Concise Total Syntheses of ∆¹²-Prostaglandin J Natural Products Using Stereoretentive Metathesis Citation Li, Jiaming (2020) Concise Total Syntheses of ∆¹²-Prostaglandin J Natural Products Using Stereoretentive Metathesis. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/Q78K-7R18. https://resolver.caltech.edu/CaltechTHESIS:11202019-023320724 Abstract ∆¹²-Prostaglandin J family is a type of secondary metabolite isolated in cell culture, and is recently discovered to have potent anticancer activity. Concise syntheses of four ∆¹²-prostaglandin J natural products (7–8 steps in the longest linear sequences) are developed, enabled by convergent stereoretentive cross-metathesis by Ru-based metathesis catalyst. Exceptional control of alkene geometry was achieved through stereoretention. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: Natural Product; Total Synthesis; Olefin Metathesis Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Grubbs, Robert H. (advisor) Stoltz, Brian M. (co-advisor) Thesis Committee: Reisman, Sarah E. (chair) Agapie, Theodor Grubbs, Robert H. Stoltz, Brian M. Defense Date: 18 November 2019 Record Number: CaltechTHESIS:11202019-023320724 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:11202019-023320724 DOI: 10.7907/Q78K-7R18 Related URLs: URL URL Type Description https://doi.org/10.1021/jacs.8b12816 DOI Article adapted for Chapter 1. https://doi.org/10.1021/acs.orglett.6b02722 DOI Article adapted for Chapter 2. ORCID: Author ORCID Li, Jiaming 0000-0001-6646-5693 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 13581 Collection: CaltechTHESIS Deposited By: Jiaming Li Deposited On: 04 Dec 2019 18:39 Last Modified: 08 Nov 2023 00:39 Thesis Files Preview PDF - Final Version See Usage Policy. 13MB Repository Staff Only: item control page

CONCISE TOTAL SYNTHESES OF ∆12PROSTAGLANDIN J NATURAL PRODUCTS USING STEREORETENTIVE METATHESIS Thesis by Jiaming Li In Partial Fulfillment of the Requirements for the degree of Doctor of Philosophy CALIFORNIA INSTITUTE OF TECHNOLOGY Pasadena, California 2020 (Defended November 18, 2019) ii ã 2019 Jiaming Li ORCID: 0000-0001-6646-5693 All Rights Reserved iii To mom and dad. iv ACKNOWLEDGEMENTS I can still remember the rainy day when I walked on San Pasqual Walk five years ago during my first visit to Caltech. At that time, I never expected I would meet so many wonderful people with their help and support at this campus. It was a winter morning when I had a casual talk with Professor Bob Grubbs in his office. He was so warm and welcoming and happily approved me to join his lab. This is Bob, who gives people unconditional support no matter who they are, or where they come from, to help them grow. This warm support makes me feel grateful every day at Caltech, and the warmth will be continued in the future. I’m also thankful to my co-advisor, Professor Brian Stoltz. I learned to be a synthetic chemist, from small details in weekly subgroups, to big ideas during conversation with him. Having both advisors was a unique experience. They both let me pursue my ideas and solve problems independently, and provided me great resources from both groups. I benefited not only from their guidance, but also from their wisdom. They are the advisors of my thesis, but also advisors in my life. I would like to thank the chair of my committee, Sarah Reisman. She always asked constructive questions in every meetings and gave me insightful advice and concepts which had a long term impact on my daily research. I’m also grateful to have had Theo Agapie as my thesis committee, who gave me many valuable suggestions. I’m also thankful for the great learning experiences from the classes instructed by Professors Dennis Dougherty, Greg Fu, Maxwell Robb, Long Cai, and Jesse Beauchamp. v I want to thank all of the Caltech staff, including Linda Syme, Beth Marshall, Lynne Martinez, Alison Ross, and Agnes Tong for their assistance. Dr. Scott Virgil is a role model to me, and I thank him for all his patient help in training me on