over a large pad of celite. The solids were washed 6x with CH2Cl2, and the resulting biphasic solution was separated respectively. The CH2Cl2 layer was washed 3x with water, followed by slow addition of saturated cold Na2CO3 (aq.) until the organic layer was only slightly acidic (pH = 5–6). The organic layer was then washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide a black solid. This residue was dissolved in minimal CH2Cl2, and purified by Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 196 flash chromatography using 10:90 EtOAc:Hexanes to provide indole 233 as a white crystalline solid (1.50 g, 54% yield).31 All spectroscopic data of arene 233 matched those reported by Black.12 1. powdered KOH DMSO, 23 °C MeO N H OMe 233 MeO N Ac 2. Ac2O, 23 °C (88% yield) OMe 252 Indole 252. To powdered KOH (0.95 g, 16.9 mmol, 3.70 equiv) was added DMSO (20.0 mL) and the suspension was stirred at ambient temperature for 10 min. Indole 233 (0.800 g, 4.52 mmol, 1.00 equiv) was then added in one portion, and the suspension was allowed to stir for 1 hour. At this stage, the resulting solution was rapidly decanted from the excess KOH and transferred to a separate round-bottom flask containing chilled Ac2O (4.00 mL, excess) (ice-bath). The excess KOH was washed rapidly with DMSO (5.00 mL) and quickly transferred to the solution of Ac2O. This solution was allowed to warm to ambient temperature, and stirred under N2 overnight. The reaction mixture was diluted with water and extracted 3x with Et2O. The organic layer was washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 10:90 EtOAc:Hexanes to provide indole 252 as a beige solid (867 g, 88% yield). All spectroscopic data of arene 252 matched those reported by Black.12 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 197 I MeO NIS N Ac OMe 252 MeO N Ac CHCl3, 23 °C (90% yield) OMe 253 Arene 253. To a solution of indole 252 (4.62 g, 21.1 mmol, 1.00 equiv) in CHCl3 (85.0 mL) at 0 °C, was added N-iodosuccinimide (5.22 g, 23.2 mmol, 1.10 equiv) in one portion, and the reaction was monitored by TLC (50:50 CH2Cl2:Hexanes). After 1 hour, the reaction was complete. The reaction mixture was diluted with water and Et2O, and the layers were separated. The aqueous layer was extracted once with Et2O, and the organic extracts were combined and washed successively with 20% Na2S2O3 (aq.), water, and brine. The Et2O layer was dried with MgSO4, filtered, and concentrated in vacuo to provide a solid. This solid was dissolved in minimial CH2Cl2, and was purified by flash chromatography using 50:50 CH2Cl2:Hexanes to obtain arene 253 as a tan solid (6.37 g, 90% yield). RF = 0.20 (15:85 EtOAc:Hexanes); 1H NMR (500 Mhz, CDCl3) δ 7.63 (d, J = 3.7 Hz, 1H), 6.58 (d, J = 3.7 Hz, 1H), 6.52 (s, 1H), 3.99 (s, 3H), 3.96 (s, 3H), 2.64 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.1, 155.8, 148.9, 138.3, 128.7, 119.4, 111.4, 94.2, 67.4, 57.5, 56.1, 25.6; IR (film) 2939, 2842, 1733, 1682, 1577, 1371, 1206, 1116, 1100 cm-1; HRMS (FAB)+ calc’d for [C12H12NO3I]+: m/z 344.9862, found 344.9849. I I MeO MeO THF: 10% NaOH (aq) N Ac OMe 253 N H (1:1), 23 °C (98% yield) OMe 254 Indole 254. Indole 253 (5.97 g, 17.3 mmol, 1.00 equiv) was dissolved in THF (80.0 mL) at ambient temperature and stirred vigorously. At this stage, 10% NaOH (aq.) (80.0 mL) was added and the reaction stirred until complete consumption of indole 253 (ca. 1 hour). Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 198 The reaction mixture was diluted with water and EtOAc, and the layers were separated. The aqueous layer was washed once with EtOAc, and the organic extracts were combined and washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide indole 254 as a light-yellow solid (5.20 g, 98% yield).32 RF = 0.25 (20:80 EtOAc:Hexanes); 1H NMR (500 MHz, DMSO-d6) δ 11.4 (br, 1H), 7.28 (t, J = 2.7 Hz, 1H), 6.60 (s, 1H), 6.18 (dt, J = 0.7, 2.2 Hz, 1H), 3.97 (s, 3H), 3.83 (s, 3H); 13C NMR (125, MHz, DMSO-d6) δ 152.4, 146.9, 132.6, 125.9, 121.1, 104.4, 91.9, 65.7, 57.9, 55.7; IR (film) cm-1; HRMS (FAB+) calc’d for [C10H10O2NI]+: m/z 302.9756, found 302.9754. I powdered KOH 20 mol% Bu4NBr TsCl MeO N H OMe 254 I MeO N Ts THF, 0 → 23 °C (75% yield) OMe 255 Arene 255. To a suspension of powdered KOH (4.95 g, 16.3 mmol, 1.15 equiv) and Bu4NBr (788 mg, 2.45 mmol, 0.15 equiv) was added THF (125 mL), and the suspension was cooled to 0 °C. Indole 254 (4.95 g, 16.3 mmol, 1.00 equiv) was then added in one portion to the reaction mixture, and the solution was allowed to stir for 45 minutes at 0 °C. At this stage, TsCl (3.57 g, 18.8 mmol, 1.15 equiv) was added to the reaction mixture in a single portion, and the mixture was allowed to stir for an additional 10 minutes at 0 °C. The reaction mixture was then allowed to warm to ambient temperature and stir overnight. TLC analysis (35:65 CH2Cl2:Hexanes) showed that minimal amounts of indole 254 remained, and thus, the reaction mixture was diluted with water and Et2O. The layers were separated, and the aqueous layer was extracted 2x with Et2O. The organic layers were combined and washed once with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to yield a tan solid. This solid was dissolved in Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 199 minimal CHCl3, and purified by flash chromatography using 35:65→ 7 5 : 2 5 CH2Cl2:Hexanes to afford indole 255 as a white solid (5.51 g, 75% yield).33 RF = 0.30 (40:60 CH2Cl2:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 3.9 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 6.64 (d, J = 3.7 Hz), 6.36 (s, 1H), 3.89 (s, 3H), 3.74 (s, 3H), 2.41 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 155.6, 148.2, 144.3, 137.7, 137.0, 129.8, 129.4, 127.3, 119.3, 110.5, 94.2, 67.1, 57.5, 55.8, 21.6; IR (film) 3148, 2939, 2845, 1578, 1463, 1352, 1255, 1213, 1171, 1134, 994 cm-1; HRMS (FAB+) calc’d for [C17H16O4INS]+: m/z 456.9845, found 456.9833. I 1. propynyl-MgBr ZnCl2, THF, 0 °C MeO N Ts OMe 255 2. 5 mol% Pd(PPh3)4 THF, 50 °C (89% yield) MeO N Ts OMe 256 Alkyne 256. ZnCl2 (2.84 mL of 0.5 M solution in THF, 1.42 mmol, 1.30 equiv) was added to THF (5.00 mL) at ambient temperature. The reaction mixture was then cooled to 0 °C, and CH3CCMgBr (2.84 mL of 0.5 M solution in THF, 1.42 mmol, 1.30 equiv) was added and a white precipitate formed. The suspension was stirred for an additional 30 minutes at 0 °C. Indole 255 (500 mg, 1.09 mmol, 1.00 equiv) was charged into a separate round-bottom flask, followed by Pd(PPh3)4 (63.1 mg, 0.0545 mmol, 0.050 equiv) and THF (1.30 mL). This solution was then transferred via cannula to the white suspension at 0 °C, and the resultant suspension was allowed to warm to ambient temperature over 10 minutes. The reaction mixture was then heated to 60 °C and monitored by TLC (30:70 EtOAc:Hexanes). After 40 minutes, the reaction was complete and allowed to cool to ambient temperature. The reaction mixture was diluted with water Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 200 and Et2O, and the layers were then separated. The aqueous layer was washed 2x with Et2O, and the Et2O layers were combined and washed 2x with water, brine, dried with MgSO4, filtered, and concentrated in vacuo to provide a solid residue. This residue was recrystalized from EtOH to provide alkyne 256 as white flakes (357 mg, 89% yield). RF = 0.40 (30:70 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 3.7 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 6.76 (d, J = 3.7 Hz, 1H), 6.30 (s, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 157.6, 147.2, 144.2, 137.0, 136.1, 129.7, 129.3, 127.2, 119.0, 106.7, 96.9, 93.6, 91.6, 73.2, 56.9, 55.6, 21.5, 4.9; IR (film) 3153, 2940, 2847, 1595, 1490, 1360, 1262, 1209, 1172, 1130, 1107 cm-1; HRMS (FAB+) calc’d for [C20H19O4NS]+: m/z 369.1035, found 369.1033. Bu3Sn 1 mol% PdCl2(PPh3)4 Bu3SnH MeO N Ts OMe 256 MeO N Ts THF (0.75 M), 23 °C (60% yield) OMe 257 Vinyl Stannane 257. To a solution of alkyne 256 (650 mg, 1.76 mmol, 1.00 equiv) in THF (2.50 mL), PdCl2(PPh3)2 (12.4 mg, 0.0176 mmol, 0.0100 equiv) was added and allowed to stir for 5 minutes at ambient temperature. At this stage, Bu3SnH (595 µL, 2.20 mmol, 1.25 equiv) was added dropwise, and the reaction was monitored by TLC (5:95 EtOAc:Hexanes). After 6 hours, the reaction mixture was concentrated, and the crude oil underwent flash chromatography using 5:95 EtOAc:Hexanes to afford vinyl stannane 257 as a pale-yellow oil (700 mg, 60% yield). RF = 0.45 (10:90 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.72 (m, 3H), 7.25 (dd, J = 0.5, 8.5 Hz, 201 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 2H), 6.36 (m, 2H), 6.00 (q, J = 6.4 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 2.40 (s, 3H), 1.56 (d, J = 6.6 Hz, 3H), 1.36 (m, 6H), 1.20 (hex, J = 7.3 Hz, 6H), 0.80 (m, 15H); 13C NMR (125 MHz, CDCl3) δ 151.5, 145.3, 143.8, 139.8, 137.5, 137.3, 131.3, 129.2, 128.8, 127.2, 119.4, 117.7, 107.3, 94.4, 56.5, 56.0, 28.9, 27.3, 21.6, 17.0, 13.6, 10.2; IR (film) 2955, 2927, 2848, 1592, 1481, 1464, 1360, 1173, 1126 cm-1; HRMS (FAB+) calc’d for [C32H46O4NSSn]+: m/z 660.2170, found 660.2198. Bu3Sn MeO N Ts OMe LiCl, CuCl 10 mol% Pd(PPh3)4 257 NO2 I TBSO 242 DMSO, 60 °C, 20 h NHTs NO2 1. NiCl2•6H2O, NaBH4 MeOH, 23 °C TBSO MeO N Ts (78% yield) OMe 258 TBSO MeO 2. TsCl, pyridine CH2Cl2, 23 °C (60% yield over two steps) N Ts OMe 259 Diene 259. A Schlenck tube (20 mL) was charged with LiCl (118 mg, 2.78 mmol, 6.00 equiv) and flame-dried under vacuum. Upon cooling to ambient temperature, Pd(PPh)4 (53.7 mg, 0.0464 mmol, 0.100 equiv) and CuCl (230 mg, 2.32 mmol, 5.00 equiv) were added, and the mixture was degassed 4x under vacuum with an Ar purge. DMSO (2.50 mL) was introduced with concomitant stirring, followed by a solution of arene 242 (195 mg, 0.464 mmol, 1.00 equiv) and vinyl stannane 257 (368 mg, 0.557 mmol, 1.20 equiv) in DMSO (800 µL, 400 µL rinse). The resulting mixture was rigorously degassed with Ar 4x by the freeze-pump-thaw process (–78 → 23 °C, Ar). The reaction mixture was stirred for an additional 30 minutes at ambient temperature, then heated to 60 °C and followed by TLC (30:70 EtOAc:Hexanes). After 20 hours, the reaction was complete and allowed to cool to ambient temperature. The reaction mixture was diluted with Et2O and washed with a 6:1 mixture of brine:5% NH4OH (aq.). A precipitate forms in the Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 202 aqueous layer, and the two layers are separated. The aqueous layer was extracted 2x with Et2O, and the Et2O extracts are combined and filtered over a small pad of celite. The filtrate was then washed 2x with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 25:75 EtOAc:Hexanes to provide diene 258 as a glue (240 mg, 78% yield). This material was used directly in the next reaction. To a solution of diene 258 (220 mg, 0.332 mmol, 1.00 equiv) in MeOH (6.60 mL) at 0 °C was added NiCl2•6H2O (13.0 mg, 0.664 mmol, 2.00 equiv), and the reaction mixture was allowed to stir until the majority of the NiCl2•6H2O was dissolved. At this stage, NaBH4 (50.2 mg, 1.33 mmol, 4.00 equiv) was added in several portions over 30 seconds, the reaction mixture was then allowed to warm to ambient temperature, and was monitored by TLC (30:70 EtOAc:Hexanes). After 90 minutes the reaction was complete and was quenched with water. The reaction mixture was diluted with Et2O and the layers are separated. The aqueous layer was extracted 3x with Et2O, and the organic extracts are combined, washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 20:80 EtOAc:Hexanes to provide an aniline as a white glue (200 mg, 95% yield). This material was used directly in the next reaction. To a solution of the aniline (96.0 mg, 0.152 mmol, 1.00 equiv) in CH2Cl2 (3.00 mL) at ambient temperature was added pyridine (132 µL, 1.22 mmol, 8.00 equiv), and the reaction mixture was stirred for 10 minutes. TsCl (31.8 mg, 0.167 mmol, 1.10 equiv) was then added in one portion, and the reaction was followed by TLC (30:70 EtOAc:Hexanes). After 8 hours, the reaction color was orange-red and was complete. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 203 The reaction mixture was concentrated in vacuo to provide a crude residue. To this residue was added heptane, and the volatiles were removed in vacuo (2x). The resulting residue was purified by flash chromatography using 20:80 EtOAc:Hexanes to provide aniline 259 as a white foam (76 mg, 63% yield). RF = 0.30 (30:70 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.78 (m, 4H), 7.68 (m, 3H), 7.30 (d, J = 8.1 Hz, 2H), 7.27 (dt, J = 1.7, 7.8 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.04 (dt, J = 1.0, 7.3 Hz, 1H), 7.00 (dd, J = 1.6, 7.4 Hz, 1H), 6.57 (s, 1H), 6.32 (d, J =3.7 Hz, 1H), 5.22 (t, J = 6.4 Hz, 1H), 5.12 (q, J = 6.8 Hz, 1H), 4.02 (s, 3H), 3.8 (s, 3H), 3.64 (dd, J = 6.4, 13.7 Hz, 1H), 3.50 (dd, J = 6.4, 13.7 Hz, 1H), 2.44 (s, 3H), 2.33 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H), 0.77 (s, 9H), –0.18 (s, 3H), –0.19 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 153.2, 147.0, 144.1, 143.4, 137.7, 137.3, 136.5, 136.3, 135.1, 133.8, 131.3, 130.5, 129.6, 129.4, 129.0, 128.6, 127.7, 127.5, 127.4, 127.38, 123.1, 119.2, 117.6, 110.5, 106.4, 94.1, 60.8, 56.9, 55.8, 25.8, 21.6, 21.5, 18.1, 15.4, –5.2, –5.3; IR (film) 3283, 2918, 2850,1598, 1493, 1349, 1254, 1168, 1092 cm-1; HRMS (FAB+) calc’d for [C42H50O7SiS2N2]+: m/z 786.2829, found 786.2862. MeO MeO NaH, PivCl N H 233 N Piv DMF, 0 → 23 °C OMe OMe (83% yield) 260 Indole 260. DMF (82 mL) was added to a round-bottom flask charged with NaH (1.33 g, 55.5 mmol, 3.00 equiv) at ambient temperature. The suspension was cooled to 0 °C and allowed to stir for 10 minutes. Subsequent dropwise addition of a solution of indole 233 (3.28 g, 18.5 mmol, 1.00 equiv) in DMF (8.00 mL, 4.00 mL rinse) to the NaH suspension resulted in bubbling. The reaction mixture was stirred for 20 minutes at 0 °C, PivCl (9.10 mL, 74.0 mmol, 4.00 equiv) was added, and the reaction mixture was allowed to slowly Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 204 warm to ambient temperature over 3 hours. After 3 additional hours of stirring, the reaction was complete by TLC (10:90 EtOAc:Hexanes). The reaction mixture was diluted with water and Et2O, and the layers were separated. The aqueous layer was extracted 3x with Et2O, and the organic extracts were combined and washed 3x with water, once with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 5:95 EtOAc:Hexanes to afford indole 260 as a clear oil (4.03 g, 83% yield). RF = 0.40 (20:80 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 3.4 Hz, 1H), 6.66 (d, J = 2.1 Hz, 1H), 6.49 (d, J = 3.4 Hz, 1H), 6.47 (d, J = 2.1 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 1.49 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 179.4, 157.0, 148.4, 131.7, 126,4, 121.7, 106.2, 96.6, 94.3, 55.8, 55.6, 42.5, 28.6; IR (film) 2968, 1719, 1612, 1592, 1478, 1287, 1204, 1174 cm-1; HRMS (FAB+) calc’d for [C15H19NO3]+: m/z 261.1365, found 261.1356. MeO HO BBr3 N Piv 260 N Piv CH2Cl2, –10 °C OMe OH (65-71% yield) 261 Bis Phenol 261. A solution of indole 260 (500 mg, 1.91 mmol, 1.00 equiv) in CH2Cl2 (38.0 mL) was cooled to –10 °C (super-saturated brine/ice bath), and stirred for 5 minutes. At this stage, BBr3 (3.83 mL of a 1.0 M solution in CH2Cl2, 3.83 mmol, 2.00 equiv) was added dropwise over 2 minutes. The reaction was monitored by TLC (20:80 EtOAc:Hexanes), and was complete after ca. 25 minutes. The reaction mixture was quenched and diluted with water, and the solution was allowed to warm to ambient temperature. The layers were separated, and the aqueous layer was extracted 3x with EtOAc, The organic extracts were combined, washed with brine, dried with MgSO4, Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 205 filtered, and concentrated in vacuo to provide a crude oil that was purified by flash chromatography using 10:90 EtOAc:Hexanes to provide indole 261 as a white solid (315 mg, 71% yield). RF = 0.45 (30:70 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 11.17 (s, 1H), 7.64 (d, J = 3.9 Hz, 1H), 6.52 (d, J = 3.9 Hz, 1H), 6.46 (d, J = 2.2 Hz, 1H), 6.42 (d, J = 2.2 Hz), 4.81 (br, 1H), 1.56 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 178.9, 154.6, 146.5, 133.4, 126.7, 119.7, 110.9, 102.2, 97.5, 41.2, 29.1; IR (film) 3370, 2982, 2936, 1646, 1603, 1462, 1412, 1340, 1300, 1190 cm-1; HRMS (FAB+) calc’d for [C13H15O3N]+: m/z 233.1052, found 233.1049. 1. TBDPSCl imidazole CH2Cl2, 23 °C HO N Piv OH 2. NaOH, Me2SO4 50 mol% Bu4NBr CH2Cl2/H2O (1:1) 261 TBDPSO N H OMe 262 (90% yield over 2 steps) Arene 262. Indole 261 (1.43 g, 6.13 mmol, 1.00 equiv) and imidazole (920 mg, 13.5 mmol, 2.20 equiv) were dissolved in CH2Cl2 (61 mL) at ambient temperature. To this solution was added TBDPSCl (1.75 mL, 6.74 mmol, 1.10 equiv), and after 1–2 minutes a white precipitate formed. The reaction mixture was allowed to stir at ambient temperature for 6–12 hours, and monitored by TLC (20:80 EtOAc:Hexanes). Upon completion, the reaction mixture was quenched with water and then diluted with Et2O. The layers were separated, the aqueous layer was washed 2x with Et2O, and the organic extracts were combined and washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was used directly in the next reaction (2.83 g, 98% yield). Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 206 To a solution of the previous product (5.85 g, 12.4 mmol, 1.00 equiv) and Bu4NBr (2.00 g, 6.20 mmol, 0.500 equiv) in CH2Cl2 (225 mL) at ambient temperature was added dimethyl sulfate (2.36 mL, 24.8 mmol, 2.00 equiv), and the reaction mixture was allowed to stir for several minutes. At this stage, a solution of NaOH (1.50 mg, 37.2 mmol, 3.00 equiv) in water (225 mL) was added, and the reaction mixture was stirred vigorously and monitored by TLC (20:80 EtOAc:Hexanes). After 3 hours, the reaction was complete, and the layers were separated. The aqueous layer was extracted once with CH2Cl2. The organic extracts were combined and washed with water, brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 7:93 EtOAc:Hexanes to provide indole 262 as a white foam (4.60 g, 92% yield, 90% yield over 2 steps). RF = 0.40 (20:80 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.06 (br, 1H), 7.78 (app. d, J = 6.8 Hz, 4H), 7.40 (m, 6H), 7.08 (s, 1H), 6.60 (s, 1H), 6.28 (s, 1H), 6.20 (s, 1H), 3.75 (s, 3H), 1.18 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 149.9, 145.7, 135.7, 133.7, 129.6, 128.4, 127.6, 123.8, 121.8, 102.6, 101.9, 97.5, 55.1, 26.7, 19.5; IR (film) 3436, 2958, 2932, 2858, 1586, 1478, 1428, 1313, 1151, 1114 cm-1; HRMS (FAB+) calc’d for [C25H27O2SiN]+: m/z 401.1811, found 401.1831. (Boc)2O 10 mol% DMAP THF, 23 °C TBDPSO N H OMe 262 then TBAF, 23 °C (70% yield) HO N Boc OMe 263 Phenol 263. To a solution of indole 262 (4.41 g, 11.0 mmol, 1.00 equiv) and DMAP (134 mg, 1.10 mmol, 0.100 equiv) in THF (110 mL) at ambient temperature was added (Boc)2O (2.92 mL, 12.7 mmol, 1.15 equiv), and the reaction was monitored by TLC (20:80 EtOAc:Hexanes). Once complete (ca. 1 h), TBAF (12.1 mL from 1.0 M solution Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 207 in THF, 12.1 mmol, 1.10 equiv) was added to the reaction and monitored by TLC (20:80 EtOAc:Hexanes). The reaction was complete after 2–3 hours, and all the volatiles were removed in vacuo to provide an oil that was purified by flash chromatography using 20:80 EtOAc:Hexanes to provide phenol 263 as a light-red oil (2.00 g, 70% yield over 2 steps). RF = 0.35 (30:70 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 3.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.39 (d, J = 3.4 Hz, 1H), 5.02 (br, 1H), 3.90 (s, 3H), 1.61 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 152.6, 149.5, 148.9, 133.9, 129.2, 119.5, 106.7, 98.0, 97.0, 83.1, 55.8, 28.0; IR (film) 3428, 2980, 2935, 1727, 1596, 1369, 1345, 1303, 1258, 1145 cm-1; HRMS (FAB+) calc’d for [C14H17O4N]+: m/z 263.1158, found 263.1167. HO TBSO N Boc OMe 263 TBSCl imidazole CH2Cl2, 23 °C (96% yield) N Boc OMe 264 Indole 264. To a solution of phenol 263 (575 mg, 2.18 mmol, 1.00 equiv) and imidazole (327 mg, 4.80 mmol, 2.20 equiv) in CH2Cl2 (21.8 mL) at ambient temperature was added TBSCl (362 mg, 2.40 mmol, 1.10 equiv), and a white precipitate formed after 1 minute. The reaction mixture was allowed to stir and monitored by TLC (5:95 EtOAc:Hexanes). After 6 hours the reaction was complete. The reaction mixture was filtered through filter paper, washed with CH2Cl2, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 3:97 EtOAc:Hexanes to provide indole 264 as a clear oil (1.05 g, 96% yield). RF = 0.40 (10:90 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 3.6 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.42 (d, J = 3.6 Hz, 1H), 6.38 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H), 1.63 (s, 9H), 1.01 (s, 3H), 0.23 (s, 6H); 13C NMR (125 MHz, Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 208 CDCl3) δ 152.3, 149.5, 148.5, 133.7, 128.9, 120.0, 106.9, 103.1, 101.5, 82.9, 55.8, 28.0, 25.8, 18.2, -4.4; IR (film) 2956, 2931, 2858, 1728, 1586, 1473, 1368, 1294, 1150 cm-1; HRMS (FAB+) calc’d for [C20H31SiNO4]+: m/z 377.2022, found 377.2005. I TBSO TBSO NIS N Boc OMe 264 CHCl3, 23 °C (81% yield) N Boc OMe 265 Arene 265. To a solution of indole 264 (765 mg, 2.03 mmol, 1.00 equiv) in CHCl3 (15.0 mL) at ambient temperature was added N-iodosuccinimide (477 mg, 2.13 mmol, 1.05 equiv) in one portion, and the reaction was monitored by TLC (5:95 EtOAc:Hexanes). The reaction mixture color changes upon the addition of NIS from colorless to wine-red over 30–60 minutes. The reaction was complete after 3 hours, and was quenched with H2O (3.00 mL). To this mixture was added 5 drops of saturated Na2S2O3 (aq.), and the mixture was allowed to stir for 20 minutes. At this stage, the layers were separated, the organic layer was diluted with Et2O, washed once with brine, dried with MgSO4, filtered, concentrated in vacuo to provide a dark oil that was purified by flash chromatography using 5:95 EtOAc:Hexanes to provide arene 265 as a clear oil (830 mg, 81% yield). RF = 0.40 (30:70 EtOAc:Hexanes); RF = 0.40 (10:90 EtOAc:Hexanes); 1H NMR (500 MHz, C6D6) δ 7.48 (d, J = 3.7 Hz, 1H), 6.58 (d, J = 3.7 Hz, 1H), 6.38 (s, 1H), 3.38 (s, 3H), 1.38 (s, 9H), 1.16 (s, 9H), 0.24 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 152.8, 149.8, 138.5, 129.8, 128.7, 120.6, 111.6, 101.0, 83.1, 71.9, 55.8, 28.1, 26.6, 19.0, -3.3; IR (film) 2957, 2931, 2858, 1732, 1574, 1469, 1360, 1292, 1271, 1209, 1158 cm-1; HRMS (FAB+) calc’d for [C20H3O4NSiI]+: m/z 503.0989, found 503.1011. 209 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 3.9 Notes and References 1 Anderton, N.; Cockrum, P. A.; Colegate, S. M.; Edgar, J. A.; Flower, K.; Gardner, D.; Willing, R. I. Phytochemistry 1999, 51, 153–157. 2 Energy minimization calculations for Spartan were accomplished using AM1, equilibration geometry. 3 Chan, C.; Li, C.; Zhang, F.; Danishefsky, S. J. Tetrahedron Lett. 2006, 47, 4839–4841. 4 The phenolic oxygen is bound to C(3) of the indole in the natural product, not C(2). 5 The mechanism for formation of phenol 213 has not been fully elucidated; however, Danishefsky proposes two possible mechanisms (ref. 3): Cl olefin isomerization NCO2Me N H SN2' 269 Cl N N H NCO2Me MeO NCO2Me OH OMe 212 [3,3] MeO OMe phenol XX O N H 213 NCO2Me 270 6 For the synthesis of racemic phalarine, see: Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2007, 46, 1448–1550. For the asymmetric synthesis, see: Trzupek, J. D.; Lee, D.; Crowley, B. M.; Marathias, V. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 8506–8512. 7 Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2007, 46, 1444–1447. 8 Gramine is 2-(N,N-dimethylaminomethylene)indole. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 9 210 The synthesis of oxindole 214 required three additional steps starting from tetrahydroβ-carboline 203. See: ref. 8 for synthetic details. 10 The mechanisms for the conversion of intermediates 224 and 225 to pentacycle 226 were shown in Schemes 3.2.1 and 3.2.2. 11 For several examples of palladium(II)-catalyzed oxidative heterocyclizations onto styrenyl olefins, see: a) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584–3585. b) Larock, R. C.; Wei, L.; Hightower, T. R. Synlett 1998, 522–524. c) Trend, R.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778–17788. 12 For the synthesis of arene 234, see: Kataoko, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553–5566. 13 For the synthesis of vinyl stannane 236, see: Miyake, H.; Yamamura, K. Chem. Lett. 1989, 18, 981–984. 14 For examples of phenol cyclizations, see: a) Larock, R. C.; Wei, L.; Hightower, T. Synlett 1998, 522–524. b) For examples of alcohol cyclizations, see, Rönn, M.; Bäckvall, J.-E.; Andersson, P. G. Tetrahedron Lett. 1995, 36, 7749–7752. c) For examples of acid cyclizations, see: Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298–5300. d) For examples of tosylamide cyclizations, see: Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584–3585, and references therein. 15 a) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2003, 42, 2892–2895. b) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778–17788. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 16 211 Most cyclizations of this type using either Stoltz’s conditions or DMSO/O2 require >12 hours for acceptable conversion (>50%). 17 Liron, F.; Garrec, P. L.; Alami, M. Synlett 1999, 246–248. 18 Liron, F.; Gervais, M.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron Lett. 2003, 44, 2789–2794. 19 Yin, Y.; Ma, W.; Chai, Z.; Zhao, G. J. Org. Chem. 2007, 72, 5731–5736. 20 a) Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.; Danishefsky, S. J. J. Org. Chem. 1989, 54, 3738–3740. b) Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267-2269. 21 Condie, G. C.; Channon, M. F.; Ivory, A. J.; Kumar, N.; Black, D. S. Tetrahedron 2005, 61, 4989–5004. 22 Slight modifications to the first two reaction conditions provided higher yields. See S.I. for reaction details. 23 Henry, L. Compt. Rend. 1895, 120, 1265. For more recent examples, see: a) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem. Int. Ed. 2005, 44, 3881–3884. b) Chung, W. K.; Chiu, P. Synlett 2005, 55–58. c) Bernardi, L.; Bomini, B. F.; Capito, E.; Dessole, G.; Comes-Franchini, M.; Fochi, M.; Ricci, A. J. Org. Chem. 2004, 69, 8168–8171. 24 Conditions screened include: BBr3, BCl3, TiCl4, TMSI, and NaSEt with Δ. 25 All other electron donating protecting groups, as well as a tosyl protecting group, led to C(2) or C(3) functionalization of indole 252. 26 Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600–7605. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 27 212 The formation of the sulfonamide was a surprisingly difficult reaction. The starting aniline and the product seemed to be sensitive to both acid and base, resulting in an unidentified impurity that made purification difficult. 28 Although we were able to test the palladium(II)-catalyzed oxidative aniline cyclization, it appears that the aniline cyclized onto the wrong olefin Even though it is not conclusive, there is no N-H stretch in the IR, and a HRMS of the products shows a mass corresponding to loss of H2. Moreover, the 1H NMR clearly shows which vinyl proton remains in the product. 29 It should be noted that demethylation with one equivalent of BBr3 cleanly afforded the C(7) mono-demethylated product. Although undesired for our studies, this selective transformation could prove valuable for the synthesis of other natural products or biologically active molecules. 30 Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126–1136. 31 a) When the reaction is run with 25 g of arene 251, the yield for indole 233 is between 40–45%. b) The synthesis of indole 233 is also reported by Borchardt; however, several attempts using this procedure resulted in 30–40% yields of indole 233, see: Sinhababu, A. K.; Borchardt, R. T. J. Org. Chem. 1983, 48, 3347–3349. 32 Indole 254 should be kept in a –20 °C freezer under Ar, away from light. 33 Indole 255 can also be recrystallized from hot EtOH. However, prolonged heating to dissolve the final 5% of solid should be avoided, as decomposition and darkening of the solution occurs. Instead, once 95% of indole 255 has dissolved, perform a hot filtration and rinse, followed by cooling to effect crystallization and avoid decomposition. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 213  213 Appendix 3.1 Spectra of Compounds Relevant to Chapter Three Ph 237 OH Figure A3.1.1 1H NMR (500 MHz, CDCl3) of compound 237 214 215 Figure A3.1.2 Infrared spectrum (film/NaCl) of compound 237 Figure A3.1.3 13C NMR (125 MHz, CDCl3) of compound 237 238 O Ph Figure A3.1.4 1H NMR (500 MHz, CDCl3) of compound 238 216 217 Figure A3.1.5 Infrared spectrum (film/NaCl) of compound 238 Figure A3.1.6 13C NMR (125 MHz, CDCl3) of compound 238 240 NO2 OTBS Figure A3.1.7 1H NMR (500 MHz, CDCl3) of compound 240 218 TBSO 241 SnBu3 NO2 Figure A3.1.8 1H NMR (500 MHz, CDCl3) of compound 241 219 220 Figure A3.1.9 Infrared spectrum (film/NaCl) of compound 241 Figure A3.1.10 13C NMR (125 MHz, CDCl3) of compound 241 242 TBSO I NO2 Figure A3.1.11 1H NMR (500 MHz, CDCl3) of compound 242 221 222 Figure A3.1.12 Infrared spectrum (film/NaCl) of compound 242 Figure A3.1.13 13C NMR (125 MHz, CDCl3) of compound 242 245 NO2 OPMB Figure A3.1.14 1H NMR (500 MHz, CDCl3) of compound 245 223 224 Figure A3.1.15 Infrared spectrum (film/NaCl) of compound 245 Figure A3.1.16 13C NMR (125 MHz, CDCl3) of compound 245 PMBO 246 SnBu3 NO2 Figure A3.1.17 1H NMR (500 MHz, CDCl3) of compound 246 225 226 Figure A3.1.18 Infrared spectrum (film/NaCl) of compound 246 Figure A3.1.19 13C NMR (125 MHz, CDCl3) of compound 246 247 NO2 OTIPS Figure A3.1.20 1H NMR (500 MHz, CDCl3) of compound 247 227 228 Figure A3.1.21 Infrared spectrum (film/NaCl) of compound 247 Figure A3.1.22 13C NMR (125 MHz, CDCl3) of compound 247 TIPSO 248 SnBu3 NO2 Figure A3.1.23 1H NMR (500 MHz, CDCl3) of compound 248 229 230 Figure A3.1.24 Infrared spectrum (film/NaCl) of compound 248 Figure A3.1.25 13C NMR (125 MHz, CDCl3) of compound 248 MeO 250 OMe NO2 Figure A3.1.26 1H NMR (300 MHz, CDCl3) of compound 250 231 MeO NO2 251 OMe NO2 Figure A3.1.27 1H NMR (300 MHz, CDCl3) of compound 251 232 MeO 233 OMe N H Figure A3.1.28 1H NMR (300 MHz, CDCl3) of compound 233 233 MeO 252 OMe N Ac Figure A3.1.29 1H NMR (300 MHz, CDCl3) of compound 252 234 MeO 253 OMe I N Ac Figure A3.1.30 1H NMR (300 MHz, CDCl3) of compound 253 235 236 Figure A3.1.31 Infrared spectrum (film/NaCl) of compound 253 Figure A3.1.32 13C NMR (125 MHz, CDCl3) of compound 253 MeO 254 OMe I N H Figure A3.1.33 1H NMR (500 MHz,d6-DMSO) of compound 254 237 238 Figure A3.1.34 Infrared spectrum (film/NaCl) of compound 254 Figure A3.1.35 13C NMR (125 MHz, d6-DMSO) of compound 254 MeO 255 OMe I N Ts Figure A3.1.36 1H NMR (500 MHz, CDCl3) of compound 255 239 240 Figure A3.1.37 Infrared spectrum (film/NaCl) of compound 255 Figure A3.1.38 13C NMR (125 MHz, CDCl3) of compound 255 MeO 256 OMe N Ts Figure A3.1.39 1H NMR (500 MHz, CDCl3) of compound 256 241 242 Figure A3.1.40 Infrared spectrum (film/NaCl) of compound 256 Figure A3.1.41 13C NMR (125 MHz, CDCl3) of compound 256 MeO Bu3Sn 257 OMe N Ts Figure A3.1.42 1H NMR (500 MHz, CDCl3) of compound 257 243 244 Figure A3.1.43 Infrared spectrum (film/NaCl) of compound 257 Figure A3.1.44 13C NMR (125 MHz, CDCl3) of compound 257 TBSO 259 MeO OMe N Ts NHTs Figure A3.1.45 1H NMR (500 MHz, CDCl3) of compound 259 245 246 Figure A3.1.46 Infrared spectrum (film/NaCl) of compound 259 Figure A3.1.47 13C NMR (125 MHz, CDCl3) of compound 259 MeO 260 OMe N Piv Figure A3.1.48 1H NMR (500 MHz, CDCl3) of compound 260 247 248 Figure A3.1.49 Infrared spectrum (film/NaCl) of compound 260 Figure A3.1.50 13C NMR (125 MHz, CDCl3) of compound 260 HO 261 OH N Piv Figure A3.1.51 1H NMR (500 MHz, CDCl3) of compound 261 249 250 Figure A3.1.52 Infrared spectrum (film/NaCl) of compound 261 Figure A3.1.53 13C NMR (125 MHz, CDCl3) of compound 261 TBDPSO 262 OMe N H Figure A3.1.54 1H NMR (500 MHz, CDCl3) of compound 262 251 252 Figure A3.1.55 Infrared spectrum (film/NaCl) of compound 262 Figure A3.1.56 13C NMR (125 MHz, CDCl3) of compound 262 HO 263 OMe N Boc Figure A3.157 1 H NMR (500 MHz, CDCl3) of compound 263 253 254 Figure A3.1.58 Infrared spectrum (film/NaCl) of compound 263 Figure A3.1.59 13C NMR (125 MHz, CDCl3) of compound 263 TBSO 264 OMe N Boc Figure A3.1.60 1H NMR (500 MHz, CDCl3) of compound 264 255 256 Figure A3.1.61 Infrared spectrum (film/NaCl) of compound 264 Figure A3.1.62 13C NMR (125 MHz, CDCl3) of compound 264 TBSO 265 OMe I N Boc Figure A3.1.63 1H NMR (500 MHz, CDCl3) of compound 265 257 258 Figure A3.1.64 Infrared spectrum (film/NaCl) of compound 265 Figure A3.1.65 13C NMR (125 MHz, CDCl3) of compound 265  PALLADIUM(II)-CATALYZED OXIDATION REACTIONS IN NATURAL PRODUCT SYNTHESIS: EFFORTS TOWARD BIELSCHOWSKYSIN AND PHALARINE Thesis by Michael Elliott Meyer In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 2011 (Defended June 28, 2010) ii © 2011 Michael Elliott Meyer All Rights Reserved iii To My Parents iv Acknowledgements “One must learn by doing the thing, for though you think you know it, you have no certainty until you try.” Aristotle During my time in the Stoltz laboratory, these words have been echoed by my boss, professor Brian Stoltz, countless times when discussing organic chemistry. It amazes me how Brian stays on top of all his research projects and still finds time to follow the Red Sox season and play with his i-phone! In all seriousness, Brian has been a terrific mentor and advisor for me. His support during the difficult times, which was the vast majority of time here, never wavered. I thank Brian for his expertise, advice, friendship, support, and most of all, his patience. Brian’s passion and enthusiasm toward organic chemistry has been a constant pillar of support, and he has always been open to my ideas and allowed the freedom for me to try my ideas in the laboratory. Although it’s taken longer than expected, the degree and experience that I have gained from the Stoltz laboratory will no doubt allow me to continue to pursue my various passions in science, as well as live a life of more comfort than I am currently used to. In addition to Brian, I must also thank my committee members: Professor Bob Grubbs, Professor Sarah Reisman, and Professor John Bercaw. I thank them specifically for their advice and patience. I’d like to also thank Lynne Martinez, Chris Smith, and Joe Drew. Lynne does an amazing job working with Brian and the group, and keeping people informed on many issues. Chris does a great job trying to find jobs for graduate students, and she’s fun to v talk with about movies, pharmaceuticals, and a whole lot more. Then there’s Joe, a guy who has become a good friend throughout the years. Joe is very good at his job, golf, and being a family man. I owe you 18 holes. As far as individuals in the Stoltz laboratory, there are many, so let me begin by thanking all the people who worked on either the palladium(II)-catalyzed oxidative kinetic resolution, or the palladium(II)-catalyzed oxidative heterocyclization methodology. Due to their tremendous efforts, I was able to further their research toward natural product synthesis. In the first half of graduate school, there are a handful of people I need to thank individually. First, the whole first class from the Stoltz lab was super talented and helpful, but being partnered up with Eric Ferreira (now a professor at Colorado State), led to a friendship that continues to this day. Eric was heavily involved in both the aforementioned methodologies, and was my partner during the initial six months of research on bielschowskysin. Besides teaching me the ropes in organic synthesis, Eric and I shared many conversations about the SF Giants and the SF 49ers, both or our teams in their respective sports. If there was a question about the chemistry, everyone went to Eric. I have no doubt that he will succeed in his research, and I thank him and wish him all the luck anyways. Second, Ernie Cruz, a man who has a great wife, sister, two awesome little boys, and a supportive extended family. Ernie has great values, is very intelligent, and has been a great friend who let me come over to watch LOST with his wife and kids, all of this after he left the Stoltz group! I hope to keep our friendship going as life moves forward. Third, Dr. Jeff Bagdanoff was my baymate for almost three years. I went to Jeff’s bachelor party and wedding, and I continue to wish he and Claire vi continued happiness. For the most part, Jeff and I enjoyed our time working next to each other, and I thank him for the support and friendship. Fourth, I need to thank Dr. John Phillips, my second partner on bielschowskysin. John made an immediate impact on our project by improving the cyclopropanation reaction, and making improvements in the scale-up process. John is a good friend, very knowledgeable, and also provided a positive outlook almost every day he was at Caltech. Although we were unable to achieve the results we strived for, the friendship and experience working with John was completely worth it. Finally, I’d like to thank Raissa Trend for proofreading various documents, she has a degree in English, and for having lots of entertaining conversations. I wish her success in her future endeavors. For the second half of graduate school, there are two people within the Stoltz group I want to thank. First, there’s Chris Gilmore, my baymate for about four years, and although our friendship has been up and down, it still exists. Also, I’m pretty sure after some time apart, and with some money accumulated for both of us, we’ll all be a little happier! I thank him for the time together, friendship, and of course the baseball talk. Second, I need to thank my first man-crush, Dr. Andy McClory, for his great friendship, continuous encouragement, and great advice while working across from me. He’s one of my best friends, and I’ve leaned on him many times, and I thank him for all of them. Furthermore, he now lives one mile from my childhood home, so I’m sure our friendship will continue to develop and hopefully we’ll soon be playing a lot of golf together. I cannot go any further without thanking the remaining Stoltz group members. From my first week in the labs in Crellin, to my last days in the labs in Schlinger, the Stoltz group has been a great source of information and continues to have a great working vii environment. I’d like to specifically thank the group members who edited my thesis: Andy McClory, Sandy Ma, Hosea Nelson, Thomas Jensen, Josh Day and Chris Gilmore. They all did a great job editing this thesis, not an easy job! Finally, I need to thank the people outside of Caltech. First, Lisa Leiberman and Cindy Yang both let me open up to them, share my 8 hours of free time, and provide me with emotional support. Cindy has really helped me the final two years with her support, friendship, and love! Next, Dr. Susana Friedlander. She has talked me down from my most stressed moments, and has taught me how to think correctly about life and various social issues. She has allowed me to feel better about myself, relax, and understand that there’s a much better life waiting for me after graduate school. Lastly, my friends and family have supported me every second of my life, and it didn’t stop during graduate school. As far as friends go, I need to thank Dave and Bobby Masuda, Jeff Chung, Dave Kasowski, and Ted Curd. As for my family, obviously I need to thank my parents, uncle Bob, aunt Jerri, and the rest of the extended family. THANK YOU friends and family, and I look forward to spending more time together than during the previous decade. viii Abstract Two types of oxidative transformations, an oxidative kinetic resolution and an oxidative heterocyclization, have been developed by several laboratories using palladium(II)-catalysis to provide enantioenriched products. The main drawback of these asymmetric transformations is the limited substrate scope for each set of conditions. To address this, the Stoltz laboratory developed a unique platform utilizing palladium(II)catalysis that provides a highly effective oxidative kinetic resolution of secondary alcohols and an asymmetric oxidative heterocyclization of phenols. Key to this platform is the use of (–)-sparteine as the chiral ligand and O2 as the stoichiometric oxidant. Both of these methodologies will be featured in this thesis as they were applied toward the total synthesis of complex natural products. Our palladium(II)-catalyzed oxidative kinetic resolution was used to access an enantioenriched intermediate in our efforts toward the synthesis of bielschowskysin, a polycyclic diterpenoid. A key disconnection in our strategy was formation of the cyclobutane core of bielschowskysin from a cyclopropane intermediate. After considerable experimentation, we were able to synthesize a cyclopropane intermediate that could be used for future research. In separate work, we hoped to use two palladium(II)-catalyzed oxidative heterocyclization reactions to provide the core of phalarine, a polycyclic alkaloid. The synthesis of a key intermediate relied on a Stille coupling reaction of a complex 4,5,7substituted indole and a nitro-arene. Model cyclization studies on an aniline substrate gave inconclusive results, while a model of a phenolic substrate has shown that cyclization onto styrenyl olefins is possible. ix Table of Contents Acknowledgements iv Abstract xiii Table of Contents ix List of Figures xi List of Schemes xviii List of Tables xx List of Abbreviations xxi Chapter 1 – Introduction 1.1 An Introduction to Oxidative Kinetic Resolution 1 1.2 Introduction to Palladium(II)-catalyzed Oxidative Heterocyclizations 10 1.3 Notes and References 20 Chapter 2 – Synthetic Efforts Toward Bielschowskysin Using a Palladium(II)catalyzed Oxidative Kinetic Resolution 2.1 Introduction and Biosynthesis 25 2.2 Outside Efforts Toward the Total Synthesis of Bielschowskysin 27 2.3 Retrosynthesis: Use of a Cyclopropane to Access the Core 29 2.4 Initial Synthetic Efforts 31 2.5 The Palladium(II)-catalyzed Oxidative Kinetic Resolution 36 2.6 Further Investigations into the Model System 37 2.7 Future Directions 43 2.8 Concluding Remarks 47 2.9 Experimental Procedures 48 2.10 Notes and References 73 Chapter 2 – Appendices App. 1 Failed Approaches Toward a Macrocyclic Intermediate 78 App. 2 Spectra of Compounds Relevant to Chapter Two 81 x App. 3 X-ray Crystallographic Data Relevant to Chapter Two 146 Chapter 3 – Synthetic Efforts Toward (–)-Phalarine Using Palladium(II)-catalyzed Oxidative Heterocyclizations 3.1 Introduction and Biosynthesis 168 3.2 Previous Efforts Toward the Total Synthesis of Phalarine 171 3.3 Retrosynthetic Analysis of Phalarine 174 3.4 Model System Studies 175 3.5 Initial Synthetic Efforts 177 3.6 Further Studies Toward the Pd(II)-catalyzed Oxidative Phenol Cycl. 181 3.7 Conclusions and Future Directions 183 3.8 Experimental Procedures 185 3.9 Notes and References 209 Chapter 3 – Appendices App. 1 Spectra of Compounds Relevant to Chapter Three 213 Index 259 Notebook Cross-Reference 260 Comprehensive Bibliography 264 About the Author 272 xi List of Figures Chapter 1 Figure 1.1.1 Kinetic Resolution Overview 2 Figure 1.1.2 Proposed Alcohol Oxidation by Palladium 6 Figure 1.1.3 Proposed β-Hydride Transition State for Each Enantiomer 8 Figure 1.1.4 Natural Products Synthesized by Palladium(II)-catalyzed OKR 8 Figure 1.1.5 Enantioenriched 2-Aryl Cylopentenols Using Original Conditions 9 F i g u r e1.1.6 Substrate for the Palladium(II)-catalyzed OKR 9 Figure 1.2.1 A Generic Heteroatom Anti Palladation 14 Figure 1.2.2 A Generic Heteroatom Syn Palladation 15 Figure 1.2.3 Heterocycles Accesses via a Pd(II)-catalyzed Ox. Heterocyclization 17 Figure 1.2.4 Natural Products Synthesized via a Pd(II)-catalyzed Ox. Cyclization 19 Figure 1.2.5 Structure of (–)-Phalarine 19 Chapter 2 Figure 2.1.1 Bielschowskysin and Related Natural Products 26 Figure 2.3.1 Model System for Studies Toward the Cyclobutane Core 29 Figure 2.3.2 Proposed Mechanism for the Formation of Cyclobutane 125 31 Figure 2.6.2 Various Cyclopropane Derivatives 41 Chapter 2 Appendices Appendix 2.2 Figure A2.2.1 1H NMR (500 MHz, CDCl3) of compound 136 82 Figure A2.2.2 Infrared spectrum (film/NaCl) of compound 136 83 Figure A2.2.3 13C NMR (125 MHz, CDCl3) of compound 136 83 Figure A2.2.4 1H NMR (500 MHz, CDCl3) of compound 128 84 Figure A2.2.5 Infrared spectrum (film/NaCl) of compound 128 85 Figure A2.2.6 13C NMR (125 MHz, CDCl3) of compound 128 85 Figure A2.2.7 1H NMR (300 MHz, CDCl3) of compound 139 86 Figure A2.2.8 Infrared spectrum (film/NaCl) of compound 139 87 xii Figure A2.2.9 1H NMR (500 MHz, C6D6) of compound 127 88 Figure A2.2.10 Infrared spectrum (film/NaCl) of compound 127 89 Figure A2.2.11 13C NMR (125 MHz, C6D6) of compound 127 89 Figure A2.2.12 1H NMR (300 MHz, CDCl3) of compound 141 90 Figure A2.2.13 Infrared spectrum (film/NaCl) of compound 141 91 Figure A2.2.14 1H NMR (300 MHz, CDCl3) of compound 143 92 Figure A2.2.15 Infrared spectrum (film/NaCl) of compound 143 93 Figure A2.2.16 13C NMR (75 MHz, CDCl3) of compound 143 93 Figure A2.2.17 1H NMR (300 MHz, CDCl3) of compound 145 94 Figure A2.2.18 Infrared spectrum (film/NaCl) of compound 145 95 Figure A2.2.19 13C NMR (75 MHz, CDCl3) of compound 145 95 Figure A2.2.20 1H NMR (300 MHz, CDCl3) of compound 147 96 Figure A2.2.21 Infrared spectrum (film/NaCl) of compound 147 97 Figure A2.2.22 13 C NMR (75 MHz, CDCl3) of compound 147 97 Figure A2.2.23 1H NMR (300 MHz, CDCl3) of compound 149 98 Figure A2.2.24 Infrared spectrum (film/NaCl) of compound 149 99 Figure A2.2.25 13C NMR (75 MHz, CDCl3) of compound 149 99 Figure A2.2.26 1H NMR (300 MHz, CDCl3) of compound 151 100 Figure A2.2.27 Infrared spectrum (film/NaCl) of compound 151 101 Figure A2.2.28 1H NMR (300 MHz, CDCl3) of compound 153 102 Figure A2.2.29 Infrared spectrum (film/NaCl) of compound 153 103 Figure A2.2.30 13C NMR (75 MHz, CDCl3) of compound 153 103 Figure A2.2.31 1H NMR (300 MHz, CDCl3) of compound 155 104 Figure A2.2.32 Infrared spectrum (film/NaCl) of compound 155 105 Figure A2.2.33 13C NMR (75 MHz, CDCl3) of compound 155 105 Figure A2.2.34 1H NMR (300 MHz, CDCl3) of compound 157 106 Figure A2.2.35 13C NMR (125 MHz, CDCl3) of compound 157 107 Figure A2.2.36 1H NMR (300 MHz, CDCl3) of compound 158 108 Figure A2.2.37 Infrared spectrum (film/NaCl) of compound 158 109 Figure A2.2.38 13C NMR (75 MHz, CDCl3) of compound 158 109 Figure A2.2.39 1H NMR (300 MHz, CDCl3) of compound 159 110 xiii Figure A2.2.40 Infrared spectrum (film/NaCl) of compound 159 111 Figure A2.2.41 13C NMR (75 MHz, CDCl3) of compound 159 111 Figure A2.2.42 1H NMR (300 MHz, CDCl3) of compound 161 112 Figure A2.2.43 Infrared spectrum (film/NaCl) of compound 161 113 Figure A2.2.44 13C NMR (125 MHz, CDCl3) of compound 161 113 Figure A2.2.45 1H NMR (300 MHz, CDCl3) of compound 163 114 Figure A2.2.46 Infrared spectrum (film/NaCl) of compound 163 115 Figure A2.2.47 13C NMR (75 MHz, CDCl3) of compound 163 115 Figure A2.2.48 1H NMR (500 MHz, CDCl3) of compound 37 116 Figure A2.2.49 Infrared spectrum (film/NaCl) of compound 37 117 Figure A2.2.50 13C NMR (125 MHz, CDCl3) of compound 37 117 Figure A2.2.51 1H NMR (500 MHz, CDCl3) of compound 164 118 Figure A2.2.52 Infrared spectrum (film/NaCl) of compound 164 119 13 Figure A2.2.53 C NMR (125 MHz, CDCl3) of compound 164 119 Figure A2.2.54 1H NMR (500 MHz, CDCl3) of compound 165 120 Figure A2.2.55 Infrared spectrum (film/NaCl) of compound 165 121 Figure A2.2.56 13C NMR (125 MHz, CDCl3) of compound 165 121 Figure A2.2.57 1H NMR (500 MHz, C6D6) of compound 166 122 Figure A2.2.58 Infrared spectrum (film/NaCl) of compound 166 123 Figure A2.2.59 13C NMR (125 MHz, C6D6) of compound 166 123 Figure A2.2.60 1H NMR (500 MHz, C6D6) of compound 171 124 Figure A2.2.61 Infrared spectrum (film/NaCl) of compound 171 125 Figure A2.2.62 13C NMR (125 MHz, C6D6) of compound 171 125 Figure A2.2.63 1H NMR (500 MHz, C6D6) of compound 172 126 Figure A2.2.64 Infrared spectrum (film/NaCl) of compound 172 127 Figure A2.2.65 13C NMR (125 MHz, C6D6) of compound 172 127 Figure A2.2.66 1H NMR (500 MHz, C6D6) of compound 168 128 Figure A2.2.67 Infrared spectrum (film/NaCl) of compound 168 129 Figure A2.2.68 13C NMR (125 MHz, CDCl3) of compound 168 129 Figure A2.2.69 1H NMR (500 MHz, C6D6) of compound 169 130 Figure A2.2.70 Infrared spectrum (film/NaCl) of compound 169 131 xiv Figure A2.2.71 13C NMR (125 MHz, C6D6) of compound 169 131 Figure A2.2.72 1H NMR (500 MHz, C6D6) of compound 173 132 Figure A2.2.73 Infrared spectrum (film/NaCl) of compound 173 133 Figure A2.2.74 13C NMR (125 MHz, C6D6) of compound 173 133 Figure A2.2.75 1H NMR (500 MHz, C6D6) of compound 174 134 Figure A2.2.76 Infrared spectrum (film/NaCl) of compound 174 135 Figure A2.2.77 13C NMR (125 MHz, CDCl3) of compound 174 135 Figure A2.2.78 1H NMR (500 MHz, C6D6) of compound 175 136 Figure A2.2.79 Infrared spectrum (film/NaCl) of compound 175 137 Figure A2.2.80 13C NMR (125 MHz, C6D6) of compound 175 137 Figure A2.2.81 1H NMR (500 MHz, C6D6) of compound 176 138 Figure A2.2.82 Infrared spectrum (film/NaCl) of compound 176 139 Figure A2.2.83 13C NMR (125 MHz, C6D6) of compound 176 139 1 Figure A2.2.84 H NMR (500 MHz, C6D6) of compound 177 140 Figure A2.2.85 Infrared spectrum (film/NaCl) of compound 177 141 Figure A2.2.86 13C NMR (125 MHz, CDCl3) of compound 177 141 Figure A2.2.87 1H NMR (300 MHz, CDCl3) of compound 181 142 Figure A2.2.88 Infrared spectrum (film/NaCl) of compound 181 143 Figure A2.2.89 13 C NMR (125 MHz, CDCl3) of compound 181 143 Figure A2.2.90 1H NMR (500 MHz, CDCl3) of compound 182 144 Figure A2.2.91 Infrared spectrum (film/NaCl) of compound 182 145 Figure A2.2.92 13C NMR (125 MHz, CDCl3) of compound 182 145 Appendix 2.3 Figure A2.3.1 Representation of Alcohol 182 147 Figure A2.3.2 Representation of Furan 169 160 Chapter 3 Figure 3.1.1 (–)-Phalarine (106) in Two and Three Dimensions 169 xv Chapter 3 Appendices Appendix 3.1 Figure A3.1.1 1H NMR (500 MHz, CDCl3) of compound 237 214 Figure A3.1.2 Infrared spectrum (film/NaCl) of compound 237 215 Figure A3.1.3 13C NMR (125 MHz, CDCl3) of compound 237 215 Figure A3.1.4 1H NMR (500 MHz, CDCl3) of compound 238 216 Figure A3.1.5 Infrared spectrum (film/NaCl) of compound 238 217 Figure A3.1.6 13C NMR (125 MHz, CDCl3) of compound 238 217 Figure A3.1.7 1H NMR (500 MHz, CDCl3) of compound 240 218 Figure A3.1.8 1H NMR (500 MHz, CDCl3) of compound 241 219 Figure A3.1.9 Infrared spectrum (film/NaCl) of compound 241 220 Figure A3.1.10 13C NMR (125 MHz, CDCl3) of compound 241 220 Figure A3.1.11 1H NMR (500 MHz, CDCl3) of compound 242 221 Figure A3.1.12 Infrared spectrum (film/NaCl) of compound 242 222 Figure A3.1.13 13C NMR (125 MHz, CDCl3) of compound 242 222 Figure A3.1.14 1H NMR (500 MHz, CDCl3) of compound 245 223 Figure A3.1.15 Infrared spectrum (film/NaCl) of compound 245 224 Figure A3.1.16 13C NMR (125 MHz, CDCl3) of compound 245 224 Figure A3.1.17 1H NMR (500 MHz, CDCl3) of compound 246 225 Figure A3.1.18 Infrared spectrum (film/NaCl) of compound 246 226 Figure A3.1.19 13C NMR (125 MHz, CDCl3) of compound 246 226 Figure A3.1.20 1H NMR (500 MHz, CDCl3) of compound 247 227 Figure A3.1.21 Infrared spectrum (film/NaCl) of compound 247 228 Figure A3.1.22 13C NMR (125 MHz, CDCl3) of compound 247 228 Figure A3.1.23 1H NMR (500 MHz, CDCl3) of compound 248 229 Figure A3.1.24 Infrared spectrum (film/NaCl) of compound 248 230 Figure A3.1.25 13C NMR (125 MHz, CDCl3) of compound 248 230 Figure A3.1.26 1H NMR (300 MHz, CDCl3) of compound 250 231 Figure A3.1.27 1H NMR (300 MHz, CDCl3) of compound 251 232 1 Figure A3.1.28 H NMR (300 MHz, CDCl3) of compound 233 233 Figure A3.1.29 1H NMR (300 MHz, CDCl3) of compound 252 234 xvi Figure A3.1.30 1H NMR (300 MHz, CDCl3) of compound 253 235 Figure A3.1.31 Infrared spectrum (film/NaCl) of compound 253 236 Figure A3.1.32 13C NMR (125 MHz, CDCl3) of compound 253 236 Figure A3.1.33 1H NMR (500 MHz,d6-DMSO) of compound 254 237 Figure A3.1.34 Infrared spectrum (film/NaCl) of compound 254 238 Figure A3.1.35 13C NMR (125 MHz, d6-DMSO) of compound 254 238 Figure A3.1.36 1H NMR (500 MHz, CDCl3) of compound 255 239 Figure A3.1.37 Infrared spectrum (film/NaCl) of compound 255 240 Figure A3.1.38 13C NMR (125 MHz, CDCl3) of compound 255 240 Figure A3.1.39 1H NMR (500 MHz, CDCl3) of compound 256 241 Figure A3.1.40 Infrared spectrum (film/NaCl) of compound 256 242 Figure A3.1.41 13C NMR (125 MHz, CDCl3) of compound 256 242 Figure A3.1.42 1H NMR (500 MHz, CDCl3) of compound 257 243 Figure A3.1.43 Infrared spectrum (film/NaCl) of compound 257 244 Figure A3.1.44 13C NMR (125 MHz, CDCl3) of compound 257 244 Figure A3.1.45 1H NMR (500 MHz, CDCl3) of compound 259 245 Figure A3.1.46 Infrared spectrum (film/NaCl) of compound 259 246 Figure A3.1.47 13C NMR (125 MHz, CDCl3) of compound 259 246 1 Figure A3.1.48 H NMR (500 MHz, CDCl3) of compound 260 247 Figure A3.1.49 Infrared spectrum (film/NaCl) of compound 260 248 Figure A3.1.50 13C NMR (125 MHz, CDCl3) of compound 260 248 Figure A3.1.51 1H NMR (500 MHz, CDCl3) of compound 261 249 Figure A3.1.52 Infrared spectrum (film/NaCl) of compound 261 250 Figure A3.1.53 13C NMR (125 MHz, CDCl3) of compound 261 250 Figure A3.1.54 1H NMR (500 MHz, CDCl3) of compound 262 251 Figure A3.1.55 Infrared spectrum (film/NaCl) of compound 262 252 Figure A3.1.56 13C NMR (125 MHz, CDCl3) of compound 262 252 Figure A3.157 1H NMR (500 MHz, CDCl3) of compound 263 253 Figure A3.1.58 Infrared spectrum (film/NaCl) of compound 263 254 Figure A3.1.59 13C NMR (125 MHz, CDCl3) of compound 263 254 Figure A3.1.60 1H NMR (500 MHz, CDCl3) of compound 264 255 xvii Figure A3.1.61 Infrared spectrum (film/NaCl) of compound 264 256 Figure A3.1.62 13C NMR (125 MHz, CDCl3) of compound 264 256 Figure A3.1.63 1H NMR (500 MHz, CDCl3) of compound 265 257 Figure A3.1.64 Infrared spectrum (film/NaCl) of compound 265 258 Figure A3.1.65 13C NMR (125 MHz, CDCl3) of compound 265 258 xviii List of Schemes Chapter 1 Scheme 1.1.1 3 Scheme 1.1.2 4 Scheme 1.1.3 5 Scheme 1.1.4 6 Scheme 1.2.1 10 Scheme 1.2.2 11 Scheme 1.2.3 12 Scheme 1.2.4 13 Scheme 1.2.5 15 Scheme 1.2.6 16 Scheme 1.2.7 18 Chapter 2 Scheme 2.1.1 26 Scheme 2.1.2 27 Scheme 2.2.1 28 Scheme 2.2.2 28 Scheme 2.3.1 30 Scheme 2.4.1 32 Scheme 2.4.2 33 Scheme 2.4.3 35 Scheme 2.4.4 36 Scheme 2.5.1 36 Scheme 2.6.1 37 Scheme 2.6.2 38 Scheme 2.6.3 39 Scheme 2.6.4 40 Scheme 2.6.5 40 xix Scheme 2.6.6 42 Scheme 2.6.7 43 Scheme 2.7.1 45 Scheme 2.7.2 46 Chapter 2 Appendices Appendix 2.1 Scheme A2.1.1 79 Scheme A2.1.2 79 Scheme A2.1.3 80 Scheme A2.1.4 80 Chapter 3 Scheme 3.1.1 169 Scheme 3.1.2 170 Scheme 3.2.1 172 Scheme 3.2.2 172 Scheme 3.2.3 173 Scheme 3.2.4 174 Scheme 3.3.1 175 Scheme 3.4.1 176 Scheme 3.5.1 177 Scheme 3.5.2 178 Scheme 3.5.3 178 Scheme 3.5.4 180 Scheme 3.5.5 180 Scheme 3.5.6 181 Scheme 3.6.1 182 Scheme 3.7.1 183 xx List of Tables Chapter 1 Table 1.1.1 Oxidative Kinetic Resolution of Secondary Alcohols 7 Table 1.2.1 Enantioselective Cyclization of Olefin-Appended Phenols 17 Chapter 2 Table 2.4.1 Esterification of Acid (139) with Heteroatom Nucleophiles 34 Chapter 3 Table 3.4.1 Attempts at the Pd(II)-catalyzed Oxidative Cyclization of Phenol 237 176 Notebook Cross-Reference Table NCR-1 Compounds Appearing in Chapter 2 260 Table NCR-2 Compounds Appearing in Chapter 3 262 xxi List of Abbreviations Å Angstrom [α]D specific rotation at wavelength of Na D-line Ac acetyl Acac acetylacetonate AIBN 2,2’-azobisisobutyronitrile Anal. Analysis app. apparent aq. aqueous Ar aryl atm atmosphere BBN borabicyclo[3.3.1]nonane Bn benzyl BQ benzoquinone br broad, broadened Bu butyl i-Bu isobutyl n-Bu n-butyl t-Bu tert-butyl Bz benzoyl c concentration for specific rotation measurements °C degrees Celsius xxii calc’d calculated cat. catalytic CDI carbonyldiimidazole comp complex conv conversion Cy cyclohexyl δ chemical shift d doublet, day(s) dt doublet of triplets dba dibenzylideneacetone DIBAL diisobutylaluminum hydride DHP dihydropyran DMAP 4-(N,N-dimethylamino)pyridine DMP Dess-Martin periodinane DMF N,N-dimethylformamide DMSO dimethylsulfoxide dppb 1,2-bis(diphenylphosphino)butane dppe 1,2-bis(diphenylphosphino)ethane dppp 1,2-bis(diphenylphosphino)propane dr diastereomeric ratio ee enantiomeric excess EI electrospray ionization elim. Elimination xxiii equiv equivalents er enantiomeric ratio esd ellipsoid Et ethyl FAB fast atom bombardment g gram GC gas chromatography [H] reduction h hour(s) HMDS hexamethyldisilazane or hexamethyldisilazide hν light HPLC high pressure liquid chromatography HRMS high resolution mass spectroscopy Hz hertz IR infrared J coupling constant kcal kilocalories L liter or neutral ligand LAH lithium aluminum hydride MMPP mono magnesium perphthalate M metal, molar m milli, multiplet, meter m/z mass to charge ratio xxiv µ micro Me methyl Mes mesityl MHz megahertz min minute(s) mol moles mp melting point MS molecular sieves Ms methanesulfonyl N normal nbd norbornadiene NBS N-bromosuccinimide NIS N-iodosuccinimide NMO N-methylmorpholine N-oxide NMR nuclear magnetic resonance NOE nuclear Overhauser effect nuc nucleophile [O] oxidation o ortho OKR oxidative kinetic resolution P para Ph phenyl PhH benzene xxv PhMe toluene pH hydrogen ion concentration in aqueous solution pKa acidity constant PIFA phenyliodine(III)bis(trifluoroacetate) ppm part(s) per million PPTS pyridinium p-toluenesulfonate i-Pr isopropyl py pyridine q quartet ref reference RF retention factor s singlet, selectivity factor sat. saturated sp (–)-sparteine stoich. stoichiometric Sub substrate t triplet td triplet of doublets TBAF tetrabutylammonium fluoride TBHP tert-butyl hydroperoxide TBS tert-butyldimethylsilyl TBSal tert-butyl salicimine TBDPS tert-butyldiphenylsilyl xxvi TEA triethylamine TES triethylsilyl Tf trifluoromethanesulfonyl TFA trifluoroacetic acid or trifluoroacetate THF tetrahydrofuran THP tetrahydropyran TLC thin layer chromatography TMEDA N,N,N’,N’-tetramethylethylenediamine TMPDA N,N,N’,N’-tetramethylpropylenediamine TMS trimethylsilyl Ts p-toluenesulfonyl TsOH p-toluenesulfonic acid UV ultraviolet v/v volume to volume w/v weight to volume X anionic ligand, halide 1 Chapter 1 – Introduction CHAPTER 1 1.1 An Introduction to Oxidative Kinetic Resolution 1.1.1 Introduction Enantiopure secondary alcohols are invaluable in organic synthesis as they are found in natural products and medicinal drugs. Furthermore, enantiopure secondary alcohols can also lead to carbon-carbon bond formation while transferring the chirality (e.g., allylic alkylation) to afford various types of complex products. One method to access enantioenriched secondary alcohols is via a kinetic resolution, which allows for the isolation of one enantioenriched alcohol from a racemic mixture via a chemical transformation, not the separation of both enantiomers.1 In an oxidative kinetic resolution of secondary alcohols, one enantiomer (e.g., (R)-1) reacts faster with the enantiopure catalyst, at a rate of kfast, to provide oxidized product 2, while the other enantiomer (e.g., (S)-1) reacts much more slowly (k slow) than its counterpart (Figure 1.1.1). Ideally, the reaction is terminated when all or most of the faster-reacting 2 Chapter 1 – Introduction enantiomer has been converted to product 2. The remaining enantioenriched alcohol ((S)-1) and ketone 2 can then be separated by standard techniques. In an efficient oxidative kinetic resolution, the selectivity factor (s), which is determined by measuring the relative rate (krel) of reaction of the two enantiomers (krel = kfast / kslow), will be high (s > 15). In practice, the selectivity factor is usually determined by measuring the total conversion of starting material to product and the enantiomeric excess of the recovered starting material.2 To achieve optimum selectivity, the chiral reagent or catalyst should maintain the same relative enantiomeric preference throughout the reaction; hence, the selectivity factor remains constant. The enantiomeric excess of the starting material will always increase with increasing conversion for any kinetic resolution with a selectivity factor greater than 1 (Figure 1.1.1). Thus, kinetic resolutions have the capacity to provide compounds with high enantioenrichment for even modestly selective processes at higher levels of conversion. Figure 1.1.1 Kinetic Resolution Overview. OH R1 OH R1 O kfast R2 R1 (R)-1 Chiral Catalyst OH kslow R2 2 R2 (±)-1 H3C R2 (S)-1 selectivity factor s = krel = OH R1 R2 (S)-1 kfast kslow = ln[(1-conv)(1-ee) ln[(1-conv)(1+ee) 3 Chapter 1 – Introduction 1.1.2 Nitroxyl Radicals in an Oxidative Kinetic Resolution of Secondary Alcohols The first approach toward a kinetic resolution via alcohol oxidation involved the catalytic use of a nitroxyl radical, which formed an active N-oxoammonium species (3) under the reaction conditions. Rychnovsky reported the oxidative kinetic resolution of secondary alcohol 4 using chiral nitroxyl radical 5 and sodium hypochlorite as the oxidizing agent (Scheme 1.1.1).3 Although modest selectivities were achieved (s = 1.5–7.1), this system represented the first example of a nonenzymatic catalytic enantioselective oxidation of secondary alcohols. Scheme 1.1.1 N-oxonnium 3 OH N O O (±)-4 NaOCl, KBr CH2Cl2/H2O, 0 °C, 30 min Cl OH 87% conversion 98% ee s = 7.1 5 6 N O 3 (+)-4 Even though improvements in enantioselectivity using this approach have been realized,4 this methodology has not been used in the context of total synthesis. 1.1.3 Transition Metals in Oxidative Kinetic Resolutions of Secondary Alcohols The other general approach to the oxidative kinetic resolution of secondary alcohols employs transition metal catalysis. The first report by Ohkubo et al.5 validated the catalytic use of a transition metal in an oxidative kinetic resolution. The reaction proceeded by transfer hydrogenation using a menthol-derived phosphine (7) ligand to 4 Chapter 1 – Introduction provide sec-phenethyl alcohol in 1.2% ee, and a selectivity factor (s) of 1.055 (Scheme 1.1.2). Since then, Noyori and Uemura have developed highly enantioselective variants of a ruthenium-catalyzed kinetic resolution of secondary alcohols. Noyori demonstrated the use of ruthenium-diamine catalyst 9 to resolve secondary alcohols with acetone as the hydrogen acceptor.6 Uemura later reported a similar system using a ruthenium- ferrocenyloxazoline complex (10).7 In both of these cases, a plethora of benzylic secondary alcohols were resolved to high enantiopurity with very high selectivity (s > 100). Furthermore, Ikariya has shown that iridium and rhodium are viable metal catalysts for the oxidative kinetic resolution of secondary alcohols. Using O2 as the stoichiometric oxidant and Noyori’s diamine ligand motif, Ikariya was able to access highly enantioenriched secondary benzylic alcohols with good selectivity factors (s > 10).8 Scheme 1.1.2 Ohkubo: PPh2 7 OH O OH RuCl2(PPh3)3 37% conv 1.221% ee s = 1.055 O (±)-4 6 (–)-4 8 180 °C, 5 h Noyori: Ts N Ru N H Ph OH Ph O OH 9 50% conv 92% ee s > 80 acetone, 28 °C, 26 h (±)-4 6 Uemura: (+)-4 O OH Fe Ph N PPh3 Ru Cl P Cl Ph2 O OH 47% conv 97% ee s = 183 10 (±)-4 NaOi-Pr, acetone 50 °C, 30 min 6 (+)-4 5 Chapter 1 – Introduction More recently, Xia initially reported an oxidative kinetic resolution of benzylic alcohols using a manganese-salen catalyst (11) and iodobenzene diacetate as the stoichiometric oxidant (Scheme 1.1.3).9 It was later reported by Xia that changes in solvent and catalyst allowed for better selectivities for some substrates.7b In addition, Toste has described a vanadium catalyst using chiral salicylaldimine ligand 13 for the asymmetric oxidation of α-hydroxy esters.10,11 High selectivities for an array of α hydroxy esters were realized, although less-activated alcohols, such as benzylic alcohols, reacted poorly when exposed to this system.12 Scheme 1.1.3 Xia: PF6– t-Bu OH N N Mn+ O O t-Bu t-Bu O t-Bu OH 52% conv 85% ee s = 23.7 11 Bu4NBr, PhI(OAc)2, H2O, 23 °C, 1 h (±)-4 6 (+)-4 t-Bu Toste: N t-Bu OEt (±)-12 OH 13 OH O OH t-Bu VO(Oi-Pr)3 O OH OEt O acetone, O2, 23 °C 14 OEt O 51% conv 99% ee s > 50 (–)-12 In addition, Sigman published a system using (–)-sparteine (17) as the chiral ligand with Pd(OAc)2 or PdCl2,13 and O2 as the stoichiometric oxidant (Scheme 1.1.4). This system was optimized to use either dichloroethane (DCE) or t-butanol (t-BuOH) as solvent to obtain modest selectivities (generally s = 5–15) for a wide range of secondary alcohols.14 Sigman has also shown that at lower catalyst loadings of (–)-sparteine (17), the rate-determining step is deprotonation of the alcohol. However, when 20 mol% of 6 Chapter 1 – Introduction (–)-sparteine is used in the optimized conditions (Scheme 1.1.4), the rate-determining step is β-hydride elimination.9c Since β -hydride elimination is directly involved in enantioselectivity, slowing this step enhances the selectivity. Scheme 1.1.4 Sigman: OH OH 5 mol% Pd[(–)-sparteine]Cl2 20 mol% (–)-sparteine DCE 65% conv 99% ee s = 15.9 O N N 65 °C, DCE or t-BuOH, O2, 20 h (±)-15 t-BuOH 61.5% conv 99% ee s = 21.9 16 (+)-15 (–)-sparteine (17) In general, the oxidation of secondary alcohols to ketones by palladium(II) most likely involves associative alcohol substitution at the palladium(II) center (18), followed by deprotonation of the resulting palladium alcohol complex (19) by base to form palladium alkoxide 20 (Figure 1.1.2). At this stage, β-hydride elimination (20→22) and subsequent dissociation from palladium provides product 23. Figure 1.1.2 Proposed Mechanism for Alcohol Oxidation by Palladium. R OH R L X Pd L L X X Pd L O H 18 X R L R X BH L Pd L O +X R 22 L H R R L O –X R Pd Pd L O 21 O L X L H R R 20 19 H Pd R R 23 1.1.4 A Pd(II)-catalyzed Oxidative Kinetic Resolution Developed by the Stoltz Laboratory In 2001, based on early work by Uemura,15 the Stoltz laboratory developed a palladium(II)-catalyzed oxidative kinetic resolution utilizing (–)-sparteine as the chiral ligand and O2 as the stoichiometric oxidant. 7 Chapter 1 – Introduction Since the initial development of the palladium(II)-catalyzed oxidative kinetic resolution of secondary alcohols using (–)-sparteine (17),16 several improvements and further optimization to the catalytic system were accomplished. The palladium(II)catalyzed oxidative kinetic resolutions can now be performed on a number of activated secondary alcohols to efficiently provide optically enriched secondary alcohols (Table 1.1.1). Table 1.1.1 Oxidative Kinetic Resolution of Secondary Alcohols. OH Ar Pd(nbd)Cl2a (–)-sparteine MS3Å OH Ar O N N Ar (–)-sparteine (17) Original b Rate Accelerated c Chloroform/O2 d Chloroform/Air e O2, PhMe 80 °C O2, PhMe, 60 °C Cs2CO3, t-BuOH O2, CHCl3, 23 °C Cs2CO3 Air, CHCl3, 23 °C Cs2CO3 96 h 67% conv 98% ee s = 12 9.5 h 67% conv 99.5% ee s = 15 48 h 63% conv 99.9% ee s = 27 24 h 62% conv 99.8% ee s = 25 40 h 69% conv 98% ee s = 16 12 h 62% conv 99% ee s = 21 24 h 58% conv 98% ee s = 28 16 h 60% conv 99.6% ee s = 28 120 h 70% conv 92% ee s = 6.6 12 h 65% conv 88% ee s = 7.5 48 h 63% conv 98.7% ee s = 18 44 h 65% conv 98.9% ee s = 16 OH MeO 24 OH 25 OH 26 a nbd = norbornadiene, s = selectivity factor, 500 mg, 3ÅMS/mmol substrate were used for all four sets of conditions. b 5 mol% palladium catalyst, 0.20 equiv (–)-sparteine (17), 0.10 M in PhMe. c 5 mol% palladium catalyst, 0.20 equiv (–)-sparteine (17), 0.50 equiv Cs2CO3, 1.5 equiv t-BuOH, 0.25 M in PhMe. d 5 mol% palladium catalyst, 0.12 equiv (–)-sparteine (17), 0.40 equiv Cs2CO3, 0.25 M in CHCl3. Reactions were run open to air through a short drying tube of Drierite. A model for selectivity in the palladium(II)-catalyzed oxidative kinetic resolution of secondary alcohols was developed by Dr. Raissa Trend, in collaboration with the Goddard laboratory, and is thoroughly discussed within her thesis.17 The key conclusions from Trend’s results are that (–)-sparteine is not behaving as a pseudo C 2 symmetric ligand; rather, it acts as a C 1 ligand allowing for selective displacement of a single 8 Chapter 1 – Introduction chloride from palladium. Furthermore, her results show that the displaced chloride ion, which has been calculated to be closely associated with palladium in an apical position under the square plane,18 affects selectivity by clashing with one of the enantiomers of the substrate bound to palladium (Figure 1.1.3). It is thought that this is the main interaction that inhibits β-hydride elimination of one of the enantiomers. Figure 1.1.3 Proposed β -Hydride Elimination Transition State for Each Enantiomer. ‡ ‡ RL RS N O Pd N N vs O H RS Cl– Pd H Cl– RL fast-reacting enantiomer N slow-reacting enantiomer To demonstrate the utility of this methodology, the Stoltz laboratory has completed the syntheses of (–)-amurensinine (27), (–)-aurantioclavine (28), (–)-lobeline (29), and (–)-sedamine (30) (Figure 1.1.4).19 Each synthesis relied upon a palladium(II)catalyzed oxidative kinetic resolution to establish a benzylic stereocenter in high enantioselectivity. Figure 1.1.4 Natural Products Synthesized via Palladium(II)-catalyzed OKR. OMe O O H N OH O OH OMe N N Me Me N Me N H (+)-amurensinine (27) (–)-aurantioclavine (28) (–)-lobeline (29) (–)-sedamine (30) The scope of secondary alcohols used in the palladium(II)-catalyzed oxidative kinetic resolution currently includes activated alcohols bearing benzylic, allylic, or cyclopropyl substituents. One class of exceptional substrates for the palladium(II)catalyzed oxidative kinetic resolution are 2-aryl cyclopentenols (Figure 1.1.5). Exposure 9 Chapter 1 – Introduction of these racemic alcohols to the original conditions (cf. Table 1.1.1) in the palladium(II)catalyzed oxidative kinetic resolution provides cyclopentenols 31–35 with excellent enantioselectivity and selectivity factors (s).20 Figure 1.1.5 Enantioenriched 2-Aryl Cyclopentenols using the Original Conditions. OH OH CF3 O OH OH OH O O 31 32 33 34 35 10 h 59.2% conv 99.0% ee s = 26 24 h 54.1% conv 99.0% ee s = 59 49 h 54% conv 87.3% ee s = 19 10 h 58.6% conv 99.0% ee s = 28 7h 57% conv 99.7% ee s = 44 These substrates led us to examine several natural products bearing an allylic secondary alcohol for the application of this methodology toward further total syntheses. One such molecule was bielschowskysin (36) (Figure 1.1.6). We envisioned using the palladium(II)-catalyzed oxidative kinetic resolution to access a key alcohol intermediate (37) in high enantioselectivity. Figure 1.1.6 Substrate for the Palladium(II)-catalyzed Ox. Kinetic Resolution. OH H H HO O O OAc OH O O H OH H bielschowskysin (36) O TBSO 37 CO2Me 10 Chapter 1 – Introduction 1.2 Introduction to Palladium(II)-Catalyzed Oxidative Heterocyclizations 1.2.1 Racemic and Enantioselective Pd(II)-catalyzed Oxidative Heterocyclizations In the well-known Wacker process, PdCl2 in the presence of O2 and a copper cocatalyst oxidizes ethylene to acetaldehyde.21 Although the Wacker process has been studied extensively, various aspects of its mechanism, such as the role of the chloride ion, are still disputed.22 For over several decades now, it has been known that using palladium(II) complexes along with a variety of oxidants can catalyze simple Wackertype cyclizations to provide racemic mixtures of products. Larock, Bäckvall, and others have demonstrated that palladium(II)-catalyzed oxidative heterocyclizations of olefinappended nucleophiles provided racemic products using O2 as the stoichiometric oxidant and DMSO as the solvent (Scheme 1.2.1).23 Scheme 1.2.1 Larock: 5 mol% Pd(dba)2 or Pd(OAc)2 KHCO2, DMSO/H2O, air 80% yield OH O 38 39 O 5 mol% Pd(OAc), O2 NaOAc, DMSO O OH O 91% yield 40 41 Bäckvall: OH 5 mol% Pd(OAc)2 O2, DMSO O 91% yield 42 43 10 mol% Pd(OAc)2 O2, DMSO NHTs 44 N Ts 93% yield 45 11 Chapter 1 – Introduction Furthermore, palladium(II)-catalyzed cyclizations have also been developed that use copper/O2 and benzoquinone as the stoichiometric oxidants. In an early example, Hosokawa showed that stoichiometric palladium(II) could be used to cyclize olefinappended phenols (Scheme 1.2.2), and that this methodology could be made catalytic in the presence of copper and O2.24 Other substrates, such as alcohols and amides, have been cyclized under similar conditions as demonstrated by Murahashi, Hegedus, and others.25 Scheme 1.2.2 PdCl2(PhCN)2 NaOMe, PhH or Hosokawa: OH 46 Murahashi: cat. Pd(OAc)2 Cu(OAc)2•H2O O2, MeOH/H2O O 47 10 mol% Pd(OAc)2 Cu(OAc)2•H2O, O2 Ph OH 48 Hegedus: MeOH/H2O (40% yield) single diastereomer Ph O 49 10 mol% PdCl2(MeCN)2 benzoquinone, LiCl NHMe 50 THF (89% yield) N Me 51 More recent examples by Yang and Gouverneur highlight recent advances in palladium(II)-catalyzed oxidative heterocyclizations. Yang has reported an oxidative cascade cyclization using N-acyl anilines (52) to afford spirocycles (53) in high diastereoselectivity and good yield (Scheme 1.2.3).26 In addition, Gouverneur has developed a palladium(II)-catalyzed oxidative cyclization of secondary alcohols (54) onto α,β-unsaturated olefins to provide 2,3-dihydro-4H-pyran-4-ones (55) in good yield.27 12 Chapter 1 – Introduction Scheme 1.2.3 Yang: O O 10 mol% Pd(OAc)2 40 mol% isoquinoline NH 12 examples 33-81% yields N O2, PhMe, 70 °C, 28 h 52 H 53 (81% yield) >24:1 diastereoselectivity Gouverneur: OH Ph O O2, DME, 4h, 50 °C 54 O 10 mol% PdCl2 10 mol% CuCl 10 mol% Na2HPO4 (79% yield) Ph O 8 examples 43-86% yields 55 Although all of these examples constitute significant advances in palladium(II)catalyzed oxidative cyclization reactions, the conditions vary for different substrate types, and many do not meet the ideal conditions for asymmetric reactions. For example, the use of additives and co-oxidants such as Cu(OAc)2 can create complex reaction conditions making optimization difficult. Furthermore, the use of highly coordinating solvents such as DMSO inhibits coordination of chiral ligands and thereby prevents the formation of any chiral palladium species necessary for an asymmetric process. Despite these obstacles, several examples of asymmetric palladium(II)-catalyzed oxidative heterocyclizations have been reported (Scheme 1.2.4). In 1981, Hosokawa described an asymmetric oxidative cyclization with a pinene-derived palladium(II) complex (57).28 More recently, Hayashi and Sasai have employed novel ligand frameworks (ligands 60 and 63, respectively) and benzoquinone (BQ) as an oxidant to obtain cyclized products with high enantioselectivity.29,30 In a proof-of-principle experiment by Bäckvall, a chiral benzoquinone generated in situ from arene 66 acted as a ligand in the enantioselective dialkoxylation of diene 65.31 13 Chapter 1 – Introduction Scheme 1.2.4 10 mol% Hosokawa: O O Pd O Pd O 57 Cu(OAc)2, O2, MeOH, 35 °C OH O 56 77% yield 18% ee H 58 Hayashi: 10 mol% Pd(TFA)2, BQ 72% yield 97% ee OH O i-Pr 59 O N 61 N i-Pr O i-pr boxax (60) Sasai: 20 mol% Pd(TFA)2, BQ OH OBz i-Pr 62 H H H i-Pr i-Pr N O N O 65% yield 95% ee OBz O 64 i-Pr 63 Bäckvall: Fe(II)(Pc): Iron(II) phthalocyanine 10 mol% Pd(OAc)2 20 mol% MeSO3H 3 mol% Fe(II)(Pc) EtO EtOH/CH2Cl2 (1:4), O2 Ph OH 65 OH N H H N i-Pr Ph i-Pr O O OEt 67 45% yield 54% ee N N N Fe N N OH N N N OH 66 These examples established the potential for enantioselective palladium(II)catalyzed oxidative heterocyclizations and dialkoxylations using benzoquinone oxidation systems. While these examples are limited in substrate scope, the examples by Sasai and Hayashi represent significant advances toward a general palladium(II)-catalyzed oxidative heterocyclization system. 