different instruments and the robot, and maintaining the catalysis center. I’m also grateful to Dr. David VanderVelde for his maintenance of the NMR lab as well as discussions with him in structural determination. I’d also like to thank Larry Henling and Mike Takase for their help with X-ray crystallography, as well as Dr. Mona Shahgholi and Naseem Torian for their assistance with mass spectrometry. I’ve spent five years in a wonderful group, and I’ve been overlapped with over 30 amazing people in this lab. I can’t list them all but they all had a very significant impact on me. Zach Wickens was the first person I met from the Grubbs lab. I was impressed with his knowledge when he drew all the reactions he had done on a small piece of paper at a coffee shop. He mentored me in the beginning, and taught me all the basics as well as how to manage a research project. Crystal Chu was so lively and offered me lots of strategic advice. I also enjoyed lots of discussions with Choonwoo Lee. A new chapter of my graduate research didn’t begin until Chen Xu joined the lab. She passed the torch to me to make me proud of being a synthetic chemist making complex natural products. In the meanwhile, I also learned a lot of metathesis from daily discussions with Tonia Ahmed. The current group members made the Grubbs lab a wonderful place to work. Willie Wolf is a cool chemist and I’m so impressed with his understanding in kinetics. I really enjoyed the time we worked and hung out together. I will also not forget spending five years moving solvent boxes up with Chris Marotta. Yan Xu and I have similar backgrounds and vi he shared so many past experiences with me. JK is a godsend and introduced me to potential postdoc opportunities, and I was always impressed by his energy and passion. Zainab Al-Saihati always brought us positive energy, and recently brought a baby to the world, and I wish her success in both family and career. I can still remember how happy Quan Gan was when I helped him set up his first column, and it was always fun to hang out with him. Jianchun Wang, Ki-Young Yoon, and Prof. Eunsung Lee just joined the group but I’m sure they will have a great experience in Grubbs lab. I also value the amazing teaching experiences I’ve had, especially in Ch5a. Although I had to sacrifice Mondays and Fridays and put lots of effort in, I felt an incomparable achievement at the moment when I passed the torch to the students, who can confidently synthesize a small molecule like steroids after taking this class. There were so much supports from friends outside the lab, especially Kai Chen, who is also graduated from Zhejiang University and now in Arnold lab. We formed a ZJU gang with Ke Ding and Danni Ma. Kai is the hardest working scientist I’ve ever seen. As a friend, he seldom says any good word to me. But he is truly a good friend who can be a mirror to reflect on what I need to improve. Hsi Lai Temple has a great Chinese community. Every time I went there it’s like my second hometown. From meditation and Buddhism classes, I learned to be more calm and not to be attached to the transient emotions. vii Thanks to my mom and dad. They never put high expectations on me, but always think about me from thousands of miles away. I’m grateful to their unconditional love and support that can never be paid back. viii ABSTRACT Prostaglandins are an important class of naturally occurring molecules which have multifaceted biological functions and widespread medical applications. Chapter 1 discusses the development of concise syntheses of four ∆12-Prostaglandin J natural products, enabled by convergent stereoretentive cross-metathesis by Ru-based metathesis catalyst. Exceptional control of alkene geometry was achieved through stereoretention. Short syntheses (7–8 steps in longest linear sequences) were realized in a modular approach. An improved route using enzymatic resolution to obtain enantiopure 15d-PGJ2 was also discussed. Chapter 2 discusses a mild palladium-catalyzed aerobic intramolecular aminoacetoxylation method. Pyrrolidine and indoline derivatives were synthesized using molecular oxygen as oxidant mediated by catalytic NOx species, which acts as an electron transfer mediator to access high-valent palladium intermediate as the presumed active oxidant. Chapter 3 presents a new, robust synthesis of gem-dialkyl acyclic diene monomers with lowcost. Telechelic gem-dialkyl polyethylenes can be made by the metathesis polymerization of the gem-dialkyl acyclic diene monomers, followed by hydrogenation. These polymers feature low glass transition temperature and can be used as elastomers in the synthesis of polyurethanes and other block polymers. ix PUBLISHED CONTENT AND CONTRIBUTIONS Li, J.; Grubbs, R. H.; Stoltz, B. M. Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate. Org. Lett. 2016, 18, 5449– 5451. doi: 10.1021/acs.orglett.6b02722. J. L. led project design, experimental work, data acquisition and analysis, and manuscript preparation. Li, J.; Ahmed, T. S.; Xu, C.; Stoltz, B. M.; Grubbs, R. H. Concise Syntheses of Δ12Prostaglandin J Natural Products via Stereoretentive Metathesis. J. Am. Chem. Soc. 2019, 141, 154–158. doi: 10.1021/jacs.8b12816. J. L. led project design, experimental work, data acquisition and analysis, and manuscript preparation. x TABLE OF CONTENTS Dedication ............................................................................................................ iii Acknowledgements ............................................................................................... iv Abstract ............................................................................................................... viii Published Content and Contributions .................................................................... ix Table of Contents ................................................................................................... x Nomenclature ...................................................................................................... xii CHAPTER 1 1 12 Concise Total Sytheses of ∆ -Prostaglandin J Natural Products Via Stereoretentive Metathesis ABSTRACT ............................................................................................................1 1.1 INTRODUCTION ............................................................................................1 1.2 PRIOR SYNTHETIC EFFORTS ..........................................................................4 1.3 INTRODUCTION OF STEREORETENTIVE METATHESIS ...............................10 1.4 RESULTS AND DISCUSSIONS .......................................................................12 1.4.1 Total Synthesis of ∆12-PGJ2, 15d-PGJ2, ∆12-PGJ3, and 15d-PGJ3 ................12 1.4.2 Improved Synthesis of Enantiopure 15d-PGJ2 ..........................................19 1.5 CONCLUSIONS.............................................................................................23 1.6 EXPERIMENTAL METHODS AND ANALYTICAL DATA ................................24 1.6.1 Materials and Methods............................................................................24 1.6.2 Experimental Procedures.........................................................................25 1.7 NOTES AND REFERENCES ............................................................................78 APPENDIX 1 Spectra Relevant to Chapter 1 83 CHAPTER 2 140 Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate xi ABSTRACT ........................................................................................................140 2.1 INTRODUCTION ........................................................................................140 2.2 PALLADIUM-CATALYZED AEROBIC TRANSFORMATIONS ......................144 2.3 OPTIMIZATION OF PALLADIUM-CATALYZED AMINOOXYGENATION REACTIONS .......................................................................................................148 2.4 SUBSTRATE SCOPE .....................................................................................153 2.5 