14 Chapter 1 – Introduction 1.2.2 Possible Mechanisms for the Pd(II)-catalyzed Oxidative Heterocyclization Palladium(II)-catalyzed nucleophilic attack onto an olefin by a heteroatom can proceed by a variety of mechanisms. One key distinction to be made among them is whether attack occurs with the metal and nucleophile on the same face (syn, internal), or on opposite faces (anti, external) of the olefin. Another subtlety is whether π-allyl palladium(II) species are involved. This section will discuss some of the evidence that has been obtained for each mechanism. A commonly employed mechanism for palladium(II)-catalyzed oxidative heterocyclization initiates with activation of olefin 68 by palladium, followed by antinucleophilic attack (e.g., anti oxypalladation, Figure 1.2.1). The resulting palladium(II) alkyl intermediate (69) then undergoes β-hydride elimination to provide product 70. Figure 1.2.1 A Generic Heteroatom anti Palladation. Nuc H anti [Pd] Nuc 68 β-H elim. H [Pd] [Pd] 69 Nuc H Nuc [Pd] 70 A second possible mechanism is heteroatom syn palladation (e.g., syn oxypalladation), which initially involves a nucleophile bound directly to palladium (71, Figure 1.2.2). The bond formed between nucleophile and olefin occurs internally via a migratory insertion, as well as on the same olefin face as the newly formed alkylpalladium bond (72). At this stage, β-hydride elimination and ligand dissociation provides product 70. 15 Chapter 1 – Introduction Figure 1.2.2 A Generic Heteroatom syn Palladation. Nuc syn [Pd] Nuc H H [Pd] [Pd] 71 Nuc H β-H elim. Nuc [Pd] 72 70 For evidence of syn oxypalladation, Hayashi and coworkers described the reaction of a stereospecifically deuterium-labeled phenol substrate (73) under their enantioselective conditions.32 As shown in Scheme 1.2.5, after the oxypalladation step, the newly formed C-O bond, palladium, and deuterium are all syn to each other (74). Subsequent syn β-deuterium elimination (74→ 75) led to the initial product 76. Compound 77 and olefin isomer 78 are also formed in the reaction as a result of olefin isomerization of product 76. Nevertheless, all three products are consistent with syn oxypalladation. Interestingly, in the presence of excess chloride ion, anti oxypalladation predominated, which suggests that subtle changes in reaction conditions can have dramatic effects on the mechanism. Scheme 1.2.5 D 10 mol% Pd(MeCN)4(BF4)2 (S,S)-i-pr-boxax (63) BQ, MeOH, 40 °C OH 73 O O 76 16% 77 46% D O D 78 29% – [Pd]D D O 74 [Pd] reinsertion, β-H elim. β-D elim. [Pd] D O 75 Further evidence of syn oxypalladation by Wolfe and coworkers shows that both oxygen and nitrogen nucleophiles can operate under this mechanism.33 Another potential reaction pathway for palladium-olefin cyclizations entails allylic C–H activation by palladium(II) to form an intermediate π-allyl species that would 16 Chapter 1 – Introduction then undergo reductive elimination with a heteroatom nucleophile. Trost has shown that Pd(TFA)2 will form π-allyl complexes by C-H activation of olefins in acetone.34 Experimental evidence for this pathway was shown in an intermolecular oxidative acetylation reaction of deuterium-labeled cyclohexene 79 (Scheme 1.2.6).35 Bäckvall reported that the reaction yielded a 1:1 mixture of products 81 and 82. This supports the intermediacy of π-allyl complex 80, whereas anti oxypalladation would produce compound 81 and 83. Scheme 1.2.6 H D Pd(OAc)2, BQ H D H OAc OAc PdOAc D HOAc, 60 °C 79 D 80 D D D OAc D 81 anti oxypalladation D not observed D OAc 81 82 1:1 H D OAc 83 1.2.3 A Pd(II)-catalyzed Oxidative Heterocyclization Developed by the Stoltz Laboratory The Stoltz laboratory has developed an enantioselective palladium(II)-catalyzed oxidative phenol cyclization using palladium(II) catalysis with (–)-sparteine as the chiral ligand, to provide electron-rich dihydrobenzofurans in modest yield and good enantioselectivity (Table 1.2.1).17c Unfortunately, other substrates examined such as amines, anilines, and acids cyclize with only moderate enantioselectivity. 17 Chapter 1 – Introduction Table 1.2.1 Enantioselective Cyclization of Olefin-Appended Phenols.a product substrate entry MeO 1. time yieldb eec 24 h 60 h @ 55 °C 64% 57% 88% 90% 36 h 47% 83% 36 h 47% 86% 24 h 60% 20% MeO O OH 84 85 t-Bu t-Bu 2. OH O 86 87 3. OH O 88 89 O O 4. O OH 90 91 a 10 mol% (sp)Pd(TFA)2, 100 mol% (–)-sparteine (17), 2.0 equiv Ca(OH)2, 500 mg 3ÅMS/mmol substrate, 1 atm O2, PhMe (0.10 M), 80 °C. b Isolated yield. c Measured by GC. Accordingly, using a Pd(TFA)2/pyridine/O2 catalyst system, 3ÅMS in toluene at 80 °C, along with an exogenous base such as Na2CO3, a variety of heteroatom substrates cyclize to provide the desired products (92-96) in good yield (Figure 1.2.3). For some substrates, it was found that omitting Na2CO3 allowed for better conversion, probably due to variations of substrate pKa. Figure 1.2.3 Heterocycles Accessed via a Pd(II)-catalyzed Oxidative Heterocyclization. O O NTs O O 92 95% yielda 93 85% yielda 94 62% yieldc 95 88% yieldb Ts N 96 90% yieldb a mol% Pd(TFA)2, 20 mol% pyridine, 2 equiv Na2CO3, 3ÅMS, 1 atm O2, 0.10 M in PhMe, 80 °C. b 5 mol% Pd(TFA)2, 20 mol% pyridine, 3ÅMS, 1 atm O2, 0.10 M in PhMe, 80 °C. c 10 mol% Pd(TFA)2, 40 mol% pyridine, 3ÅMS, 1 atm O2, 0.10 M in PhMe, 80 °C. In addition, further studies found that the mechanism for the palladium(II)catalyzed oxidative heterocyclization changes between syn and anti heteroatom palladation depending on the substrate. Using deuterium-labeled substrates, it was found 18 Chapter 1 – Introduction that alcohol 97 reacted via syn oxypalladation to provide tetrahydrofurans 98 and 99 in a 4:1 ratio, whereas acid 100 cyclized via anti oxypalladation to provide γ-lactone 101 (Scheme 1.2.7).36 These changes in mechanism might be attributed to differences in the pKa of the two substrates (97 and 100); however, the exact reasons for the switch in mechanism has not been fully elucidated.37 Scheme 1.2.7 OH CO2Et CO2Et D PhMe, O2, 80 °C, 4.5 h O CO2H CO2Et CO2Et CO2Et CO2Et D 100 98 (30% yield) CO2Et CO2Et D 4:1 99 O 10 mol% (py)Pd(TFA)2 20 mol% pyridine Na2CO3 (2 equiv) PhMe, O2, 80 °C, 4.5 h O syn oxypalladation (91% yield) 97 D 10 mol% (py)Pd(TFA)2 30 mol% pyridine Na2CO3 (2 equiv) O CO2Et CO2Et H 101 SM anti oxypalladation (recovered 34% yield) To demonstrate the application of this methodology in natural product synthesis, the Stoltz laboratory has completed the formal total synthesis of both enantiomers of cephalotaxine (104), as well as the asymmetric total synthesis of (–)-drupacine (105). All three were derived from intermediate 103, which was accessed in excellent yield via a palladium(II)-catalyzed oxidative heterocyclization to form the spirocyclic amine moiety in intermediate 102 (Figure 1.2.4).38 19 Chapter 1 – Introduction Figure 1.2.4 Natural Products Synthesized via a Pd(II)-catalyzed Oxidative Heterocyclization. via Pd(II)-catalyzed Oxidative Amino Cyclization TsN 99% yield 102 OH N O O O O N O Br separable diastereomers (103) H HO O N O H HO OMe OMe (+) and (–)-Cephalotaxine (104) (–)-Drupacine (105) The Stoltz laboratory is always searching for biologically active natural products that could be efficiently synthesized using developed group methodologies. For one such molecule, phalarine (106), we envisioned using two palladium(II)-catalyzed oxidative heterocyclizations to form the dihydrofuran (red) and dihydropyrrole (blue) rings respectively (Figure 1.2.5). Figure 1.2.5 Structure of (–)-Phalarine. Me OMe N O NH N H via two palladium(II)-catalyzed oxidative heterocyclizations NMe2 Phalarine (106) This thesis will describe efforts toward an enantioselective total synthesis of bielschowskysin using a palladium(II)-catalyzed oxidative kinetic resolution to provide an enantioenriched early intermediate. Moreover, attempts toward the synthesis of phalarine using two palladium(II)-catalyzed oxidative heterocyclizations to construct the core of the natural product will also be discussed. Chapter 1 – Introduction 20 1.3 Notes and References 1 Ten Brink, G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Adv. Synth. Catal. 2002, 344, 355–369. 2 a) Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry; Eliel, E. L., Ed.; Wiley & Sons: New York, 1988; Vol. 18, pp. 249–330. b) Stahl, S. S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am. Chem. Soc. 2001, 123, 7188–7189. 3 Rychnovsky, S. D.; McLernon, T. L.; Rajapakse, J. J. Org. Chem. 1996, 61, 1194–1195. 4 a) Kashiwagi, Y.; Kurashima, F.; Kikuchi, C.; Anzai, J.; Osa, T.; Bobbitt, J. M. Tetrahedron Lett. 1999, 40, 6469–6472. b) Kuroboshi, M.; Yoshihisa, H.; Cortona, M. N.; Kawakami, Y.; Gao, Z.; Tanaka, H. Tetrahedron Lett. 2000, 41, 8131–8135. c) Kashiwagi, Y.; Yanagisawa, Y.; Kurashima, F.; Anzai, J.; Osa, T.; Bobbitt, J. M. Chem. Commun. 1996, 2745–2746. 5 Ohkubo, K.; Hirata, K.; Yoshinaga, K.; Okada, M. Chem. Lett. 1976, 183–184. 6 Hashiguchi, S.; Fujii, A.; Haack, K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew. Chem. Int. Ed. 1997, 36, 288–290. 7 a) Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai, M Organometallics 1999, 18, 2291–2293. b) Nishibayashi, Y.; Yamauchi, A.; Onodera, G.; Uemura, S. J. Org. Chem. 2003, 68, 5875–5880. 8 a) Arita, S.; Koike, T.; Kayaki, Y.; Ikariya, T. Angew. Chem. 2008, 120, 2481–2483. b) Wills, M. Angew. Chem. Int. Ed. 2008, 47, 4264–4267. Chapter 1 – Introduction 9 21 a) Sun, W.; Wang, H.; Xia, C. G.; Li, J.; Zhao, P. Angew. Chem. Int. Ed. 2003, 42, 1042–1044. b) Li, Z.; Tang, Z. H.; Hu, X. X.; Xia, C. G. Chem. Eur. J. 2005, 11, 1210–1216. 10 Radosevich, A. T.; Musich, C.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 1090–1091. 11 For a related vanadium system, see: a) Pawar, V. D.; Bettigeri, S.; Weng, S.-S., Kao, J.-Q.; Chen, C.-T. J. Am. Chem. Soc. 2006, 128, 6308–6309. b) Weng, S.-S.; Shen, M.-W.; Kao, J.-Q.; Munot, Y. S.; Chen, C.-T. Proc. Natl. Acad. Sic. U.S.A. 2006, 103, 3522–3527. c) Chen, C.-T.; Bettigeri, S.; Weng, S.-S.; Pawar, V. D.; Lin, Y.-H.; Liu, C.-Y.; Lee, W.-Z. J. Org. Chem. 2007, 72, 8175–8185. 12 Alcohols that cannot undergo two-point binding give poor selectivities. 13 Initially Sigman consistently used Pd(OAc)2; however, after publications from the Stoltz laboratory, Sigman switched to PdCl2 due to overall higher selectivities. 14 a) Mandal, S. K.; Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Org. Chem. 2003, 68, 4600–4603. b) Jensen, D. R.; Sigman, M. S. Org. Lett. 2003, 5, 63–65. c) Mueller, J. A.; Jensen, D. R.; Sigman, M. S. J. Am. Chem. Soc. 2002, 124, 8202–8203. 15 Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64, 6750–6755. 16 Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725–7726. 17 a) Trend, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 4482–4483. b) Trend, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 15957–15966. c) Trend, R. M. Concerning the Mechanism and Selectivity of Palladium(II)-catalyzed Aerobic Oxidation Reactions. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, 2006. Chapter 1 – Introduction 18 22 Nielson, R. J.; Keith, J. M.; Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc. 2004, 126, 7967–7974. 19 a) Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752–11753. b) Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C.; Ramtohul, Y. K.: Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745–13754. 20 Ebner, D. C. Development and Applications of the Palladium-catalyzed Enantioselective Oxidation of Secondary Alcohols. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, 2009. 21 a) Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, S.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80–88. b) Moiseev, I. I.; Vargaftik, M. N.; Syrkin, Ya. K. Dokl. Akad. Nauk. SSSR 1963, 153, 140. c) Henry, P. M. J. Am. Chem. Soc. 1964, 86, 32463250. d) Jira, R.; Sedlmeier, J.; Smidt, J. Ann. Chem. 1966 , 693, 99. e) Phillips, F. C. Am. Chem. J. 1984, 16, 255–277. 22 For instance, [Cl-] has large effects on the mechanism, see: a) Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. b) Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem. Soc. 1979, 101, 2411–2416. c) Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681–682. d) Gregor, N.; Zaw, K.; Henry, P. M. Organometallics, 1984, 3, 1251–1256. e) Hamed, O.; Henry P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745–7750. 23 For examples of phenol cyclizations, see: a) Larock, R. C.; Wei, L.; Hightower, T. Synlett 1998, 522–524. b) For examples of alcohol cyclizations, see, Rönn, M.; Bäckvall, J.-E.; Andersson, P. G. Tetrahedron Lett. 1995, 36, 7749–7752. c) For 23 Chapter 1 – Introduction examples of acid cyclizations, see: Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298–5300. d) For examples of tosylamide cyclizations, see: Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584–3585, and references therein. 24 Hosokawa, T.; Ohkata, H.; Moritani, I. Bull. Chem. Soc. Japan 1975, 48, 1533–1536. 25 a) For examples of racemic alcohol cyclizations that employ the copper/O2 system, see: Hosokawa, T.; Hirata, M.; Murahashi, S.-I.: Sonoda, A. Tetrahedron Lett. 1976, 21, 1821–1824. b) For examples of racemic systems that employ benzoquinone, see: Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800–5807. c) For oxidative carbon-carbon bond forming aryl/olefin cyclizations, see: Zhang, H.; Ferreira, E. M.; Stoltz B. M. Angew. Chem. Int. Ed. 2004, 43, 6144–6148. 26 Yip, K.-T.; Zhu, N.-Y.; Yang, D. Org. Lett. 2009, 11, 1911–1914. 27 Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91–94. 28 a) Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S. J. Am. Chem. Soc. 1981, 103, 2318–2323. b) Hosokawa, T.; Okuda, C.; Murahashi, S. J. Org. Chem. 1985, 50, 1282–1287. 29 a) Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997, 119, 5063–5064. b) Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071–5075. c) Uozumi, Y.; Kyota, H. Ogasawara, M; Hayashi, T. J. Org. Chem. 1999, 64, 1620–1625. 30 Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907–2908. Chapter 1 – Introduction 31 24 a) Thorarensen, A.; Palmgren, A.; Itami, K.; Bäckvall, J.-E. Tetrahedron Lett. 1997, 38, 8541–8544. b) Itami, K.; Palmgren, A.; Thorarensen, A.; Bäckvall, J.-E. J. Org. Chem. 1998, 63, 6466–6471. c) Cotton, H. K.; Verboom, R. C.; Johansson, L.; Plietker, B. J.; Bäckvall, J.-E. Organometallics 2002, 21, 3367–3375. 32 Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036–3037. 33 For systems containing oxygen nucleophiles, see: Hay, M. B.; Hardin, A. R.; Wolfe, J. P. J. Org. Chem. 2005, 70, 3099–3107. For systems containing nitrogen nucleophiles, see: a) Ney, J. E.; Wolfe, J. P. Angew. Chem. Int. Ed. 2004, 43, 3605–3608. b) Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644–8657. 34 Trost, B. M.; Metzner, P. J. J. Am. Chem. Soc. 1980, 102, 3572–3577. 35 Grennberg, H.; Simon, V.; Bäckvall, J.-E. Chem. Eur. J. 1998, 4, 1083–1089. 36 For further details, see: a) ref. 29. b) Ferreira, E. M. The Design and Development of Palladium-catalyzed Aerobic Oxidative Transformations. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, 2005. 37 It was also shown that anilines can react via syn or anti aminopalladation depending on the ligand used. In one case, use of a bisoxazoline ligand resulted in product formation via syn aminopalladation, while use of pyridine as the ligand led to a 1:1 product mixture resulting from both syn and anti aminopalladation. See ref. 33b for further details. 38 Liu, Q.; Ferreira, E. M.; Stoltz, B. M. J. Org. Chem. 2007, 72, 7352–7358. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 25 CHAPTER 2 Synthetic Efforts Toward Bielschowskysin Using a Palladium(II)-catalyzed Oxidative Kinetic Resolution 2.1 Introduction and Biosynthesis In 2003, several novel natural products were isolated from the Caribbean gorgonian octocoral Pseudopterogorgia kallos. The structure of one of these compounds, bielschowskysin (36), eluded characterization until an X-ray crystal structure was obtained approximately one year later.1 Bielschowskysin belongs to a sub-class of molecules called pseudopteranes, and is one of several structurally and biosynthetically related diterpenes (Figure 2.1.1).2 Furthermore, bielschowskysin has been identified as a potent inhibitor of EKVX lung cancer cells (GI50 = 10 nM). 26 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Figure 2.1.1 Bielschowskysin and Related Natural Products. O O H O OH H OH H H HO O OAc H O OH O O OH H O O H O O H H H H O O O H O OH O H H H O O O bielschowskysin verrillin ineleganolide scabrolide A 36 107 108 109 A characteristic feature of these molecules is a cis-fused [5,5] oxa-bicycle, as well as a dihydrofuran unit that is sometimes disguised as a 1,4 diketone moiety.3 Bielschowskysin is arguably the most structurally complex member of this group due to its polycyclic ring system bearing eleven stereocenters, one of which is a quaternary stereocenter contained in a tetrasubstituted cyclobutane ring that is also fused to a substituted oxocane ring, resulting in a highly strained cage-like structure.4 Although the biosynthetic pathway of bielschowskysin has not been confirmed, Trauner has hypothesized that bielschowskysin is obtained from bipinnatin J (110) via a stereo- and chemoselective epoxidation of the Δ7,8 olefin (110), followed by the addition of water furan 111, and subsequent [2+2] cycloaddition of intermediate 112 provides the cyclobutane core (113) (Scheme 2.1.1).5 Scheme 2.1.1 OH OH OH OH H HO 7 O 8 [O] O O O + H2O O O HO OH [2+2] O O O O O bipinnatin J (110) 111 112 O H OH O 113 Along with all of the molecules in Figure 2.1.1, bipinnatin J is also a member of the larger cembranoid class of natural products, which are biosynthesized by intramolecular SN1 attack of geranylgeranyldiphosphate (114) and quenching of the Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 27 resultant tertiary carbocation to form the cembrane core (115) (Scheme 2.1.2). The cembrane core can undergo various enzymatic oxidations and transformations to provide an array of natural products.6 Scheme 2.1.2 -OPP SN1 H PPO geranylgeranyl diphosphate (114) cembrane core 115 2.2 Outside Efforts Toward the Total Synthesis of Bielschowskysin Although there are no reported total syntheses of bielschowskysin, there are two reported partial syntheses of the cyclobutane core found in the natural product. First, Doroh and Sulikowski subject alcohol 116 to a [2+2] photocycloaddition providing cyclobutane 117 in 50% yield with a 3.6:1 diastereomeric ratio (Scheme 2.2.1).7 It is thought that this reaction occurs through an unobserved diradical intermediate 118, which then proceeds to form cyclobutane 117. The diastereoselectivity of this reaction is notable in consideration of the observed isomerization of alcohol 116 to isomer 119 under the reaction conditions. Additionally, possible σ-bond rotation of diradical intermediate 118 to its diasterotopic isomer 120, which could also be formed from allylic alcohol 119, could lead to the undesired diastereomer 121.8 28 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.2.1 OH H HO O O O O hν O O H Me2CO H O (50% yield) 3.6:1 dr 116 O 117 OH O OH hν O O O O O 116 O H HO O 119 O O H HO O O H H O O O H HO O 120 118 H H HO O O O O H H O H O O 117 O 121 A second approach, reported by Lear and coworkers, uses a similar method to form the core cyclobutane via photocylcoaddition of allene 123 (Scheme 2.2.2).9 The synthesis of allene 123 is accomplished in twelve steps beginning with commercially available L-malic acid (122). Treatment of allene 123 with UV light in a nonpolar cosolvent provides the desired exo-cyclobutene 124 in 70% yield. Scheme 2.2.2 H H TMSO OH TMSO O • 12 steps HO hν H hexane/CH2Cl2 23 °C, 12 h O OH O L-malic acid (122) O 123 O (70% yield) 6 H O 124 Although these partial syntheses provide access to the strained cyclobutane found in bielschowskysin, they do not address the formation of either the critical C(6) Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 29 quaternary stereocenter or the pendant oxocane ring. As such, a [2+2] cycloaddition to form the quaternary stereocenter on a larger system bearing these components would not be without significant challenges. While a well-organized transition state might be feasible via an enzymatic pathway, practical synthetic limitations encouraged us to envision forming bielschowskysin by other methods such as an aldol condensation or Michael addition. 2.3 Retrosynthesis: Use of a Cyclopropane to Access the Cyclobutane Core While planning an initial synthetic route to bielschowskysin (36), a suitable model system was designed to investigate the key formation of the cyclobutane core and the quaternary stereocenter. Hence, our first synthetic target was cyclobutane 125 (Figure 2.3.1). Unlike the previous partial syntheses, this model system includes the quaternary stereocenter found in the natural product. Figure 2.3.1 Model System for Studies Toward Bielshowskysin's Cyclobutane Core. OH H H HO O H O O OAc O OH H bielschowskysin (36) OH CO2Me H O O H O O O 125 Thus, we predicated our synthetic strategy upon the formation of cyclobutane 125 via a Lewis acid–mediated cyclopropane fragmentation of ketone 126, followed by a 1,4 Michael addition (Scheme 2.3.1). We envisioned cyclopropane 126 arising from αdiazo-β-ketoester 127 by a cyclopropanation reaction using either a copper or rhodium 30 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR catalyst. In turn, α-diazo-β-ketoester 127 can be obtained from allylic alcohol 128 via esterification and diazotization. The latter compound, alcohol 128, can be prepared via Suzuki coupling between iodide 129 and boronic acid 130. Moreover, we postulated that allylic alcohol 128 could lead to a suitable substrate for a palladium(II)-catalyzed oxidative kinetic resolution to provide a secondary alcohol in high enantioselectivity, thus, providing access to an enantioselective synthesis of bielschowskysin. Scheme 2.3.1 O OH CO2Me H O O H O O O CO2Me O H O cyclopropane O fragmentation/ Michael addition O cyclopropanation O O 125 O O O 126 127 O O O HO CO2Me esterification N2 dizaotization I CO2Me (HO)2B O CO2Me TBSO 128 Suzuki coupling 129 130 The proposed key step in our synthesis of cyclobutane 125 is a Lewis acid–mediated cyclopropane fragmentation resulting in an enolate and an enone. We envision that these species will react via a Michael addition to provide the cyclobutane moiety (Figure 2.3.2). Complexation of the Lewis acid to the β-ketoester in compound 126 will lead to weakening of the bridging σ-bond of the cyclopropane ring shown in intermediate 131. Lone pair donation by the furan will result in fragmentation to form a stabilized enolate 132. The latter bond cleavage is preferred for two reasons: first, fragmentation of the most strained bond will relieve ring strain and lower the overall energy of the molecule; second, the π * orbitals of the β-ketoester moiety have good overlap with the breaking C–C σ-bond, leading to favorable enolate generation. Following fragmentation, 1,4-addition produces cyclobutane 133, which can undergo 31 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR rapid tautomerization to provide charged species 134, followed by the addition of water to furnish dihydrofuran 125.10 Figure 2.3.2 Proposed Mechanism for the Formation of Cyclobutane 125. L.A. O L.A. O CO2Me O O Lewis acid H O O O L M O O L L 131 L.A. O O O tautomerization O O 133 1,4 addition M O L 132 O CO2Me H CO2Me O O O 126 H fragmentation H O O CO2Me H O H O O CO2Me O O 134 H2O OH CO2Me H O H O O O 125 2.4 Initial Synthetic Efforts The synthesis began with furan 135, 11 which underwent magnesium-halogen exchange using conditions developed by Knochel,12 followed by a sequential quench of trimethyl borate and 1 M HCl to furnish boronic acid 130 in 85% yield (Scheme 2.4.1). Coupling of enone 129 with boronic acid 130 under similar conditions reported by Johnson provided compound 136 in excellent yield.13,14 At this stage, cleavage of the TBS group under acidic conditions provided allylic alcohol 128 in 98% yield. Exposure of allylic alcohol 118 to diketene and a catalytic amount of 4-(N ,Ndimethylamino)pyridine (DMAP) afforded unstable β-ketoester 137. Unfortunately, immediate treatment of β-ketoester 137 with p-ABSA and Et3N did not yield the desired diazo product; instead, a complex mixture of byproducts was obtained. This mixture of byproducts is the likely result of a Michael addition by the β-ketoester moiety, as well as 32 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR subsequent deprotonation at C(α) followed by β-elimination of the carboxylate functionality. Scheme 2.4.1 O I 1. i-PrMgCl, -35 °C, 1h 2. B(OMe)3, –35 °C → 23 °C Br O CO2Me 3. 1 M HCl, 0 °C, THF TBSO (HO)2B 135 O CO2Me 129 O Ag2O, 8 mol% AsPh3 5 mol% PdCl2(PhCN)2 THF:H2O (500:1) TBSO 130 CO2Me O 136 (85% yield over 2 steps) O O AcCl O MeOH, 0 °C (98% yield) HO 128 CO2Me diketene 5 mol% DMAP α THF, 0 °C O (75% yield) O O CO2Me p-ABSA, Et3N MeCN, 23 °C O complex mixture 137 To circumvent this problem, we postulated that the diazotization of β-ketoester 137 should be examined under neutral conditions. Moreover, we realized that the previous step, the synthesis of β-ketoester 137, is accomplished in a neutral environment. These observations led us to consider 2-diazoacetoacetic acid as an amenable partner in a DCC coupling reaction with allylic alcohol 128.15 The synthesis of 2-diazoacetoacetic acid (139) was carried out from α diazobenzylacetoacetate (138)16 by facile hydrogenolysis of the benzyl group, which provided the desired product along with a minor amount of acetoacetic acid in >95% conversion and purity.17 To our delight, the planned DCC coupling reaction between 2diazoacetoacetic acid (139) and alcohol 128 occurred in a straightforward manner to furnish targeted enone 127 in 75% yield (Scheme 2.4.2). 33 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.4.2 O O O 10% Pd/C (7% w/w) H2 balloon BnO O O HO N2 THF, 40-60 min, 23 °C O N2 HO 138 (>95% conversion) 139 128 CO2Me O acid 139, DCC 10 mol% DMAP O CH2Cl2, 23 °C (75% yield) O CO2Me N2 O O 127 The generation and coupling of 2-diazoacetoacetic acid (139) with allylic alcohol 128 was crucial for the synthesis of enone 127, as these conditions minimized the risk of side reactions, and simplified the standard two-step procedure. With this more efficient route to enone 127, we next investigated the esterification of 2-diazoacetoacetic acid (139) with a number of heteroatom nucleophiles to test the generality of this reaction and compare it with the two-step standard method. Gratifyingly, esterification of 2-diazoacetoacetic acid occurs efficiently for a variety of alcohols (Table 2.4.1). Primary and secondary alcohols couple with acid 139 in good to excellent yields (entries 1-6). Allylic alcohols are also competent substrates, and lead to their respective α-diazo-β-ketoesters in good yields (entries 7-10).18 As shown in entry 11, phenols are also viable substrates in the coupling reaction. Furthermore, the coupling of acid 139 with phenethylamine (162) to produce the α-diazoβ-ketoamide 163 in 95% yield illustrates that amines are also tolerated under these conditions (entry 12).19 34 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Table 2.4.1 Esterification of 2-diazoacetoacetic acid (139) with Heteroatom Nucleophiles. Entry Substratea Product OH O Yieldb O 1 140 O2 N O 141 O2 N O OH 2 142 O 143 O 85 N2 O Me 3 8 OH 92 N2 Me 144 8 O O 145 80 147 77 149 81 N2 O 4d OH 146 O O N2 O OH 5d O O 148 N2 H 3 H H 6d H 3 H 150 H H 151 O H OH O 87 O N2 O OH 7 O O 152 153 82 N2 O O 154 8 OH O R 10 O OH 160 O O O 77 R=H 157 R = NO2 159 95 77 N2 O 11d N2 O R R=H 156 R = NO2 OH 158 9c,d 155 O O O 161 O 75 N2 O 12 NH2 162 N H O 163 95 N2 a Standard conditions: 0.50 mmol substrate, 2-diazoacetic acid (139, 2.2 equiv), DCC (2.0 equiv), DMAP (0.10 equiv), 3.30 mL CH2Cl2, 23 °C, 60–90 min. b Isolated yield. c 0.30 mmol substrate. d Reaction at 40 °C, 60–90 min. With our study of 2-diazoacetoacetic acid couplings complete, our attention returned to enone 1 2 7 , and we began to investigate its ability to undergo Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 35 cyclopropanation. We initiated our studies with Cu(TBSal)2 as the catalyst because it has proven to be a robust catalyst system for cyclopropanation in similar systems.20 Unfortunately, when enone 127 was treated with a variety of rhodium and copper catalysts, including Cu(TBSal)2, cyclopropane 126 was never observed (Scheme 2.4.3).21 In searching the literature, no examples of an α-diazo-β-ketoester undergoing cyclopropanation with an enone were found. Therefore, we hypothesized that the enone functionality contributed to a withdrawal of electron density from the olefin, and thus inhibited cyclopropanation. Scheme 2.4.3 O O O O N2 CO2Me PhMe, 110 °C, O O 2 mol% Cu(TBSal)2 or other Rh and Cu catalysts H O O O 127 CO2Me Cu(TBSal)2: NOT OBSERVED N O Cu O N O 126 Following these initial cyclopropanation studies, we elected to modify the synthesis by reducing the ketone functionality in compound 136 (Scheme 2.4.1). We hypothesized that this would increase the electron density and the corresponding nucleophilicity of the olefin to facilitate cyclopropanation. Furthermore, 1,2-reduction of the enone functionality in compound 136 would provide the necessary substrate (37) with which to explore the palladium(II)-catalyzed oxidative kinetic resolution. The synthesis of alcohol 37 is accomplished from enone 136 via a Luche reduction in high yield and excellent diastereoselectivity (Scheme 2.4.4).22 The observed diastereoselectivity in this reduction is attributed to the bulky siloxy moiety at C(4), that likely prevents the approach of the hydride species from the β-face.23 36 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.4.4 O OH CeCl3•7H2O NaBH4 O CO2Me TBSO MeOH;CH2Cl2, (1:1) –25 °C CO2Me TBSO (95% yield) 10:1 dr (syn:anti) 136 O 4 37 2.5 The Palladium(II)-catalyzed Oxidative Kinetic Resolution As stated previously, we envisioned using the palladium(II)-catalyzed oxidative kinetic resolution as a method to establish the absolute stereochemistry of the C(4) stereocenter that is present in alcohol 37. Thus, with allylic alcohol 37 in hand, we examined the palladium(II)-catalyzed oxidative kinetic resolution. To our delight, treatment of racemic alcohol 37 under the original conditions developed for the palladium(II)-catalyzed oxidative kinetic resolution furnished ketone 136 in 57% conversion, and more importantly, afforded enantioenriched alcohol 37 in ≥ 95% ee and high selectivity for the overall process (s = 23, Scheme 2.5.1).24 Scheme 2.5.1 OH OH 5 mol% Pd(nbd)Cl2 20 mol% (–)-sparteine O CO2Me O MS3Å, O2 (1 atm), PhMe, 80 °C, 24 h TBSO O CO2Me TBSO (57% conversion) single diastereomer CO2Me TBSO ≥ 95% ee (±)-37 O (4S)-136 (1R,4R)-37 s = 23 enantiomers (1S,4S)-37 CeCl3•7H2O, NaBH4 MeOH, -20 °C Furthermore, the opposite enantiomer of alcohol can be obtained by treating (4S)enone 136 under the previously optimized Luche conditions to provide (1S, 4S)-alcohol 37 (Scheme 2.5.1).25 Since the absolute configuration of bielschowskysin is unknown, accessing both enantiomers of alcohol 37 in this fashion is important as it provides a route to potentially synthesize either enantiomer of the natural product. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 37 2.6 Further Investigations into the Model System Given the success of the critical palladium(II)-catalyzed oxidative kinetic resolution, our efforts were now solely focused on the synthesis of intermediate 126 and subsequent investigation into the formation of cyclobutane 127 (Scheme 2.6.1). Scheme 2.6.1 O O H O CO2Me OH CO2Me H Lewis acid O H O O O O O O 126 125 Beginning with furan 37, acetate protection of the alcohol and subsequent cleavage of the silyl ether unveiled allylic alcohol 164 in 85% overall yield (Scheme 2.6.2). The latter compound underwent esterification with diketene and subsequent diazotization to furnish α-diazo-β-ketoester 165 in good overall yield. Although the synthesis of compound 165 could be accomplished by coupling of alcohol 37 with 2diazoacetoacetic acid (139), the traditional two-step procedure ultimately proceeded in overall higher yield in this case. Initially, attempts to form the cyclopropane ring using rhodium catalysts, such as Rh2(oct)4, did not provide any of the desired product. Furthermore, the use of various copper sources, such as copper bronze or Cu(acac)2, led only to trace amounts of the desired product. Gratifyingly, formation of the cyclopropane was accomplished using 2 mol% Cu(TBSal)2 in either refluxing toluene or heating in a microwave using 1,2-dichloroethane as solvent to provide cyclopropane 166 in 55% yield. In general, the microwave conditions furnished cleaner reactions and more consistent yields during the scale-up process. In obtaining cyclopropane 166, we verified Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 38 our hypothesis that the olefin in enone 136 was simply too electron deficient to undergo cyclopropanation. Scheme 2.6.2 O O OH CO2Me O TBSO OAc 1. Ac2O, 10 mol% DMAP CH2Cl2 1. 5 mol% DMAP, THF, 0 °C 37 CO2Me O 2. TBAF, THF, 0 °C (85% yield over 2 steps) HO 2. MsN3, Et3N, MeCN, 0 °C 164 OAc O O O (55% yield) 165 OAc 2 mol% Cu(TBSal)2 PhMe, 110 °C or 10 mol% Cu(TBSal)2 µwave, DCE, Δ N2 O CO2Me (65% yield over 2 steps) O CO2Me H O O O 166 Although the synthesis of cyclopropane 166 was a significant accomplishment, this intermediate still needed to be elaborated to ketone 126. Initially, it was thought that cyclopropane 166 would undergo acetate cleavage to provide alcohol 167, followed by Dess-Martin periodinane oxidation to arrive at ketone 126 (Scheme 2.6.3).26 Gratifyingly, when cyclopropane 166 was subjected to these conditions, the desired ketone (126) appeared to be obtained in high overall yield. We next investigated the Lewis acid–mediated cyclopropane fragmentation and subsequent Michael addition en route to cyclobutane 125. Initial screening with several lanthanide Lewis acids found that treatment of ketone 126 with La(OTf)3 in methanol at 55 °C provided one product (168) as a single diastereomer in a 55% yield (unoptimized). Unfortunately, we were unable to confirm the structure of compound 168 by NMR; thus, we chose to esterify compound 168 to yield compound 169 in 79% yield. This enabled us to grow crystals of compound 169 suitable for analysis by X-ray crystallography. To our dismay, the X-ray data showed the structure of an unexpected product, β-ketoester 168. 39 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.6.3 O OAc OH O H O K2CO3, MeOH, 0 °C O CO2Me H (80% yield) O O 166 I OAc AcO OAc O 1 4 O (55% yield) H O O 126 167 La(OTf)3 O O O p-BrBzCl, Et3N CO2Me O 168 O Br O O O CO2Me O (97% yield) OH MeOH, 55 °C 1-2 h O CH2Cl2, 23 °C O O O O CO2Me CH2Cl2, 0 °C → 23 °C O H O O O CO2Me O (70% yield) O 169 Br X-ray structure obtained Upon examination of the connectivity of β-ketoester 169, we noticed that the oxidation states of C(1) and C(4) were opposite to those of desired ketone 126. This is the likely result of an undesired trans-esterification reaction that occurs when cyclopropane 166 undergoes acetate cleavage (Scheme 2.6.4). Treatment of cyclopropane 166 with K2CO3 in methanol presumably provided alkoxide 170. This alkoxide could potentially undergo a trans-esterification reaction and protonation to form alcohol 171. Finally, treatment of alcohol 171 with Dess-Martin periodinane provided αcyclopropyl ketone 172, which was originally misassigned as ketone 126. 40 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.6.4 OAc O O O K2CO3 HA CO2Me O O workup esterification O 166 O trans- HA MeOH, 0 °C O O O O CO2Me O O CO2Me HA O 170 O O O O O O I OAc AcO OAc O 1 O 4 CO2Me O CH2Cl2, 23 °C HA HO O CO2Me HA O 171 172 To confirm this undesired rearrangement, we partially incorporated deuterium at C(1), allowing us to follow the chemical shifts of the protons on both C(1) and C(4) during the course of acetate removal (Scheme 2.6.5). As hypothesized, the C(1) proton of intermediate 166 underwent a downfield shift in the 1H NMR, while the C(4) proton exhibited a slight upfield shift. Furthermore, cyclopropyl proton HA exhibits a 0.50 ppm shift that we have attributed to conformational changes that result from transesterification.27 These results confirmed that the trans-lactonization reaction did in fact occur during acetate removal. Scheme 2.6.5 O O (D)H OAc 1 4 O HA CO2Me K2CO3 O (D)H MeOH, 0 °C O O O 166 Δδ for HA = 0.5 ppm 1 O 4 HO CO2Me HA 171 In an effort to circumvent the trans-lactonization reaction, we synthesized a variety of compounds similar to cyclopropane 166 that differed only in the hydroxyl protecting group at C(1) (Figure 2.6.2).28 We postulated that these protecting groups may be removed under conditions that suppress the formation of alcohol 171. Unfortunately, 41 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR all attempts to deprotect compounds 173–177 in Figure 2.7.2 led solely to undesired alcohol 171. This result led us to conclude that the undesired lactone (171) is likely the thermodynamic product.29 Figure 2.6.2 Various Cyclopropane Derivatives. OBOM 1 OMOM O CO2Me O H O OSEM O 173 OTBS O H O O CO2Me O O 174 O H O OMEM CO2Me O 175 O H O O CO2Me CO2Me H O O O 176 O O 177 Other interesting observations can be made from the Lewis acid–mediated fragmentation reaction of cyclopropyl ketone 172 to provide unexpected alcohol 168 (Scheme 2.6.3). Beginning with ketone 172 in Scheme 2.6.6, we believe that Lewis acidic activation weakens the cyclopropane ring to allow the furan ring to assist in fragmentation to form an enolate and extended oxocarbenium ion in intermediate 178, both of which are quenched respectively by the overall addition of methanol to provide ketone 179.30 Thus, fragmentation of the cyclopropane ring occurred as anticipated; however, the addition of methanol preserved the aromaticity in the furan ring rather than undergoing a 1,2-addition into the oxocarbenium ion. We hypothesized that the driving force for the observed chemoselectivity in the methanol addition is due to rearomatization. Furthermore, under these conditions, an additional molecule of methanol can add into ketone 179 from the less-hindered α-face to form a hemiketal at C(4), which in turn, can undergo trans-esterification to produce alcohol 168. Notably, formation of the hemiketal at C(4) can occur at any point in the reaction; however, transesterification to generate the fused lactone is not favorable until the cyclopropane ring undergoes fragmentation. Another possible reason for the trans-esterification in Scheme Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 42 2.6.6 is the increased steric interaction that the bridged lactone in compound 179 would sustain with the furan moiety, compared to the fused lactone in alcohol 168. Scheme 2.6.6 L.A. O O L.A. O O O O O O O O CO2Me O O + MeOH CO2Me 4 O 172 + MeOH CO2Me O 178 179 O O OH O O transO HO O O O CO2Me esterification O H O CO2Me O O 180 O O 168 To examine our hypothesis of trans-esterification, we subjected compound 171 to identical Lewis acidic conditions that resulted in the formation of alcohol 181 in 65% yield as a single diastereomer (Scheme 2.6.7). Alcohol 181 can undergo subsequent functionalization to provide compound 182, allowing for suitable X-ray analysis (Figure 2.6.3). We initially believed that the hemiketal in intermediate 180 might force the alcohol into a pseudo-axial position and promote trans-esterification. However, by forming alcohol 181 without the ability for ketalization, we have shown that transesterification is facile once the cyclopropane ring has fragmented, regardless of the C(4) oxidation state. 43 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.6.7 O O OH OH O O O p-BrBzCl, Et3N La(OTf)3 O 4 CO2Me MeOH, 55 °C 1-2 h HO 171 (65% yield) H O CO2Me O O O CH2Cl2, 0 °C → 23 °C (79% yield) H O O O CO2Me O O 181 Br 182 X-ray crystal obtained 2.7 Future Directions Since the formation of alcohol 171 could not be averted, we decided to evaluate an alternative synthetic strategy focusing on initial construction of a macrocyclic intermediate.31 By beginning with macrocycle 188 (Scheme 2.8.1), we can reinforce chemo- and diastereoselectivity later in the synthesis. We believe there are at least two possible routes that could provide the cyclobutane core and the substituted oxocane ring found in bielschowskysin. The first route relies on a Michael addition and subsequent aldol reaction to provide the cyclobutane core, while the second route employs a reduction of an intermediate cyclopropane ring followed by a similar aldol addition to arrive at the highly strained core.32 We believe that ester 183 in Scheme 2.7.1 would serve as an excellent starting point since the enantio- and diastereoselective syntheses of similar compounds has been disclosed previously. Conversion of ester 183 to furan 185 could be accomplished in Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 44 three transformations: LiAlH4 reduction of the ester to the primary alcohol, Dess-Martin periodinane oxidation, followed by Grignard addition of reagent 184 into the newly formed aldehyde. With furan 185 in hand, deoxygenation of the secondary alcohol followed by acidic hydrolysis of the ketal will provide aldehyde 186. At this stage, removal of the MEM protecting group, followed by formation of the α-diazoacetate moiety would provide intermediate 187. It is thought that exposure of compound 187 to SnCl2 would effect the key intramolecular Roskamp reaction to provide macrocycle 188.33 Once formed, treating macrocycle 188 with monomagnesium peroxyphthalate (MMPP),34 a mild oxidizing agent, would oxidize the furan to provide enedione 189. This compound is now ready to undergo critical, sequential enolate additions to furnish the cyclobutane core. Hence, treatment of enedione 189 with DBU would first deprotonate the β-ketoester moiety resulting in a 1,4 Michael addition to form lactone 190. It is thought that protonation of the resulting enolate from the Michael addition will occur from the less-hindered α-face to provide the desired diastereomer needed for the Aldol addition. Once lactone 190 has formed, another equivalent of DBU could again deprotonate the β-ketoester moiety to promote an aldol addition and subsequent hemiketalization to afford cyclobutane 191. 45 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR Scheme 2.7.1 OPMB O CO2Me OPMB 1. LiAlH4, THF 2. DMP, CH2Cl2 OH O 3. THF, Mg MEMO 183 O O 3. 1M HCl:THF 0 °C MEMO 184 O OPMB 1. NaH, CS2, MeI 2. AIBN, Bu3SnH MEMO O Br 185 H O O H 186 OPMB 1. ZnBr2, CH2Cl2 OPMB O 2. ClCOCNNHTs, Et3N, CH2Cl2 O CH2Cl2 N2 MMPP O O O O O O O 187 188 OPMB H DBU Michael addition O CH2Cl2 H O O OPMB SnCl2 HO O O O 190 189 OH PMBO O H DBU Aldol addition O O H O O O 191 A second approach, although not as rapid as above, utilizes our knowledge of the cyclopropane system to build the γ-lactone moiety and subsequently set the relative stereochemistry at C(2) by reduction of the cyclopropane ring. Starting with macrocycle 192 (Scheme 2.7.1), standard diazotization of the β-ketoester moiety followed by copper catalyzed cyclopropanation would afford cyclopropane 193. At this stage, removal of the TBS group followed by a Dess-Martin periodinane oxidation would provide ketone 194. Treating this product with La(OTf)3 and NaBH4 is expected to reduce the cyclopropane ring at C(2) as well as the C(7) ketone to provide alcohol 195 in high diastereoselectivity. We believe that the desired diastereoselectivity in the cyclopropane reduction is favored as a result of the observed selectivity that methanol showed in the model system in Scheme 2.6.6. Furthermore, with the macrocycle in place, hydride addition into the C(7) ketone should occur from the accessible α-face to provide the correct diastereomer. Protection of the alcohol in compound 195 as a MEM ether preserves the C(7)-oxygen’s 46 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR ability to direct. Hence, treating this compound with mCPBA should result in a regioand diastereoselective epoxidation of the furan to produce epoxide 196. At this stage, electron donation by the furan should be facile and lead to epoxide opening and the formation of oxocarbenium ion 197. This intermediate is in equilibrium with enol 198, which could undergo an aldol addition into the oxocarbenium ion followed by epimerization of the hemiketal to provide cyclobutane 199. Scheme 2.7.2 OPMB OPMB 1. p-ABSA, Et3N, MeCN O OTBS O O H 2. 2 mol% Cu(TBSal)2 µwave, 1,2-DCE, Δ O 194 O O 1. MEMCl, Et3N, CH2Cl2 OH 2. mCPBA, CH2Cl2 O H O O OMEM H OH PMBO O O OMEM aldol addition H O H OMEM and epimerization O 197 epoxide opening O OPMB H O OMEM 196 OPMB H O furan assisted O O 195 O O OPMB H O O 7 O O OPMB H H O O 193 NaBH4, Ln(OTf)3 O H 2. DMP, CH2Cl2 O O 192 H 2 1. TBAF, THF OTBS O O THF, –20 °C OPMB O OH 198 O O O 199 Both routes discussed above use similar macrocycles as key intermediates in the synthesis of compounds 191 and 199 respectively. The macrocycle is vital in both of these routes as it controls the diastereoselectivity at several stereocenters. Thus, future studies toward bielschowskysin should focus on the formation of either macrocycle 188 or macrocycle 192 prior to any investigations into the cyclobutane core. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 47 2.8 Concluding Remarks Although the cyclopropane route did not achieve its ultimate goal in synthesizing the cyclobutane ring, several successful aspects of our research can be extracted. Foremost, we have successfully implemented the palladium(II)-catalyzed oxidative kinetic resolution early in the synthesis to provide alcohol 37 in ≥95% ee and 43% yield. Moreover, this methodology could allow for rapid access to either enantiomer of allylic alcohol 37, an important intermediate in synthesizing advanced compounds within our synthetic efforts. Secondly, we have effectively developed a general method for obtaining α-diazo-β-ketoesters using 2-diazoacetoacetic acid (139). The latter reagent is readily generated, and has been synthesized on reasonable scale (ca. 5.0 mmol) in a straightforward manner from commercially available starting materials. The coupling of 2-diazoacetoacetic acid (139) using DCC under neutral conditions provided the desired products in high yields and tolerated a variety of alcohols. In addition, amines can be used as substrates for the amidation with 2-diazoacetoacetic acid, thus providing access to α-diazo-β-ketamides. Although our synthetic endeavors did not yield the cyclobutane core found in bielschowskysin, we did discover an important trans-esterification process that was later observed during synthetic efforts toward ineleganolide (108, Figure 2.1.1).35 Finally, an understanding of the reactivity of these molecules has been gained, thus allowing for efficient synthetic revisions and paving the way for further research. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 48 2.9 Experimental Procedures 2.9.1 Materials and Methods Unless otherwise stated, reactions were performed at ambient temperature (typically 20–22 ºC) in flame-dried glassware under an argon or nitrogen atmosphere using dry solvents. Solvents were dried by passage through an activated alumina column under argon. Et3N, iPr2NH, iPr2NEt, and pyridine were freshly distilled from CaH2. Trifluoroacetic acid (99%) was purchased from Aldrich. Tf2O was freshly distilled from P2O5. All other commercially obtained reagents were used as received. Reaction temperatures were controlled by an IKAmag temperature modulator. Thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, anisaldehyde, KMnO4, or CAM staining. ICN silica gel (particle size 0.032–0.063 mm) was used for flash chromatography. Optical rotations were measured with a Jasco P-1010 polarimeter at 589 nm. 1H and 13C NMR spectra were recorded on a Varian Mercury 300 (at 300 MHz and 75 MHz respectively), or a Varian Inova 500 (at 500 MHz and 125 MHz respectively) and are reported relative to solvent for 1H NMR (CHCl3 = 7.27 ppm, C6H6 = 7.16 ppm, CH2Cl2 = 5.30 ppm, DMSO = 2.51 ppm) and 13C NMR (CDCl3 = 77.0 ppm, C6D6 = 128.4 ppm). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicitiy, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, dt = doublet of triplets, td = triplet of doublets, dd = doublet of doublets, m = multiplet, comp. m = complex multiplet, app. = apparent, bs = broad singlet. IR spectra were recorded on a Perkin Elmer BX-11 FT-IR spectrometer and are reported in frequency of absorption (cm-1). High resolution mass 49 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR spectra were obtained from the California Institute of Technology Mass Spectral Facility. Crystallographic analyses were performed at the California Institute of Technology Beckman Institute X-Ray Crystallography Laboratory. Crystallographic data have been deposited at the CCDC, 12 Union Road, Cambridge CB2 1EZ, UK and copies can be obtained on request, free of charge, from the CCDC by quoting the publication citation and the deposition number (see Appendix 3 for deposition numbers). 2.9.2 Preparation of Compounds O I 1. i-PrMgCl, -35 °C, 1h 2. B(OMe)3, –35 °C → 23 °C Br O 135 CO2Me 3. 1 M HCl, 0 °C, THF TBSO (HO)2B O 130 CO2Me 129 Ag2O, 8 mol% AsPh3 5 mol% PdCl2(PhCN)2 THF:H2O (500:1) TBSO O O CO2Me 136 (85% yield over 2 steps) Enone 136. To a solution of furan 135 (609 mg, 2.78 mmol, 1.00 equiv) in THF (15 mL) at –35 °C, was added a 1.84 M solution (THF) of iPrMgCl (1.96 mL, 3.61 mmol, 1.30 equiv) to the reaction. The reaction stirred for 45 minutes and the temperature was maintained between -40 and -30 °C. At this stage, trimethylborate (1.24 mL, 11.1 mmol, 4.00 equiv) was added rapidly at -30 °C, and the reaction was allowed to warm to ambient temperature and stir overnight. The reaction was cooled to 0 °C, 1 M HCl was added, and the mixture stirred for 30 minutes. The reaction was diluted with EtOAc and H2O, and the layers were separated. The aqueous layer was then washed 2x with EtOAc. The organic layers were combined, and washed with saturated K2CO3 (aq.) until the aqueous layer was basic. The basic aqueous layer was then acidified using 1 M HCl, and then washed 5x with EtOAc. The latter batch of EtOAc was washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to afford boronic acid 130 (375 mg, Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 50 73%) as a light-brown solid. This compound was used directly in the following Suzuki coupling reaction. To a solution of vinyl iodide 129 (87.0 mg, 0.260 mmol, 1.00 equiv), boronic acid 130 (71.0 mg, 0.390 mmol, 1.50 equiv), Ag2O (180 mg, 0.770 mmol, 3.00 equiv), and Ph3As (8.00 mg, 0.0260 mmol, 0.100 equiv) in THF (1.30 mL) was added PdCl2(PhCN)2 (5.00 mg, 0.0130 mmol, 0.0500 equiv) and H2O (50.0 µL). The reaction was stirred until consumption of vinyl iodide 129 as indicated by TLC (ca. 1.5 h) and filtered through a pad of celite. The solvent was concentrated in vacuo, and the residue was purified by flash chromatography using 3:97→5:95 EtOAc:hexanes to afford furan 136 as a white solid (74 mg, 80%). RF 0.15 (90:10 hexanes:EtOAc, UV); 1H NMR (500 MHz, CDCl3) δ 7.74 (d, J = 2.7 Hz, 1H), 7.03 (s, 1H), 5.03 (m, 1H), 3.90 (s, 3H), 2.88 (dd, J = 5.9, 18.3 Hz, 1H), 2.42 (dd, J = 2.2, 18.6 Hz, 1H), 2.34 (s, 3H), 0.91 (s, 9H), 0.15 (s, 3H), 0.14 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 201.8, 160.1, 156.0, 147.4, 140.0, 133.7, 132.6, 116.1, 68.9, 51.8, 45.9, 25.8, 18.3, 11.5, -4.8; IR (film) 3133, 2949, 2928, 2891, 2857, 1721, 1703, 1594, 1509, 1448 cm-1; HRMS (FAB+) calc’d for [C18H26SiO5]+: m/z 350.1550, found 350.1542. O O O TBSO 136 CO2Me AcCl O MeOH, 0 °C (98% yield) HO CO2Me 128 Alcohol 128. To a solution of acetyl chloride (50.5 µL, 0.710 mmol, 5.00 equiv) in MeOH (570 µL) at 0 °C, was added enone 136 (52.5 mg, 0.150 mmol, 1.00 equiv) in one portion. Enone 136 dissolved slowly over 20–30 minutes at 0 °C, and once completely in solution, the reaction stirred for 45 minutes at 0 °C. The reaction was then diluted with Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 51 brine and EtOAc. These layers were separated, and the aqueous layer was washed 2x with EtOAc. The organic layers were combined, washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. This semi-solid was diluted with toluene, and then reconcentrated under vacuum (repeated 3x). Upon final concentration in vacuo, alcohol 128 was obtained as a white solid (35.3 mg, 99%). 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 2.9 Hz, 1H), 7.02 (s, 1H), 5.21 (br, 1H), 3.90 (s, 3H), 2.96 (dd, J = 6.1, 18.8 Hz, 1H), 2.71 (d, J = 5.40 Hz, 1H), 2.49 (dd, J = 2.2, 18.8 Hz, 1H), 2.34 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 201.8, 160.0, 154.9, 147.1, 139.9, 134.1, 132.4, 116.1, 68.3, 51.7, 45.2, 11.6; IR (film) 3447, 2920, 2850, 1716, 1506, 1440, 1405, 1295, 1167, 1102 cm-1; HRMS (FAB+) calc’d for [C12H13O5]+: m/z 237.0763, found 237.0763. O O O 10% Pd/C (7% w/w) H2 balloon BnO O HO N2 138 THF, 40-60 min, 23 °C (>95% conversion) N2 139 Acid 139. 10% Pd/C (17.5 mg, 7% w/w) was added to a solution of benzyl ester 138 (250 mg, 1.15 mmol, 1.00 equiv) in THF (11.5 mL) at 23 °C. The N2 atmosphere was evacuated and backfilled with H2 (balloon), this was repeated three additional times. The reaction was complete within 40–60 minutes as monitored by TLC (4:6 EtOAc:Hexanes). Once finished, the reaction mixture was passed through a short pad of celite (Et2O eluent), and the solvent was concentrated in vacuo to obtain 2-diazoacetoacetic acid (139) as a pale-yellow solid that was used directly in the esterification step. Compound 139 was ca. 95% pure by 1H NMR. Note: A pure (98%) sample of acid 139 was obtained by crystallization using Et2O/Heptane and cooling at -20 °C. 1H NMR (300 MHz, CDCl3) δ Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 52 2.46 (s, 3H); IR (film) 2932, 2150, 1722, 1601, 1302 cm-1; HRMS (EI+) calc’d for [C4H4N2O3]+: m/z 128.0222; found, 128.0227. O O HO CO2Me O CH2Cl2, 23 °C (75% yield) 128 O acid 139, DCC 10 mol% DMAP O CO2Me N2 O O 127 Enone 127. To a solution of alcohol 128 (71.0 mg, 0.300 mmol, 1.00 equiv), acid 139 (92.1 mg, 0.720 mmol, 2.40 equiv), and DMAP (3.67 mg, 0.0300 mmol, 0.100 equiv) in CH2Cl2 (2.00 mL) at 23 °C, was added DCC (206 mg, 1.00 mmol, 2.0 equiv) in one portion. After the addition of DCC, the reaction was heated to 40 °C for 90 minutes. The reaction was allowed to cool to ambient temperature, filtered through a plug of celite (Et2O eluent), and the resulting filtrate was partitioned between H2O and Et2O. The aqueous layer was extracted 2x with Et2O. The organic extracts were combined, washed once with H2O, and then once with brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The product was purified by flash chromatography using 25:75 EtOAc:Hexanes to afford compound 127 as a light-yellow solid (78 mg, 75% yield). 1H NMR (500 MHz, C6D6) δ 7.30 (s, 1H), 7.23 (s, 1H), 5.24 (m, 1H), 3.46 (s, 3H), 2.33 (dd, J = 6.6, 18.6 Hz, 1H), 2.24 (s, 3H), 2.18 (s, 3H), 1.90 (d, J = 18.6 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 199.3, 188.6, 160.8, 159.9, 149.1, 147.3, 141.4, 136.4, 132.7, 117.5, 71.2, 51.5, 42.0, 28.4, 11.8; IR (film) 2954, 2145, 1715, 1660, 1366, 1312, 1155, 1062; HRMS (FAB+) calc’d for [C16H14N2O7]+: m/z 346.0801; found, 346.0817. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR O O O DCC, RXH 10 mol% DMAP HO 53 O RX CH2Cl2, 23 °C, 60-90 min N2 N2 X = O, NH 139 General Procedure for the Esterification of Acid 139 (Table 2.4.1). To a solution of substrate (0.500 mmol, 1 equiv), acid 139 (1.20 mmol, 2.4 equiv), and DMAP (0.0500 mmol, 0.10 equiv) in CH2Cl2 (3.30 mL) at 23 °C, was added DCC (1.00 mmol, 2.0 equiv) in one portion. Note: For 1° alcohols, the reaction remained at 23 °C. However, for 2° alcohols, the reaction was heated to 40 °C after the addition of DCC. The reaction was monitored by TLC, and the reaction was complete in 60–90 minutes. The reaction was filtered through a plug of celite (Et2O eluent), and the resulting filtrate was partitioned between H2O and Et2O. The aqueous layer was extracted 2x with Et2O. The organic extracts were combined, washed with NaHCO3 (saturated), and then with brine. The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The products were purified by flash chromatography. O O O O2 N 141 N2 Substrate 141.36 See General Procedure for the Esterification of Acid 139 (92% yield). Product was purified by flash chromatography (20:80 EtOAc:Hexanes). RF = 0.40 (30:70 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 8.23 (d, J = 8.7 Hz, 2H), 7.53 (d, J = 8.7 Hz, 2H), 5.35 (s, 2H), 2.47 (s, 2H); IR (film) 2148, 1711, 1344 cm-1. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR O 54 O 143 O N2 Substrate 143. See General Procedure for the Esterification of Acid 139 (85% yield). Product was purified by flash chromatography (17:83 EtOAc:Hexanes). RF = 0.45 (30:70 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 7.32-7.27 (m, 2H), 7.23-7.16 (m, 2H), 4.27 (t, J = 6.3 Hz, 2H), 2.71 (t, J = 7.2 Hz, 2H), 2.47 (s, 3H), 2.08-2.01 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 190.0, 161.2, 140.6, 128.4, 128.2, 126.1, 64.6, 32.0, 30.0, 28.1; IR (film) 2141, 1716, 1660, 1314 cm-1; HRMS (EI+) calc'd for [C13H15N2O3]+: m / z 247.1083; found, 247.1089. O Me 8 O 145 O N2 Substrate 145. See General Procedure for the Esterification of Acid 139 (80% yield). Product was purified by flash chromatography (5:95 EtOAc:Hexanes). RF = 0.50 (20:80 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 4.24 (t, J = 6.6 Hz, 2H), 2.49 (s, 3H), 1.71-1.66 (m, 2H), 1.33-1.27 (m, 14H), 0.89 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 190.2, 161.5, 65.5, 31.8, 29.4, 29.4, 29.2, 29.1, 28.6, 28.2, 25.7, 22.6, 14.1; IR (film) 2927, 2856, 2138, 1721, 1663, 1313 cm-1; HRMS (EI+) calc'd for [C14H25N2O3]+: m/z 269.1865; found, 269.1864. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR O 55 O 147 O N2 Substrate 147. See General Procedure for the Esterification of Acid 139 (77% yield). Product was purified by flash chromatography (10:90 EtOAc:Hexanes). All spectroscopic data is identical to that reported by Doyle.37 O O O 149 N2 Substrate 149. See General Procedure for the Esterification of Acid 139 (81% yield). Product was purified by flash chromatography (10:90 EtOAc:Hexanes). RF = 0.20 (10:90 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 7.90-7.83 (m, 4H), 7.55-7.50 (m, 3H), 6.21 (q, J = 6.6 Hz, 1H), 2.49 (s, 3H), 1.72 (d, J = 6.6 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 190.0, 160.7, 138.0, 133.1, 133.0, 128.6, 128.0, 127.6, 126.4, 126.3, 125.2, 123.6, 73.8, 28.2, 22.1; IR (film) 2140, 1715, 1658, 1305 cm-1; HRMS (FAB+) calc'd for [C16H15N2O3]+: m/z 283.1083; found, 283.1079. H 3 H H 151 O H O O N2 Substrate 151. See General Procedure for the Esterification of Acid 139 (87% yield). Product was purified by flash chromatography (5:95 EtOAc:Hexanes). 1H NMR (CDCl3) is identical to that reported by Doyle.38 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR O 56 O O 153 N2 Substrate 153. See General Procedure for the Esterification of Acid 139 (82% yield). Product was purified by flash chromatography (15:85 EtOAc:Hexanes). RF = 0.50 (20:80 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 7.44-7.28 (m, 5H), 6.70 (d, J = 15.6 Hz, 1H), 6.31 (dt, J = 6.6, 15.6 Hz, 1H), 4.90 (dd, J = 1.5, 6.6 Hz, 2H), 2.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 190.0, 161.1, 135.7, 135.3, 128.6, 128.3, 126.6, 122.2, 65.8, 28.2; IR (film) 2140, 1716, 1659, 1316 cm-1; HRMS (EI+) calc'd for [C13H12N2O3]+: m/z 244.0848; found, 244.0839. O O 155 O N2 Substrate 155. See General Procedure for the Esterification of Acid 139 (77% yield). Product was purified by flash chromatography (10:90 EtOAc:Hexanes). RF = 0.50 (20:80 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 5.37 (dt, J = 1.2, 3.6 Hz, 1H), 5.10-5.04 (m, 1H), 4.75 (d, J = 7.2 Hz, 2H), 2.49 (s, 3H), 2.13-2.05 (m, 4H), 1.74 (s, 3H), 1.68 (s, 3H), 1.61 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 190.1, 161.4, 143.4, 131.9, 123.5, 117.6, 62.1, 39.4, 28.1, 26.1, 25.6, 17.6, 16.4; IR (film) 2138, 1717, 1662, 1309 cm-1; HRMS (FAB+) calc'd for [C14H21N2O3]+, m/z 265.1552; found, 265.1548. O O O 157 O N2 Substrate 157.39 See General Procedure for the Esterification of Acid 139 (95% yield). Product was purified by flash chromatography (15:85 EtOAc:Hexanes). RF = 0.40 (30:70 57 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 7.76-7.73 (m, 2H), 7.68 (d, J = 2.7 Hz, 1H), 7.42-7.40 (m, 2H), 6.05 (dt, J = 2.4, 6.6 Hz, 1H), 3.10 (dd, J = 6.6, 18.6 Hz, 1H), 2.66 (dd, J = 1.8, 18.6 Hz, 1H), 2.50 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 202.0, 189.6, 160.9, 150.8, 146.3, 129.7, 129.6, 128.5, 127.6, 70.7, 42.4, 28.3; IR (film) 2144, 1716, 1654, 1313 cm-1; HRMS (FAB+) calc'd for [C15H13N2O4]+: m / z 285.0875; found, 285.0869. O I O O2N B O TBSO 129 1. Ag2O, 10 mol% AsPh3, 5.8 mol% PdCl2(PhCN)2, THF:H2O (19:1), 23 °C O O2N 2. AcCl, MeOH, 0 °C OH 158 Hydroxy Enone 158. A flask containing 4-(tert-butyldimethylsilyloxy)-2-iodocyclopent2-enone40 (400 mg, 1.60 mmol, 1.40 equiv) was charged with p-nitrophenyl pinacolato borate (388 mg, 1.15 mmol, 1.00 equiv),41 silver(I) oxide (800 mg, 3.45 mmol, 3.00 equiv), and Ph3As (35.2 mg, 0.120 mmol, 0.100 equiv) at 23 °C. THF (5.5 mL) and H2O (290 µL) were added, followed by addition of PdCl2(PhCN)2 (22.1 mg, 0.0580 mmol). The reaction mixture was stirred for 15 minutes at 23 °C, at which point TLC (5:95 EtOAc:Hexanes) indicated the reaction was complete. The reaction was passed through a pad of celite (EtOAc eluent), and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (7:93 EtOAc:Hexanes) to afford the Suzuki product as an oil (405 mg, 95% yield). This product (125 mg, 0.370 mmol, 1.00 equiv) was then added to a solution of AcCl (130 µL, 1.90 mmol, 5.10 equiv) in MeOH (7.5 mL) at 0 °C. The reaction was allowed to stir for 20 minutes, upon which TLC (40:60 EtOAc:Hexanes) showed consumption of the Suzuki product. The reaction was diluted with brine and EtOAc. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 58 The layers were separated, and the aqueous layer was washed 2x with EtOAc. The organic layers were combined, washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. TBSOH was removed azeotropically with toluene to afford alcohol 158 (80 mg, 99% yield). RF = 0.20 (50:50 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 8.25-8.20 (m, 2H), 7.91-7.87 (m, 2H), 7.82 (d, J = 2.4 Hz, 1H), 5.15 (m, 1H), 3.05 (dd, J = 6.6, 18.9 Hz, 1H), 2.60 (dd, J = 2.1, 18.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 203.2, 159.3, 147.8, 142.1, 136.7, 128.4, 123.7, 67.7, 45.7; IR (film) 3415, 1711, 1516, 1348 cm-1; HRMS (EI+): calc’d for [C11H9NO4]+: m/z 219.0532; found, 219.0506. O2N O O O 159 O N2 Substrate 159. See General Procedure for the Esterification of Acid 139 (77% yield). Product was purified by flash chromatography (50:50 EtOAc:Hexanes). RF = 0.30 (30:70 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3): δ 8.28 (m, 2H), 7.97-7.93 (m, 2H), 7.87 (d, J = 2.7 Hz, 1H), 6.09 (dt, J = 2.7, 6.6 Hz, 1H), 3.18 (dd, J = 6.6, 18.9 Hz, 1H), 2.70 (dd, J = 2.1, 18.9 Hz, 1H), 2.51 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 201.0, 189.4, 160.9, 153.8, 148.3, 144.4, 135.9, 128.6, 124.0, 70.4, 42.3, 28.3; IR (film) 2145, 1717, 1519, 1350, 1317 cm-1; HRMS (EI+) calc'd for [C15H11N3O6]+: m/z 329.0648; found, 329.0647. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR O O 59 O 161 O N2 Substrate 161. See General Procedure for the Esterification of Acid 139 (75% yield). Product was purified by flash chromatography (15:85 EtOAc:Hexanes). RF = 0.20 (20:80 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 7.28-7.23 (m, 2H), 7.13-7.08 (m, 2H), 4.00 (s, 3H), 2.71 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 189.9, 160.4, 157.6, 143.0, 122.3, 114.5, 55.6, 28.3; IR (film) 2142, 1732, 1507, 1324, 1191 cm-1; HRMS (FAB+) calc'd for [C11H11N2O4]+: m/z 235.0179; found, 235.0174. O N H O 163 N2 Substrate 163. See General Procedure for the Esterification of Acid 139 (95% yield). Product was purified by flash chromatography (40:60 EtOAc:Hexanes). RF = 0.25 (40:60 EtOAc:Hexanes); 1H NMR (300 MHz, CDCl3) δ 8.21 (br, 1H), 7.32-7.19 (m, 5H), 3.60 (q, J = 6.9 Hz, 2H), 2.84 (t, J = 7.4 Hz, 2H), 2.29 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 189.8, 160.5, 138.9, 129.0, 128.8, 126.8, 41.4, 36.1, 26.9; IR (film) 3309, 2124, 1667, 1538, 1312 cm-1; HRMS (EI+) calc'd for [C12H13N3O2]+: m/z 231.1008; found, 231.1007. O OH CeCl3•7H2O NaBH4 O TBSO 136 CO2Me MeOH;CH2Cl2, (1:1) –25 °C (95% yield) 10:1 dr (syn:anti) O CO2Me TBSO 37 Alcohol 37. To a solution of furan 136 (100 mg, 0.290 mmol, 1.00 equiv) and CeCl3•7H2O (430 mg, 1.10 mmol, 4.00 equiv) in MeOH:CH2Cl2 (4.90 mL, 1:1) at -25 °C, was added sodium borohydride (43.0 mg, 1.10 mmol, 4.00 equiv) portionwise while Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 60 maintaining the reaction between -25 and -20 °C. Upon consumption of the ketone as visualized by TLC (ca. 30 min.), the reaction was diluted with EtOAc and H2O. The solution was allowed to warm to ambient temperature and the layers were separated. The aqueous layer was extracted 3x with EtOAc, and the organic layers were combined and washed with brine. The EtOAc layer was dried with Na2SO4, filtered, and concentrated in vacuo to provide allylic alcohol 137 as a yellow oil (96 mg, 95%). RF = 0.20 (20:80 EtOAc:hexanes, UV); 1H NMR (500 MHz, CDCl3) δ 6.58 (s, 1H), 6.39 (s, 1H), 4.84 (m, 1H), 4.79 (m, 1H), 3.91 (s, 3H), 2.76 (dt, J = 6.9, 14.2 Hz, 1H), 2.36 (s, 3H), 1.98 (d, J = 9.3 Hz, 1H), 1.77 (d, J = 14.2 Hz, 1H), 0.92 (s, 9H); 13C NMR (75 MHz, CDCl3) δ 160.0, 151.7, 139.5, 136.2, 133.0, 132.6, 113.7, 74.8, 74.2, 51.5, 44.7, 25.8, 18.1, 11.6, -4.6, 4.7; IR (film) 3420, 2954, 2930, 2857, 1711, 1440, 1298, 1101 cm-1; HRMS (FAB+) calc'd for [C18H27O5Si]+: m/z 351.1628; found 351.1632. OH O CO2Me O MS3Å, O2 (1 atm), PhMe, 80 °C, 24 h TBSO OH 5 mol% Pd(nbd)Cl2 20 mol% (–)-sparteine CO2Me TBSO ≥ 95% ee (±)-37 (57% conversion) (1R,4R)-37 s ≈ 23 (1R,4R)-Alcohol 37. A 10 mL Schlenk tube equipped with a magnetic stir bar was charged with powdered molecular sieves (3ÅMS, 150 mg) and flame-dried under vacuum. After cooling under dry N2, Pd(nbd)Cl2 (0.380 mg, 1.42 µmol, 0.0500 equiv) was added, followed by toluene (285 µL). To this yellow suspension was added (–)sparteine (1.33 mg, 5.67 µmol, 0.200 equiv), and the top of the Schlenk tube was then fitted with an O2 balloon. The reaction was purged under vacuum and replaced with O2, and this process was repeated 4x's. The light yellow suspension was stirred at ambient Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 61 temperature for 10 minutes, then heated to 80 °C for an additional 10 minutes. The reaction mixture darkened to an orange suspension. Upon completion of the 10 minutes, racemic alcohol 37 (10.0 mg, 28.4 µmol, 1.00 equiv, in 100µL of PhMe) was added to the reaction mixture. The suspension was then heated to 80 °C for 24 hours. The reaction was allowed to cool to ambient temperature, and was then filtered through a small pad of celite using toluene as eluent. The filtrate was concentrated in vacuo, and the 1H NMR of this material indicated a 43% yield of (1R,4R)-alcohol 37 (4.3 mg, 43% yield, 95% ee). [α]D24.98 +26.4 (c = 0.15, EtOAc).42 OH O TBSO 37 CO2Me OAc 1. Ac2O, 10 mol% DMAP CH2Cl2 O 2. TBAF, THF, 0 °C (85% yield over 2 steps) HO CO2Me 164 Allylic Alcohol 164. To a solution of alcohol 37 (96.0 mg, 0.270 mmol, 1.00 equiv) in pyridine (2.70 mL, 0.100 M) was added acetic anhydride (0.270 mL, 2.50 mmol, 9.00 equiv) and DMAP (3.30 mg, 0.0270, 0.100 equiv) at ambient temperature. The reaction was stirred until consumption of allylic alcohol 37 as monitored by TLC (ca. 30 min). The solution was cooled to 0 °C and diluted with EtOAc:brine (1:1). The aqueous solution was extracted 2x with EtOAc. The combined organic layer was successively washed with sat. CuSO4 (aq.), H2O, sat. NaHCO3 (aq.), and brine. The organic layer was then dried with Na2SO4, filtered, and concentrated in vacuo to yield an allylic acetate (101 mg, 95%). 1H NMR (300 MHz, CDCl3) δ 6.49 (dd, J = 0.9, 2.1 Hz, 1H), 6.26 (s, 1H), 5.85 (dd, J = 4.2, 7.5 Hz, 1H), 4.84 (m, 1H), 3.90 (s, 3H), 2.96 (dt, J = 7.5, 14.4 Hz, 1H), 2.33 (s, 3H), 2.10 (s, 3H), 1.73 (m, 1H), 0.91 (s, 9H), 0.11 (s, 3H), 0.11 (s, 3H). Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 62 A solution of TBAF (0.290 mL of 1M solution in THF, 0.289 mmol, 1.20 equiv) was added to the crude silyl ether (95 mg, 0.241 mmol, 1.00 equiv) in THF (4.8 mL) at 0 °C and under N2. The reaction was allowed to warm to ambient temperature and monitored by TLC. Once complete, the reaction was diluted with H2O, and the reaction was extracted 3x with EtOAc. The combined organic extracts were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The crude solid was purified by flash chromatography (50:50, EtOAc:hexanes) to provide allylic alcohol 164 as a white solid (64 mg, 85% from alcohol 37).: RF 0.2 (40:60, EtOAc:hexanes, UV); 1H NMR (500 MHz, CDCl3) δ 6.60 (d, J = 2.4 Hz, 1H), 6.29 (s, 1H), 5.88 (dd, J = 2.9, 7.3 Hz, 1H), 4.83 (m, 1H), 3.88 (s, ,3H), 2.88 (app dt, J = 14.7, 7.1, 1H), 2.32 (s, 3H), 2.07 (s, 3H), 1.81 (app dt, J = 12.2, 2.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 170.8, 160.0, 150.6, 140.1, 134.6, 133.6, 132.6, 113.8, 75.7, 74.4, 51.7, 41.5, 21.3, 11.7; IR (film) 3424, 2953, 1712, 1598, 1511, 1440, 1374, 1297, 1240, 1197, 1104, 1035 cm-1; HRMS (EI+) calc’d for [C14H16O6]+: m/z 280.2804, found 280.2800. O O OAc OAc 1. 5 mol% DMAP THF, 0 °C O HO 164 CO2Me 2. MsN3, Et3N MeCN, 0 °C (65% yield) O O CO2Me N2 O O 165 Ester 165. A solution of allylic alcohol 164 (15.0 mg, 0.0540 mmol, 1.00 equiv) and diketene (8.00 µL, 0.110 mmol, 2.00 equiv) in THF (1.10 mL) was cooled to 0 °C, and DMAP (0.350 mg, 0.00270 mmol, 0.0500 equiv) was added. The reaction was stirred at 0 °C for 10 minutes, and was then allowed to warm to ambient temperature. Once Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 63 complete by TLC (ca. 30 min), the reaction was concentrated in vacuo and carried on directly. 1H NMR (300 MHz, CDCl3) δ 6.59 (d, J = 1.8 Hz, 1H), 6.34 (s, 1H), 5.99 (dd, J = 2.7, 7.2 Hz, 1H), 5.73 (m, 1H), 3.90 (s, 3H), 3.48 (s, 2H), 3.00 (dt, J = 7.8, 15.6 Hz, 1H), 2.34 (s, 3H), 2.10 (s, 3H), 1.94 (dt, J = 7.8, 15.6 Hz, 1H). The crude β-ketoester (380 mg, 1.0 mmol, 1.0 equiv) was dissolved in MeCN (10.4 mL), and MsN3 (630 mg, 5.20 mmol, 5.00 equiv) followed by Et3N (0.870 mL, 6.20 mmol, 6.00 equiv) was added to the reaction. The resulting solution was stirred at ambient temperature until complete by TLC (ca. 6 h). The reaction was concentrated in vacuo, and the resulting crude oil was purified by silica gel chromatography (80:20→75:25, hexanes:EtOAc) to yield ester 165 as a light-yellow solid (338 mg, 65% average). 1H NMR (500 MHz, CDCl3) δ 6.60 (d, J = 2.2 Hz, 1H), 6.30 (s, 1H), 6.19 (m, 1H), 6.07 (m, 1H), 3.88 (s, 3H), 2.47 (s, 3H), 2.44 (m, 2H), 2.33 (s, 3H), 2.08 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 190.0, 170.8, 161.2, 159.8, 149.9, 140.5, 136.2, 132.5, 130.5, 114.7, 79.0, 76.2, 51.8, 39.1, 28.4, 21.2, 11.7; IR (film) 2142, 1713, 1657, 1295, 1237 cm-1; HRMS (EI+) calc’d for [C18H18N2O8]+: m/z 390.1063, found 390.1061. OAc O O CO2Me 10 mol% Cu(TBSal)2 µwave, DCE, Δ N2 O (55% yield) O 165 OAc 2 mol% Cu(TBSal)2 PhMe, 110 °C or O CO2Me H O O O 166 Cyclopropane 166. µwave conditions: The microwave is pre-warmed by undergoing an actual run with just DCE in the reaction tube. A solution of compound 165 (45.0 mg, 0.120 mmol, 1.00 equiv) and Cu(TBSal)2 (5.00 mg, 0.0120 mmol, 0.100 equiv) in DCE (3.00 mL) was heated for 20 min at 105 °C in the microwave. The following parameters Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 64 for the µwave are as follows: Power = 150 W, Temperature = 105 °C, Pressure = 200 atm, Ramp = 1 minute, Run Time = 20 minutes. The reaction was concentrated in vacuo, and the resulting crude oil was purified by silica gel chromatography (40:60 EtOAc:hexanes) to yield cyclopropane 166 as a white solid (21 mg, 55%). 1H NMR (500 MHz, C6D6) δ 6.20 (s, 1H), 5.47 (dd, J = 1.7, 7.3 Hz, 1H), 4.01 (m, 1H), 3.53 (d, J = 4.6 Hz, 1H), 3.39 (s, 3H), 2.39 (s, 3H), 2.13 (s, 3H), 1.73 (d, J = 14.4 Hz, 1H), 1.71 (s, 3H), 1.29 (ddd, J = 3.4, 7.6, 14.6 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 195.7, 170.8, 170.5, 160.0, 150.8, 141.5, 132.8, 116.2, 81.6, 78.4, 52.8, 51.9, 50.4, 46.0, 45.8, 29.7, 20.8, 12.0; IR (film) 2954, 1770, 1747, 1714, 1230 cm-1; HRMS (EI+) calc’d for [C18H19O8]+: m/z 363.1080, found 363.1085. Thermal conditions: A solution of Cu(TBSal)2 (1.30 mg, 0.00300 mmol, 0.0200 equiv) in toluene (2.40 mL) was heated, under Ar, to 108 °C. A warm solution of diazo 165 (62.0 mg, 0.150 mmol, 1.00 equiv) in toluene (0.400 mL) was added dropwise over 6 minutes. The reaction was heated to 112 °C, and monitored by TLC (40:60 EtOAc:hexanes). After 100 minutes, the reaction was complete, and allowed to cool to ambient temperature. The solvent was removed in vacuo, and the dark residue was purified by flash chromatography (40:60 EtOAc:hexanes) to provide cyclopropane 166 (35 mg, 56%). Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR OAc 65 O O O CO2Me K2CO3, MeOH, 0 °C H O O O (80% yield) O O CO2Me H HO 171 166 Alcohol 171. K2CO3 (32.0 mg, 0.240 mmol, 2.00 equiv) was added to a solution of cyclopropane 166 (43.0 mg, 0.120 mmol, 1.00 equiv) in MeOH (2.30 mL) at 0 °C. The reaction was stirred at 0 °C and monitored by TLC. Once complete, the reaction was diluted with saturated NH4Cl (aq.) and EtOAc, the layers were then separated, and the aqueous layer was further extracted 2x with EtOAc. The organic layers were combined, washed with H2O and brine, dried with Na2SO4, filtered, and concentrated in vacuo to afford a crude oil. The latter was purified by silica gel chromatography (50:50 EtOAc:Hexanes) to provide alcohol 171 as a glue (30 mg, 80%). 