CONCLUSIONS...........................................................................................157 2.6 EXPERIMENTAL METHODS AND ANALYTICAL DATA ..............................158 2.6.1 Materials and Methods..........................................................................158 2.6.2 Experimental Procedures.......................................................................158 2.7 NOTES AND REFERENCES ..........................................................................175 APPENDIX 2 Spectra Relevant to Chapter 2 178 CHAPTER 3 228 A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization ABSTRACT ........................................................................................................228 3.1 INTRODUCTION ........................................................................................228 3.2 DEVELOPMENT OF SYNTHETIC ROUTES TO GEM-DIALKYL DIENES ......232 3.3 ADMET POLYMERIZATION OF GEM-DIALKYL DIENES ............................237 3.4 CONCLUSIONS...........................................................................................240 3.5 EXPERIMENTAL METHODS AND ANALYTICAL DATA ..............................241 3.5.1 Materials and Methods..........................................................................241 3.5.2 Experimental Procedures.......................................................................241 3.6 NOTES AND REFERENCES ..........................................................................261 APPENDIX 3 Spectra Relevant to Chapter 3 264 ABOUT THE AUTHOR 310 xii NOMENCLATURE [a]D specific rotation at wavelength of sodium D line °C degrees Celsius Å Ångstrom Ac acetyl Acac acetylacetonate AcOH acetic acid ADH alcohol dehydrogenase Adm adamantyl ALB aluminum-lanthanum-BINOL complex All allyl An anisole APCI atmospheric pressure chemical ionization app apparent aq aqueous Ar aryl atm atmosphere BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl BINOL 1,1-binaphthol Bn benzyl Boc tert-butyloxycarbonyl BOX bis(oxazoline) bp boiling point br broad xiii Bu butyl Bz benzoyl c concentration for specific rotation measurements (g/100 mL) ca. about (Latin circa) calc’d calculated cat catalytic CDI 1,1'-carbonyldiimidazole cm–1 wavenumber(s) cod 1,5-cyclooctadiene Cp cyclopentadienyl Cp* pentamethyl-cyclopentadienyl CSA camphorsulfonic acid Cy cyclohexyl d doublet D deuterium DABCO 1,4-diazabicyclo[2.2.2]octane dba dibenzylideneacetone DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DCC N,N'-Dicyclohexylcarbodiimide DCE 1,2-dichloroethane DCM dichloromethane DDQ 2,3-dichloro-5,6-dicyano-p-benzoquinone DIBAL diisobutylaluminum hydride DIC N,N′-Diisopropylcarbodiimide DIFLUORPHOS 5,5'-Bis(diphenylphosphino)-2,2,2',2'-tetrafluoro4,4'-bi-1,3-benzodioxole xiv DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine dmdba bis(3,5-dimethoxybenzylidene)acetone DMDO dimethyldioxirane DME 1,2-dimethoxyethane DMF N,N-dimethylformamide DMP Dess–Martin periodinane DMPU N, N′-Dimethylpropyleneurea DMS dimethyl sulfide DMSO dimethyl sulfoxide DPPA diphenyl phosphoryl azide dr diastereomeric ratio DTBM di-t-butyl-methoxy E trans (entgegen) olefin geometry e.g. for example (Latin exempli gratia) EDC N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide ee enantiomeric excess EI+ electron impact equiv equivalent(s) ESI electrospray ionization Et ethyl EtOAc ethyl acetate EWG electron withdrawing group FAB fast atom bombardment Fu furanyl xv g gram(s) G2 Grubbs catalyst 2nd generation GC gas chromatography gCOSY gradient-selected correlation spectroscopy h hour(s) HG-II Hoveyda-Grubbs catalyst 2nd generation hmim 2-methylimidazole HMBC heteronuclear multiple bond correlation HMDS 1,1,1,3,3,3-hexamethyldisilazane HMPA hexamethylphosphoramide (HMPT) HPLC high-performance liquid chromatography HRMS high-resolution mass spectroscopy HSQC heteronuclear single quantum correlation Hz hertz hn light i- iso- i-Pr isopropyl i.e. that is (Latin id est) IBX 2-iodoxybenzoic acid IL-6 interleukin 6 IPA isopropanol, 2-propanol