1H NMR (500 MHz, C6D6) δ 5.66 (s, 1H), 4.69 (m, 1H), 4.03 (app. q, J = 1.7, 5.6 Hz, 1H), 3.42 (s, 3H), 3.34 (d, J = 5.6 Hz, 1H), 2.28 (s, 3H), 2.12 (s, 3H), 1.53 (d, J = 14.4 Hz, 1H), 1.13 (ddd, J = 3.4, 7.3, 14.4 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 209.4, 196.2, 171.1, 159.6, 148.7, 141.6, 132.3, 114.6, 84.0, 71.5, 58.4, 51.4, 46.8, 45.9, 29.8, 11.8; IR (film) 3469, 1770, 1706, 1299, 1081 cm-1; HRMS (EI+) calc’d for [C16H16O7Na]+: m/z 343.0794, found 343.0811. O O O OAc AcO OAc O HO O O O I O CO2Me O CH2Cl2, 23 °C H (97% yield) 171 O O CO2Me H 172 Ketone 172. To a solution of alcohol 171 (62.0 mg, 0.190 mmol, 1.00 equiv) in CH2Cl2 (3.90 mL) was added Dess-Martin periodinane (160 mg, 0.390 mmol, 2.00 equiv), and Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 66 the resulting slurry stirred until consumption of starting material (ca. 1 h). The reaction was diluted with EtOAc and a 1:1 ratio of saturated Na2S2O4 (aq.) to saturated NaHCO3(aq.), and stirred vigorously for 5 minutes. The layers were separated and the organic layer was washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo to yield crude ketone 172 as a colorless oil (60 mg, 97%). The ketone was carried on crude as attempts toward further purification resulted in decomposition. 1H NMR (500 MHz, C6D6) δ 5.53 (s, 1H), 4.59 (dd, J = 1.2, 4.4 Hz, 1H), 3.49 (d, J = 1.2 Hz, 1H), 3.43 (s, 3H), 2.07 (s, 3H), 2.00 (s, 3H), 1.90 (d, J = 17.6 Hz, 1H), 1.66 (dd, J = 4.6, 17.6 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 202.0, 193.2, 168.7, 159.6, 146.2, 140.0, 142.4, 132.3, 115.9, 78.4, 54.4, 52.6, 51.6, 49.9, 45.3, 29.5, 11.8; IR (film) 2924, 2854, 1180, 1750, 1715, 1559, 1438, 1294, 1102 cm-1; HRMS (EI+) calc’d for [C16H14O7]+: m/z 318.0740, found 318.0732. OH O O O La(OTf)3 O O O O H CO2Me MeOH, 55 °C 1-2 h (55% yield) 172 O CO2Me O O O 168 Alcohol 168. Crude ketone 172 (11.0 mg, 0.0340 mmol, 1.00 equiv) and La(OTf)3 (20.0 mg, 0.0340 mmol, 1.00 equiv) were dissolved in MeOH (0.670 mL) at ambient temperature, then heated to 55 °C and stirred until the majority of starting material appeared consumed by TLC. The reaction was diluted with EtOAc and H2O and the aqueous layer was extracted 3x with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using 66:34 EtOAc:Hexanes to afford alcohol 168 as an oil (8.0 mg, 55%).; 1H NMR (500 MHz, C6D6) δ 5.90 (s, 1H), 4.26 (dd, J = 1.7, 5.6 Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 67 Hz, 1H), 4.24 (m, 1H), 4.04 (d, J = 5.8 Hz, 1H), 3.38 (s, 3H), 3.20 (s, 3H), 2.80 (s, 3H), 2.56 (dd, J = 4.2, 14.2 Hz, 1H), 2.26 (s, 3H), 2.20 (d, J = 14.2 Hz, 1H), 2.15 (s, 3H), 1.84 (d, J = 2.7 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 199.3, 170.6, 159.8, 154.1, 140.9, 132.0, 119.4, 115.9, 87.4, 76.9, 60.5, 52.0, 51.5, 51.4, 48.0, 43.7, 29.5, 11.8; IR (film) 3465, 2955, 1771, 1722, 1441, 1297, 1197, 1102 cm-1; HRMS (EI+) calc’d for [C18H22O9]+: m/z 382.1264, found 382.1259. O OH 1 4 O O O p-BrBzCl, Et3N CO2Me O O O 168 O Br O CH2Cl2, 0 °C → 23 °C O H O O O CO2Me O (70% yield) O 169 Br X-ray structure obtained Furan 169. Triethylamine (19.0 mL, 0.140 mmol, 2.40 equiv) was added at ambient temperature to a solution of alcohol 168 (22.0 mg, 0.0580 mmol, 1.00 equiv) in CH2Cl2 (310 mL). DMAP (0.700 mg, 0.00580 mmol, 0.100 equiv) and p-bromobenzoyl bromide (28.0 mg, 0.130 mmol, 2.20 equiv) were then added, and the reaction stirred for 1 hour at ambient temperature. The reaction was diluted with EtOAc and H2O, the layers were separated, and the aqueous layer was washed once with EtOAc. The EtOAc layers were combined, washed with saturated NaHCO3 (aq.), washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. Crystals suitable for X-ray analysis were obtained by crystallization of crude furan 169 (30 mg, yield 70%) from EtOAc:heptane. 1H NMR (500 MHz, C6D6) δ 7.97 (m, 2H), 7.39 (m, 2H), 7.25 (m, 2H), 7.10 (m, 2H), 5.99 (s, 1H), 5.73 (m, 1H), 3.93 (s, 1H), 3.24 (s, 3H), 3.13 (s, 3H), 2.88 (s, 3H), 2.54 (s, 3H), 2.49 (m, 2H), 2.15 (s, 3H); 13C NMR (125 MHz, C6D6) δ 168.1, 164.6, 161.9, 161.6, 159.2, 152.9, Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 68 141.0, 132.1, 132.0, 132.0, 131.8, 131.4, 129.3, 128.8, 128.6, 127.7, 114.9, 114.7, 114.2, 87.4, 78.1, 55.5, 52.3, 51.6, 50.1, 39.3, 17.4, 11.4; IR (film) 2948, 1762, 1725, 1589, 1227, 1101, 1070, 1010 cm-1; HRMS (FAB+) calc’d for [C32H30O11Br81Br]+: m/z 750.0135, found 750.0159. mp = 175-177 °C (heptane/EtOAc). OBOM O CO2Me H O O O 173 Cyclopropane 173. Cyclopropane 173 was obtained from allylic alcohol 37 using the same route employed to obtain cyclopropane 1 6 6 (Scheme 2.6.2). For the cyclopropanation reaction, cyclopropane 173 was obtained as an oil (3.5 mg, 74 %). 1H NMR (500 MHz, C6D6) δ 7.30 (d, J = 8.3 Hz, 2H), 7.13 (d, J = 7.6 Hz, 1H), 7.06 (t, J = 7.3 Hz, 2H), 5.93 (s, 1H), 4.93 (d, J = 7.1 Hz, 1H), 4.63 (d, J = 7.1 Hz, 1H), 4.60 (s, 2H), 4.11 (m, 1H), 3.42 (d, J = 4.6 Hz, 1H), 3.39 (s, 3H), 2.42 (s, 3H), 2.12 (s, 3H), 1.86 (d, J = 14.2 Hz, 1H), 1.20 (dd, J = 3.2, 14.2 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 195.0, 169.4, 158.9, 150.4, 140.4, 138.0, 131.4, 128.2, 114.2, 93.3, 80.7, 69.7, 51.4, 50.6, 50.3, 44.8, 28.6, 11.1; IR (film) 2952, 1769, 1713, 1297, 1102, 1037 cm-1; HRMS (EI+) calc’d for [C24H23DO8]+: m/z 441.1534, found 441.1523. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 69 OMOM O CO2Me H O O O 174 Cyclopropane 174. Cyclopropane 174 was obtained from allylic alcohol 37 using the same route employed to obtain cyclopropane 1 6 6 (Scheme 2.6.2). For the cyclopropanation reaction, cyclopropane 174 was obtained as an oil (2.3 mg, 62%). 1H NMR (500 MHz, C6D6) δ 5.95 (s, 1H), 4.78 (d, J = 7.1 Hz, 1H), 4.48 (d, J = 7.1 Hz), 4.09 (m, 1H), 3.43 (d, J = 4.9, 1H), 3.39 (s, 3H), 3.23 (s, 3H), 2.43 (s, 3H), 2.13 (s, 3H), 1.82 (d, J = 14.2, 1H), 1.20 (dd, J = 3.4, 14.2 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 196.0, 170.3, 159.8, 151.3, 141.2, 132.3, 115.0, 96.1, 81.5, 56.3, 52.3, 51.5, 51.1, 45.8, 45.7, 29.4, 12.0; IR (film) 2926, 1767, 1711, 1402, 1297, 1100 cm-1; HRMS (EI+) calc’d for [C18H19DO8]+: m/z 365.1221, found 365.1216. OSEM O CO2Me H O O O 175 Cyclopropane 175. Cyclopropane 175 was obtained from allylic alcohol 37 using the same route employed to obtain cyclopropane 1 6 6 (Scheme 2.6.2). For the cyclopropanation reaction, cyclopropane 175 was obtained as an oil (2.9 mg, 62%). 1H NMR (500 MHz, C6D6) δ 6.02 (s, 1H), 4.94 (d, J = 7.1Hz, 1H), 4.65 (d, J = 7.1 Hz, 1H), 4.13-4.11 (m, 1H), 3.78-3.73 (m, 1H), 3.46 (d, J = 4.6Hz, 1H), 3.42 (s, 3H), 2.44 (s, 3H), 2.15 (s, 3H), 1.93 (d, J = 14.2 Hz, 1H), 1.27 (dd, J = 3.2, 13.9 Hz, 1H), 0.94-0.90 (m), 0.01 (s, 9H); 13C NMR (125 MHz, C6D6) δ 196.0, 170.3, 159.8, 151.5, 141.2, 132.4, Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 70 115.2, 94.3, 81.6, 66.5, 56.2, 51.6, 51.1, 45.9, 46.0, 29.5, 18.6, 12.0, -0.80; IR (film) 2953, 1770, 1713, 1440, 1297 cm-1; HRMS (FAB+) calc’d for [C22H29DO8SiNa]+: m/z 474.1773, found 474.1675. OTBS O CO2Me H O O O 176 Cyclopropane 176. Cyclopropane 176 was obtained from allylic alcohol 37 using the same route employed to obtain cyclopropane 1 6 6 (Scheme 2.6.2). For the cyclopropanation reaction, cyclopropane 176 was obtained as an oil (6.5 mg, 71%). 1H NMR (500 MHz, C6D6) δ 5.71 (s, 1H), 4.15-4.13 (m, 1H), 3.42 (s, 3H), 3.33 (d, J = 4.6 Hz, 1H), 2.45 (s, 3H), 2.13 (s, 3H), 1.63 (d, J = 13.7 Hz, 1H), 1.21 (dd, J = 3.4, 13.7 Hz, 1H), 1.09 (s, 9H), 0.29 (s, 3H), 0.10 (s, 3H); 13C NMR (125 MHz, C6D6) δ 196.3, 170.2, 159.7, 151.2, 141.4, 132.0, 114.4, 81.6, 53.6, 52.6, 51.4, 48.2, 45.3, 29.4, 26.3, 18.8, 11.9, -4.5, -4.6; IR (film) 2953, 2930, 2857, 1770, 1714, 1297, 1113 cm-1; HRMS (FAB+) calc’d for [C22H29DO7SiNa]+: m/z 459.1800, found 458.1749. OMEM O CO2Me H O O O 177 Cyclopropane 177. Cyclopropane 177 was obtained from allylic alcohol 37 using the same route employed to obtain cyclopropane 1 6 6 (Scheme 2.6.2). For the cyclopropanation reaction, thermal conditions were used, and cyclopropane 177 was Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 71 obtained as an oil (9.1 mg, 42%). 1H NMR (500 MHz, CDCl3) δ 6.23 (s, 1H), 5.11 (m, 1H), 5.02 (d, J = 7.1 Hz, 1H), 4.92 (d, J = 7.1 Hz, 1H), 3.99 (d, J = 4.9 Hz, 1H), 3.86 (s, 3H), 3.83 (q, J = 4.4 Hz, 2H), 3.58 (t, J = 4.4 Hz, 2H), 3.39 (s, 3H), 2.46 (s, 3H), 2.34 (d, J = 14.2 Hz, 1H), 2.29 (s, 3H), 2.20 (dd, J = 3.2, 14.2 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 196.2, 170.1, 159.4, 149.8, 140.2, 131.9, 114.7, 94.3, 81.5, 71.6, 67.4, 59.0, 51.6, 51.4, 50.9, 45.4, 45.2, 29.1, 11.6; IR (film) 2925, 1767, 1711, 1613, 1548, 1440, 1297, 1198, 1099, 1037 cm-1; HRMS (EI+) calc'd for [C20H23DNaO9]+: m/z 432.1381, found 432.1365. O O OH O O La(OTf)3 O CO2Me MeOH, 55 °C 1-2 h HO 171 (65% yield) HO CO2Me O O O 181 Alcohol 181. Furan 171 (49.0 mg, 0.153 mmol, 1.00 equiv) and La(OTf)3 (89.5 mg, 0.153 mmol, 1.00 equiv) were dissolved in MeOH (3.00 mL) at ambient temperature, and then heated to 55 °C and stirred for 1–2 hours. The reaction was diluted with EtOAc and H2O and the aqueous layer was extracted 3x with EtOAc. The combined organic layers were washed with brine, dried with Na2SO4, filtered, and concentrated in vacuo. The residue was purified by flash chromatography using 60:40 EtOAc:Hexanes to afford alcohol 181 as an oil (35 mg, 65%). 1H NMR (300 MHz, CDCl3) δ 6.34 (s, 1H), 5.30 (br, 1H), 5.17 (t, J = 7.3 Hz, 1H), 4.64 (d, J = 3.8 Hz, 1H), 4.10 (t, J = 6.7 Hz, 1H), 3.91 (d, J = 5.5 Hz, 1H), 3.89 (s, 3H), 3.03 (s, 3H) 2.50 (ddd, J = 4.1, 7.1, 15.4 Hz, 1H), 2.43 (s, 3H), 2.47 (s, 3H), 2.20 (d, J = 15.4 Hz, 1H); 13C NMR (125 MHz, C6D6) δ 200.0, 172.4, 159.9, 154.3, 140.9, 132.1, 116.2, 88.5, 83.5, 77.0, 58.6, 51.4, 51.4, 45.9, 40.0, 29.6, Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 72 11.8; IR (film) 3474, 2952, 1769, 1717, 1297, 1195, 1098 cm-1; HRMS (EI+) calc'd for [C17H21O8Na]+: m/z 353.1236, found 353.1246. OH OH O O p-BrBzCl, Et3N H O CO2Me O O O CH2Cl2, 0 °C → 23 °C (79% yield) CO2Me Br O H O O O O 181 182 Furan 182. Triethylamine (43.0 µL , 306 µmol, 4.00 equiv) was added at 0 °C and under N2, to a solution of alcohol 181 (27.0 mg, 76.6 µmol, 1.00 equiv) in CH2Cl2 (955 µL). After 1 minute, p-bromobenzoyl bromide (42.0 mg, 192 µmol, 2.50 equiv) was added, and the reaction was stirred for 30 minutes at 0 °C. The reaction was allowed to warm to ambient temperature and stir for an additional 1 hour. The reaction was then diluted with Et2O and H2O, the layers were separated, and the aqueous layer was washed once with Et2O. The Et2O layers were combined, washed with saturated NaHCO3 (aq.), washed with brine, dried with MgSO4, filtered, and concentrated in vacuo. Crystals suitable for X-ray analysis were obtained by crystallization of crude furan 182 (54 mg, 98% yield) from EtOAc:heptane. 1H NMR (500 MHz, CDCl3) δ 7.78 (d, J = 8.5 Hz, 2H), 7.62 (d, J = 8.5 Hz, 2H), 6.38 (s, 1H)5.06 (t, J = 6.4 Hz, 1H), 4.46 (q, J = 7.2, 3.5 Hz, 1H), 3.80 (m, 4H), 3.18 (s, 3H), 2.45 (s, 3H), 2.37 (m, 1H), 2.33 (s, 3H), 2.28 (d, J = 3.9 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 169.5, 162.0, 159.9, 153.5, 139.9, 132.0, 131.9, 131.6, 129.2, 129.0, 127.6, 115.8, 115.3, 88.7, 79.8, 52.6, 52.3, 51.5, 38.5, 17.1, 11.6; IR (film) 3445, 2950, 1749, 1705, 1589, 1439, 1399, 1300, 1231, 1070, 1010 cm-1; HRMS (EI+) calc'd for [C24H23BrO9]+: m/z 557.0423, found 557.0427. mp = 158-159 °C (EtOAc:Heptane). Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 73 2.10 Notes and References 1 Marrero, J.; Rodriguez, A. D.; Baran, P.; Raptis, R. G.; Sanchez, J. A.; Ortega-Barria, E.; Capson, T. L. Org. Lett. 2004, 6, 1661–1664. 2 For verrillin, see: Rodriguez, A. D.; Shi, Y. P. J. Org. Chem. 2000, 65, 5839–5842.; For ineleganolide, see: Duh, C. Y.; Wang, S. K.; Chiang, M. Y. Tetrahedron Lett. 1999, 40, 6033–6035.; For scabrolide A, see; Sheu, J. H.; Ahmed, A. F.; Shiue, R. T.; Dai, C. F.; Kuo Y. H. J. Nat. Prod. 2002, 65, 1904–1908. 3 The dihydrofuran unit actually disguises a 1,4 enedione moiety. However, as in ineleganolide (108) and scabrolide A (109), the olefin may further undergo various reactions such as 1,4-hetero-Michael addition or an olefin migration, respectively. 4 An oxocane is an 8-membered ethereal ring that is fully saturated. 5 (a) Roethle, P. A.; Trauner, D. Org. Lett. 2006, 8, 345–347. (b) Roethle, P. A.; Hernandez, P. T.; Trauner, D. Org. Lett. 2006, 8, 5901–5904. 6 For example, bipinnatin A can undergo two different cycloisomerization reactions to provide two known natural products. For examples, see: (a) Rodriguez, A. D.; Shi, J.G. J. Org. Chem. 1998, 63, 420–421. (b) Rodriguez, A. D.; Shi, J.-G.; Huang, S. D. J. Org. Chem. 1998, 63, 4425–4432. 7 Doroh, B.; Sulikowski, G. A. Org. Lett. 2006, 8, 903–906. 8 Although this is possible, it is also feasible that the undesired diradical intermediate 120 is higher in energy and undergoes σ-bond rotation to the desired diradical intermediate 118. Since neither diradical intermediate 118 or 120 has been observed, Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 74 one can only speculate as to how prevalent σ-bond rotation is, as well as its impact on the diastereoselectivity. 9 Miao, R.; Subramanian, G. G.; Lear, M. L. Tetrahedron Lett. 2009, 50, 1731–1733. 10 Although the addition of water into the oxocarbenium ion is shown as the last step of the mechanism, it is possible that this may occur at any point after cyclopropane fragmentation. 11 Khatuya, J. Tetrahedron Lett. 2001, 42, 2643–2644. 12 (a) Knochel, P.; Cahiez, G.; Rottlander, M.; Boymond, L. Angew. Chem., Int. Ed. Engl. 1998, 37, 1701–1703. (b) Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. Engl. 2004, 43, 3333–3336. 13 Myers, A.; Dragovich, P. S. J. Am. Chem. Soc. 1993, 115, 7021–7022. 14 Johnson, C. R.; Braun, M. P.; Ruel, F. S. Org. Synth. 1996, 75, 69–72. 15 For a related system that provides nonsymmetrical α-diazomalonates, see: Kido, F.; Yamaji, K.; Abiko, T.; Kato, M. J. Chem. Res. 1993, 18–19. 16 Prepared using standard diazotization conditions (see S.I.). 17 Although the crude product could be crystallized to higher purity using 95% EtOH at –20 °C overnight, the crude solid was used in the coupling reaction and still provided acceptable yields. 18 Meyer, M. E.; Ferreira, E. M.; Stoltz, B. M. Chem. Commun. 2006, 1316–1318. 19 For examples of α-diazo-β-ketoamides, see: (a) Jeganathan, A.; Richardson, S. K.; Mani, R. S.; Haley, E. B.; Watt, D. S. J. Org. Chem. 1986, 51, 5362–5367. (b) Padwa, Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 75 A.; Zhi, L. J. Am. Chem. Soc. 1990, 112, 2037–2038. (c) Padwa, A.; Dean, D. C.; Fairfax, D. J.; Xu, S. L. J. Org. Chem. 1993, 58, 4646–4655. 20 For examples of Cu(TBSal)2 being used in total synthesis, see: (a) Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559–3562. (b) Corey, E. J.; Wess, G.; Xiang, Y. B.; Singh, A. K. J. Am. Chem. Soc. 1987, 109, 4717–4718. (c) Singh, A. K.; Bakshi, R. K.; Corey, E. J. J. Am. Chem. Soc. 1987, 109, 6187–6189. (d) Fukuyama, T.; Chen, X. J. Am. Chem. Soc. 1994, 116, 3125–3126. (e) Fernandez, M. A.; Barba, L. J. Org. Chem. 1995, 60, 3580–3585. 21 The only isolated product from this reaction other than starting material was an αhydroxy-β-ketoester that resulted from the overall addition of water to the "carbene". 22 Germal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454–5459. 23 For a study of reduction conditions for a similar enone, see: Curran, T. T.; Hay, D. A.; Koegel, C. P. Tetrahedron 1997, 53, 1983–2004. 24 Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725–7726. 25 In a separate run, ketone 136 was obtained in 40% yield and 93% ee after 18 hours. 26 Dess, D. B.; Martin, J. C. J. Org. Chem. 1991, 113, 7277–7287. 27 Deuterium labeling may not be needed if the 1H NMR spectra of cyclopropane 166, alcohol 171, and ketone 172, are attained in C6D6, and each spectrum is analyzed and compared. The spectra, in C6D6, for these three compounds are in Appendix 2.2 (Spectra of Compounds Relevant to Chapter 2). 28 All compounds in Figure 2.6.2 had partial deuterium incorporation at C(1) similar to cyclopropane 166 in Scheme 2.6.5. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 29 76 Spartan calculations (semi-empirical, AM1) show that undesired alcohol 171 is 4.3 kcal lower in energy than desired alcohol 167. 30 For examples of nucleophilic addition into a cyclopropane ring, see: (a) Danishefsky, S.; Dynak, J. J. Org. Chem. 1974, 39, 1979–1980. (b) Isobe, M.; Lio, H.; Kawai, T.; Goto, T. J. Am. Chem. Soc. 1978, 100, 1940–1942. (c) Callant, P.; Wilde, H. D.; Vaderwalle, M. Tetrahedron 1981, 37, 2079–2084. 31 32 See Appendix 2.1 for our attempts to form a macrocycle. For an example of a domino Michael addition followed by an aldol addition to provide a fused cyclobutane ring, see: (a) Ihara, M.; Toyota, M.; Fukumoto, K. J. Chem. Soc. Perkin Trans. I 1986, 2151–2161. (b) Ihara, M.; Ohnishi, M.; Takano, M. J. Am. Chem. Soc. 1992, 114, 4408–4410. (c) Ihara, M.; Taniguchi, T.; Makita, K.; Takano, M.; Ohnishi, M.; Taniguchi, N.; Fukumoto, K.; Kabuto, C. J. Am. Chem. Soc. 1993, 115, 8107–8115. (d) Takasu, K.; Misawa, K.; Ihara, M. Tetrahedron Lett. 2001, 42, 8489–8491. (e) Stelmakh, A.; Stellfeld, T.; Kalesse, M. Org. Lett. 2006, 8, 3485–3488. 33 (a) Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258–3260. (b) Holmquist, C. R.; Roskamp, E. J. Tetrahedron Lett. 1992, 33, 1131–1134. (c) Kanemasa, S.; Kanai, T.; Araki, T.; Wada, E. Tetrahedron Lett. 1999, 40, 5055–5058. Chapter 2 – Synthetic efforts toward bielschowskysin using a palladium(II)-catalyzed OKR 34 77 Furan 200 can be treated with MMPP to provide enedione 202 in an unoptomized 63% yield: OTBS Furan Oxidation O Decomposition CO2Me MMPP: O TESO O 1. DIBAL 2. TBSCl imid. DMF OTBS OTBS O TESO 35 O 200 O Mg OH HO O O O O OTBS MMPP OTBS O (63% yield) 201 TESO O 202 Roizen, J. L.; Progress Toward an Enantioselective Total Synthesis of Ineleganolide. Ph.D. Thesis, California Institute of Technology, Pasadena, CA, 2009. 36 Ueda, Y.; Roberge, G.; Vinet, V. Can. J. Chem. 1984, 62, 2936–2939. 37 Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115, 958–964. 38 Doyle, M. P.; Davies, S. B.; May, E. J. J. Org. Chem. 2001, 66, 8112–8119. 39 This starting alcohol (156) was prepared in the same manner as compound 158, using phenyl boronic acid as the coupling partner. It was also made via a known route, see: D’Auria, M. Heterocycles 2000, 52, 185–194. 40 Reul, F. S.; Braun, M. P.; Johnson, C. R. Org. Synth. 1996, 75, 69–72. 41 Zhu, L.; Duquette, J.; Zhang, M. J. Org. Chem. 2003, 68, 3729–3732. 42 For a separate sample, alcohol 37 at 70% ee, gave an [α]D24.9 +16.9. 78 Ch. 2 Appendices Appendix 2.1 Failed Synthetic Approaches Toward a Macrocyclic Intermediate (All Characterization Data Obtained for Compounds i–xx in Appendix 2.1 can be found in “JHP Characterized Compounds” binder) 79 Ch. 2 Appendices Scheme A2.1.1 Stille coupling route: formation of vinyl halide and vinyl stannane. O OPMB 1. NaBH4, CeCl3·7H2O THF:CH2Cl2 (1:1) I 2. PMB-TCA, 20 mol% La(OTf)3 MeCN, 23 °C TESO i OPMB 10 mol% Pd(PPh3)4 (Bu3Sn)2 I SnBu3 NaHCO3, PhMe, Δ TESO ii (69% yield over 2 steps) TESO iii (50% yield) OPMB SnBu3 1. TBAF, THF O 2. O NNHTs Cl DMA, CH2CH2, then Et3N O N2 (71% yield over 2 steps) iv 1. Mg0, THF, 0 °C CO2Me O N Br 2. Br2, MeCN O O Br OMe Br O O 2. 2M HCl:THF (1:1) O (60% yield over 2 steps) v H O 1. HCl·NHMe(OMe) iPrMgCl, THF, -10 °C O (86% yield over 2 steps) vi vii Scheme A2.1.2 Stille coupling route: Attempts at macrocyclization. OPMB OPMB SnBu3 H Br O O N2 iv O O CH2Cl2, 23 °C O O vii O O OPMB O viii N N O ix (32% yield) (32% yield) Br O O O O O viii Various Stille Conditions O O Br OPMB SnBu3 O SnBu3 Br SnCl2 O O OPMB SnBu3 O O O O NOT OBSERVED x O Sampling of conditions tried: Pd(PPh3)4, LiCl, CuCl, DMSO, 60 °C Pd2(dba)3, iPr2NEt, DMF CuTC, NMP Pd2(dba)3, AsPh3, NMP Pd2(dba)3, TFP, NMP Pd2(dba)3, P(o-tol)3, NMP 80 Ch. 2 Appendices Scheme A2.1.3 Intramolecular esterification route. O CO2Me O OH 1. NaBH4, CeCl3·7H2O THF:CH2Cl2 (1:1), -30 °C 1. Cs2CO3, NaI, DMF CO2H O 2. KOTMS, THF, 0 °C TBSO TBSO (88% yield over 2 steps) xi O xii O Br O 2. Ac2O, DMAP, pyridine (45% yield over 2 steps) OAc OAc O O O O TBAF O TBSO O 3ÅMS O HO THF PhMe (10-4 M), Δ O (81% yield) O O O O xiii xiii OAc OAc O O intramolecular O HO O esterification O O NOT OBSERVED O • O O xiii O xiv OAc OAc O over time O -CO2 O O O trace H2O O HO HO O O O OH xv xvi Scheme A2.1.4 Ring closing metathesis route. OPMB OPMB Ag2O, 8 mol% AsPh3 5 mol% PdCl2(PhCN)2 I Br O CO2Me TESO xvii O THF:H2O (500:1) XX CO2Me 2. Mg0, 4-Br-1-butene, THF, 23 °C TESO xviii (90% yield) OPMB 1. HCl·NHMe(OMe) iPrMgCl, THF, -10 °C (76% yield over 2 steps) OPMB O O 1. AcCl, MeOH, 0 °C O 2. cinnamoyl chloride, NEt3, CH2Cl2, 23 °C TESO PhH or CH2Cl2 or 1,2-DCE O Ph G = Grubbs GH = Grubbs-Hoveyda O (75% yield over 2 steps) xix G-2, GH-2, G-3, GH-3 O xx OPMB OPMB O O O O O Ph O O O ONLY ISOLABLE PRODUCT TRACE AMOUNTS NOT OBSERVED xxi xxii O 81 Ch. 2 Appendices Appendix 2.2 Spectra of Compounds Relevant to Chapter Two TBSO O 136 O CO2Me Figure A2.2.1 1H NMR (500 MHz, CDCl3) of compound 136 Ch. 2 Appendices 82 83 Ch. 2 Appendices Figure A2.2.2 Infrared spectrum (film/NaCl) of compound 136 Figure A2.2.3 13C NMR (125 MHz, CDCl3) of compound 136 HO O 128 O CO2Me Figure A2.2.4 1H NMR (500 MHz, CDCl3) of compound 128 Ch. 2 Appendices 84 85 Ch. 2 Appendices Figure A2.2.5 Infrared spectrum (film/NaCl) of compound 128 Figure A2.2.6 13C NMR (125 MHz, CDCl3) of compound 128 HO O 139 N2 O Figure A2.2.7 1H NMR (300 MHz, CDCl3) of compound 139 Ch. 2 Appendices 86 87 Ch. 2 Appendices Figure A2.2.8 Infrared spectrum (film/NaCl) of compound 139 O O O O N2 127 O CO2Me Figure A2.2.9 1H NMR (500 MHz, C6D6) of compound 127 Ch. 2 Appendices 88 89 Ch. 2 Appendices Figure A2.2.10 Infrared spectrum (film/NaCl) of compound 127 Figure A2.2.11 13C NMR (125 MHz, C6D6) of compound 127 O2N 141 O O N2 O Figure A2.2.12 1H NMR (300 MHz, CDCl3) of compound 141 Ch. 2 Appendices 90 Ch. 2 Appendices Figure A2.2.13 Infrared spectrum (film/NaCl) of compound 141 91 143 O O N2 O Figure A2.2.14 1H NMR (300 MHz, CDCl3) of compound 143 Ch. 2 Appendices 92 93 Ch. 2 Appendices Figure A2.2.15 Infrared spectrum (film/NaCl) of compound 143 Figure A2.2.16 13C NMR (75 MHz, CDCl3) of compound 143 Me 8 145 O O N2 O Figure A2.2.17 1H NMR (300 MHz, CDCl3) of compound 145 Ch. 2 Appendices 94 95 Ch. 2 Appendices Figure A2.2.18 Infrared spectrum (film/NaCl) of compound 145 Figure A2.2.19 13C NMR (75 MHz, CDCl3) of compound 145 147 O O N2 O Figure A2.2.20 1H NMR (300 MHz, CDCl3) of compound 147 Ch. 2 Appendices 96 97 Ch. 2 Appendices Figure A2.2.21 Infrared spectrum (film/NaCl) of compound 147 Figure A2.2.22 13C NMR (75 MHz, CDCl3) of compound 147 149 O O N2 O Figure A2.2.23 1H NMR (300 MHz, CDCl3) of compound 149 Ch. 2 Appendices 98 99 Ch. 2 Appendices Figure A2.2.24 Infrared spectrum (film/NaCl) of compound 149 Figure A2.2.25 13C NMR (75 MHz, CDCl3) of compound 149 H 3 H H H 151 O O N2 O Figure A2.2.26 1H NMR (300 MHz, CDCl3) of compound 151 Ch. 2 Appendices 100 Ch. 2 Appendices Figure A2.2.27 Infrared spectrum (film/NaCl) of compound 151 101 153 O O N2 O Figure A2.2.28 1H NMR (300 MHz, CDCl3) of compound 153 Ch. 2 Appendices 102 103 Ch. 2 Appendices Figure A2.2.29 Infrared spectrum (film/NaCl) of compound 153 Figure A2.2.30 13C NMR (75 MHz, CDCl3) of compound 153 155 O O O N2 Figure A2.2.31 1H NMR (300 MHz, CDCl3) of compound 155 Ch. 2 Appendices 104 105 Ch. 2 Appendices Figure A2.2.32 Infrared spectrum (film/NaCl) of compound 155 Figure A2.2.33 13C NMR (75 MHz, CDCl3) of compound 155 157 O O O N2 O Figure A2.2.34 1H NMR (300 MHz, CDCl3) of compound 157 Ch. 2 Appendices 106 107 Ch. 2 Appendices Figure A2.2.35 13C NMR (125 MHz, CDCl3) of compound 157 158 O OH Figure A2.2.36 1H NMR (300 MHz, CDCl3) of compound 158 O2N Ch. 2 Appendices 108 109 Ch. 2 Appendices Figure A2.2.37 Infrared spectrum (film/NaCl) of compound 158 Figure A2.2.38 13C NMR (75 MHz, CDCl3) of compound 158 O2N 159 O O O N2 O Figure A2.2.39 1H NMR (300 MHz, CDCl3) of compound 159 Ch. 2 Appendices 110 111 Ch. 2 Appendices Figure A2.2.40 Infrared spectrum (film/NaCl) of compound 159 Figure A2.2.41 13C NMR (75 MHz, CDCl3) of compound 159 O 161 O O N2 O Figure A2.2.42 1H NMR (300 MHz, CDCl3) of compound 161 Ch. 2 Appendices 112 113 Ch. 2 Appendices Figure A2.2.43 Infrared spectrum (film/NaCl) of compound 161 Figure A2.2.44 13C NMR (125 MHz, CDCl3) of compound 161 163 N H O N2 O Figure A2.2.45 1H NMR (300 MHz, CDCl3) of compound 163 Ch. 2 Appendices 114 115 Ch. 2 Appendices Figure A2.2.46 Infrared spectrum (film/NaCl) of compound 163 Figure A2.2.47 13C NMR (75 MHz, CDCl3) of compound 163 TBSO OH 37 O CO2Me Figure A2.2.48 1H NMR (500 MHz, CDCl3) of compound 37 Ch. 2 Appendices 116 117 Ch. 2 Appendices Figure A2.2.49 Infrared spectrum (film/NaCl) of compound 37 Figure A2.2.50 13C NMR (125 MHz, CDCl3) of compound 37 HO OAc 164 O CO2Me Figure A2.2.51 1H NMR (500 MHz, CDCl3) of compound 164 Ch. 2 Appendices 118 119 Ch. 2 Appendices Figure A2.2.52 Infrared spectrum (film/NaCl) of compound 164 Figure A2.2.53 13C NMR (125 MHz, CDCl3) of compound 164 O O O N2 OAc 165 O CO2Me Figure A2.2.54 1H NMR (500 MHz, CDCl3) of compound 165 Ch. 2 Appendices 120 121 Ch. 2 Appendices Figure A2.2.55 Infrared spectrum (film/NaCl) of compound 164 Figure A2.2.56 13C NMR (125 MHz, CDCl3) of compound 164 O O OAc 166 O H O CO2Me Figure A2.2.57 1H NMR (500 MHz, C6D6) of compound 166 Ch. 2 Appendices 122 123 Ch. 2 Appendices Figure A2.2.58 Infrared spectrum (film/NaCl) of compound 166 Figure A2.2.59 13C NMR (125 MHz, C6D6) of compound 166 HO O H O O 171 O CO2Me Figure A2.2.60 1H NMR (500 MHz, C6D6) of compound 171 Ch. 2 Appendices 124 125 Ch. 2 Appendices Figure A2.2.61 Infrared spectrum (film/NaCl) of compound 171 Figure A2.2.62 13C NMR (125 MHz, C6D6) of compound 171 O O H O O 172 O CO2Me Figure A2.2.63 1H NMR (500 MHz, C6D6) of compound 172 Ch. 2 Appendices 126 127 Ch. 2 Appendices Figure A2.2.64 Infrared spectrum (film/NaCl) of compound 172 Figure A2.2.65 13C NMR (125 MHz, C6D6) of compound 172 O O O OH O 168 O O CO2Me Figure A2.2.66 1H NMR (500 MHz, C6D6) of compound 168 Ch. 2 Appendices 128 129 Ch. 2 Appendices Figure A2.2.67 Infrared spectrum (film/NaCl) of compound 168 Figure A2.2.68 13C NMR (125 MHz, CDCl3) of compound 168 Br O O O O 169 O O H O O CO2Me Br O Figure A2.2.69 1H NMR (500 MHz, C6D6) of compound 169 Ch. 2 Appendices 130 131 Ch. 2 Appendices Figure A2.2.70 Infrared spectrum (film/NaCl) of compound 169 Figure A2.2.71 13C NMR (125 MHz, C6D6) of compound 169 O O O 173 O H OBOM CO2Me Figure A2.2.72 1H NMR (500 MHz, C6D6) of compound 173 Ch. 2 Appendices 132 133 Ch. 2 Appendices Figure A2.2.73 Infrared spectrum (film/NaCl) of compound 173 Figure A2.2.74 13C NMR (125 MHz, C6D6) of compound 173 O O O 174 O H OMOM CO2Me Figure A2.2.75 1H NMR (500 MHz, C6D6) of compound 174 Ch. 2 Appendices 134 135 Ch. 2 Appendices Figure A2.2.76 Infrared spectrum (film/NaCl) of compound 174 Figure A2.2.77 13C NMR (125 MHz, CDCl3) of compound 174 O O O 175 O H OSEM CO2Me Figure A2.2.78 1H NMR (500 MHz, C6D6) of compound 175 Ch. 2 Appendices 136 137 Ch. 2 Appendices Figure A2.2.79 Infrared spectrum (film/NaCl) of compound 175 Figure A2.2.80 13C NMR (125 MHz, C6D6) of compound 175 O O O 176 O H OTBS CO2Me Figure A2.2.81 1H NMR (500 MHz, C6D6) of compound 176 Ch. 2 Appendices 138 139 Ch. 2 Appendices Figure A2.2.82 Infrared spectrum (film/NaCl) of compound 176 Figure A2.2.83 13C NMR (125 MHz, C6D6) of compound 176 O O O 177 O H OMEM CO2Me Figure A2.2.84 1H NMR (500 MHz, C6D6) of compound 177 Ch. 2 Appendices 140 141 Ch. 2 Appendices Figure A2.2.85 Infrared spectrum (film/NaCl) of compound 177 Figure A2.2.86 13C NMR (125 MHz, CDCl3) of compound 177 O O OH 181 O H O O CO2Me Figure A2.2.87 1H NMR (300 MHz, CDCl3) of compound 181 Ch. 2 Appendices 142 143 Ch. 2 Appendices Figure A2.2.88 Infrared spectrum (film/NaCl) of compound 181 Figure A2.2.89 13C NMR (125 MHz, CDCl3) of compound 181 O O OH O O O 182 H CO2Me Br O Figure A2.2.90 1H NMR (500 MHz, CDCl3) of compound 182 Ch. 2 Appendices 144 145 Ch. 2 Appendices Figure A2.2.91 Infrared spectrum (film/NaCl) of compound 182 Figure A2.2.92 13C NMR (125 MHz, CDCl3) of compound 182 146 Ch. 2 Appendices Appendix 2.3 X-Ray Crystallographic Data Relevant to Chapter Two 147 Ch. 2 Appendices CALIFORNIA INSTITUTE OF TECHNOLOGY BECKMAN INSTITUTE X-RAY CRYSTALLOGRAPHY LABORATORY Crystal Structure Analysis of: Alcohol 182 (CCDC 606989) Contents Table 1.Crystal data Table 2.Atomic Coordinates Table 3.Full bond distances and angles Table 4.Anisotropic displacement parameters Table 5.Hydrogen atomic coordinates Table 6.Hydrogen bond distances and angles Figure A2.3.1 Representation of alcohol 182. Br O O O O H O MeO2C 182 O OH 148 Ch. 2 Appendices Table 1. Crystal data and structure refinement for alcohol 182 (CCDC 606989). Empirical formula C24H23O9Br Formula weight 535.33 Crystallization Solvent Ethyl acetate/hexanes Crystal Habit Fragment Crystal size 0.34 x 0.26 x 0.18 mm3 Crystal color Colorless Data Collection Type of diffractometer Bruker SMART 1000 Wavelength 0.71073 Å MoKα Data Collection Temperature 100(2) K θ range for 20114 reflections used in lattice determination 2.43 to 41.82° Unit cell dimensions a = 11.1074(2) Å b = 13.5443(3) Å c = 16.7177(4) Å α= 106.8590(10)° β= 104.9520(10)° γ = 98.6060(10)° Volume 2255.89(8) Å3 Z 4 Crystal system Triclinic Space group P-1 Density (calculated) 1.576 Mg/m3 F(000) 1096 Data collection program Bruker SMART v5.630 θ range for data collection 1.71 to 42.84° Completeness to θ = 42.84° 87.4 % Index ranges -21 ≤ h ≤ 21, -24 ≤ k ≤ 25, -31 ≤ l ≤ 31 Data collection scan type ω scans at 8 φ settings Data reduction program Bruker SAINT v6.45A Reflections collected 68261 Independent reflections 28932 [Rint= 0.0502] Absorption coefficient 1.876 mm-1 Absorption correction Semi-empirical from equivalents Max. and min. transmission 1.000000 and 0.820201 149 Ch. 2 Appendices Table 1 (cont.) Structure solution and Refinement Structure solution program Bruker XS v6.12 Primary solution method Direct methods Secondary solution method Difference Fourier map Hydrogen placement Difference Fourier map Structure refinement program Bruker XL v6.12 Refinement method Full matrix least-squares on F2 Data / restraints / parameters 28932 / 0 / 797 Treatment of hydrogen atoms Unrestrained Goodness-of-fit on F2 1.189 Final R indices [I>2σ(I), 18290 reflections] R1 = 0.0407, wR2 = 0.0734 R indices (all data) R1 = 0.0831, wR2 = 0.0812 Type of weighting scheme used Sigma Weighting scheme used w=1/σ2(Fo2) Max shift/error 0.007 Average shift/error 0.000 Largest diff. peak and hole 0.844 and -0.543 e.Å-3 Special Refinement Details Refinement of F2 against ALL reflections. The weighted R-factor (wR) and goodness of fit (S) are based on F2, conventional R-factors (R) are based on F, with F set to zero for negative F2. The threshold expression of F2 > 2σ( F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger. All esds (except the esd in the dihedral angle between two l.s. planes) are estimated using the full covariance matrix. The cell esds are taken into account individually in the estimation of esds in distances, angles and torsion angles; correlations between esds in cell parameters are only used when they are defined by crystal symmetry. An approximate (isotropic) treatment of cell esds is used for estimating esds involving l.s. planes. 150 Ch. 2 Appendices Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for alcohol 182 (CCDC 606989). U(eq) is defined as the trace of the orthogonalized Uij tensor. ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1) 11019(1) 1482(1) 10581(1) 19(1) O(1A) 4709(1) 873(1) 8210(1) 34(1) O(2A) 5774(1) 1287(1) 7327(1) 20(1) O(3A) 2091(1) 777(1) 5288(1) 36(1) O(4A) 2261(1) 2445(1) 6087(1) 25(1) O(5A) 5897(1) 4595(1) 7735(1) 19(1) O(6A) 4432(1) 3010(1) 5395(1) 20(1) O(7A) 7570(1) 3438(1) 7662(1) 16(1) O(8A) 10665(1) 2911(1) 8096(1) 26(1) O(9A) 9571(1) 3647(1) 8987(1) 18(1) C(1A) 9361(1) 1314(1) 9804(1) 16(1) C(2A) 9229(1) 1148(1) 8922(1) 20(1) C(3A) 8037(1) 1072(1) 8348(1) 18(1) C(4A) 6990(1) 1154(1) 8661(1) 15(1) C(5A) 7140(1) 1289(1) 9543(1) 18(1) C(6A) 8330(1) 1375(1) 10125(1) 18(1) C(7A) 5707(1) 1080(1) 8070(1) 18(1) C(8A) 4599(1) 1014(1) 6651(1) 22(1) C(9A) 4200(2) -138(1) 6108(1) 34(1) C(10A) 4018(1) 1783(1) 6549(1) 19(1) C(11A) 2731(1) 1566(1) 5895(1) 24(1) C(12A) 3206(1) 3353(1) 6785(1) 22(1) C(13A) 4414(1) 2941(1) 7101(1) 17(1) C(14A) 5506(1) 3668(1) 6955(1) 15(1) C(15A) 4787(1) 3946(1) 6159(1) 17(1) C(16A) 3600(1) 4196(1) 6402(1) 21(1) C(17A) 6832(1) 5468(1) 7761(1) 25(1) C(18A) 6643(1) 3217(1) 6874(1) 14(1) C(19A) 6986(1) 2623(1) 6200(1) 16(1) C(20A) 8221(1) 2463(1) 6582(1) 16(1) C(21A) 8535(1) 2986(1) 7470(1) 16(1) C(22A) 8979(1) 1840(1) 6099(1) 22(1) C(23A) 9698(1) 3171(1) 8201(1) 17(1) C(24A) 10696(1) 3849(1) 9740(1) 20(1) Br(2) O(1B) O(2B) O(3B) O(4B) O(5B) O(6B) O(7B) O(8B) O(9B) C(1B) C(2B) 3493(1) 9806(1) 8714(1) 12418(1) 12534(1) 9146(1) 10420(1) 7219(1) 4007(1) 5099(1) 5143(1) 5228(1) 3385(1) 4309(1) 3943(1) 4788(1) 3196(1) 747(1) 2346(1) 1646(1) 1961(1) 1226(1) 3643(1) 3750(1) -883(1) 1640(1) 2530(1) 4624(1) 3826(1) 2103(1) 4444(1) 2160(1) 1733(1) 841(1) -75(1) 794(1) 18(1) 28(1) 19(1) 30(1) 23(1) 20(1) 19(1) 16(1) 21(1) 18(1) 15(1) 17(1) Ch. 2 Appendices C(3B) 6417(1) 3885(1) 1395(1) 17(1) C(4B) 7512(1) 3913(1) 1131(1) 14(1) C(5B) 7415(1) 3819(1) 261(1) 17(1) C(6B) 6229(1) 3685(1) -347(1) 17(1) C(7B) 8798(1) 4077(1) 1764(1) 17(1) C(8B) 9866(1) 4308(1) 3237(1) 19(1) C(9B) 10039(1) 5424(1) 3807(1) 28(1) C(10B) 10611(1) 3636(1) 3334(1) 18(1) C(11B) 11900(1) 3974(1) 4011(1) 21(1) C(12B) 11713(1) 2235(1) 3104(1) 22(1) C(13B) 10398(1) 2503(1) 2764(1) 17(1) C(14B) 9408(1) 1648(1) 2882(1) 16(1) C(15B) 10213(1) 1430(1) 3687(1) 18(1) C(16B) 11459(1) 1343(1) 3466(1) 22(1) C(17B) 8407(1) -225(1) 2091(1) 25(1) C(18B) 8174(1) 1940(1) 2947(1) 14(1) C(19B) 7771(1) 2456(1) 3621(1) 15(1) C(20B) 6467(1) 2480(1) 3241(1) 14(1) C(21B) 6179(1) 1972(1) 2353(1) 15(1) C(22B) 5613(1) 2941(1) 3728(1) 20(1) C(23B) 4983(1) 1725(1) 1626(1) 15(1) C(24B) 3965(1) 998(1) 90(1) 20(1) ________________________________________________________________________________ 151 Ch. 2 Appendices Table 3. Bond lengths [Å] and angles [°] for alcohol 182 (CCDC 606989). _______________________________________________________________________________ Br(1)-C(1A) 1.8967(11) C(20A)-C(21A) 1.3699(16) O(1A)-C(7A) 1.2006(15) C(20A)-C(22A) 1.4966(15) O(2A)-C(7A) 1.3673(15) C(21A)-C(23A) 1.4612(15) O(2A)-C(8A) 1.4031(14) C(22A)-H(22A) 0.86(2) O(3A)-C(11A) 1.2030(18) C(22A)-H(22B) 0.89(2) O(4A)-C(11A) 1.3573(18) C(22A)-H(22C) 0.91(2) O(4A)-C(12A) 1.4575(16) C(24A)-H(24A) 0.945(19) O(5A)-C(17A) 1.4344(17) C(24A)-H(24B) 0.950(18) O(5A)-C(14A) 1.4363(14) C(24A)-H(24C) 0.921(17) O(6A)-C(15A) 1.4308(15) Br(2)-C(1B) 1.8886(10) O(6A)-H(6A) 0.76(2) O(1B)-C(7B) 1.2031(14) O(7A)-C(18A) 1.3641(13) O(2B)-C(7B) 1.3679(14) O(7A)-C(21A) 1.3745(12) O(2B)-C(8B) 1.4040(13) O(8A)-C(23A) 1.2169(13) O(3B)-C(11B) 1.2033(17) O(9A)-C(23A) 1.3406(14) O(4B)-C(11B) 1.3588(17) O(9A)-C(24A) 1.4513(14) O(4B)-C(12B) 1.4660(16) C(1A)-C(6A) 1.3878(15) O(5B)-C(17B) 1.4358(18) C(1A)-C(2A) 1.3900(17) O(5B)-C(14B) 1.4305(13) C(2A)-C(3A) 1.3897(16) O(6B)-C(15B) 1.4301(15) C(2A)-H(2A) 0.969(18) O(6B)-H(6B) 0.79(2) C(3A)-C(4A) 1.3984(15) O(7B)-C(18B) 1.3659(13) C(3A)-H(3A) 0.929(18) O(7B)-C(21B) 1.3763(12) C(4A)-C(5A) 1.3950(16) O(8B)-C(23B) 1.2158(13) C(4A)-C(7A) 1.4795(15) O(9B)-C(23B) 1.3397(14) C(5A)-C(6A) 1.3897(16) O(9B)-C(24B) 1.4497(14) C(5A)-H(5A) 0.891(17) C(1B)-C(6B) 1.3940(14) C(6A)-H(6A1) 0.951(16) C(1B)-C(2B) 1.3935(16) C(8A)-C(10A) 1.3341(19) C(2B)-C(3B) 1.3865(16) C(8A)-C(9A) 1.489(2) C(2B)-H(2B) 0.901(16) C(9A)-H(9A1) 0.88(2) C(3B)-C(4B) 1.3958(15) C(9A)-H(9A2) 0.97(2) C(3B)-H(3B) 0.927(18) C(9A)-H(9A3) 0.96(2) C(4B)-C(5B) 1.3976(16) C(10A)-C(11A) 1.4857(15) C(4B)-C(7B) 1.4823(15) C(10A)-C(13A) 1.5001(18) C(5B)-C(6B) 1.3904(15) C(12A)-C(16A) 1.525(2) C(5B)-H(5B) 0.910(18) C(12A)-C(13A) 1.5563(15) C(6B)-H(6B1) 0.944(15) C(12A)-H(12A) 0.902(19) C(8B)-C(10B) 1.3346(18) C(13A)-C(14A) 1.5609(16) C(8B)-C(9B) 1.4872(19) C(13A)-H(13A) 0.941(16) C(9B)-H(9B1) 0.91(2) C(14A)-C(18A) 1.5024(14) C(9B)-H(9B2) 0.99(2) C(14A)-C(15A) 1.5430(16) C(9B)-H(9B3) 0.93(2) C(15A)-C(16A) 1.5315(15) C(10B)-C(11B) 1.4851(15) C(15A)-H(15A) 0.966(16) C(10B)-C(13B) 1.4994(18) C(16A)-H(16A) 0.928(17) C(12B)-C(16B) 1.522(2) C(16A)-H(16B) 0.958(17) C(12B)-C(13B) 1.5604(15) C(17A)-H(17A) 0.95(2) C(12B)-H(12B) 0.921(16) C(17A)-H(17B) 0.95(2) C(13B)-C(14B) 1.5654(17) C(17A)-H(17C) 0.88(2) C(13B)-H(13B) 0.937(16) C(18A)-C(19A) 1.3602(15) C(14B)-C(18B) 1.5037(14) C(19A)-C(20A) 1.4326(15) C(14B)-C(15B) 1.5461(16) C(19A)-H(19A) 0.968(16) C(15B)-C(16B) 1.5338(15) 152 153 Ch. 2 Appendices C(15B)-H(15B) C(16B)-H(16C) C(16B)-H(16D) C(17B)-H(17D) C(17B)-H(17E) C(17B)-H(17F) C(18B)-C(19B) C(19B)-C(20B) C(19B)-H(19B) C(20B)-C(21B) C(20B)-C(22B) C(21B)-C(23B) C(22B)-H(22D) C(22B)-H(22E) C(22B)-H(22F) C(24B)-H(24D) C(24B)-H(24E) C(24B)-H(24F) 0.959(16) 0.941(18) 0.940(19) 0.965(17) 0.967(18) 0.940(19) 1.3621(15) 1.4325(14) 1.020(17) 1.3693(15) 1.4940(14) 1.4673(15) 0.88(2) 0.92(2) 0.95(2) 0.925(17) 0.949(19) 0.96(2) C(7A)-O(2A)-C(8A) C(11A)-O(4A)-C(12A) C(17A)-O(5A)-C(14A) C(15A)-O(6A)-H(6A) C(18A)-O(7A)-C(21A) C(23A)-O(9A)-C(24A) C(6A)-C(1A)-C(2A) C(6A)-C(1A)-Br(1) C(2A)-C(1A)-Br(1) C(3A)-C(2A)-C(1A) C(3A)-C(2A)-H(2A) C(1A)-C(2A)-H(2A) C(2A)-C(3A)-C(4A) C(2A)-C(3A)-H(3A) C(4A)-C(3A)-H(3A) C(3A)-C(4A)-C(5A) C(3A)-C(4A)-C(7A) C(5A)-C(4A)-C(7A) C(6A)-C(5A)-C(4A) C(6A)-C(5A)-H(5A) C(4A)-C(5A)-H(5A) C(1A)-C(6A)-C(5A) C(1A)-C(6A)-H(6A1) C(5A)-C(6A)-H(6A1) O(1A)-C(7A)-O(2A) O(1A)-C(7A)-C(4A) O(2A)-C(7A)-C(4A) C(10A)-C(8A)-O(2A) C(10A)-C(8A)-C(9A) O(2A)-C(8A)-C(9A) C(8A)-C(9A)-H(9A1) C(8A)-C(9A)-H(9A2) H(9A1)-C(9A)-H(9A2) C(8A)-C(9A)-H(9A3) H(9A1)-C(9A)-H(9A3) 115.48(9) 112.39(9) 115.97(9) 108.2(15) 106.33(8) 114.99(9) 121.98(10) 120.04(9) 117.97(8) 119.10(10) 117.5(11) 123.2(11) 119.89(11) 120.5(11) 119.6(11) 119.86(10) 121.46(10) 118.68(10) 120.73(10) 121.7(11) 117.5(11) 118.40(11) 122.4(10) 119.2(10) 122.51(11) 125.43(12) 112.05(10) 118.54(12) 128.62(12) 112.79(12) 110.0(14) 108.7(12) 112.6(18) 107.5(13) 111.6(18) H(9A2)-C(9A)-H(9A3) C(8A)-C(10A)-C(11A) C(8A)-C(10A)-C(13A) C(11A)-C(10A)-C(13A) O(3A)-C(11A)-O(4A) O(3A)-C(11A)-C(10A) O(4A)-C(11A)-C(10A) O(4A)-C(12A)-C(16A) O(4A)-C(12A)-C(13A) C(16A)-C(12A)-C(13A) O(4A)-C(12A)-H(12A) C(16A)-C(12A)-H(12A) C(13A)-C(12A)-H(12A) C(10A)-C(13A)-C(12A) C(10A)-C(13A)-C(14A) C(12A)-C(13A)-C(14A) C(10A)-C(13A)-H(13A) C(12A)-C(13A)-H(13A) C(14A)-C(13A)-H(13A) O(5A)-C(14A)-C(18A) O(5A)-C(14A)-C(15A) C(18A)-C(14A)-C(15A) O(5A)-C(14A)-C(13A) C(18A)-C(14A)-C(13A) C(15A)-C(14A)-C(13A) O(6A)-C(15A)-C(16A) O(6A)-C(15A)-C(14A) C(16A)-C(15A)-C(14A) O(6A)-C(15A)-H(15A) C(16A)-C(15A)-H(15A) C(14A)-C(15A)-H(15A) C(12A)-C(16A)-C(15A) C(12A)-C(16A)-H(16A) C(15A)-C(16A)-H(16A) C(12A)-C(16A)-H(16B) C(15A)-C(16A)-H(16B) H(16A)-C(16A)-H(16B) O(5A)-C(17A)-H(17A) O(5A)-C(17A)-H(17B) H(17A)-C(17A)-H(17B) O(5A)-C(17A)-H(17C) H(17A)-C(17A)-H(17C) H(17B)-C(17A)-H(17C) C(19A)-C(18A)-O(7A) C(19A)-C(18A)-C(14A) O(7A)-C(18A)-C(14A) C(18A)-C(19A)-C(20A) C(18A)-C(19A)-H(19A) C(20A)-C(19A)-H(19A) C(21A)-C(20A)-C(19A) C(21A)-C(20A)-C(22A) C(19A)-C(20A)-C(22A) C(20A)-C(21A)-O(7A) C(20A)-C(21A)-C(23A) 106.3(17) 122.62(12) 128.54(10) 108.45(11) 119.81(12) 131.28(14) 108.86(11) 109.45(10) 106.21(11) 107.12(9) 105.6(12) 114.7(12) 113.4(12) 103.48(9) 117.70(9) 103.81(10) 109.9(10) 113.2(10) 108.6(10) 109.54(9) 109.05(10) 116.10(9) 102.55(8) 115.37(10) 103.20(9) 110.76(10) 107.37(10) 101.58(9) 111.0(9) 115.1(9) 110.4(9) 104.43(10) 110.8(11) 108.7(11) 110.1(10) 113.1(10) 109.6(14) 112.3(12) 106.5(12) 109.6(16) 109.7(15) 110.7(18) 108.0(18) 110.52(9) 135.62(10) 113.85(9) 107.01(10) 126.8(10) 126.2(10) 105.30(9) 128.17(10) 126.52(10) 110.82(9) 131.59(10) 154 Ch. 2 Appendices O(7A)-C(21A)-C(23A) C(20A)-C(22A)-H(22A) C(20A)-C(22A)-H(22B) H(22A)-C(22A)-H(22B) C(20A)-C(22A)-H(22C) H(22A)-C(22A)-H(22C) H(22B)-C(22A)-H(22C) O(8A)-C(23A)-O(9A) O(8A)-C(23A)-C(21A) O(9A)-C(23A)-C(21A) O(9A)-C(24A)-H(24A) O(9A)-C(24A)-H(24B) H(24A)-C(24A)-H(24B) O(9A)-C(24A)-H(24C) H(24A)-C(24A)-H(24C) H(24B)-C(24A)-H(24C) C(7B)-O(2B)-C(8B) C(11B)-O(4B)-C(12B) C(17B)-O(5B)-C(14B) C(15B)-O(6B)-H(6B) C(18B)-O(7B)-C(21B) C(23B)-O(9B)-C(24B) C(6B)-C(1B)-C(2B) C(6B)-C(1B)-Br(2) C(2B)-C(1B)-Br(2) C(3B)-C(2B)-C(1B) C(3B)-C(2B)-H(2B) C(1B)-C(2B)-H(2B) C(2B)-C(3B)-C(4B) C(2B)-C(3B)-H(3B) C(4B)-C(3B)-H(3B) C(3B)-C(4B)-C(5B) C(3B)-C(4B)-C(7B) C(5B)-C(4B)-C(7B) C(6B)-C(5B)-C(4B) C(6B)-C(5B)-H(5B) C(4B)-C(5B)-H(5B) C(1B)-C(6B)-C(5B) C(1B)-C(6B)-H(6B1) C(5B)-C(6B)-H(6B1) O(1B)-C(7B)-O(2B) O(1B)-C(7B)-C(4B) O(2B)-C(7B)-C(4B) C(10B)-C(8B)-O(2B) C(10B)-C(8B)-C(9B) O(2B)-C(8B)-C(9B) C(8B)-C(9B)-H(9B1) C(8B)-C(9B)-H(9B2) H(9B1)-C(9B)-H(9B2) C(8B)-C(9B)-H(9B3) H(9B1)-C(9B)-H(9B3) H(9B2)-C(9B)-H(9B3) C(8B)-C(10B)-C(11B) C(8B)-C(10B)-C(13B) 117.52(9) 109.5(13) 109.0(13) 113.7(18) 113.4(14) 107.2(18) 104.0(18) 124.47(11) 123.07(11) 112.46(9) 109.4(11) 104.7(11) 114.6(15) 110.5(10) 110.9(15) 106.6(14) 115.66(9) 112.32(9) 115.45(10) 106.6(16) 106.33(8) 115.07(8) 121.43(10) 120.97(8) 117.56(8) 119.09(10) 118.7(10) 122.2(10) 120.33(10) 118.2(11) 121.5(11) 119.95(10) 121.41(10) 118.61(9) 120.25(10) 119.5(11) 120.2(11) 118.94(10) 119.9(9) 121.2(9) 122.88(10) 125.44(11) 111.68(9) 118.62(11) 129.16(11) 112.17(11) 108.9(13) 108.8(11) 111.2(17) 110.2(13) 109.1(17) 108.6(16) 122.54(12) 128.24(10) C(11B)-C(10B)-C(13B) O(3B)-C(11B)-O(4B) O(3B)-C(11B)-C(10B) O(4B)-C(11B)-C(10B) O(4B)-C(12B)-C(16B) O(4B)-C(12B)-C(13B) C(16B)-C(12B)-C(13B) O(4B)-C(12B)-H(12B) C(16B)-C(12B)-H(12B) C(13B)-C(12B)-H(12B) C(10B)-C(13B)-C(12B) C(10B)-C(13B)-C(14B) C(12B)-C(13B)-C(14B) C(10B)-C(13B)-H(13B) C(12B)-C(13B)-H(13B) C(14B)-C(13B)-H(13B) O(5B)-C(14B)-C(18B) O(5B)-C(14B)-C(15B) C(18B)-C(14B)-C(15B) O(5B)-C(14B)-C(13B) C(18B)-C(14B)-C(13B) C(15B)-C(14B)-C(13B) O(6B)-C(15B)-C(16B) O(6B)-C(15B)-C(14B) C(16B)-C(15B)-C(14B) O(6B)-C(15B)-H(15B) C(16B)-C(15B)-H(15B) C(14B)-C(15B)-H(15B) C(12B)-C(16B)-C(15B) C(12B)-C(16B)-H(16C) C(15B)-C(16B)-H(16C) C(12B)-C(16B)-H(16D) C(15B)-C(16B)-H(16D) H(16C)-C(16B)-H(16D) O(5B)-C(17B)-H(17D) O(5B)-C(17B)-H(17E) H(17D)-C(17B)-H(17E) O(5B)-C(17B)-H(17F) H(17D)-C(17B)-H(17F) H(17E)-C(17B)-H(17F) C(19B)-C(18B)-O(7B) C(19B)-C(18B)-C(14B) O(7B)-C(18B)-C(14B) C(18B)-C(19B)-C(20B) C(18B)-C(19B)-H(19B) C(20B)-C(19B)-H(19B) C(21B)-C(20B)-C(19B) C(21B)-C(20B)-C(22B) C(19B)-C(20B)-C(22B) C(20B)-C(21B)-O(7B) C(20B)-C(21B)-C(23B) O(7B)-C(21B)-C(23B) C(20B)-C(22B)-H(22D) C(20B)-C(22B)-H(22E) 108.95(10) 120.34(11) 130.84(13) 108.76(11) 109.34(10) 106.11(10) 107.02(9) 103.6(10) 115.6(10) 114.6(10) 103.30(9) 117.00(9) 103.80(10) 112.2(10) 111.4(10) 108.7(10) 109.68(8) 109.46(10) 115.52(9) 102.99(9) 115.51(10) 102.78(9) 111.39(10) 106.82(10) 101.42(9) 111.5(9) 114.3(9) 110.7(9) 104.35(10) 112.9(11) 111.9(11) 111.3(12) 108.7(12) 107.6(15) 111.8(10) 105.7(11) 107.5(14) 111.6(11) 109.7(15) 110.4(15) 110.36(9) 134.82(10) 114.81(9) 107.13(9) 129.1(10) 123.7(10) 105.29(9) 128.21(10) 126.48(10) 110.88(9) 130.75(9) 118.37(9) 112.6(13) 111.6(13) 155 Ch. 2 Appendices H(22D)-C(22B)-H(22E) C(20B)-C(22B)-H(22F) H(22D)-C(22B)-H(22F) H(22E)-C(22B)-H(22F) O(8B)-C(23B)-O(9B) O(8B)-C(23B)-C(21B) O(9B)-C(23B)-C(21B) O(9B)-C(24B)-H(24D) O(9B)-C(24B)-H(24E) H(24D)-C(24B)-H(24E) O(9B)-C(24B)-H(24F) H(24D)-C(24B)-H(24F) H(24E)-C(24B)-H(24F) 110.7(18) 107.9(13) 108.0(18) 105.6(18) 124.50(10) 123.17(10) 112.32(9) 111.4(10) 107.6(11) 107.5(14) 109.6(11) 109.1(15) 111.6(15) 156 Ch. 2 Appendices Table 4. Anisotropic displacement parameters (Å2x 104 ) for alcohol 182 (CCDC 606989). The anisotropic displacement factor exponent takes the form: -2π2 [ h2 a*2U 11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ Br(1) 146(1) 261(1) 176(1) 80(1) 24(1) 90(1) O(1A) 132(4) 651(8) 255(5) 227(5) 30(3) 27(4) O(2A) 141(3) 272(5) 191(4) 141(3) 1(3) 29(3) O(3A) 266(5) 363(6) 294(6) 129(5) -109(4) -32(4) O(4A) 120(3) 405(6) 231(4) 158(4) -4(3) 56(3) O(5A) 164(3) 229(4) 146(4) 15(3) 41(3) 60(3) O(6A) 186(3) 296(5) 108(4) 66(3) 31(3) 101(3) O(7A) 113(3) 235(4) 120(3) 52(3) 32(3) 71(3) O(8A) 138(3) 413(6) 195(4) 45(4) 41(3) 119(4) O(9A) 129(3) 280(4) 136(4) 62(3) 27(3) 68(3) C(1A) 139(4) 167(5) 153(5) 58(4) 20(3) 59(4) C(2A) 169(4) 287(6) 186(5) 88(5) 69(4) 112(4) C(3A) 170(4) 245(6) 148(5) 81(4) 47(4) 82(4) C(4A) 140(4) 165(5) 161(5) 75(4) 32(3) 32(4) C(5A) 129(4) 256(6) 171(5) 88(4) 50(4) 40(4) C(6A) 152(4) 226(6) 152(5) 73(4) 36(4) 42(4) C(7A) 151(4) 212(5) 186(5) 97(4) 26(4) 31(4) C(8A) 157(4) 274(6) 187(5) 120(5) -6(4) -10(4) C(9A) 345(7) 232(7) 320(8) 102(6) -71(6) 0(6) C(10A) 132(4) 275(6) 146(5) 108(4) 7(3) 21(4) C(11A) 154(4) 342(7) 211(6) 158(5) -20(4) 11(4) C(12A) 135(4) 384(7) 144(5) 92(5) 46(4) 110(4) C(13A) 115(4) 285(6) 117(4) 83(4) 30(3) 65(4) C(14A) 124(4) 208(5) 123(4) 46(4) 37(3) 64(4) C(15A) 169(4) 226(5) 144(5) 77(4) 52(4) 87(4) C(16A) 190(5) 311(7) 157(5) 77(5) 47(4) 143(4) C(17A) 214(5) 221(6) 275(7) 41(5) 46(5) 56(5) C(18A) 112(4) 194(5) 124(4) 61(4) 31(3) 50(3) C(19A) 132(4) 214(5) 130(5) 53(4) 38(3) 54(4) C(20A) 132(4) 188(5) 163(5) 67(4) 59(3) 57(4) C(21A) 113(4) 210(5) 161(5) 74(4) 49(3) 61(3) C(22A) 174(5) 281(6) 196(6) 42(5) 74(4) 101(4) C(23A) 131(4) 214(5) 163(5) 66(4) 37(4) 49(4) C(24A) 139(4) 276(6) 168(5) 68(4) 18(4) 43(4) Br(2) O(1B) O(2B) O(3B) O(4B) O(5B) O(6B) O(7B) O(8B) O(9B) 116(1) 129(3) 126(3) 251(4) 104(3) 137(3) 161(3) 97(3) 131(3) 120(3) 277(1) 509(6) 287(5) 294(5) 370(5) 262(4) 297(5) 248(4) 308(5) 273(4) 151(1) 203(4) 155(4) 232(5) 184(4) 155(4) 114(4) 115(3) 183(4) 128(4) 84(1) 165(4) 117(3) 88(4) 100(4) 1(3) 66(3) 45(3) 55(3) 50(3) 26(1) 39(3) 11(3) -79(4) -9(3) 29(3) 14(3) 21(2) 41(3) 18(3) 65(1) 30(4) 22(3) -27(4) 25(3) 61(3) 82(3) 59(3) 89(3) 60(3) Ch. 2 Appendices C(1B) 116(4) 195(5) 132(4) 60(4) 22(3) 39(3) C(2B) 138(4) 241(6) 150(5) 71(4) 58(4) 58(4) C(3B) 149(4) 226(6) 130(5) 71(4) 42(3) 49(4) C(4B) 120(4) 170(5) 140(4) 62(4) 30(3) 30(3) C(5B) 128(4) 237(6) 164(5) 81(4) 48(4) 39(4) C(6B) 139(4) 250(6) 130(5) 79(4) 42(3) 46(4) C(7B) 137(4) 217(5) 141(5) 78(4) 31(3) 37(4) C(8B) 143(4) 259(6) 144(5) 88(4) 11(4) 2(4) C(9B) 261(6) 229(6) 276(7) 70(5) -1(5) 26(5) C(10B) 121(4) 283(6) 110(4) 75(4) 8(3) 2(4) C(11B) 146(4) 313(7) 150(5) 110(5) -6(4) -2(4) C(12B) 107(4) 382(7) 132(5) 51(5) 20(3) 67(4) C(13B) 100(4) 294(6) 110(4) 62(4) 14(3) 50(4) C(14B) 107(4) 233(5) 109(4) 31(4) 15(3) 56(4) C(15B) 134(4) 240(6) 153(5) 64(4) 19(3) 69(4) C(16B) 136(4) 309(7) 189(5) 51(5) 19(4) 103(4) C(17B) 158(5) 254(6) 273(7) 15(5) 36(4) 52(4) C(18B) 99(4) 213(5) 109(4) 50(4) 18(3) 42(3) C(19B) 127(4) 204(5) 117(4) 61(4) 33(3) 50(3) C(20B) 127(4) 174(5) 141(4) 66(4) 53(3) 51(3) C(21B) 105(4) 209(5) 135(4) 65(4) 41(3) 51(3) C(22B) 167(4) 261(6) 174(5) 54(4) 78(4) 90(4) C(23B) 118(4) 194(5) 148(5) 70(4) 37(3) 44(3) C(24B) 137(4) 256(6) 154(5) 51(4) 7(4) 40(4) ______________________________________________________________________________ 157 Ch. 2 Appendices 158 Table 5. Hydrogen coordinates ( x 104) and isotropic displacement parameters (Å2x 10 3) for alcohol 182 (CCDC 606989). ________________________________________________________________________________ x y z Uiso ________________________________________________________________________________ H(6A) 4022(19) 3125(16) 5005(13) 34(5) H(2A) 9944(17) 1133(14) 8691(12) 29(5) H(3A) 7926(17) 956(14) 7756(12) 29(5) H(5A) 6455(17) 1346(14) 9721(11) 25(4) H(6A1) 8415(15) 1494(12) 10728(10) 16(4) H(9A1) 3480(20) -272(16) 5676(14) 44(6) H(9A2) 4130(20) -548(16) 6491(14) 43(6) H(9A3) 4890(20) -310(17) 5886(14) 45(6) H(12A) 2831(18) 3565(15) 7202(12) 33(5) H(13A) 4643(15) 3019(12) 7703(10) 16(4) H(15A) 5328(15) 4527(12) 6094(10) 15(4) H(16A) 3834(16) 4872(13) 6823(11) 22(4) H(16B) 2907(16) 4157(13) 5905(11) 20(4) H(17A) 7453(19) 5236(15) 7498(13) 36(5) H(17B) 7248(19) 5884(16) 8368(14) 39(5) H(17C) 6440(20) 5868(18) 7502(15) 53(7) H(19A) 6485(16) 2343(13) 5581(11) 20(4) H(22A) 9760(20) 1990(16) 6439(13) 39(5) H(22B) 8910(20) 1969(17) 5596(14) 42(6) H(22C) 8670(20) 1125(18) 5922(14) 50(6) H(24A) 10882(17) 3196(15) 9758(12) 29(5) H(24B) 10482(17) 4239(14) 10234(12) 28(5) H(24C) 11386(16) 4291(13) 9709(10) 19(4) H(6B) 10850(20) 2237(17) 4856(14) 45(6) H(2B) 4532(16) 3722(13) 977(11) 20(4) H(3B) 6458(17) 3951(14) 1970(12) 27(4) H(5B) 8127(17) 3839(14) 87(11) 26(4) H(6B1) 6152(15) 3634(12) -935(10) 15(4) H(9B1) 9470(20) 5439(16) 4110(14) 43(6) H(9B2) 9907(19) 5870(16) 3429(13) 38(5) H(9B3) 10870(20) 5685(16) 4206(13) 42(6) H(12B) 12161(15) 2122(12) 2706(10) 17(4) H(13B) 10187(16) 2419(13) 2165(11) 21(4) H(15B) 9775(15) 799(13) 3743(10) 18(4) H(16C) 12138(17) 1399(14) 3962(12) 27(4) H(16D) 11321(18) 673(15) 3039(12) 33(5) H(17D) 8936(16) -580(13) 2410(11) 19(4) H(17E) 8073(17) -680(14) 1479(12) 29(5) H(17F) 7731(18) -109(14) 2320(12) 30(5) H(19B) 8272(17) 2803(14) 4277(12) 28(5) H(22D) 4980(20) 3105(15) 3392(13) 37(5) H(22E) 6070(20) 3520(17) 4226(14) 45(6) H(22F) 5250(20) 2420(18) 3935(14) 50(6) H(24D) 3248(16) 632(13) 160(11) 20(4) H(24E) 4109(18) 552(15) -413(12) 31(5) H(24F) 3812(18) 1649(15) 20(12) 32(5) ________________________________________________________________________________ Ch. 2 Appendices Table 6. Hydrogen bonds for alcohol 182 (CCDC 606989) [Å and °]. ____________________________________________________________________________ D-H...A d(D-H) d(H...A) d(D...A) <(DHA) ____________________________________________________________________________ O(6A)-H(6A)...O(4B)#1 0.76(2) 2.26(2) 3.0125(12) 169(2) O(6B)-H(6B)...O(4A)#2 0.79(2) 2.16(2) 2.9238(12) 163(2) ____________________________________________________________________________ Symmetry transformations used to generate equivalent atoms: #1 x-1,y,z #2 x+1,y,z 159 160 Ch. 2 Appendices CALIFORNIA INSTITUTE OF TECHNOLOGY BECKMAN INSTITUTE X-RAY CRYSTALLOGRAPHY LABORATORY Crystal Structure Analysis of: Furan 169 (CCDC 602164) Contents Table 1.Crystal data Table 2.Atomic Coordinates Table 3.Full bond distances and angles Table 4.Anisotropic displacement parameters Figure A2.3.2 Representation of Furan 169. Br O O O O O O H O O MeO2C O 169 Br 161 Ch. 2 Appendices Table 1. Crystal data and structure refinement for furan 169 (CCDC 602164). Empirical formula C32H28O11Br2 Formula weight 748.36 Crystallization Solvent Ethylacetate/n-heptane Crystal Habit Blade Crystal size 0.31 x 0.24 x 0.11 mm3 Crystal color Colorless Data Collection Type of diffractometer Bruker SMART 1000 Wavelength 0.71073 Å MoKα Data Collection Temperature 100(2) K θ range for 10496 reflections used in lattice determination 2.30 to 28.23° Unit cell dimensions a = 17.2333(11) Å b = 10.2395(7) Å c = 18.3237(12) Å β= 104.5150(10)° Volume 3130.2(4) Å3 Z 4 Crystal system Monoclinic Space group P21/c Density (calculated) 1.588 Mg/m3 F(000) 1512 Data collection program Bruker SMART v5.630 θ range for data collection 1.22 to 28.58° Completeness to θ = 28.58° 93.7 % Index ranges -22 ≤ h ≤ 22, -13 ≤ k ≤ 13, -23 ≤ l ≤ 23 Data collection scan type ω scans at 5 φ settings Data reduction program Bruker SAINT v6.45A Reflections collected 49507 Independent reflections 49509 [Rint= 0.0820] Absorption coefficient 2.651 mm-1 Absorption correction TWINABS Max. and min. transmission 1.0000 and 0.6884 162 Ch. 2 Appendices Table 1 (cont.) Structure solution and Refinement Structure solution program Bruker XS v6.12 Primary solution method Direct methods Secondary solution method Difference Fourier map Hydrogen placement Geometric positions Structure refinement program Bruker XL v6.12 Refinement method Full matrix least-squares on F2 Data / restraints / parameters 49509 / 0 / 412 Treatment of hydrogen atoms Riding Goodness-of-fit on F2 1.273 Final R indices [I>2σ(I), 35818 reflections] R1 = 0.0465, wR2 = 0.0991 R indices (all data) R1 = 0.0708, wR2 = 0.1032 Type of weighting scheme used Sigma Weighting scheme used w=1/σ2(Fo2) Max shift/error 0.002 Average shift/error 0.000 Largest diff. peak and hole 1.202 and -0.725 e.Å-3 Special Refinement Details The crystal is twinned. CELL_NOW was used to define the two domains and produce a matrix for the twin law as follows; 751 reflections within 0.100 of an integer index assigned to domain 1, 751 of them exclusively; 248 reflections not yet assigned to a domain Rotated from first domain by 179.7 degrees about reciprocal axis 1.000 0.002 0.000 and real axis 1.000 -0.003 0.237 474 reflections within 0.100 of an integer index assigned to domain 2, 233 of them exclusively; 14 reflections not yet assigned to a domain Twin Law: Transforms h1 -> h2 1.00010 -0.00089 0.47107 0.00022 -0.99985 0.00031 -0.00044 -0.00057 -1.00002 The data was integrated with SAINT then TWINABS was used to write the file used for refinement. From TWINABS; 13830 data ( 3969 unique ) involve component 1 only, mean I/sigma 7.8 13557 data ( 3916 unique ) involve component 2 only, mean I/sigma 5.4 23827 data ( 6687 unique ) involve 2 components, mean I/sigma 7.3 36 data ( 36 unique ) involve 3 components, mean I/sigma 4.0 Refinement using an HKLF 5 type file produced a final set of atomic parameters and a scale factor between the two domains, BASF=0.33261 Refinement of F2 against ALL reflections. The weighted R-factor (wR) and goodness of fit (S) are based 2 on F , conventional R-factors (R) are based on F, with F set to zero for negative F2. The threshold expression of F2 > Ch. 2 Appendices 163 2σ( F2) is used only for calculating R-factors(gt) etc. and is not relevant to the choice of reflections for refinement. R-factors based on F2 are statistically about twice as large as those based on F, and R-factors based on ALL data will be even larger. Ch. 2 Appendices 164 Table 2. Atomic coordinates ( x 104) and equivalent isotropic displacement parameters (Å2x 103) for furan 169 (CCDC 602164). U(eq) is defined as the trace of the orthogonalized Uij tensor. ________________________________________________________________________________ x y z Ueq ________________________________________________________________________________ Br(1) 1046(1) 2805(1) -1563(1) 22(1) Br(2) 6652(1) 13142(1) 1456(1) 27(1) O(1) 1187(1) 9543(1) -1711(1) 35(1) O(2) 2058(1) 9038(1) -609(1) 20(1) O(3) 3071(1) 12918(1) 41(1) 21(1) O(4) 2149(1) 12868(1) 709(1) 19(1) O(5) 786(1) 12476(1) 499(1) 23(1) O(6) 1221(1) 9189(1) 1375(1) 22(1) O(7) 4613(1) 6506(1) 716(1) 22(1) O(8) 4502(1) 8654(1) 420(1) 23(1) O(9) 3103(1) 8783(1) 845(1) 16(1) O(10) 3048(1) 10949(1) 1772(1) 17(1) O(11) 3322(1) 12169(1) 2836(1) 25(1) C(1) 1757(1) 6474(2) -736(1) 18(1) C(2) 1655(1) 5142(2) -808(1) 21(1) C(3) 1145(1) 4653(2) -1455(1) 16(1) C(4) 728(1) 5454(2) -2020(1) 20(1) C(5) 839(1) 6796(2) -1941(1) 21(1) C(6) 1362(1) 7304(2) -1303(1) 17(1) C(7) 1500(1) 8738(2) -1257(1) 20(1) C(8) 2396(1) 10292(2) -517(1) 17(1) C(9) 2936(1) 10604(2) -1014(1) 25(1) C(10) 2250(1) 10981(2) 45(1) 14(1) C(11) 2562(1) 12316(2) 235(1) 17(1) C(12) 1542(1) 11995(2) 853(1) 18(1) C(13) 607(1) 13733(2) 765(1) 32(1) C(14) 1668(1) 10657(2) 502(1) 14(1) C(15) 1918(1) 9702(2) 1191(1) 17(1) C(16) 684(1) 8458(2) 792(1) 30(1) C(17) 2263(1) 10637(2) 1858(1) 17(1) C(18) 1709(1) 11803(2) 1706(1) 19(1) C(19) 2474(1) 8589(2) 1155(1) 15(1) C(20) 2489(1) 7352(2) 1426(1) 19(1) C(21) 3171(1) 6719(2) 1281(1) 18(1) C(22) 3450(1) 5356(2) 1519(1) 28(1) C(23) 3523(1) 7618(2) 921(1) 15(1) C(24) 4257(1) 7678(2) 656(1) 17(1) C(25) 5373(1) 6476(2) 504(1) 26(1) C(26) 3520(1) 11758(2) 2291(1) 19(1) C(27) 4283(1) 12027(2) 2093(1) 16(1) C(28) 4504(1) 11392(2) 1500(1) 17(1) C(29) 5210(1) 11697(2) 1320(1) 17(1) C(30) 5693(1) 12672(2) 1724(1) 19(1) C(31) 5490(1) 13312(2) 2315(1) 19(1) C(32) 4787(1) 12986(2) 2499(1) 18(1) ________________________________________________________________________________ Ch. 2 Appendices Table 3. Bond lengths [Å] and angles [°] for furan 169 (CCDC 602164). _______________________________________________________________________________ Br(1)-C(3) 1.9056(18) C(11)-O(4)-C(12) 111.90(14) Br(2)-C(30) 1.900(2) C(12)-O(5)-C(13) 114.44(15) O(1)-C(7) 1.198(2) C(15)-O(6)-C(16) 116.16(14) O(2)-C(7) 1.363(2) C(24)-O(7)-C(25) 114.82(15) O(2)-C(8) 1.402(2) C(19)-O(9)-C(23) 106.47(14) O(3)-C(11) 1.196(2) C(26)-O(10)-C(17) 118.12(15) O(4)-C(11) 1.376(2) C(2)-C(1)-C(6) 120.62(18) O(4)-C(12) 1.450(2) C(1)-C(2)-C(3) 118.70(18) O(5)-C(12) 1.392(2) C(4)-C(3)-C(2) 122.03(18) O(5)-C(13) 1.438(2) C(4)-C(3)-Br(1) 119.91(15) O(6)-C(15) 1.425(2) C(2)-C(3)-Br(1) 118.05(14) O(6)-C(16) 1.437(2) C(3)-C(4)-C(5) 118.68(18) O(7)-C(24) 1.340(2) C(6)-C(5)-C(4) 120.12(18) O(7)-C(25) 1.458(2) C(1)-C(6)-C(5) 119.81(18) O(8)-C(24) 1.206(2) C(1)-C(6)-C(7) 121.52(18) O(9)-C(19) 1.357(2) C(5)-C(6)-C(7) 118.65(17) O(9)-C(23) 1.385(2) O(1)-C(7)-O(2) 123.04(19) O(10)-C(26) 1.366(2) O(1)-C(7)-C(6) 127.05(19) O(10)-C(17) 1.436(2) O(2)-C(7)-C(6) 109.91(17) O(11)-C(26) 1.209(2) C(10)-C(8)-O(2) 115.29(18) C(1)-C(2) 1.377(2) C(10)-C(8)-C(9) 129.09(19) C(1)-C(6) 1.383(2) O(2)-C(8)-C(9) 115.29(16) C(2)-C(3) 1.381(2) C(8)-C(10)-C(11) 123.14(18) C(3)-C(4) 1.374(2) C(8)-C(10)-C(14) 127.04(18) C(4)-C(5) 1.390(2) C(11)-C(10)-C(14) 109.23(16) C(5)-C(6) 1.386(2) O(3)-C(11)-O(4) 120.67(18) C(6)-C(7) 1.486(3) O(3)-C(11)-C(10) 131.11(19) C(8)-C(10) 1.324(2) O(4)-C(11)-C(10) 108.22(17) C(8)-C(9) 1.489(2) O(5)-C(12)-O(4) 109.29(15) C(10)-C(11) 1.478(2) O(5)-C(12)-C(18) 115.84(17) C(10)-C(14) 1.495(2) O(4)-C(12)-C(18) 107.84(16) C(12)-C(18) 1.529(2) O(5)-C(12)-C(14) 109.33(16) C(12)-C(14) 1.552(2) O(4)-C(12)-C(14) 106.62(15) C(14)-C(15) 1.570(2) C(18)-C(12)-C(14) 107.52(15) C(15)-C(19) 1.502(3) C(10)-C(14)-C(12) 102.71(15) C(15)-C(17) 1.548(2) C(10)-C(14)-C(15) 120.16(16) C(17)-C(18) 1.511(2) C(12)-C(14)-C(15) 104.72(14) C(19)-C(20) 1.359(2) O(6)-C(15)-C(19) 108.41(15) C(20)-C(21) 1.423(3) O(6)-C(15)-C(17) 102.80(15) C(21)-C(23) 1.361(2) C(19)-C(15)-C(17) 112.34(16) C(21)-C(22) 1.504(2) O(6)-C(15)-C(14) 110.07(16) C(23)-C(24) 1.467(3) C(19)-C(15)-C(14) 119.06(16) C(26)-C(27) 1.475(3) C(17)-C(15)-C(14) 102.90(15) C(27)-C(32) 1.397(3) O(10)-C(17)-C(18) 111.90(16) C(27)-C(28) 1.398(2) O(10)-C(17)-C(15) 103.75(15) C(28)-C(29) 1.374(3) C(18)-C(17)-C(15) 104.04(15) C(29)-C(30) 1.388(2) C(17)-C(18)-C(12) 103.76(15) C(30)-C(31) 1.384(2) O(9)-C(19)-C(20) 110.22(17) C(31)-C(32) 1.377(3) O(9)-C(19)-C(15) 119.53(17) C(20)-C(19)-C(15) 130.16(19) C(7)-O(2)-C(8) 119.53(15) C(19)-C(20)-C(21) 107.29(18) 165 166 Ch. 2 Appendices C(23)-C(21)-C(20) C(23)-C(21)-C(22) C(20)-C(21)-C(22) C(21)-C(23)-O(9) C(21)-C(23)-C(24) O(9)-C(23)-C(24) O(8)-C(24)-O(7) O(8)-C(24)-C(23) O(7)-C(24)-C(23) O(11)-C(26)-O(10) O(11)-C(26)-C(27) O(10)-C(26)-C(27) C(32)-C(27)-C(28) C(32)-C(27)-C(26) C(28)-C(27)-C(26) C(29)-C(28)-C(27) C(28)-C(29)-C(30) C(31)-C(30)-C(29) C(31)-C(30)-Br(2) C(29)-C(30)-Br(2) C(32)-C(31)-C(30) C(31)-C(32)-C(27) 105.73(17) 128.2(2) 125.96(18) 110.29(17) 135.72(19) 113.77(16) 125.31(19) 124.23(19) 110.46(17) 123.0(2) 126.35(19) 110.68(17) 119.08(19) 118.29(17) 122.59(19) 120.74(19) 118.97(18) 121.5(2) 119.30(16) 119.23(15) 119.16(19) 120.55(18) 167 Table 4. Anisotropic displacement parameters (Å2x 104 ) for furan 169 (CCDC 602164). The anisotropic displacement factor exponent takes the form: -2π2 [ h2 a*2U 11 + ... + 2 h k a* b* U12 ] ______________________________________________________________________________ U11 U22 U33 U23 U13 U12 ______________________________________________________________________________ Br(1) 259(1) 175(1) 232(1) -2(1) 60(1) -29(1) Br(2) 217(1) 295(1) 321(1) -33(1) 84(1) -52(1) O(1) 409(12) 190(8) 336(9) 75(7) -96(8) 28(8) O(2) 278(10) 146(8) 156(8) -5(6) 22(7) -13(7) O(3) 187(9) 183(8) 266(8) 10(7) 98(7) -23(7) O(4) 202(9) 162(8) 232(8) -2(6) 101(7) 6(7) O(5) 163(9) 238(9) 276(8) 6(6) 50(7) 74(7) O(6) 161(9) 270(9) 240(8) 29(6) 98(7) -26(7) O(7) 190(9) 174(8) 288(8) -13(6) 64(7) 32(7) O(8) 256(10) 190(8) 273(8) 27(7) 119(7) 14(7) O(9) 163(9) 151(7) 180(7) 25(6) 57(7) 5(6) O(10) 149(9) 199(8) 161(7) -36(6) 39(7) -12(7) O(11) 250(9) 324(9) 186(8) -78(7) 87(7) 4(8) C(1) 176(13) 181(12) 158(11) -17(9) 2(10) -4(10) C(2) 213(14) 201(12) 191(12) 42(9) 30(11) -11(10) C(3) 184(13) 135(11) 176(11) -18(9) 72(10) 6(10) C(4) 208(13) 229(12) 150(11) -37(9) 22(10) -9(10) C(5) 231(14) 200(12) 178(11) 35(9) 14(10) 33(10) C(6) 201(13) 150(11) 168(11) 1(9) 72(9) 21(10) C(7) 183(14) 225(12) 189(12) -11(10) 50(10) 12(11) C(8) 207(14) 113(11) 174(11) 51(9) 5(10) 19(10) C(9) 322(15) 188(12) 250(12) -10(10) 115(11) 16(11) C(10) 132(12) 131(11) 153(11) 47(9) 15(10) 18(9) C(11) 165(13) 184(12) 134(11) 34(9) 7(10) 42(10) C(12) 144(13) 179(12) 208(11) 3(9) 56(10) 35(10) C(13) 287(15) 274(13) 411(15) 14(11) 101(12) 117(12) C(14) 125(12) 159(11) 144(11) 9(9) 21(9) 12(9) C(15) 135(13) 194(12) 188(12) 26(9) 72(10) -18(10) C(16) 183(14) 335(14) 345(14) 41(11) 18(11) -110(11) C(17) 138(13) 236(12) 145(11) 18(9) 59(10) 11(10) C(18) 153(13) 230(12) 198(11) 4(9) 87(10) 35(10) C(19) 110(12) 199(12) 125(11) 2(9) 17(9) -8(10) C(20) 174(13) 191(12) 190(11) -3(10) 44(10) -45(10) C(21) 182(14) 187(11) 147(11) -20(9) -24(10) -6(10) C(22) 338(16) 166(12) 330(14) 39(10) 67(12) -22(11) C(23) 172(13) 119(11) 142(11) -10(9) 9(9) 36(9) C(24) 147(13) 197(12) 136(11) -28(9) -20(9) -4(10) C(25) 201(14) 243(13) 332(13) -28(10) 62(11) 77(11) C(26) 203(14) 134(11) 193(11) 43(9) -5(10) 24(10) C(27) 180(13) 143(11) 128(10) 24(9) 14(9) 44(10) C(28) 213(14) 120(11) 152(11) -15(9) 11(10) 7(10) C(29) 181(13) 163(11) 171(11) -23(9) 48(10) 41(10) C(30) 184(13) 177(11) 214(11) 34(10) 44(10) 39(10) C(31) 208(14) 135(11) 199(12) -13(9) -12(10) 24(10) C(32) 218(14) 159(12) 137(11) -11(9) -3(10) 48(10) ___________________________________________________________________ Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 168 CHAPTER 3 Synthetic Efforts Toward (–)-Phalarine Using Palladium(II)-catalyzed Oxidative Heterocyclizations 3.1 Introduction and Biosynthesis In 1999, (–)-phalarine (106) was isolated from Phalaris coerulescens and displayed a [4.3.3.0] fused tricyclic core structure including a novel furanobisindole ring system (Figure 3.1.1).1,2 In addition, the natural product contains vicinal stereocenters that are contained within the propellar-like core. Although (–)-phalarine (106) is not reported to be biologically active, the properties of this molecule still warrants medicinal evaluation since many alkaloids isolated from the genus Phalaris have proven to be poisonous to livestock when the native plant was ingested (e.g., canary grass, P . arundinacea). 169 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations Figure 3.1.1 (–)-Phalarine (106) in Two and Three Dimensions. Me OMe N O NH N H Hydrogens omitted for clarity NMe2 (–)-Phalarine (106) Although the biosynthesis of (–)-phalarine (106) has not been fully elucidated, it is proposed by the isolation chemists that (–)-phalarine (106) is obtained via an oxidative coupling of known tetrahydro-β-carboline 203 with a functionalized indole akin to phenol 204 (Scheme 3.1.1).3 It is hypothesized that indole 204 is oxidized to an intermediate similar to arene 205. This activated intermediate undergoes addition by tetrahydro-β-carboline 203 to provide cationic species 206, which will undergo rapid tautomerization to provide enol 207. Formation of the natural product (106) is accomplished by the addition of the phenol in intermediate 207 onto the benzylic cation. Scheme 3.1.1 Me OMe N O HO N H NMe2 NMe OMe 203 N H [O] and NH N H cyclization NMe2 204 Phalarine (106) NMe2 Proposed Mechanism: X N H O O NMe2 C–C bond NMe OMe 203 206 Me NMe2 OMe N O phenol cyclization HO NH N H OMe NMe N H 205 tautomerization NH formation N H OMe NMe 207 NH N H NMe2 Phalarine (106) 170 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations Initial synthetic efforts by the Danishefsky laboratory to access the skeletal framework of the natural product using a biosynthetic approach proved unsuccessful. Their first attempt began with oxidation of phenol 208 to generate intermediate 209 (Scheme 3.1.2). Treatment of this intermediate with tetrahydro-β-carboline 210 provided polycycle 211 exclusively; however, the reaction occurred with undesired regioselectivity in the formation of the bridging dihydobenzofuran functionality.4 A second generation approach employed oxidation of tetrahydro-β-carboline 210 with t-butyl hypochlorite to yield α-chloroimine 212. Unfortunately, exposing imine 212 to phenol 208 in the presence of a catalytic amount of camphorsulfonic acid (CSA) in refluxing benzene afforded indole 213 as the sole product.5 Scheme 3.1.2 MeO OMe PIFA: HO OMe OMe PIFA X O OMe MeCN OMe 208 TFA 3 N H 209 2 NCO2Me N H 210 210 CH2Cl2 208 cat. CSA N 212 NCO2Me TFA phenol t-BuOCl NCO2Me 2 211 Cl N H I O 3 NCO2Me N H NCO2Me OH PhH, 85 °C MeO OMe 213 In the end, Danishefsky's efforts to synthesize the core of (–)-phalarine using a biomimetic strategy failed due to the lack of regio-control in the oxidative coupling step. These results infer that the proposed biosynthesis of (–)-phalarine (106) are likely catalyzed in a chiral environment that effects the key oxidative coupling reaction to provide the correct regiochemistry. Despite these synthetic challenges, Danishefsky's laboratory persisted, and in 2007 accomplished a total synthesis of racemic phalarine. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 171 More recently, Danishefsky’s laboratory completed an asymmetric synthesis of (–)phalarine using a C(2)-functionalized tryptophan. The results of their work will be discussed in the next section. 3.2 Previous Efforts Toward the Total Synthesis of Phalarine The only total syntheses of phalarine were reported by the Danishefsky laboratory in 2007 and 2010.6 The synthesis of racemic phalarine was accomplished using a key retro-Mannich reaction followed by a Pictet-Spengler cyclization to provide the core of the natural product (Scheme 3.2.1). The key steps of the synthesis began with addition of lithiated arene 215 into oxindole 214 to provide ketone 216 in excellent yield. Exposing ketone 216 to two sequential organic acids first cleaved the MOM group, and then facilitated the condensation of the aniline onto the pendant ketone to provide iminium 217. This activated species underwent a retro-Mannich reaction to generate intermediate 218, which cyclized in a Pictet-Spengler fashion to form cationic intermediate 219. Finally, cyclization of the phenol moiety furnished the core of phalarine (220) in 72% yield from ketone 216. 172 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations Scheme 3.2.1 NMe TsHN NMe O OMOM 1. TFA, CH2Cl2, 0 °C n-BuLi Br O OMOM THF, –78 °C N Ts MeO 214 2. CSA, PhMe, 130 °C (96% yield) (72% yield) OMe 215 NMe HO N Ts 216 N retro-Mannich N Ts HO OMe 217 NMe OH Pictet-Spengler N Ts OMe OMe 218 cyclization Me N O 219 Me OMe N O OMe 6 steps NH N H N Ts NMe2 220 (±)-Phalarine (106) Although an alternate mechanism invoking a Wagner-Meerwein ring-expansion is plausible (Scheme 3.2.2), Danishefsky found that treatment of enantioenriched ketone 217 under the same conditions provided product 220 as a racemic mixture.7 This result indicates the formation of an achiral intermediate, such as iminium 218, prior to product formation. Scheme 3.2.2 NMe HO NMe OH Wagner-Meerwein N Ts OMe 217 shift N Ts 219 cyclization Me O N OMe N Ts OMe 220 With a rapid synthesis of pentacycle 220 complete, Danishefsky sought to complete the molecule by synthesizing the indole unit and appending the gramine side chain (Scheme 3.2.3).8 Although the synthesis of pentacycle 220 is rapid, the completion of phalarine required an additional six steps to synthesize the gramine moiety of the natural product. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 173 Scheme 3.2.3 Me N O Me OMe N O OMe 6 steps NH N H N Ts 220 NMe2 (±)-Phalarine (106) Danishefsky’s synthesis of racemic phalarine (106) required nine synthetic steps starting from oxindole 2149 and provided the core of the natural product via a retroMannich reaction/Pictet-Spengler addition cascade sequence. Unfortunately, this reaction sequence occurred through an achiral intermediate, thus initially negating an asymmetric synthesis. However, Danishefsky recently published an asymmetric synthesis of (–)phalarine utilizing a chiral variant of iminium 218 (cf. Scheme 3.2.1). In an ingenuous attempt, Danishefsky began with L-tryptophan methyl ester (221) to synthesize indole 222 in nine steps (Scheme 3.2.4). Exposing indole 222 to formalin under acidic conditions provided iminium 223. This species underwent a Pictet-Spengler cyclization with either C(2) or C(3) of the indole moiety to provide intermediates 224 and 225, respectively. Although it is unclear which mechanism is operative,10 the desired pentacycle (226) is obtained as a single diastereomer in 91% yield beginning from indole 222. At this stage, an additional ten synthetic operations provided the desired natural product. 174 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations Scheme 3.2.4 CO2Me CO2Me NHBn NHBn 9 steps formalin, CSA, 4ÅMS OMe (20% yield over 9 steps) N H N Ts 221 PhMe, 125 °C HO (91% yield) 222 CO2Me NBn C(3) cyclize OMe a N Ts CO2Me N Bn a Bn O N 224 b N Ts MeO2C HO Ar CO2Me 223 C(2) cyclize b N Ts NBn 226 OH single diastereomer N Ts 225 OMe OMe 3.3 Retrosynthetic Analysis of Phalarine Our retrosynthetic analysis of phalarine (106) began with late-stage formation of the bridging piperidine ring via a double reductive amination of bis-aldehyde 227 and methylamine (Scheme 3.3.1). We envisioned unveiling the two aldehyde units by an ozonolysis of a terminal olefin and hydrolysis of a PMB vinyl ether, which led us to intermediate 228. We anticipated the formation of pentacycle 228 via a double palladium(II)-catalyzed oxidative heterocyclization beginning from diene 229. At this stage, we planned to synthesize diene 229 from a Stille coupling between vinyl iodide 230 and vinyl stannane 231. The synthesis of vinyl iodide 230 was seen to arise from known compound 232 by a Sonogashira coupling. However, we anticipated that the synthesis of vinyl stannane 231 would be difficult since fully differentiated 4,5,7substituted indoles lack an efficient synthetic route that is compatible with many common 175 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations functional groups. Instead of addressing this problem prior to indole formation, we sought out indole 233 as a suitable starting point to effect differentiation between C(5) and C(7), and allow for selective C(4) functionalization. Scheme 3.3.1 double reductive amination Me N O PdII catalyzed ox. cyclization O OMe NH N H NMe2 N Ts nucleophilic addition PMBO OMe O NBoc NBoc N Ts O PdII catalyzed ox. cyclization ozonolysis 227 Phalarine (106) OMe O 228 NO2 NO2 I reduction/protection I PMBO NHTs 230 Sonogashira coupling PMBO HO Stille coupling 232 Bu3Sn N Boc Negishi coupling TBSO 229 OMe N Boc OMe 231 4 MeO 5 7 N H OMe 233 3.4 Model System Studies There are very few examples of palladium(II)-catalyzed oxidative heterocyclizations onto styrenyl or conjugated olefins.11 Thus, we decided to investigate the palladium(II)-catalyzed oxidative phenol cyclization using a model system. We envisioned phenol 237 (Scheme 3.4.1) as a suitable substrate to test the palladium(II)-catalyzed oxidative cyclization since it possessed a trisubstituted styrenyl olefin that is similar to diene 229 (cf. Scheme 3.3.1). The synthesis of phenol 237 began with a radical bromination of arene 234 to provide benzyl bromide 235 in excellent yield.12 From here, Stille coupling using known vinyl stannane 236 provided the desired product, which then underwent silyl cleavage to arrive at phenol 237 in 50% yield.13 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 176 Scheme 3.4.1 1. hν NBS OTBS OH Ph Bu3Sn Br CCl4 (85% yield) 234 236 OTBS 235 10 mol% Pd(PPh3)4 30 mol% AsPh3 DME, 80 °C 237 2. TBAF, THF, 23 °C (50% yield over two steps) With the model substrate in hand, phenol 237 was subjected to the DMSO/O2 conditions as well as conditions for the palladium(II)-catalyzed oxidative cyclization previously developed in our group.14,15 As shown in Table 3.4.1, using the DMSO/O2 conditions without NaOAc allowed for an 80% yield of dihydrobenzofuran 238 in only 4 hours.16 Under our optimized conditions (Entry 3), the formation of dihydrobenzofuran 238 was significantly slower than the DMSO/O2 conditions. Nevertheless, all entries in Table 3.4.1 provided dihydrobenzofuran 238 as the only observable product, with the remaining mass recovered as unreacted starting material. Table 3.4.1 Attempts at the Pd(II)-catalyzed Oxidative Cyclization of Phenol 237. Pd(II)-catalyzed oxidative cyclization OH Ph O 237 238 Entry 1. 2. a Ph Conditions 5 mol% Pd(TFA)2 20 mol% pyridine 3ÅMS, Na2CO3, O2 PhMe, 80 °C Time (h) Yield (%)a 3 30 18 60 3. 10 mol% Pd(OAc)2 40 mol% pyridine 3ÅMS, O2 PhMe, 80 °C 2 25 4. 10 mol% Pd(OAc)2, O2 DMSO, 60 °C 4 80 5. 5 mol% Pd(OAc)2, NaOAc (2 equiv), O2 DMSO, 60 °C 3 20 Isolated yield. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 177 3.5 Initial Synthetic Efforts Our initial synthetic efforts focused on the synthesis of diene 229, which could be used to test both the phenol and aniline palladium(II)-catalyzed oxidative heterocyclizations. Thus, beginning with 2-nitro iodobenzene (232), Sonogashira coupling of alkyne 239 provided arene 240 in high yield (Scheme 3.5.1). Regioselective hydrostannylation of alkyne 240 using conditions developed by Alami, provided vinyl stannane 241 in 65% yield.17 Subsequent exposure of this intermediate to I2 in acetonitrile provided vinyl iodide 242 in 76% yield.18 Scheme 3.5.1 OTBS 239 NO2 2 mol% PdCl2(PPh3)2 6 mol% CuI I i-Pr2NH, 23 °C 232 2 mol% PdCl2(PPh3)2 Bu3SnH NO2 OTBS (95% yield) (89% yield) 240 NO2 SnBu3 NO2 I2 MeCN, 23 °C TBSO THF (0.75 M), 23 °C I TBSO (76% yield) 241 242 Although we were confident that the TBS moiety in vinyl iodide 242 would be stable in upcoming transformations, we decided to synthesize vinyl stannanes 246 and 248. We hypothesized that the TIPS group would provide greater bulk and stability, while the PMB moiety was an orthogonal functional group that would allow for a silyl protecting group on indole fragment 231 (Scheme 3.5.2). Accordingly, exposure of alcohol 24319 to 20 mol% La(OTf)3 and trichloroacetimidate 24420 provided alkyne 245 in 86% yield. Hydrostannylation of this product provided vinyl stannane 246 in 63% yield. The analogous TIPS protected intermediate was obtained via the aforementioned strategy. Silylation of alcohol 243 with TIPSCl proceeded in 83% yield, affording nitro- 178 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations arene 247. As expected, hydrostannylation of alkyne 247 proceeded regioselectively to furnish vinyl stannane 248 in 74% yield. Scheme 3.5.2 NH Cl3C NO2 OH 244 OPMB NO2 20 mol% La(OTf)3 2 mol% PdCl2(PPh3)2 Bu3SnH PhMe, 23 °C THF, 23 °C OPMB NO2 SnBu3 PMBO 243 (86% yield) 245 (63% yield) 246 NO2 TIPSCl imidazole NO2 1 mol% PdCl2(PPh3)2 Bu3SnH NO2 OH DMF, 23 °C (83% yield) 243 SnBu3 THF, 23 °C OTIPS TIPSO (74% yield) 247 248 The second coupling partner needed for the Stille coupling, substituted indole 231, was obtained from 5,7-dimethoxy indole (233).21,22 The synthesis of this indole is shown below in Scheme 3.5.3. Initial exposure of commercially available 3,5-dimethoxy benzaldehyde (249) to nitromethane under acidic conditions effected a Henry reaction to provide arene 250 in 72% yield.23 Subsequent nitration using copper(II)nitrate in acetic anhydride provided nitro-arene 251 in 98% yield. At this stage, reductive cyclization afforded indole 233, which underwent protection of the indole nitrogen as an amide, providing N-acyl indole 252 in 88% yield. Scheme 3.5.3 MeO CHO MeO MeNO2, NH4OAc NO2 glacial AcOH, 120 °C Cu(NO3)2•5/2H2O MeO Ac2O, 45 °C OMe NO2 OMe (72% yield) 249 Fe powder 250 OMe (98% yield) powdered KOH DMSO, 23 °C MeO 80% AcOH (aq), 80 °C (54% yield) NO2 N H OMe 233 251 MeO N Ac then Ac2O, 23 °C (88% yield) OMe 252 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 179 With the synthesis of indole 252 complete, we attempted to demethylate the two methoxy substituents on the indole core. Dimethoxy indole 252 proved surprisingly difficult to demethylate and all attempts were unsuccessful.24 Hence, we elected to use this dimethylated system to probe the feasibility of the palladium(II)-catalyzed oxidative aniline cyclization. To this end, we needed to first functionalize, and then transform, C(4) of indole 252 to the appropriate vinyl stannane for the Stille coupling. Black has shown that formylation of 5,7-dimethoxyindoles occurs exclusively at C(4), rather than at C(3), when an acyl group (e.g., Ac, Piv, or Boc) is protecting the indole nitrogen.25 Hence, selective C(4) functionalization commenced with iodination of indole 252 using NIS to provide intermediate 253 in excellent yield (Scheme 3.5.4). At this stage, it was found that the acetyl moiety was not stable toward further functionalization at C(4) via a Negishi coupling. To address this chemoselectivity issue, we sought a more robust protecting group. Thus, cleavage of the acyl amide provided indole 254 in nearly quantitative yield. Reprotection of the indole nitrogen in arene 254 as a sulfonamide afforded indole 255 in 75% yield. Further elaboration at C(4) occurred smoothly via a Negishi coupling providing alkyne 256 in excellent yield. Completion of the Stille coupling partner (257) was accomplished in 65% yield using a regioselective palladiumcatalyzed hydrostannylation reaction.10 180 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations Scheme 3.5.4 I MeO 4 NIS N Ac I MeO THF: 10% NaOH (aq) N Ac CHCl3, 23 °C OMe N H (1:1), 23 °C OMe (90% yield) 252 powdered KOH 15 mol% Bu4NBr TsCl MeO (98% yield) 253 THF, 0 → 23 °C OMe (75% yield) 254 Bu3Sn I 5 mol% Pd(PPh3)4 THF, 23 °C MeO N Ts 1 mol% PdCl2(PPh3)2 Bu3SnH MeO N Ts OMe then propynyl-MgBr ZnCl2, THF, 0→60 °C OMe 255 (89% yield) 256 MeO N Ts THF (0.75 M), 23 °C OMe (60% yield) 257 With both Stille coupling fragments in hand, we attempted the carbon-carbon bond-forming reaction. In the event, coupling of arene 242 with indole 257 provided intermediate 258 in good yield using conditions developed by Han, Stoltz, and Corey (Scheme 3.5.5).26 At this stage, reduction of the nitro functionality was accomplished under pH-neutral conditions, followed by formation of a sulfonamide to afford diene 259 in 55% yield over the two steps.27 Scheme 3.5.5 Bu3Sn MeO N Ts OMe LiCl, CuCl 10 mol% Pd(PPh3)4 257 NO2 I TBSO 242 DMSO, 60 °C, 20 h NHTs NO2 1. NiCl2•6H2O, NaBH4 MeOH, 23 °C TBSO MeO N Ts (78% yield) TBSO MeO 2. TsCl, pyridine CH2Cl2, 23 °C OMe 258 (60% yield over two steps) N Ts OMe 259 We then subjected tosyl aniline 259 to our conditions developed for the palladium(II)-catalyzed oxidative cyclization conditions (Scheme 3.5.6). Unfortunately, these conditions afforded an intractable mixture of products. We also tried DMSO/O2, although the same mixture of products was formed.28 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 181 Scheme 3.5.6 NHTs TBSO 5 mol% Pd(TFA)2 20 mol% pyridine 3ÅMS, Na2CO3 O2 balloon PhMe, 80 °C AND MeO N Ts OMe 5 mol% Pd(OAc)2 O2 balloon DMSO, 80 °C intractable mixture of products 259 Since our phenolic model system was successful, we reconcentrated our efforts toward accessing the C(5) phenol contained on the indole fragment. 3.6 Further Studies Toward the Pd(II)-catalyzed Oxidative Phenol Cyclization As previously stated, attempts to demethylate N-acetyl 5,7-dimethoxyindole (252, cf. Scheme 3.5.3) were unsuccessful. We speculated that the acetyl unit was cleaved when demethylation was attempted using BBr3. Thus, we replaced the acetyl moiety with a pivaloyl group to provide greater stability and steric bulk, as well as to preserve exclusive functionalization at C(4) (Scheme 3.6.1). Beginning with 5,7-dimethoxyindole (233), protection of the indole nitrogen using pivaloyl chloride provided arene 260 in 83% yield. To our delight, demethylation of indole 260 occurred smoothly at –10 °C using BBr3 to provide bis-phenol 261 in good yield.29 At this stage, selective silylation of the C(5) phenol using TBDPSCl under standard conditions, followed by methylation at C(7) and pivaloate removal led to indole 262 in 90% overall yield. Further functionalization of indole 262 was accomplished by a two-step sequence beginning with Boc protection of the indole nitrogen, followed by silyl cleavage to arrive at phenol 263 in 70% overall yield. It was found that the TBDPS group prevented iodination at C(4) of 182 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations the indole, likely because of steric hindrance, and thus, was replaced with a TBS group. With phenol 263 in hand, protection as a TBS silyl ether occurred readily to yield arene 264. Subsequent iodination using NIS provided indole 265 in 80% yield. By accessing indole 265, we have accomplished our goal of synthesizing a differentially substituted 4,5,7-substituted indole from indole 233. Furthermore, indole 265 should provide vinyl stannane 231 in two additional synthetic transformations. Scheme 3.6.1 MeO MeO HO BBr3 NaH, PivCl N H N Piv DMF, 0 → 23 °C OMe CH2Cl2, –10 °C 7 OMe (83% yield) 233 1. TBDPSCl imidazole CH2Cl2, 23 °C 5 N Piv 2. NaOH, Me2SO4 50 mol% Bu4NBr CH2Cl2/H2O (1:1) OH (65-71% yield) 260 261 (90% yield over 2 steps) (Boc)2O 10 mol% DMAP THF, 23 °C TBDPSO N H OMe 262 HO TBSCl imidazole N Boc then TBAF, 23 °C OMe 263 (70% yield) NIS N Boc CH2Cl2, 23 °C OMe 264 (96% yield) I TBSO TBSO 2 steps TBSO N Boc 265 (81% yield) Bu3Sn 4 OMe CHCl3, 23 °C N Boc OMe 231 Although we are now able to access the C(5) phenol, further functionalization at C(4) is required to reach vinyl stannane 231, which is needed for a Stille coupling and subsequent palladium(II)-catalyzed oxidative phenol cyclization. Thus, optimization of our protecting group strategy, as well as the synthesis of vinyl stannane 231 must occur to continue the synthesis. 183 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 3.7 Conclusions and Future Directions The efforts described in this chapter have established an efficient synthesis to advanced intermediates that can be further functionalized and modified en route to phalarine. In general, the synthesis of 4,5,7 differentially substituted indoles can be difficult; nevertheless, we have developed an efficient route that allows for selective functionalization at each position, and thus allows for the possibility of accessing novel indoles that may be bioactive or found in nature. The key aspects of the proposed synthesis of phalarine involved two palladium(II)-catalyzed oxidative heterocyclizations. Due to the efforts in this chapter, the aniline cyclization can be tested immediately. Furthermore, the synthesis of phenol 267, needed for testing the other palladium(II)-catalyzed oxidative cyclization, is only several synthetic operations away from being synthesized (Scheme 3.7.1). Scheme 3.7.1 NHTs Pd(II)-catalyzed Oxidative TBSO NTs TBSO Aniline Cyclization MeO MeO N Ts N Ts OMe OMe 259 266 Bu3Sn TBSO 1. N Boc OMe LiCl, CuCl 10 mol% Pd(PPh3)4 231 NO2 I PMBO 230 DMSO, 60 °C NO2 NO2 PMBO Pd(II)-catalyzed Oxidative HO PMBO O Phenol Cyclization 2. TBAF, THF N Boc OMe 267 N Boc OMe 268 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 184 Once results from the two palladium(II)-catalyzed oxidative heterocyclizations, shown in Scheme 3.7.1, have been obtained, it should become evident as to how to complete the synthesis of phalarine. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 185 3.8 Experimental Procedures 3.8.1 Materials and Methods Unless otherwise stated, reactions were performed at ambient temperature (typically 20–22 ºC) in flame-dried glassware under an argon or nitrogen atmosphere using dry solvents. Solvents were dried by passage through an activated alumina column under argon. Et3N, iPr2NH, iPr2NEt, and pyridine were freshly distilled from CaH2. Trifluoroacetic acid (99%) was purchased from Aldrich. Tf2O was freshly distilled from P2O5. All other commercially obtained reagents were used as received. Reaction temperatures were controlled by an IKAmag temperature modulator. Thin-layer chromatography (TLC) was performed using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, anisaldehyde, KMnO4, or CAM staining. ICN silica gel (particle size 0.032–0.063 mm) was used for flash chromatography. Optical rotations were measured with a Jasco P-1010 polarimeter at 589 nm. 1H and 13C NMR spectra were recorded on a Varian Mercury 300 (at 300 MHz and 75 MHz respectively), or a Varian Inova 500 (at 500 MHz and 125 MHz respectively) and are reported relative to solvent for 1H NMR (CHCl3 = 7.27 ppm, C6H6 = 7.16 ppm, CH2Cl2 = 5.30 ppm, DMSO = 2.51 ppm) and 13C NMR (CDCl3 = 77.0 ppm, C6D6 = 128.4 ppm). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicitiy, coupling constant (Hz), integration). Multiplicities are reported as follows: s = singlet, d = doublet, t = triplet, q = quartet, hex = hextet, dq = doublet of quartets, dt = doublet of triplets, td = triplet of doublets, dd = doublet of doublets, m = multiplet, comp. m = complex multiplet, app. = apparent, bs = broad singlet. IR spectra were recorded on a Perkin Elmer BX-11 FT-IR spectrometer and are reported in Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 186 frequency of absorption (cm-1). High resolution mass spectra were obtained from the California Institute of Technology Mass Spectral Facility. For reactions involving UV light, a Mercury UV-lamp was used. 3.8.2 Preparation of Compounds OTBS OTBS hν Br CCl4 234 (85% yield) 235 Benzyl Bromide 235. To a solution of arene 23412 (1.00 g, 4.50 mmol, 1.00 equiv) in CCl4 (40 mL) at ambient temperature was added NBS (881 mg, 4.95 mmol, 1.10 equiv). A reflux condenser was fitted onto the reaction (no water) as a precaution. The reaction mixture was then stirred for 2 hours with continuous irradiation using UV light. At this time, TLC (100% Hexanes) showed the reaction was complete. The reaction mixture was filtered with filter paper, washed with minimal CH2Cl2, and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography using 100% Hexanes to provide a clear oil (1.15 g, 85%). All spectroscopic data of benzyl bromide 235 matched those reported by Hartwig.12 1. 236 OTBS Bu3Sn Br 235 10 mol% Pd(PPh3)4 30 mol% AsPh3 DME, 80 °C OH Ph 237 2. TBAF, THF, 23 °C (50% yield over two steps) Phenol 237. A round-bottom flask was charged with benzyl bromide 235 (510 mg, 1.69 mmol, 1.00 equiv) and vinyl stannane 23613 (825 mg, 2.03 mmol, 1.20 equiv), followed Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 187 by DME (17 mL). This solution was sparged for 10 minutes with argon, followed by the sequential addition of AsPh3 (155 mg, 0.507 mmol, 0.300 equiv) and Pd(PPh3)4 (195 mg, 0.169 mmol, 0.100 equiv) at ambient temperature, and fitted with a reflux condenser (no water). The reaction mixture was heated to 80 °C, and monitored by TLC (100% Hexanes). After 6–8 hours, the reaction was complete and diluted with Et2O to provide a white precipitate. This suspension was filtered through a small pad of celite, and the Et2O layer was washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide a crude oil. To this oil was added THF (17 mL) at ambient temperature, followed by TBAF (2.03 mL of 1.0 M solution in THF, 2.03 mmol, 1.20 equiv). After 1 hour , TLC (10:90 EtOAc:Hexanes) showed the reaction was complete. The reaction was diluted with Et2O and water, and the layers were separated. The aqueous layer was extracted 2x with Et2O, and the Et2O layers were combined and washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil. This crude oil was purified by flash chromatography using 7:93 EtOAc:Hexanes to provide phenol 237 as a clear oil (189 mg, 50% yield over two steps). RF = 0.40 (15:85 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.32 (t, J = 7.3 Hz, 2H), 7.24 (t, J = 7.3 Hz, 1H), 7.14 (m, 3H), 7.02 (d, J = 6.8 Hz, 1H), 6.82 (t, J = 8.3 Hz, 2H), 5.64 (q, J = 6.8 Hz, 1H), 5.04 (s, 1H), 3.68 (s, 2H), 1.62 (d, J = 6.8 Hz, 3H); 13C NMR (125 MHz, CDCl3) δ 154.5, 140.2, 139.8, 131.1, 128.3, 128.2, 127.9, 126.8, 124.9, 123.4, 120.8, 115.9, 40.5, 14.7; IR (film) 3468, 3030, 2914, 1592, 1489, 1455, 1215 cm-1; HRMS (FAB+) calc’d for [C16H16O]+: m/z 224.1201, found 224.1206. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations OH Ph 10 mol% Pd(OAc)2, O2 O 188 Ph DMSO, 60 °C, 4 h XX (80% yield) XX Dihydrobenzofuran 238. To a 14/20 fitted glass tube (6.00 mL capacity) containing phenol 237 (10.0 mg, 44.6 µmol, 1.00 equiv) was added Pd(OAc)2 (1.00 mg, 4.46 µmol, 0.100 equiv) followed immediately by DMSO (890 µL) at ambient temperature. A 14/20 fitted glass three-way adapter containing an O2 balloon was attached accordingly. The reaction mixture was purged under vacuum and backfilled with O2, and repeated 4x. The reaction mixture was then heated to 60 °C and monitored by TLC (20:80 EtOAc:Hexanes). After 4 hours the reaction was complete. The reaction mixture was allowed to cool to ambient temperature, and the dark solution was transferred to a biphasic system of Et2O:brine (2:1). The layers were separated, and the aqueous layer was extracted 3x with Et2O. The Et2O layers were combined and washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 20:80 EtOAc:Hexanes to provide dihydrobenzofuran 238 as a colorless oil (8.00 mg, 80%). RF = 0.35 (30:70 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 7.3 Hz, 2H), 7.36 (t, J = 7.6 Hz, 2H), 7.28 (app. d, J = 7.3 Hz, 1H), 7.16 (m, 2H), 6.94 (d, J = 7.8 Hz, 1H), 6.86 (t, J = 7.6 Hz, 1H), 6.23 (dd, J = 10.5, 17.1 Hz, 1H), 5.30 (dd, J = 0.9, 17.1 Hz, 1H), 5.18 (dd, J = 0.9, 10.5 Hz, 1H), 3.60 (d, J = 15.4 Hz, 1H), 3.56 (d, J = 15.4 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ 158.7, 144.0, 141.0, 128.3, 128.2, 127.3, 125.9, 125.4, 124.9, 120.7, 114.0, 109.5, 90.7, 42.8; IR (film) 3056, 3031, 1598, 1480, 1462, 1241; HRMS (FAB+) calc’d for [C16H14O]+: m/z 222.1045, found 222.1035. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 189 OTBS 239 NO2 2 mol% PdCl2(PPh3)4 6 mol% CuI I i-Pr2NH, 23 °C 232 NO2 OTBS (95% yield) 240 Alkyne 240. To a solution of arene 232 (2.50 g, 10.0 mmol, 1.00 equiv) and alkyne 239 (5.11 g, 30.0 mmol, 3.00 equiv) in N,N-diisopropylamine (33 mL) at ambient temperature, PdCl2(PPh3)2 (140 mg, 0.200 mmol, 0.0200 equiv) and CuI (115 mg, 0.600 mmol, 0.0600 equiv) were added sequentially to the reaction. A slurry formed after several minutes, and the reaction mixture was monitored by TLC (20:80 EtOAc:Hexanes). After 30–60 minutes, the reaction was complete, and diluted with saturated NaHCO3 (aq.). The aqueous layer was extracted 3x with Et2O, and the Et2O layer was then washed 2x with water, once with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 5:95 EtOAc:Hexanes to provide alkyne 2 4 0 as an oil (2.77 g, 95% yield). All spectroscopic data were identical to those reported by Sakamoto.30 OTBS 240 NO2 1 mol% PdCl2(PPh3)4 Bu3SnH NO2 SnBu3 THF (0.75 M), 23 °C TBSO (89% yield) 241 Vinyl Stannane 241. To a solution of alkyne 240 (1.00 g, 3.43 mmol, 1.00 equiv) and PdCl2(PPh3)2 (24.0 mg, 0.0343 mmol, 0.0100 equiv) in THF (4.60 mL) at ambient temperature was added Bu3SnH (1.10 mL, 4.12 mmol, 1.20 equiv) over 30 seconds, and the reaction was monitored by TLC (5:95 EtOAc:Hexanes). After 3 hours, the reaction was complete and was concentrated in vacuo to provide a dark oil that was purified by flash chromatography using 1:99 EtOAc:Hexanes to provide vinyl stannane 241 as a Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 190 yellow oil (1.78 g, 89% yield). RF = 0.35 (5:95 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.04 (d, J = 8.3 Hz, 1H), 7.54 (dt, J = 0.7, 7.5 Hz, 1H), 7.33 (dt, J = 1.0, 7.3 Hz, 1H), 7.10 (d, J = 7.8 Hz, 1H), 5.94 (t, J = 5.6 Hz, 1H), 4.02 (t, J = 5.8 Hz, 2H), 1.44 (m, 6H), 1.30 (hex, J = 7.3 Hz, 6H), 0.97–0.84 (m, 24H), 0.020 (s, 3H), 0.00 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 146.0, 143.7, 141.0, 139.9, 133.0, 129.2, 126.0, 124.5, 61.7, 28.8, 27.3, 25.8, 18.2, 13.6, 10.6, –5.2, –5.3; IR (film) 2957, 2929, 2856, 1523, 1464, 1343, 1254, 1102 cm-1; HRMS (FAB+) calc’d for [C27H48SiSnO3N]+: m/z 582.2426, found 582.2451. NO2 SnBu3 NO2 I2 MeCN, 23 °C TBSO I TBSO (76% yield) 241 242 Vinyl Iodide 242. To a solution vinyl stannane 241 (1.10 g, 1.89 mmol, 1.00 equiv) in MeCN (19.0 mL) at ambient temperature was added I2 (528 mg, 2.08 mmol, 1.10 equiv) in several portions, and the reaction was monitored by TLC (5:95 EtOAc:Hexanes). After 1 hour, the reaction was complete, and was quenched with 5% Na2S2O3 (aq.). The reaction mixture was diluted with water and Et2O, and the layers were then separated. The Et2O layer was washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 2:98→5:95 EtOAc:Hexanes to provide vinyl iodide 242 as a pale-yellow oil (600 mg, 76% yield) RF = 0.40 (10:90 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.00 (dd, J = 1.1, 8.2 Hz, 1H), 7.62 (dt, J = 1.2, 7.5 Hz, 1H), 7.48 (dt, J = 1.5, 8.2 Hz, 1H), 7.38 (dd, J = 1.2, 7.6 Hz, 1H), 6.63 (t, J = 6.5 Hz, 1H), 3.88 (dq, J = 6.5, 13.2 Hz, 2H), 0.82 (s, 9H), –0.060 (s, 3H), –0.072 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 147.0, 143.2, 136.3, Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 191 133.3, 130.7, 129.4, 124.7, 88.5, 61.9, 25.8, 18.2, –5.4, –5.5; IR (film) 2954, 2929, 2857, 1529, 1472, 1348, 1257, 1103 cm-1; HRMS (FAB+) calc’d for [C15H23O3NISi]+: m/z 470.0492, found 420.0480. NH Cl3C NO2 244 OPMB NO2 20 mol% La(OTf)3 OH 243 PhMe, 23 °C (86% yield) OPMB 245 Alkyne 245. To a solution of alcohol 243 (448 mg, 2.53 mmol, 1.00 equiv) and reagent 24420a (1.00 g, 3.54 mmol, 1.40 equiv) in PhMe (12.7 mL) at ambient temperature was added La(OTf)3 (296 mg, 0.506 mmol, 0.200 equiv), and the reaction was monitored by TLC (20:80 EtOAc:Hexanes). After 24 hours the reaction was complete by TLC, and quenched with water. The reaction mixture was diluted with Et2O, and the layers are separated. The organic extract was washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide a crude oil that was purified by flash chromatography using 15:85 EtOAc:Hexanes to obtain alkyne 245 as a red-orange semisolid (650 mg, 86% yield). RF = 0.40 (30:70 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.06 (d, J = 7.8 Hz, 1H), 7.65 (dd, J = 1.0, 7.8 Hz, 1H), 7.59 (dt, J = 1.0, 7.8 Hz, 1H), 7.48 (dt, J = 1.5, 7.8 Hz, 1H), 7.36 (d, J = 8.8 Hz, 2H), 6.92 (d, J = 8.8 Hz, 2H), 4.67 (s, 2H), 4.44 (s, 2H), 3.82 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 159.5, 149.8, 134.9, 132.8, 130.0, 129.3, 128.8, 124.6, 118.1, 113.9, 93.6, 81.6, 71.3, 57.3, 55.3; IR (film) 2838, 1610, 1525, 1514, 1343, 1248, 1073, 1034 cm-1; HRMS (FAB+) calc’d for [C17H15O4N]+: m/z 297.1001, found 297.1007. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations NO2 NO2 2 mol% PdCl2(PPh3)4 Bu3SnH OPMB 245 THF, 23 °C 192 SnBu3 PMBO 246 (63% yield) Vinyl Stannane 246. To a solution of alkyne 245 (605 mg, 2.03 mmol, 1.00 equiv) and PdCl2(PPh3)2 (28.5 mg, 0.0406 mmol, 0.0200 equiv) in THF (2.70 mL) at ambient temperature was added Bu3SnH (655 µL, 2.44 mmol, 1.20 equiv) over 60 seconds. The reaction was monitored by TLC (20:80 EtOAc:Hexanes), and was complete after 30 minutes. The reaction mixture was concentrated in vacuo, and the residue was purified by flash chromatography using 6:94 EtOAc:Hexanes to provide vinyl stannane 246 as a neon oil (755 mg, 63% yield). RF = 0.35 (20:80 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.00 (d, J = 8.3 Hz, 1H), 7.48 (dt, J = 1.0, 7.8 Hz, 1H), 7.28 (dt, J = 1.5, 8.3 Hz, 1H), 7.18 (d, J = 8.3 Hz, 2H), 7.04 (dd, J = 1.0, 7.8 Hz, 1H), 6.84 (d, J = 8.3 Hz, 2H), 5.96 (t, J = 5.9 Hz, 1H), 4.32 (d, J = 11.2 Hz, 1H), 4.30 (d, J = 11.2 Hz, 1H), 3.80 (comp. m, 5H), 1.44 (hex, J = 7.3 Hz, 6H), 1.26 (hex., J = 7.3 Hz, 6H), 0.88 (m, 15H); 13C NMR (125 MHz, CDCl3) δ 159.1,147.2, 145.9, 140.9, 136.7, 133.0, 130.3, 129.3, 129.1, 126.1, 124.5, 113.7, 71.8, 67.9, 55.2, 28.8, 27.3, 13.6, 10.7; IR (film) 2956, 2927, 2853, 1613, 1517, 1464, 1342, 1285, 1080, 1038 cm-1; HRMS (FAB+) calc’d for [C25H34SnO4N]+ (–Bu group): m/z 532.1510, found 532.1524. NO2 TIPSCl imidazole OH 243 NO2 DMF, 23 °C (83% yield) OTIPS 247 Alkyne 247. To a solution of alcohol 243 (2.49 g, 14.1 mmol, 1.00 equiv) and imidazole (2.01g, 29.6 mmol, 2.10 equiv) in DMF (56.0 mL) at 0 °C was added TIPSCl (3.04 mL, 14.8 mmol, 1.05 equiv). The reaction mixture was allowed to warm to ambient Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 193 temperature and stir overnight. TLC analysis (30:70 EtOAc:Hexanes) revealed the reaction was complete. The reaction mixture was diluted with water and Et2O, and the layers were separated. The aqueous layer was extracted 3x with Et2O, the Et2O layers were combined, washed 3x with water, once with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 5:95 EtOAc:Hexanes to provide alkyne 247 as a light-yellow oil (3.92 g, 83% yield). RF = 0.30 (10:90 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.10 (dd, J = 1.2, 8.3 Hz, 1H), 7.63 (dd, J = 1.5, 7.8 Hz, 1H), 7.54 (dt, J = 1.2, 7.8 Hz, 1H), 4.69 (s, 2H), 1.20 (comp. m, 21H); 13C NMR (125 MHz, CDCl3) δ 149.4, 134.9, 132.7, 128.6, 124.5, 118.4, 96.2, 79.6, 52.6, 17.9, 12.0; IR (film) 2944, 2866, 1609, 1569, 1530, 1463, 1344, 1261, 1098 cm-1; HRMS (FAB+) calc’d for [C18H28NSiO3]+: m/z 334.1838, found 334.1843. NO2 OTIPS 247 NO2 1 mol% PdCl2(PPh3)4 Bu3SnH SnBu3 THF, 23 °C TIPSO (74% yield) 248 Vinyl Stannane 248. To a solution of alkyne 247 (3.90 g, 11.7 mmol, 1.00 equiv) and PdCl2(PPh3)2 (82.1 mg, 0.117 mmol, 0.0100 equiv) in THF (16.0 mL) at ambient temperature was added Bu3SnH (3.47 mL, 12.9 mmol, 1.10 equiv) over 30–45 seconds. The reaction darkens, and was monitored by TLC (5:95 EtOAc:Hexanes). After stirring overnight, the reaction mixture was concentrated in vacuo to provide a crude oil that was purified by flash chromatography using 2:98 EtOAc:Hexanes to provide vinyl stannane 248 as a neon-yellow liquid (5.44 g, 74% yield). RF = 0.40 (5:95 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.0 (dd, J = 1.2, 8.2 Hz, 1H), 7.50 (dt, J = 1.2, 7.6 Hz, 1H), 7.28 (dt, J = 1.5, 8.3 Hz, 1H), 7.08 (dd, J = 1.5, 7.8 Hz, 1H), 5.93 (t, J = 5.5 Hz, 1H), 4.02 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 194 (m, 2H), 1.44 (hex, J = 7.1 Hz, 6H), 1.25 (hex, J = 7.3 Hz, 6H), 1.00 (s, 18H), 0.86 (m, 18H); 13C NMR (125 MHz, CDCl3) δ 146.1, 143.2, 141.0, 140.3, 133.0, 129.2, 126.0, 124.5, 61.9, 28.8, 27.3, 17.9, 13.6, 12.0, 10.7; IR (film) 2957, 2867, 1524, 1464, 1342, 1105, 1064 cm-1; HRMS (FAB+) calc’d for [C26H46O3NSnSi]+: m/z 568.2269, found 568.2268. MeO CHO MeNO2, NH4OAc MeO NO2 glacial AcOH, 120 °C OMe OMe (72% yield) 249 250 Arene 250. 3,5-dimethoxybenzaldehyde (249) (50.0g, 0.301 mol, 1.00 equiv), nitromethane (50.1 mL, 0.923 mol, 3.07 equiv), and ammonium acetate (76.0 g, 0.998 mol, 1.07 equiv) were dissolved in glacial acetic acid (615 mL) and refluxed for 2 h. The reaction mixture was allowed to cool to ambient temperature, at which time yellow crystals form. The suspension was placed in an ice bath for 30 minutes, and the product was then filtered and washed with cold 95% ethanol to provide compound 250 as yellow needles (45.3 g, 72% yield). All spectroscopic data of arene 250 matched those reported by Black.12 MeO NO2 Cu(NO3)2•5/2H2O MeO NO2 Ac2O, 45 °C OMe 250 NO2 OMe (98% yield) 251 Arene 251. To a flask containing acetic anhydride (380 mL) warmed to 65 °C was added compound 250 (40.0 g, 0.191 mol, 1.00 equiv). This suspension was stirred at 65 °C until all of compound 250 had dissolved. Once homogeneous, the solution was allowed to cool to 45 °C, and Cu(NO3)2•5/2 H2O (30.9 g, 0.105 mol, 0.550 equiv) was added in Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 195 4–5 portions over 1–2 minutes. A slight exotherm occurs, and once brown fumes appeared (ca. 5 min), the reaction was complete and allowed to cool to ambient temperature. The reaction mixture was poured over ice and allowed to stir and warm to ambient temperature overnight. The resulting yellow solid was filtered and washed with water 3x to provide arene 251 (47.6 g, 98% yield). All spectroscopic data of arene 251 matched those reported by Black.12 MeO NO2 NO2 OMe 251 Fe powder MeO 80% AcOH (aq), 80 °C (54% yield) N H OMe 233 Indole 233. Iron powder (32.0 g, 576 mmol, 38.5 equiv) was added to a solution of arene 251 (4.00 g, 15.7 mmol, 1 equiv) in 80% acetic acid (130 mL) and the suspension was stirred mechanically. After an exotherm that lasts approximately 30 minutes, 40 mL of water was added and the suspension was heated to 80 °C for 1 hour. The reaction mixture was then allowed to cool to ambient temperature. Upon cooling, the reaction mixture hardens to become a single solid. This solid was partially dissolved by adding CH2Cl2 and 10% HCl (aq.), followed by manual irritation using a sturdy spatula until stirring with a mechanical stirrer became possible. This suspension stirred for an additional hour, and was then filtered over a large pad of celite. The solids were washed 6x with CH2Cl2, and the resulting biphasic solution was separated respectively. The CH2Cl2 layer was washed 3x with water, followed by slow addition of saturated cold Na2CO3 (aq.) until the organic layer was only slightly acidic (pH = 5–6). The organic layer was then washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide a black solid. This residue was dissolved in minimal CH2Cl2, and purified by Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 196 flash chromatography using 10:90 EtOAc:Hexanes to provide indole 233 as a white crystalline solid (1.50 g, 54% yield).31 All spectroscopic data of arene 233 matched those reported by Black.12 1. powdered KOH DMSO, 23 °C MeO N H OMe 233 MeO N Ac 2. Ac2O, 23 °C (88% yield) OMe 252 Indole 252. To powdered KOH (0.95 g, 16.9 mmol, 3.70 equiv) was added DMSO (20.0 mL) and the suspension was stirred at ambient temperature for 10 min. Indole 233 (0.800 g, 4.52 mmol, 1.00 equiv) was then added in one portion, and the suspension was allowed to stir for 1 hour. At this stage, the resulting solution was rapidly decanted from the excess KOH and transferred to a separate round-bottom flask containing chilled Ac2O (4.00 mL, excess) (ice-bath). The excess KOH was washed rapidly with DMSO (5.00 mL) and quickly transferred to the solution of Ac2O. This solution was allowed to warm to ambient temperature, and stirred under N2 overnight. The reaction mixture was diluted with water and extracted 3x with Et2O. The organic layer was washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 10:90 EtOAc:Hexanes to provide indole 252 as a beige solid (867 g, 88% yield). All spectroscopic data of arene 252 matched those reported by Black.12 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 197 I MeO NIS N Ac OMe 252 MeO N Ac CHCl3, 23 °C (90% yield) OMe 253 Arene 253. To a solution of indole 252 (4.62 g, 21.1 mmol, 1.00 equiv) in CHCl3 (85.0 mL) at 0 °C, was added N-iodosuccinimide (5.22 g, 23.2 mmol, 1.10 equiv) in one portion, and the reaction was monitored by TLC (50:50 CH2Cl2:Hexanes). After 1 hour, the reaction was complete. The reaction mixture was diluted with water and Et2O, and the layers were separated. The aqueous layer was extracted once with Et2O, and the organic extracts were combined and washed successively with 20% Na2S2O3 (aq.), water, and brine. The Et2O layer was dried with MgSO4, filtered, and concentrated in vacuo to provide a solid. This solid was dissolved in minimial CH2Cl2, and was purified by flash chromatography using 50:50 CH2Cl2:Hexanes to obtain arene 253 as a tan solid (6.37 g, 90% yield). RF = 0.20 (15:85 EtOAc:Hexanes); 1H NMR (500 Mhz, CDCl3) δ 7.63 (d, J = 3.7 Hz, 1H), 6.58 (d, J = 3.7 Hz, 1H), 6.52 (s, 1H), 3.99 (s, 3H), 3.96 (s, 3H), 2.64 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 169.1, 155.8, 148.9, 138.3, 128.7, 119.4, 111.4, 94.2, 67.4, 57.5, 56.1, 25.6; IR (film) 2939, 2842, 1733, 1682, 1577, 1371, 1206, 1116, 1100 cm-1; HRMS (FAB)+ calc’d for [C12H12NO3I]+: m/z 344.9862, found 344.9849. I I MeO MeO THF: 10% NaOH (aq) N Ac OMe 253 N H (1:1), 23 °C (98% yield) OMe 254 Indole 254. Indole 253 (5.97 g, 17.3 mmol, 1.00 equiv) was dissolved in THF (80.0 mL) at ambient temperature and stirred vigorously. At this stage, 10% NaOH (aq.) (80.0 mL) was added and the reaction stirred until complete consumption of indole 253 (ca. 1 hour). Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 198 The reaction mixture was diluted with water and EtOAc, and the layers were separated. The aqueous layer was washed once with EtOAc, and the organic extracts were combined and washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide indole 254 as a light-yellow solid (5.20 g, 98% yield).32 RF = 0.25 (20:80 EtOAc:Hexanes); 1H NMR (500 MHz, DMSO-d6) δ 11.4 (br, 1H), 7.28 (t, J = 2.7 Hz, 1H), 6.60 (s, 1H), 6.18 (dt, J = 0.7, 2.2 Hz, 1H), 3.97 (s, 3H), 3.83 (s, 3H); 13C NMR (125, MHz, DMSO-d6) δ 152.4, 146.9, 132.6, 125.9, 121.1, 104.4, 91.9, 65.7, 57.9, 55.7; IR (film) cm-1; HRMS (FAB+) calc’d for [C10H10O2NI]+: m/z 302.9756, found 302.9754. I powdered KOH 20 mol% Bu4NBr TsCl MeO N H OMe 254 I MeO N Ts THF, 0 → 23 °C (75% yield) OMe 255 Arene 255. To a suspension of powdered KOH (4.95 g, 16.3 mmol, 1.15 equiv) and Bu4NBr (788 mg, 2.45 mmol, 0.15 equiv) was added THF (125 mL), and the suspension was cooled to 0 °C. Indole 254 (4.95 g, 16.3 mmol, 1.00 equiv) was then added in one portion to the reaction mixture, and the solution was allowed to stir for 45 minutes at 0 °C. At this stage, TsCl (3.57 g, 18.8 mmol, 1.15 equiv) was added to the reaction mixture in a single portion, and the mixture was allowed to stir for an additional 10 minutes at 0 °C. The reaction mixture was then allowed to warm to ambient temperature and stir overnight. TLC analysis (35:65 CH2Cl2:Hexanes) showed that minimal amounts of indole 254 remained, and thus, the reaction mixture was diluted with water and Et2O. The layers were separated, and the aqueous layer was extracted 2x with Et2O. The organic layers were combined and washed once with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to yield a tan solid. This solid was dissolved in Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 199 minimal CHCl3, and purified by flash chromatography using 35:65→ 7 5 : 2 5 CH2Cl2:Hexanes to afford indole 255 as a white solid (5.51 g, 75% yield).33 RF = 0.30 (40:60 CH2Cl2:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.86 (d, J = 3.9 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.27 (d, J = 8.1 Hz, 1H), 6.64 (d, J = 3.7 Hz), 6.36 (s, 1H), 3.89 (s, 3H), 3.74 (s, 3H), 2.41 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 155.6, 148.2, 144.3, 137.7, 137.0, 129.8, 129.4, 127.3, 119.3, 110.5, 94.2, 67.1, 57.5, 55.8, 21.6; IR (film) 3148, 2939, 2845, 1578, 1463, 1352, 1255, 1213, 1171, 1134, 994 cm-1; HRMS (FAB+) calc’d for [C17H16O4INS]+: m/z 456.9845, found 456.9833. I 1. propynyl-MgBr ZnCl2, THF, 0 °C MeO N Ts OMe 255 2. 5 mol% Pd(PPh3)4 THF, 50 °C (89% yield) MeO N Ts OMe 256 Alkyne 256. ZnCl2 (2.84 mL of 0.5 M solution in THF, 1.42 mmol, 1.30 equiv) was added to THF (5.00 mL) at ambient temperature. The reaction mixture was then cooled to 0 °C, and CH3CCMgBr (2.84 mL of 0.5 M solution in THF, 1.42 mmol, 1.30 equiv) was added and a white precipitate formed. The suspension was stirred for an additional 30 minutes at 0 °C. Indole 255 (500 mg, 1.09 mmol, 1.00 equiv) was charged into a separate round-bottom flask, followed by Pd(PPh3)4 (63.1 mg, 0.0545 mmol, 0.050 equiv) and THF (1.30 mL). This solution was then transferred via cannula to the white suspension at 0 °C, and the resultant suspension was allowed to warm to ambient temperature over 10 minutes. The reaction mixture was then heated to 60 °C and monitored by TLC (30:70 EtOAc:Hexanes). After 40 minutes, the reaction was complete and allowed to cool to ambient temperature. The reaction mixture was diluted with water Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 200 and Et2O, and the layers were then separated. The aqueous layer was washed 2x with Et2O, and the Et2O layers were combined and washed 2x with water, brine, dried with MgSO4, filtered, and concentrated in vacuo to provide a solid residue. This residue was recrystalized from EtOH to provide alkyne 256 as white flakes (357 mg, 89% yield). RF = 0.40 (30:70 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.80 (d, J = 3.7 Hz, 1H), 7.68 (d, J = 8.3 Hz, 2H), 7.24 (d, J = 8.3 Hz, 2H), 6.76 (d, J = 3.7 Hz, 1H), 6.30 (s, 1H), 3.90 (s, 3H), 3.81 (s, 3H), 2.40 (s, 3H), 2.19 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 157.6, 147.2, 144.2, 137.0, 136.1, 129.7, 129.3, 127.2, 119.0, 106.7, 96.9, 93.6, 91.6, 73.2, 56.9, 55.6, 21.5, 4.9; IR (film) 3153, 2940, 2847, 1595, 1490, 1360, 1262, 1209, 1172, 1130, 1107 cm-1; HRMS (FAB+) calc’d for [C20H19O4NS]+: m/z 369.1035, found 369.1033. Bu3Sn 1 mol% PdCl2(PPh3)4 Bu3SnH MeO N Ts OMe 256 MeO N Ts THF (0.75 M), 23 °C (60% yield) OMe 257 Vinyl Stannane 257. To a solution of alkyne 256 (650 mg, 1.76 mmol, 1.00 equiv) in THF (2.50 mL), PdCl2(PPh3)2 (12.4 mg, 0.0176 mmol, 0.0100 equiv) was added and allowed to stir for 5 minutes at ambient temperature. At this stage, Bu3SnH (595 µL, 2.20 mmol, 1.25 equiv) was added dropwise, and the reaction was monitored by TLC (5:95 EtOAc:Hexanes). After 6 hours, the reaction mixture was concentrated, and the crude oil underwent flash chromatography using 5:95 EtOAc:Hexanes to afford vinyl stannane 257 as a pale-yellow oil (700 mg, 60% yield). RF = 0.45 (10:90 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.72 (m, 3H), 7.25 (dd, J = 0.5, 8.5 Hz, 201 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 2H), 6.36 (m, 2H), 6.00 (q, J = 6.4 Hz, 1H), 3.74 (s, 3H), 3.70 (s, 3H), 2.40 (s, 3H), 1.56 (d, J = 6.6 Hz, 3H), 1.36 (m, 6H), 1.20 (hex, J = 7.3 Hz, 6H), 0.80 (m, 15H); 13C NMR (125 MHz, CDCl3) δ 151.5, 145.3, 143.8, 139.8, 137.5, 137.3, 131.3, 129.2, 128.8, 127.2, 119.4, 117.7, 107.3, 94.4, 56.5, 56.0, 28.9, 27.3, 21.6, 17.0, 13.6, 10.2; IR (film) 2955, 2927, 2848, 1592, 1481, 1464, 1360, 1173, 1126 cm-1; HRMS (FAB+) calc’d for [C32H46O4NSSn]+: m/z 660.2170, found 660.2198. Bu3Sn MeO N Ts OMe LiCl, CuCl 10 mol% Pd(PPh3)4 257 NO2 I TBSO 242 DMSO, 60 °C, 20 h NHTs NO2 1. NiCl2•6H2O, NaBH4 MeOH, 23 °C TBSO MeO N Ts (78% yield) OMe 258 TBSO MeO 2. TsCl, pyridine CH2Cl2, 23 °C (60% yield over two steps) N Ts OMe 259 Diene 259. A Schlenck tube (20 mL) was charged with LiCl (118 mg, 2.78 mmol, 6.00 equiv) and flame-dried under vacuum. Upon cooling to ambient temperature, Pd(PPh)4 (53.7 mg, 0.0464 mmol, 0.100 equiv) and CuCl (230 mg, 2.32 mmol, 5.00 equiv) were added, and the mixture was degassed 4x under vacuum with an Ar purge. DMSO (2.50 mL) was introduced with concomitant stirring, followed by a solution of arene 242 (195 mg, 0.464 mmol, 1.00 equiv) and vinyl stannane 257 (368 mg, 0.557 mmol, 1.20 equiv) in DMSO (800 µL, 400 µL rinse). The resulting mixture was rigorously degassed with Ar 4x by the freeze-pump-thaw process (–78 → 23 °C, Ar). The reaction mixture was stirred for an additional 30 minutes at ambient temperature, then heated to 60 °C and followed by TLC (30:70 EtOAc:Hexanes). After 20 hours, the reaction was complete and allowed to cool to ambient temperature. The reaction mixture was diluted with Et2O and washed with a 6:1 mixture of brine:5% NH4OH (aq.). A precipitate forms in the Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 202 aqueous layer, and the two layers are separated. The aqueous layer was extracted 2x with Et2O, and the Et2O extracts are combined and filtered over a small pad of celite. The filtrate was then washed 2x with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 25:75 EtOAc:Hexanes to provide diene 258 as a glue (240 mg, 78% yield). This material was used directly in the next reaction. To a solution of diene 258 (220 mg, 0.332 mmol, 1.00 equiv) in MeOH (6.60 mL) at 0 °C was added NiCl2•6H2O (13.0 mg, 0.664 mmol, 2.00 equiv), and the reaction mixture was allowed to stir until the majority of the NiCl2•6H2O was dissolved. At this stage, NaBH4 (50.2 mg, 1.33 mmol, 4.00 equiv) was added in several portions over 30 seconds, the reaction mixture was then allowed to warm to ambient temperature, and was monitored by TLC (30:70 EtOAc:Hexanes). After 90 minutes the reaction was complete and was quenched with water. The reaction mixture was diluted with Et2O and the layers are separated. The aqueous layer was extracted 3x with Et2O, and the organic extracts are combined, washed with water and brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 20:80 EtOAc:Hexanes to provide an aniline as a white glue (200 mg, 95% yield). This material was used directly in the next reaction. To a solution of the aniline (96.0 mg, 0.152 mmol, 1.00 equiv) in CH2Cl2 (3.00 mL) at ambient temperature was added pyridine (132 µL, 1.22 mmol, 8.00 equiv), and the reaction mixture was stirred for 10 minutes. TsCl (31.8 mg, 0.167 mmol, 1.10 equiv) was then added in one portion, and the reaction was followed by TLC (30:70 EtOAc:Hexanes). After 8 hours, the reaction color was orange-red and was complete. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 203 The reaction mixture was concentrated in vacuo to provide a crude residue. To this residue was added heptane, and the volatiles were removed in vacuo (2x). The resulting residue was purified by flash chromatography using 20:80 EtOAc:Hexanes to provide aniline 259 as a white foam (76 mg, 63% yield). RF = 0.30 (30:70 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.78 (m, 4H), 7.68 (m, 3H), 7.30 (d, J = 8.1 Hz, 2H), 7.27 (dt, J = 1.7, 7.8 Hz, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.04 (dt, J = 1.0, 7.3 Hz, 1H), 7.00 (dd, J = 1.6, 7.4 Hz, 1H), 6.57 (s, 1H), 6.32 (d, J =3.7 Hz, 1H), 5.22 (t, J = 6.4 Hz, 1H), 5.12 (q, J = 6.8 Hz, 1H), 4.02 (s, 3H), 3.8 (s, 3H), 3.64 (dd, J = 6.4, 13.7 Hz, 1H), 3.50 (dd, J = 6.4, 13.7 Hz, 1H), 2.44 (s, 3H), 2.33 (s, 3H), 1.22 (d, J = 6.8 Hz, 3H), 0.77 (s, 9H), –0.18 (s, 3H), –0.19 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 153.2, 147.0, 144.1, 143.4, 137.7, 137.3, 136.5, 136.3, 135.1, 133.8, 131.3, 130.5, 129.6, 129.4, 129.0, 128.6, 127.7, 127.5, 127.4, 127.38, 123.1, 119.2, 117.6, 110.5, 106.4, 94.1, 60.8, 56.9, 55.8, 25.8, 21.6, 21.5, 18.1, 15.4, –5.2, –5.3; IR (film) 3283, 2918, 2850,1598, 1493, 1349, 1254, 1168, 1092 cm-1; HRMS (FAB+) calc’d for [C42H50O7SiS2N2]+: m/z 786.2829, found 786.2862. MeO MeO NaH, PivCl N H 233 N Piv DMF, 0 → 23 °C OMe OMe (83% yield) 260 Indole 260. DMF (82 mL) was added to a round-bottom flask charged with NaH (1.33 g, 55.5 mmol, 3.00 equiv) at ambient temperature. The suspension was cooled to 0 °C and allowed to stir for 10 minutes. Subsequent dropwise addition of a solution of indole 233 (3.28 g, 18.5 mmol, 1.00 equiv) in DMF (8.00 mL, 4.00 mL rinse) to the NaH suspension resulted in bubbling. The reaction mixture was stirred for 20 minutes at 0 °C, PivCl (9.10 mL, 74.0 mmol, 4.00 equiv) was added, and the reaction mixture was allowed to slowly Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 204 warm to ambient temperature over 3 hours. After 3 additional hours of stirring, the reaction was complete by TLC (10:90 EtOAc:Hexanes). The reaction mixture was diluted with water and Et2O, and the layers were separated. The aqueous layer was extracted 3x with Et2O, and the organic extracts were combined and washed 3x with water, once with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 5:95 EtOAc:Hexanes to afford indole 260 as a clear oil (4.03 g, 83% yield). RF = 0.40 (20:80 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.36 (d, J = 3.4 Hz, 1H), 6.66 (d, J = 2.1 Hz, 1H), 6.49 (d, J = 3.4 Hz, 1H), 6.47 (d, J = 2.1 Hz, 1H), 3.91 (s, 3H), 3.87 (s, 3H), 1.49 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 179.4, 157.0, 148.4, 131.7, 126,4, 121.7, 106.2, 96.6, 94.3, 55.8, 55.6, 42.5, 28.6; IR (film) 2968, 1719, 1612, 1592, 1478, 1287, 1204, 1174 cm-1; HRMS (FAB+) calc’d for [C15H19NO3]+: m/z 261.1365, found 261.1356. MeO HO BBr3 N Piv 260 N Piv CH2Cl2, –10 °C OMe OH (65-71% yield) 261 Bis Phenol 261. A solution of indole 260 (500 mg, 1.91 mmol, 1.00 equiv) in CH2Cl2 (38.0 mL) was cooled to –10 °C (super-saturated brine/ice bath), and stirred for 5 minutes. At this stage, BBr3 (3.83 mL of a 1.0 M solution in CH2Cl2, 3.83 mmol, 2.00 equiv) was added dropwise over 2 minutes. The reaction was monitored by TLC (20:80 EtOAc:Hexanes), and was complete after ca. 25 minutes. The reaction mixture was quenched and diluted with water, and the solution was allowed to warm to ambient temperature. The layers were separated, and the aqueous layer was extracted 3x with EtOAc, The organic extracts were combined, washed with brine, dried with MgSO4, Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 205 filtered, and concentrated in vacuo to provide a crude oil that was purified by flash chromatography using 10:90 EtOAc:Hexanes to provide indole 261 as a white solid (315 mg, 71% yield). RF = 0.45 (30:70 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 11.17 (s, 1H), 7.64 (d, J = 3.9 Hz, 1H), 6.52 (d, J = 3.9 Hz, 1H), 6.46 (d, J = 2.2 Hz, 1H), 6.42 (d, J = 2.2 Hz), 4.81 (br, 1H), 1.56 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 178.9, 154.6, 146.5, 133.4, 126.7, 119.7, 110.9, 102.2, 97.5, 41.2, 29.1; IR (film) 3370, 2982, 2936, 1646, 1603, 1462, 1412, 1340, 1300, 1190 cm-1; HRMS (FAB+) calc’d for [C13H15O3N]+: m/z 233.1052, found 233.1049. 1. TBDPSCl imidazole CH2Cl2, 23 °C HO N Piv OH 2. NaOH, Me2SO4 50 mol% Bu4NBr CH2Cl2/H2O (1:1) 261 TBDPSO N H OMe 262 (90% yield over 2 steps) Arene 262. Indole 261 (1.43 g, 6.13 mmol, 1.00 equiv) and imidazole (920 mg, 13.5 mmol, 2.20 equiv) were dissolved in CH2Cl2 (61 mL) at ambient temperature. To this solution was added TBDPSCl (1.75 mL, 6.74 mmol, 1.10 equiv), and after 1–2 minutes a white precipitate formed. The reaction mixture was allowed to stir at ambient temperature for 6–12 hours, and monitored by TLC (20:80 EtOAc:Hexanes). Upon completion, the reaction mixture was quenched with water and then diluted with Et2O. The layers were separated, the aqueous layer was washed 2x with Et2O, and the organic extracts were combined and washed with brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was used directly in the next reaction (2.83 g, 98% yield). Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 206 To a solution of the previous product (5.85 g, 12.4 mmol, 1.00 equiv) and Bu4NBr (2.00 g, 6.20 mmol, 0.500 equiv) in CH2Cl2 (225 mL) at ambient temperature was added dimethyl sulfate (2.36 mL, 24.8 mmol, 2.00 equiv), and the reaction mixture was allowed to stir for several minutes. At this stage, a solution of NaOH (1.50 mg, 37.2 mmol, 3.00 equiv) in water (225 mL) was added, and the reaction mixture was stirred vigorously and monitored by TLC (20:80 EtOAc:Hexanes). After 3 hours, the reaction was complete, and the layers were separated. The aqueous layer was extracted once with CH2Cl2. The organic extracts were combined and washed with water, brine, dried with MgSO4, filtered, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 7:93 EtOAc:Hexanes to provide indole 262 as a white foam (4.60 g, 92% yield, 90% yield over 2 steps). RF = 0.40 (20:80 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 8.06 (br, 1H), 7.78 (app. d, J = 6.8 Hz, 4H), 7.40 (m, 6H), 7.08 (s, 1H), 6.60 (s, 1H), 6.28 (s, 1H), 6.20 (s, 1H), 3.75 (s, 3H), 1.18 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 149.9, 145.7, 135.7, 133.7, 129.6, 128.4, 127.6, 123.8, 121.8, 102.6, 101.9, 97.5, 55.1, 26.7, 19.5; IR (film) 3436, 2958, 2932, 2858, 1586, 1478, 1428, 1313, 1151, 1114 cm-1; HRMS (FAB+) calc’d for [C25H27O2SiN]+: m/z 401.1811, found 401.1831. (Boc)2O 10 mol% DMAP THF, 23 °C TBDPSO N H OMe 262 then TBAF, 23 °C (70% yield) HO N Boc OMe 263 Phenol 263. To a solution of indole 262 (4.41 g, 11.0 mmol, 1.00 equiv) and DMAP (134 mg, 1.10 mmol, 0.100 equiv) in THF (110 mL) at ambient temperature was added (Boc)2O (2.92 mL, 12.7 mmol, 1.15 equiv), and the reaction was monitored by TLC (20:80 EtOAc:Hexanes). Once complete (ca. 1 h), TBAF (12.1 mL from 1.0 M solution Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 207 in THF, 12.1 mmol, 1.10 equiv) was added to the reaction and monitored by TLC (20:80 EtOAc:Hexanes). The reaction was complete after 2–3 hours, and all the volatiles were removed in vacuo to provide an oil that was purified by flash chromatography using 20:80 EtOAc:Hexanes to provide phenol 263 as a light-red oil (2.00 g, 70% yield over 2 steps). RF = 0.35 (30:70 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 3.4 Hz, 1H), 6.56 (d, J = 2.4 Hz, 1H), 6.41 (d, J = 2.4 Hz, 1H), 6.39 (d, J = 3.4 Hz, 1H), 5.02 (br, 1H), 3.90 (s, 3H), 1.61 (s, 9H); 13C NMR (125 MHz, CDCl3) δ 152.6, 149.5, 148.9, 133.9, 129.2, 119.5, 106.7, 98.0, 97.0, 83.1, 55.8, 28.0; IR (film) 3428, 2980, 2935, 1727, 1596, 1369, 1345, 1303, 1258, 1145 cm-1; HRMS (FAB+) calc’d for [C14H17O4N]+: m/z 263.1158, found 263.1167. HO TBSO N Boc OMe 263 TBSCl imidazole CH2Cl2, 23 °C (96% yield) N Boc OMe 264 Indole 264. To a solution of phenol 263 (575 mg, 2.18 mmol, 1.00 equiv) and imidazole (327 mg, 4.80 mmol, 2.20 equiv) in CH2Cl2 (21.8 mL) at ambient temperature was added TBSCl (362 mg, 2.40 mmol, 1.10 equiv), and a white precipitate formed after 1 minute. The reaction mixture was allowed to stir and monitored by TLC (5:95 EtOAc:Hexanes). After 6 hours the reaction was complete. The reaction mixture was filtered through filter paper, washed with CH2Cl2, and concentrated in vacuo to provide an oil that was purified by flash chromatography using 3:97 EtOAc:Hexanes to provide indole 264 as a clear oil (1.05 g, 96% yield). RF = 0.40 (10:90 EtOAc:Hexanes); 1H NMR (500 MHz, CDCl3) δ 7.50 (d, J = 3.6 Hz, 1H), 6.60 (d, J = 2.0 Hz, 1H), 6.42 (d, J = 3.6 Hz, 1H), 6.38 (d, J = 2.0 Hz, 1H), 3.91 (s, 3H), 1.63 (s, 9H), 1.01 (s, 3H), 0.23 (s, 6H); 13C NMR (125 MHz, Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 208 CDCl3) δ 152.3, 149.5, 148.5, 133.7, 128.9, 120.0, 106.9, 103.1, 101.5, 82.9, 55.8, 28.0, 25.8, 18.2, -4.4; IR (film) 2956, 2931, 2858, 1728, 1586, 1473, 1368, 1294, 1150 cm-1; HRMS (FAB+) calc’d for [C20H31SiNO4]+: m/z 377.2022, found 377.2005. I TBSO TBSO NIS N Boc OMe 264 CHCl3, 23 °C (81% yield) N Boc OMe 265 Arene 265. To a solution of indole 264 (765 mg, 2.03 mmol, 1.00 equiv) in CHCl3 (15.0 mL) at ambient temperature was added N-iodosuccinimide (477 mg, 2.13 mmol, 1.05 equiv) in one portion, and the reaction was monitored by TLC (5:95 EtOAc:Hexanes). The reaction mixture color changes upon the addition of NIS from colorless to wine-red over 30–60 minutes. The reaction was complete after 3 hours, and was quenched with H2O (3.00 mL). To this mixture was added 5 drops of saturated Na2S2O3 (aq.), and the mixture was allowed to stir for 20 minutes. At this stage, the layers were separated, the organic layer was diluted with Et2O, washed once with brine, dried with MgSO4, filtered, concentrated in vacuo to provide a dark oil that was purified by flash chromatography using 5:95 EtOAc:Hexanes to provide arene 265 as a clear oil (830 mg, 81% yield). RF = 0.40 (30:70 EtOAc:Hexanes); RF = 0.40 (10:90 EtOAc:Hexanes); 1H NMR (500 MHz, C6D6) δ 7.48 (d, J = 3.7 Hz, 1H), 6.58 (d, J = 3.7 Hz, 1H), 6.38 (s, 1H), 3.38 (s, 3H), 1.38 (s, 9H), 1.16 (s, 9H), 0.24 (s, 6H); 13C NMR (125 MHz, CDCl3) δ 152.8, 149.8, 138.5, 129.8, 128.7, 120.6, 111.6, 101.0, 83.1, 71.9, 55.8, 28.1, 26.6, 19.0, -3.3; IR (film) 2957, 2931, 2858, 1732, 1574, 1469, 1360, 1292, 1271, 1209, 1158 cm-1; HRMS (FAB+) calc’d for [C20H3O4NSiI]+: m/z 503.0989, found 503.1011. 209 Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 3.9 Notes and References 1 Anderton, N.; Cockrum, P. A.; Colegate, S. M.; Edgar, J. A.; Flower, K.; Gardner, D.; Willing, R. I. Phytochemistry 1999, 51, 153–157. 2 Energy minimization calculations for Spartan were accomplished using AM1, equilibration geometry. 3 Chan, C.; Li, C.; Zhang, F.; Danishefsky, S. J. Tetrahedron Lett. 2006, 47, 4839–4841. 4 The phenolic oxygen is bound to C(3) of the indole in the natural product, not C(2). 5 The mechanism for formation of phenol 213 has not been fully elucidated; however, Danishefsky proposes two possible mechanisms (ref. 3): Cl olefin isomerization NCO2Me N H SN2' 269 Cl N N H NCO2Me MeO NCO2Me OH OMe 212 [3,3] MeO OMe phenol XX O N H 213 NCO2Me 270 6 For the synthesis of racemic phalarine, see: Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2007, 46, 1448–1550. For the asymmetric synthesis, see: Trzupek, J. D.; Lee, D.; Crowley, B. M.; Marathias, V. M.; Danishefsky, S. J. J. Am. Chem. Soc. 2010, 132, 8506–8512. 7 Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2007, 46, 1444–1447. 8 Gramine is 2-(N,N-dimethylaminomethylene)indole. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 9 210 The synthesis of oxindole 214 required three additional steps starting from tetrahydroβ-carboline 203. See: ref. 8 for synthetic details. 10 The mechanisms for the conversion of intermediates 224 and 225 to pentacycle 226 were shown in Schemes 3.2.1 and 3.2.2. 11 For several examples of palladium(II)-catalyzed oxidative heterocyclizations onto styrenyl olefins, see: a) Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584–3585. b) Larock, R. C.; Wei, L.; Hightower, T. R. Synlett 1998, 522–524. c) Trend, R.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778–17788. 12 For the synthesis of arene 234, see: Kataoko, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553–5566. 13 For the synthesis of vinyl stannane 236, see: Miyake, H.; Yamamura, K. Chem. Lett. 1989, 18, 981–984. 14 For examples of phenol cyclizations, see: a) Larock, R. C.; Wei, L.; Hightower, T. Synlett 1998, 522–524. b) For examples of alcohol cyclizations, see, Rönn, M.; Bäckvall, J.-E.; Andersson, P. G. Tetrahedron Lett. 1995, 36, 7749–7752. c) For examples of acid cyclizations, see: Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298–5300. d) For examples of tosylamide cyclizations, see: Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584–3585, and references therein. 15 a) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2003, 42, 2892–2895. b) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778–17788. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 16 211 Most cyclizations of this type using either Stoltz’s conditions or DMSO/O2 require >12 hours for acceptable conversion (>50%). 17 Liron, F.; Garrec, P. L.; Alami, M. Synlett 1999, 246–248. 18 Liron, F.; Gervais, M.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron Lett. 2003, 44, 2789–2794. 19 Yin, Y.; Ma, W.; Chai, Z.; Zhao, G. J. Org. Chem. 2007, 72, 5731–5736. 20 a) Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.; Danishefsky, S. J. J. Org. Chem. 1989, 54, 3738–3740. b) Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267-2269. 21 Condie, G. C.; Channon, M. F.; Ivory, A. J.; Kumar, N.; Black, D. S. Tetrahedron 2005, 61, 4989–5004. 22 Slight modifications to the first two reaction conditions provided higher yields. See S.I. for reaction details. 23 Henry, L. Compt. Rend. 1895, 120, 1265. For more recent examples, see: a) Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem. Int. Ed. 2005, 44, 3881–3884. b) Chung, W. K.; Chiu, P. Synlett 2005, 55–58. c) Bernardi, L.; Bomini, B. F.; Capito, E.; Dessole, G.; Comes-Franchini, M.; Fochi, M.; Ricci, A. J. Org. Chem. 2004, 69, 8168–8171. 24 Conditions screened include: BBr3, BCl3, TiCl4, TMSI, and NaSEt with Δ. 25 All other electron donating protecting groups, as well as a tosyl protecting group, led to C(2) or C(3) functionalization of indole 252. 26 Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600–7605. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 27 212 The formation of the sulfonamide was a surprisingly difficult reaction. The starting aniline and the product seemed to be sensitive to both acid and base, resulting in an unidentified impurity that made purification difficult. 28 Although we were able to test the palladium(II)-catalyzed oxidative aniline cyclization, it appears that the aniline cyclized onto the wrong olefin Even though it is not conclusive, there is no N-H stretch in the IR, and a HRMS of the products shows a mass corresponding to loss of H2. Moreover, the 1H NMR clearly shows which vinyl proton remains in the product. 29 It should be noted that demethylation with one equivalent of BBr3 cleanly afforded the C(7) mono-demethylated product. Although undesired for our studies, this selective transformation could prove valuable for the synthesis of other natural products or biologically active molecules. 30 Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126–1136. 31 a) When the reaction is run with 25 g of arene 251, the yield for indole 233 is between 40–45%. b) The synthesis of indole 233 is also reported by Borchardt; however, several attempts using this procedure resulted in 30–40% yields of indole 233, see: Sinhababu, A. K.; Borchardt, R. T. J. Org. Chem. 1983, 48, 3347–3349. 32 Indole 254 should be kept in a –20 °C freezer under Ar, away from light. 33 Indole 255 can also be recrystallized from hot EtOH. However, prolonged heating to dissolve the final 5% of solid should be avoided, as decomposition and darkening of the solution occurs. Instead, once 95% of indole 255 has dissolved, perform a hot filtration and rinse, followed by cooling to effect crystallization and avoid decomposition. Chapter 3 – Synthetic efforts toward (–)-phalarine using palladium(II)-catalyzed oxidative heterocyclizations 213 213 Appendix 3.1 Spectra of Compounds Relevant to Chapter Three Ph 237 OH Figure A3.1.1 1H NMR (500 MHz, CDCl3) of compound 237 214 215 Figure A3.1.2 Infrared spectrum (film/NaCl) of compound 237 Figure A3.1.3 13C NMR (125 MHz, CDCl3) of compound 237 238 O Ph Figure A3.1.4 1H NMR (500 MHz, CDCl3) of compound 238 216 217 Figure A3.1.5 Infrared spectrum (film/NaCl) of compound 238 Figure A3.1.6 13C NMR (125 MHz, CDCl3) of compound 238 240 NO2 OTBS Figure A3.1.7 1H NMR (500 MHz, CDCl3) of compound 240 218 TBSO 241 SnBu3 NO2 Figure A3.1.8 1H NMR (500 MHz, CDCl3) of compound 241 219 220 Figure A3.1.9 Infrared spectrum (film/NaCl) of compound 241 Figure A3.1.10 13C NMR (125 MHz, CDCl3) of compound 241 242 TBSO I NO2 Figure A3.1.11 1H NMR (500 MHz, CDCl3) of compound 242 221 222 Figure A3.1.12 Infrared spectrum (film/NaCl) of compound 242 Figure A3.1.13 13C NMR (125 MHz, CDCl3) of compound 242 245 NO2 OPMB Figure A3.1.14 1H NMR (500 MHz, CDCl3) of compound 245 223 224 Figure A3.1.15 Infrared spectrum (film/NaCl) of compound 245 Figure A3.1.16 13C NMR (125 MHz, CDCl3) of compound 245 PMBO 246 SnBu3 NO2 Figure A3.1.17 1H NMR (500 MHz, CDCl3) of compound 246 225 226 Figure A3.1.18 Infrared spectrum (film/NaCl) of compound 246 Figure A3.1.19 13C NMR (125 MHz, CDCl3) of compound 246 247 NO2 OTIPS Figure A3.1.20 1H NMR (500 MHz, CDCl3) of compound 247 227 228 Figure A3.1.21 Infrared spectrum (film/NaCl) of compound 247 Figure A3.1.22 13C NMR (125 MHz, CDCl3) of compound 247 TIPSO 248 SnBu3 NO2 Figure A3.1.23 1H NMR (500 MHz, CDCl3) of compound 248 229 230 Figure A3.1.24 Infrared spectrum (film/NaCl) of compound 248 Figure A3.1.25 13C NMR (125 MHz, CDCl3) of compound 248 MeO 250 OMe NO2 Figure A3.1.26 1H NMR (300 MHz, CDCl3) of compound 250 231 MeO NO2 251 OMe NO2 Figure A3.1.27 1H NMR (300 MHz, CDCl3) of compound 251 232 MeO 233 OMe N H Figure A3.1.28 1H NMR (300 MHz, CDCl3) of compound 233 233 MeO 252 OMe N Ac Figure A3.1.29 1H NMR (300 MHz, CDCl3) of compound 252 234 MeO 253 OMe I N Ac Figure A3.1.30 1H NMR (300 MHz, CDCl3) of compound 253 235 236 Figure A3.1.31 Infrared spectrum (film/NaCl) of compound 253 Figure A3.1.32 13C NMR (125 MHz, CDCl3) of compound 253 MeO 254 OMe I N H Figure A3.1.33 1H NMR (500 MHz,d6-DMSO) of compound 254 237 238 Figure A3.1.34 Infrared spectrum (film/NaCl) of compound 254 Figure A3.1.35 13C NMR (125 MHz, d6-DMSO) of compound 254 MeO 255 OMe I N Ts Figure A3.1.36 1H NMR (500 MHz, CDCl3) of compound 255 239 240 Figure A3.1.37 Infrared spectrum (film/NaCl) of compound 255 Figure A3.1.38 13C NMR (125 MHz, CDCl3) of compound 255 MeO 256 OMe N Ts Figure A3.1.39 1H NMR (500 MHz, CDCl3) of compound 256 241 242 Figure A3.1.40 Infrared spectrum (film/NaCl) of compound 256 Figure A3.1.41 13C NMR (125 MHz, CDCl3) of compound 256 MeO Bu3Sn 257 OMe N Ts Figure A3.1.42 1H NMR (500 MHz, CDCl3) of compound 257 243 244 Figure A3.1.43 Infrared spectrum (film/NaCl) of compound 257 Figure A3.1.44 13C NMR (125 MHz, CDCl3) of compound 257 TBSO 259 MeO OMe N Ts NHTs Figure A3.1.45 1H NMR (500 MHz, CDCl3) of compound 259 245 246 Figure A3.1.46 Infrared spectrum (film/NaCl) of compound 259 Figure A3.1.47 13C NMR (125 MHz, CDCl3) of compound 259 MeO 260 OMe N Piv Figure A3.1.48 1H NMR (500 MHz, CDCl3) of compound 260 247 248 Figure A3.1.49 Infrared spectrum (film/NaCl) of compound 260 Figure A3.1.50 13C NMR (125 MHz, CDCl3) of compound 260 HO 261 OH N Piv Figure A3.1.51 1H NMR (500 MHz, CDCl3) of compound 261 249 250 Figure A3.1.52 Infrared spectrum (film/NaCl) of compound 261 Figure A3.1.53 13C NMR (125 MHz, CDCl3) of compound 261 TBDPSO 262 OMe N H Figure A3.1.54 1H NMR (500 MHz, CDCl3) of compound 262 251 252 Figure A3.1.55 Infrared spectrum (film/NaCl) of compound 262 Figure A3.1.56 13C NMR (125 MHz, CDCl3) of compound 262 HO 263 OMe N Boc Figure A3.157 1 H NMR (500 MHz, CDCl3) of compound 263 253 254 Figure A3.1.58 Infrared spectrum (film/NaCl) of compound 263 Figure A3.1.59 13C NMR (125 MHz, CDCl3) of compound 263 TBSO 264 OMe N Boc Figure A3.1.60 1H NMR (500 MHz, CDCl3) of compound 264 255 256 Figure A3.1.61 Infrared spectrum (film/NaCl) of compound 264 Figure A3.1.62 13C NMR (125 MHz, CDCl3) of compound 264 TBSO 265 OMe I N Boc Figure A3.1.63 1H NMR (500 MHz, CDCl3) of compound 265 257 258 Figure A3.1.64 Infrared spectrum (film/NaCl) of compound 265 Figure A3.1.65 13C NMR (125 MHz, CDCl3) of compound 265 259 Index Index aniline 11, 16, 24, 171, 177, 179, 180, 183 bielschowskysin 9, 19, 25–30, 36, 43, 46, 47 cyclobutane 26–31, 37, 38, 43, 44, 46, 47 cyclopropane 29, 30, 35, 37–43, 45, 47 diene 12, 174, 175, 177, 180 furan 27, 30, 31, 37, 41–44, 46 heterocyclization 10–14, 16–19, 168, 175, 177, 183, 184 indole 169–175, 177–183 Negishi coupling 179 oxidative kinetic resolution 1–9, 19, 25, 30, 35–37, 47 palladation 14–18 Pictet-Spengler 171, 173 Phalarine 19, 168–174, 183, 184 Phenol 11, 15–17, 33, 170–172, 175, 177, 181–183 Stille coupling 174, 175, 178–180, 182 Suzuki coupling 30 trans-esterification 39–42, 47 260 Notebook Cross-Reference The following notebook cross-reference has been included to facilitate access to the original spectroscopic data obtained for the compounds presented in this thesis. All of the spectroscopic data for every compound listed below can also be found in a hardcopy characterization binder labeled “MEM-CHARACTER”, which can be found in the Stoltz archives. Table NCR-1 Compounds Appearing in Chapter 2. Compound 1 Enone 136 H NMR 13 C NMR IR JHP-1-29 JHP-1-29 JHP-1-29 Alcohol 128 MEM-16-299 MEM-16-299 MEM-16-299 Acid 139 MEM-6-153 N/A MEM-6-149 Enone 127 MEM-17-63 MEM-17-63 MEM-17-63 Substrate 141 MEM-6-151 N/A MEM-6-151 Substrate 143 MEM-6-165 MEM-6-165 MEM-6-165 Substrate 145 MEM-6-187 MEM-6-187 MEM-6-187 261 Substrate 147 MEM-6-199 N/A MEM-6-199 Substrate 149 MEM-6-195 MEM-6-195 MEM-6-195 Substrate 151 MEM-6-207 N/A MEM-6-207 Substrate 153 MEM-6-159 MEM-6-159 MEM-6-159 Substrate 155 MEM-6-165 MEM-6-165 MEM-6-165 Substrate 157 MEM-6-227 MEM-6-227 MEM-6-227 Hydroxy Enone 158 MEM-6-267 MEM-6-257 MEM-6-267 Substrate 159 MEM-6-261 MEM-6-261 MEM-6-261 Substrate 161 MEM-6-287 MEM-6-287 MEM-6-287 Substrate 163 MEM-6-203 MEM-6-203 MEM-6-203 Alcohol 37 MEM-17-71 MEM-17-71 MEM-17-71 Allylic Alcohol 164 JHP-1-49 JHP-1-49 JHP-1-49 Ester 165 JHP-1-149 JHP-1-149 JHP-1-149 Cyclopropane 166 JHP-1-237 JHP-1-237 JHP-1-237 Alcohol 171 JHP-1-243 JHP-1-243 JHP-1-243 Ketone 172 JHP-2-131 JHP-2-131 JHP-2-131 Alcohol 168 JHP-2-207 JHP-2-207 JHP-2-207 Furan 169 JHP-3-43 JHP-3-43 JHP-3-43 Cyclopropane 173 JHP-3-181 JHP-3-181 JHP-3-181 Cyclopropane 174 JHP-3-179 JHP-3-179 JHP-3-179 Cyclopropane 175 JHP-3-183 JHP-3-183 JHP-3-183 Cyclopropane 176 JHP-3-303 JHP-3-303 JHP-3-303 262 Cyclopropane 177 MEM-9-83 MEM-9-83 MEM-9-83 Furan 182 MEM-8-231 MEM-8-231 MEM-8-231 Table NCR-2 Compounds Appearing in Chapter 3. Compound 1 H NMR 13 C NMR IR Phenol 237 MEM-17-109 MEM-17-109 MEM-17-109 Dihydrobenzofuran 238 MEM-16-167 MEM-16-167 MEM-16-167 Alkyne 240 MEM-12-143 N/A MEM-12-143 Vinyl Stannane 241 MEM-14-163 MEM-14-163 MEM-14-163 Vinyl Iodide 242 MEM-14-167 MEM-14-167 MEM-14-167 Alkyne 245 MEM-17-49 MEM-17-49 MEM-17-49 Vinyl Stannane 246 MEM-17-51 MEM-17-51 MEM-17-51 Alkyne 247 MEM-15-197 MEM-15-197 MEM-15-197 Vinyl Stannane 248 MEM-15-199 MEM-15-199 MEM-15-199 Arene 250 MEM-12-261 N/A N/A Arene 251 MEM-12-265 N/A N/A Indole 233 MEM-13-35 N/A N/A Indole 252 MEM-13-253 N/A N/A Arene 253 MEM-14-133 MEM-14-133 MEM-14-133 Indole 254 MEM-15-177 MEM-15-177 MEM-15-177 Arene 255 MEM-14-195 MEM-14-195 MEM-14-195 Alkyne 256 MEM-14-209 MEM-14-209 MEM-14-209 263 Vinyl Stannane 257 MEM-15-119 MEM-15-119 MEM-15-119 Diene 259 MEM-15-107(103) MEM-15-107(103) MEM-15-107 Indole 260 MEM-16-175 MEM-16-175 MEM-16-175 Bis Phenol 261 MEM-16-177 MEM-16-177 MEM-16-177 Arene 262 MEM-16-207(203) MEM-16-207(203) MEM-16-207 Phenol 263 MEM-16-221 MEM-16-221 MEM-16-221 Indole 264 MEM-17-127 MEM-17-127 MEM-17-127 Arene 265 MEM-17-129 MEM-17-129 MEM-17-129 All notebook entries (e.g., MEM-16-207) refer not only to notebook page, but also the NMR file. If (#) follows the notebook entry, this means that the NMR file was incorrectly saved with the wrong page number (e.g., Arene 262’s notebook reference is MEM-16-207, but its NMR file is MEM-16-203). Comprehensive Bibliography 264 COMPREHENSIVE BIBLIOGRAPHY Anderton, N.; Cockrum, P. A.; Colegate, S. M.; Edgar, J. A.; Flower, K.; Gardner, D.; Willing, R. I. Phytochemistry 1999, 51, 153–157. Arai, M. A.; Kuraishi, M.; Arai, T.; Sasai, H. J. Am. Chem. Soc. 2001, 123, 2907–2908. Arita, S.; Koike, T.; Kayaki, Y.; Ikariya, T. Angew. Chem. 2008, 120, 2481–2483. Audia, J. E.; Boisvert, L.; Patten, A. D.; Villalobos, A.; Danishefsk, S. J. J. Org. Chem. 1989, 54, 3738–3740. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Chem. Soc., Chem. Commun. 1977, 264. Bäckvall, J.-E.; Åkermark, B.; Ljunggren, S. O. J. Am. Chem. Soc. 1979, 101, 2411–2416. Bagdanoff, J. T.; Ebner, D. C.; Ramtohul, Y. K.: Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745–13754. Bernardi, L.; Bomini, B. F.; Capito, E.; Dessole, G.; Comes-Franchini, M.; Fochi, M.; Ricci, A. J. Org. Chem. 2004, 69, 8168–8171. Comprehensive Bibliography 265 Callant, P.; Wilde, H. D.; Vaderwalle, M. Tetrahedron 1981, 37, 2079–2084. Chan, C.; Li, C.; Zhang, F.; Danishefsky, S. J. Tetrahedron Lett. 2006, 47, 4839–4841. Chen, C.-T.; Bettigeri, S.; Weng, S.-S.; Pawar, V. D.; Lin, Y.-H.; Liu, C.-Y.; Lee, W.-Z. J. Org. Chem. 2007, 72, 8175–8185. Chung, W. K.; Chiu, P. Synlett 2005, 55–58. Condie, G. C.; Channon, M. F.; Ivory, A. J.; Kumar, N.; Black, D. S. Tetrahedron 2005, 61, 4989–5004. Corey, E. J.; Myers, A. G. Tetrahedron Lett. 1984, 25, 3559–3562. Corey, E. J.; Wess, G.; Xiang, Y. B.; Singh, A. K. J. Am. Chem. Soc. 1987, 109, 4717–4718. Cotton, H. K.; Verboom, R. C.; Johansson, L.; Plietker, B. J.; Bäckvall, J.-E. Organometallics 2002, 21, 3367–3375. Curran, T. T.; Hay, D. A.; Koegel, C. P. Tetrahedron 1997, 53, 1983–2004. Danishefsky, S.; Dynak, J. J. Org. Chem. 1974, 39, 1979–1980. D’Auria, M. Heterocycles 2000, 52, 185–194. Dess, D. B.; Martin, J. C. J. Org. Chem. 1991, 113, 7277–7287. Doroh, B.; Sulikowski, G. A. Org. Lett. 2006, 8, 903–906. Doyle, M. P.; Westrum, L. J.; Wolthuis, W. N. E.; See, M. M.; Boone, W. P.; Bagheri, V.; Pearson, M. M. J. Am. Chem. Soc. 1993, 115, 958–964. Doyle, M. P.; Davies, S. B.; May, E. J. J. Org. Chem. 2001, 66, 8112–8119. Duh, C. Y.; Wang, S. K.; Chiang, M. Y. Tetrahedron Lett. 1999, 40, 6033–6035. Ferreira, E. M.; Stoltz, B. M. J. Am. Chem. Soc. 2001, 123, 7725–7726. Fernandez, M. A.; Barba, L. J. Org. Chem. 1995, 60, 3580–3585. Comprehensive Bibliography 266 Fukuyama, T.; Chen, X. J. Am. Chem. Soc. 1994, 116, 3125–3126. Germal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454–5459. Gregor, N.; Henry, P. M. J. Am. Chem. Soc. 1981, 103, 681–682. Gregor, N.; Zaw, K.; Henry, P. M. Organometallics, 1984, 3, 1251–1256. Grennberg, H.; Simon, V.; Bäckvall, J.-E. Chem. Eur. J. 1998, 4, 1083–1089. Hamed, O.; Henry P. M.; Thompson, C. J. Org. Chem. 1999, 64, 7745–7750. Han, X.; Stoltz, B. M.; Corey, E. J. J. Am. Chem. Soc. 1999, 121, 7600–7605. Hashiguchi, S.; Fuji, A.; Haack, K.-J.; Matsumura, K.; Ikariya, T.; Noyori, R. Angew. Chem. Int. Ed. 1997, 36, 288–290. Hay, M. B.; Hardin, A. R.; Wolfe, J. P. J. Org. Chem. 2005, 70, 3099–3107. Hayashi, T.; Yamasaki, K.; Mimura, M.; Uozumi, Y. J. Am. Chem. Soc. 2004, 126, 3036–3037. Hegedus, L. S.; Allen, G. F.; Bozell, J. J.; Waterman, E. L. J. Am. Chem. Soc. 1978, 100, 5800–5807. Henry, L. Compt. Rend. 1895, 120, 1265. Henry, P. M. J. Am. Chem. Soc. 1964, 86, 3246-3250. Hiroya, K.; Itoh, S.; Sakamoto, T. J. Org. Chem. 2004, 69, 1126–1136. Holmquist, C. R.; Roskamp, E. J. J. Org. Chem. 1989, 54, 3258–3260. Holmquist, C. R.; Roskamp, E. J. Tetrahedron Lett. 1992, 33, 1131–1134. Hosokawa, T.; Ohkata, H.; Moritani, I. Bull. Chem. Soc. Japan 1975, 48, 1533–1536. Hosokawa, T.; Hirata, M.; Murahashi, S.-I.: Sonoda, A. Tetrahedron Lett. 1976, 21, 1821–1824. Hosokawa, T.; Uno, T.; Inui, S.; Murahashi, S. J. Am. Chem. Soc. 1981, 103, 2318–2323. Comprehensive Bibliography 267 Hosokawa, T.; Okuda, C.; Murahashi, S. J. Org. Chem. 1985, 50, 1282–1287. Ihara, M.; Toyota, M.; Fukumoto, K. J. Chem. Soc. Perkin Trans. I 1986, 2151–2161. Ihara, M.; Ohnishi, M.; Takano, M. J. Am. Chem. Soc. 1992, 114, 4408–4410. Ihara, M.; Taniguchi, T.; Makita, K.; Takano, M.; Ohnishi, M.; Taniguchi, N.; Fukumoto, K.; Kabuto, C. J. Am. Chem. Soc. 1993, 115, 8107–8115. Isobe, M.; Lio, H.; Kawai, T.; Goto, T. J. Am. Chem. Soc. 1978, 100, 1940–1942. Itami, K.; Palmgren, A.; Thorarensen, A.; Bäckvall, J.-E. J. Org. Chem. 1998, 63, 6466–6471. Jeganathan, A.; Richardson, S. K.; Mani, R. S.; Haley, E. B.; Watt, D. S. J. Org. Chem. 1986, 51, 5362–5367. Jensen, D. R.; Sigman, M. S. Org. Lett. 2003, 5, 63–65. Jira, R.; Sedlmeier, J.; Smidt, J. Ann. Chem. 1966 , 693, 99. Johnson, C. R.; Braun, M. P.; Ruel, F. S. Org. Synth. 1996, 75, 69–72. Kagan, H. B.; Fiaud, J. C. In Topics in Stereochemistry; Eliel, E. L., Ed.; Wiley & Sons: New York, 1988; Vol. 18, pp. 249-330. Kanemasa, S.; Kanai, T.; Araki, T.; Wada, E. Tetrahedron Lett. 1999, 40, 5055–5058. Kashiwagi, Y.; Yanagisawa, Y.; Kurashima, F.; Anzai, J.; Osa, T.; Bobbitt, J. M. Chem. Commun. 1996, 2745–2746. Kashiwagi, Y.; Kurashima, F.; Kikuchi, C.; Anzai, J.; Osa, T.; Bobbitt, J. M. Tetrahedron Lett. 1999, 40, 6469–6472. Kataoko, N.; Shelby, Q.; Stambuli, J. P.; Hartwig, J. F. J. Org. Chem. 2002, 67, 5553–5566. Khatuya, J. Tetrahedron Lett. 2001, 42, 2643–2644. Comprehensive Bibliography 268 Kido, F.; Yamaji, K.; Abiko, T.; Kato, M. J. Chem. Res. 1993, 18–19. Knochel, P.; Cahiez, G.; Rottlander, M.; Boymond, L. Angew. Chem., Int. Ed. Engl. 1998, 37, 1701–1703. Krasovskiy, A.; Knochel, P. Angew. Chem., Int. Ed. Engl. 2004, 43, 3333–3336. Krishnan, S.; Bagdanoff, J. T.; Ebner, D. C.; Ramtohul, Y. K.: Tambar, U. K.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 13745–13754. Kuroboshi, M.; Yoshihisa, H.; Cortona, M. N.; Kawakami, Y.; Gao, Z.; Tanaka, H. Tetrahedron Lett. 2000, 41, 8131–8135. Larock, R. C.; Hightower, T. R. J. Org. Chem. 1993, 58, 5298–5300. Larock, R. C.; Hightower, T. R.; Hasvold, L. A.; Peterson, K. P. J. Org. Chem. 1996, 61, 3584–3585. Larock, R. C.; Wei, L.; Hightower, T. Synlett 1998, 522–524. Li, Z.; Tang, Z. H.; Hu, X. X.; Xia, C. G. Chem. Eur. J. 2005, 11, 1210–1216. Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2007, 46, 1444–1447. Li, C.; Chan, C.; Heimann, A. C.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2007, 46, 1448–1550. Liron, F.; Garrec, P. L.; Alami, M. Synlett 1999, 246–248. Liron, F.; Gervais, M.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Tetrahedron Lett. 2003, 44, 2789–2794. Liu, Q.; Ferreira, E. M.; Stoltz, B. M. J. Org. Chem. 2007, 72, 7352–7358. Comprehensive Bibliography 269 Mandal, S. K.; Jensen, D. R.; Pugsley, J. S.; Sigman, M. S. J. Org. Chem. 2003, 68, 4600–4603. Marrero, J.; Rodriguez, A. D.; Baran, P.; Raptis, R. G.; Sanchez, J. A.; Ortega-Barria, E.; Capson, T. L. Org. Lett. 2004, 6, 1661–1664. Meyer, M. E.; Ferreira, E. M.; Stoltz, B. M. Chem Commun. 2006, 1316–1318 Miao, R.; Subramanian, G. G.; Lear, M. L. Tetrahedron Lett. 2009, 50, 1731–1733. Miyake, H.; Yamamura, K. Chem. Lett. 1989, 18, 981–984. Moiseev, I. I.; Vargaftik, M. N.; Syrkin, Ya. K. Dokl. Akad. Nauk. SSSR 1963, 153, 140. Mueller, J. A.; Jensen, D. R.; Sigman, M. S. J. Am. Chem. Soc. 2002, 124, 8202–8203. Myers, A.; Dragovich, P. S. J. Am. Chem. Soc. 1993, 115, 7021–7022. Ney, J. E.; Wolfe, J. P. Angew. Chem. Int. Ed. 2004, 43, 3605–3608. Ney, J. E.; Wolfe, J. P. J. Am. Chem. Soc. 2005, 127, 8644–8657. Nielson, R. J.; Keith, J. M.; Stoltz, B. M.; Goddard, W. A. J. Am. Chem. Soc. 2004, 126, 7967–7974. Nishibayashi, Y.; Takei, I.; Uemura, S.; Hidai, M Organometallics 1999, 18, 2291–2293. Nishibayashi, Y.; Yamauchi, A.; Onodera, G.; Uemura, S. J. Org. Chem. 2003, 68, 5875–5880. Nishimura, T.; Onoue, T.; Ohe, K.; Uemura, S. J. Org. Chem. 1999, 64, 6750–6755. Ohkubo, K.; Hirata, K.; Yoshinaga, K.; Okada, M. Chem. Lett. 1976, 183–184. Padwa, A.; Zhi, L. J. Am. Chem. Soc. 1990, 112, 2037–2038. Padwa, A.; Dean, D. C.; Fairfax, D. J.; Xu, S. L. J. Org. Chem. 1993, 58, 4646–4655. Palomo, C.; Oiarbide, M.; Laso, A. Angew. Chem. Int. Ed. 2005, 44, 3881–3884. Pawar, V. D.; Bettigeri, S.; Weng, S.-S., Kao, J.-Q.; Chen, C.-T. J. Am. Chem. Soc. 2006, 128, 6308–6309. Comprehensive Bibliography 270 Phillips, F. C. Am. Chem. J. 1984, 16, 255–277. Radosevich, A. T.; Musich, C.; Toste, F. D. J. Am. Chem. Soc. 2005, 127, 1090–1091. Rai, A. N.; Basu, A. Tetrahedron Lett. 2003, 44, 2267–2269. Reiter, M.; Ropp, S.; Gouverneur, V. Org. Lett. 2004, 6, 91–94. Reul, F. S.; Braun, M. P.; Johnson, C. R. Org. Synth. 1996, 75, 69–72. Rodriguez, A. D.; Shi, J.-G. J. Org. Chem. 1998, 63, 420–421. Rodriguez, A. D.; Shi, J.-G.; Huang, S. D. J. Org. Chem. 1998, 63, 4425–4432. Rodriguez, A. D.; Shi, Y. P. J. Org. Chem. 2000, 65, 5839–5842. Roethle, P. A.; Trauner, D. Org. Lett. 2006, 8, 345–347. Roethle, P. A.; Hernandez, P. T.; Trauner, D. Org. Lett. 2006, 8, 5901–5904. Rönn, M.; Bäckvall, J.-E.; Andersson, P. G. Tetrahedron Lett. 1995, 36, 7749–7752. Rychnovsky, S. D.; McLernon, T. L.; Rajapakse, J. J. Org. Chem. 1996, 61, 1194–1195. Sheu, J. H.; Ahmed, A. F.; Shiue, R. T.; Dai, C. F.; Kuo Y. H. J. Nat. Prod. 2002, 65, 1904–1908. Singh, A. K.; Bakshi, R. K.; Corey, E. J. J. Am. Chem. Soc. 1987, 109, 6187–6189. Sinhababu, A. K.; Borchardt, R. T. J. Org. Chem. 1983, 48, 3347–3349. Smidt, J.; Hafner, W.; Jira, R.; Sieber, R.; Sedlmeier, S.; Sabel, A. Angew. Chem. Int. Ed. Engl. 1962, 1, 80–88. Stelmakh, A.; Stellfeld, T.; Kalesse, M. Org. Lett. 2006, 8, 3485–3488. Stahl, S. S.; Thorman, J. L.; Nelson, R. C.; Kozee, M. A. J. Am. Chem. Soc. 2001, 123, 7188–7189. Sun, W.; Wang, H.; Xia, C. G.; Li, J.; Zhao, P. Angew. Chem. Int. Ed. 2003, 42, 1042–1044. Comprehensive Bibliography 271 Takasu, K.; Misawa, K.; Ihara, M. Tetrahedron Lett. 2001, 42, 8489–8491. Tambar, U. K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752–11753. Ten Brink, G.-J.; Arends, I. W. C. E.; Sheldon, R. A. Adv. Synth. Catal. 2002, 344, 355–369. Thorarensen, A.; Palmgren, A.; Itami, K.; Bäckvall, J.-E. Tetrahedron Lett. 1997, 38, 8541–8544. Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2003, 42, 2892–2895. Trend, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2004, 126, 4482–4483. Trend, R.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778–17788. Trend, R. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008, 130, 15957–15966. Trost, B. M.; Metzner, P. J. J. Am. Chem. Soc. 1980, 102, 3572–3577. Ueda, Y.; Roberge, G.; Vinet, V. Can. J. Chem. 1984, 62, 2936–2939. Uozumi, Y.; Kato, K.; Hayashi, T. J. Am. Chem. Soc. 1997, 119, 5063–5064. Uozumi, Y.; Kato, K.; Hayashi, T. J. Org. Chem. 1998, 63, 5071–5075. Uozumi, Y.; Kyota, H. Ogasawara, M; Hayashi, T. J. Org. Chem. 1999, 64, 1620–1625. Weng, S.-S.; Shen, M.-W.; Kao, J.-Q.; Munot, Y. S.; Chen, C.-T. Proc. Natl. Acad. Sci. U.S.A. 2006, 103, 3522–3527. Wills, M. Angew. Chem. Int. Ed. 2008, 47, 4264–4267. Yin, Y.; Ma, W.; Chai, Z.; Zhao, G. J. Org. Chem. 2007, 72, 5731–5736. Yip, K.-T.; Zhu, N.-Y.; Yang, D. Org. Lett. 2009, 11, 1911–1914. Zhang, H.; Ferreira, E. M.; Stoltz B. M. Angew. Chem. Int. Ed. 2004, 43, 6144–6148. Zhu, L.; Duquette, J.; Zhang, M. J. Org. Chem. 2003, 68, 3729–3732. Comprehensive Bibliography 272 About the Author Michael was born in 1980 and was raised in San Mateo throughout his adolescent years. Apparently Michael was a handful as a baby, and his mother quickly declared “No more!” Thus, he is an only child. Instead of being a good jewish boy and going to Sunday school, he was learning and playing baseball every weekend of each year. Michael became a huge sports fan by growing up watching the SF Giants, 49ers, Oakland Warriors, and Cal Bears. In high school, during Mr. Tong’s chemistry class, Michael discovered the direction in his life when he couldn’t solve a chemistry problem, and ended up creating his own equation, now called Meyer’s Law in Mr. Tong’s class, that provided him with more than just the answer to the problem, it provided him a guide to his career. In college, Michael had to let go of organized baseball, and become a full time student majoring in chemistry. Fortunately for him, as one hobby disappeared, he found a new hobby with organic chemistry. He excelled in his chemistry courses, cruised in his general courses, applied to graduate schools, and then left for London for one final quarter. In London, Michael had an amazing time traveling Europe and experiencing different cultures. Upon his return to the States, he found out he was accepted to Caltech. After 9 months of reacclimation, Michael began his studies in the Stoltz laboratory researching natural product synthesis. Although it has been a long and difficult ride, his experiences at Caltech will no doubt prove invaluable as he moves forward and begins his adult life. Michael is looking forward to a life of chemistry, baseball, golf, more golf, dogs and cats, vacations, seeing friends, and eventually starting a family.