Ipc diisopinocampheyl IR infrared (spectroscopy) J coupling constant K Kelvin(s) (absolute temperature) kcal kilocalorie KPi potassium phosphate xvi L liter; ligand L* chiral ligand LDA lithium diisopropylamide LG leaving group lit. literature value LSB lanthanum-sodium-BINOL m multiplet; milli m meta M metal; molar; molecular ion; Mega m-CPBA meta-chloroperoxybenzoic acid m/z mass to charge ratio Me methyl mg milligram(s) min minute(s) MM mixed method MOC methoxycarbonyl mol mole(s) MOP 2-(diphenylphosphino)-2′-methoxy-1,1′-binaphthyl mp melting point Ms methanesulfonyl (mesyl) MS molecular sieves MTBE methyl tert-butyl ether n nano N normal n- normal- NADP nicotinamide adenine dinucleotide phosphate Naph naphthyl xvii NBS N-bromosuccinimide NHC N-heterocyclic carbene NMO N-methylmorpholine N-oxide NMR nuclear magnetic resonance Nu nucleophile o ortho p para Pd/C palladium on carbon pen pentyl Ph phenyl pH hydrogen ion concentration in aqueous solution PHOX phosphinooxazoline Pin 2,3-dimethylbutane-2,3-diol (pinacol) Piv trimethylacetyl, pivaloyl pKa pK for association of an acid pmdba bis(4-methoxybenzylidene)acetone PMP para-methoxy phenyl ppm parts per million PPTS pyridinium p-toluenesulfonate Pr propyl Proton sponge 1,8-bis(dimethylamino)naphthalene Py pyridine q quartet R generic for any atom or functional group RCM ring-closing metathesis Ref. reference Rf retention factor xviii RRCM relay ring-closing metathesis s singlet s- sec- sat. saturated SEGPHOS 5,5′-Bis(diphenylphosphino)-4,4′-bi-1,3benzodioxole SFC supercritical fluid chromatography Solv solvent t triplet t- tert- T-Hydro 70% TBHP in water TBAF tetrabutylammonium fluoride TBAI tetrabutylammonium iodide TBAT tetrabutylammonium difluorotriphenylsilicate TBD 1,3,4-triazabicyclo[4.4.0]dec-5-ene TBDPS tert-butyldiphenylsilyl TBHP tert-butyl hydroperoxide TBS tert-butyldimethylsilyl TES triethylsilyl Tf trifluoromethanesulfonyl (triflyl) TFA trifluoroacetic acid TFAA trifluoroacetic anhydride TFE 2,2,2-trifluoroethanol THF tetrahydrofuran TIPS triisopropylsilyl TLC thin-layer chromatography TMEDA N,N,N’,N’-tetramethylethylenediamine xix TMS trimethylsilyl TMP tetramethylpiperidine TOF time-of-flight Tol tolyl tR retention time TRAP 2,2"-bis[1 -(diphenylphosphino)ethyl]-1,1"- biferrocene TRIS tris(hydroxymethyl)aminomethane Ts p-toluenesulfonyl (tosyl) UV ultraviolet v/v volume to volume Val valine w weak w/v weight to volume X anionic ligand or halide XPhos 2-dicyclohexylphosphino-2′,4′,6′triisopropylbiphenyl l wavelength µ micro Z cis (zusammen) olefin geometry Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 1 CHAPTER 1 Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis† ABSTRACT ∆12-Prostaglandin J family is a type of secondary metabolite isolated in cell culture, and is recently discovered to have potent anticancer activity. Concise syntheses of four ∆12-Prostaglandin J natural products (7–8 steps in the longest linear sequences) are developed, enabled by convergent stereoretentive cross-metathesis by Ru-based metathesis catalyst. Exceptional control of alkene geometry was achieved through stereoretention. 1.1 INTRODUCTION Prostaglandins are an important class of naturally occurring molecules that are found in mammalian tissues and exhibit a broad range of biological functions and widespread medical applications.1 The recently discovered ∆12-prostaglandin J family (1–4, Figure 1.1.1) features a unique cross-conjugated dienone motif and has multifaceted biological properties that are uniquely different from other components of the PG family and have appealing anti-cancer activity.2 † Adapted with permission from Li, J.; Ahmed, T. S.; Xu, C.; Stoltz, B. M.; Grubbs, R. H. “Concise Syntheses of Δ12-Prostaglandin J Natural Products via Stereoretentive Metathesis”, J. Am. Chem. Soc., 2019, 141, 154–158 Copyright © 2019, American Chemical Society Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 2 Figure 1.1.1. Structures of ∆12 Prostaglandin J Natural Products COOH Me O Me ∆12-prostaglandin J2 (1) (∆12-PGJ2) Me Me O O OH COOH COOH COOH O OH ∆12-prostaglandin J3 (3) (∆12-PGJ3) 15-deoxy-∆12,14-prostaglandin J2 (2) (15d-PGJ2) 15-deoxy-∆12,14-prostaglandin J3 (4) (15d-PGJ3) The proposed biosynthetic pathway to ∆12-prostaglandin J family is shown in Figure 1.1.2. Arachidonic acid (ARA) is released from membrane phospholipids, and then is converted by cyclooxygenase (COX; also known as PGH synthase) to PGH2. This pivotal intermediate is converted enzymatically to a variety of biologically active prostaglandins, including PGD2 , PGΕ2, PGF2α , and PGI2. PGD2 can spontaneously undergo non-enzymatic dehydration and isomerization Figure 1.1.2. Biosynthesis of ∆12 Prostaglandin J Natural Products 8 9 3 5 6 7 4 2 13 16 18 COOH 10 11 12 14 15 17 Me 8 9 1 6 3 5 7 4 2 COOH 1 10 20 11 19 12 13 16 14 15 17 18 19 Me 20 eicosapentaenoic acid (EPA) arachidonic acid (ARA) cyclooxygenase O COOH O Me PGH2 OH Other Prostaglandins: PGD synthase PGE2, PGF2α, PGI2 HO 9 6 5 1 Me Me O 13 PGD2 OH COOH COOH COOH dehydration O PGJ2 Me O OH PGJ3 OH isomerization isomerization α-chain 1 5 8 8 1 5 COOH COOH O OH ω-chain 17 15 Me 15 12 Me 12 O OH ∆12-PGJ3 ∆12-PGJ2 dehydration dehydration 9 COOH COOH O 13 14 15d-PGJ2 Me Me O 15d-PGJ3 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 3 to form ∆12-PGJ2.3 Further dehydration by loss of the 15-hydroxyl group results in the formation of 15d-PGJ2. A similar biosynthetic pathway was known to account for the formation of ∆12-PGJ3 from the ω-3 eicosapentaenoic acid (EPA, Figure 1.1.2).4 15d-PGJ2 is the most well-studied cyclopentenone prostaglandin and is reported to exert its effects on cells by binding the peroxisome proliferator activated receptor. It was demonstrated for the first time in 1995 that 15d-PGJ2 is an endogenous ligand for PPAR-γ.5 15d-PGJ2 upregulates the expression, transcriptional activity, and DNA binding activity of PPAR-γ, and many of other cellular events mediated by 15d-PGJ2 have been shown to be PPAR-γ-dependent.6 PPARs are a family of ligand-activated nuclear transcription factors, which modulate gene expression through binding to specific DNA sequences, termed PPAR response elements (PPREs) in the enhancer regions. PPARs play an important role in physiological processes such as adipogenesis, glucose metabolism, and macrophage function, and also in regulation of cancer cell proliferation, survival, apoptosis, and tumor growth.7 Crystallography data showed that 15d-PGJ2 is the natural high affinity ligand to PPAR-γ and can form a covalent bond with cysteine C285 through a Michael addition (Figure 1.1.3) at C13. Furthermore, the carboxyl group of 15d-PGJ2 is required for the formation of a hydrogen bond with Y327 residue.8 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 4 Figure 1.1.3. 15d-PGJ2 Bind to PPAR-γ 9 ∆12-PGJ3 (3) was recently identified in 2011 to have activity against leukemia stem cells with high potency, without adverse activity against the normal cells.4 The interest in cancer stem cells (CSCs) is due to their inherent resistance against conventional chemotherapies which allow for relapse and metastasis. ∆12-PGJ3 showed impressive in vitro potency and selectivity of against chronic myelogenous leukemia (CML) stem cells (IC50 = 12 nm), and exceptional ability to effectively cure this form of leukemia in a mouse model. Studies of its stability, bioavailability, and hypersensitivity make ∆12-PGJ3 a lead compound for further investigation in search of new therapies for the treatment of acute and chronic myelogenous leukemia (AML and CML).10 1.2 PRIOR SYNTHETIC EFFORTS Efforts directed toward the synthesis of various prostaglandins has had a profound effect on the development of new strategies and tactics employed in the field of synthetic chemistry, emanating from the seminal studies of Corey beginning in the 1960’s.11 Elegant contribution to the total synthesis of ∆12-PGJ3 (3) was reported by Nicolaou and co-workers in 2014 (Scheme Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 5 1.2.1). 12 The synthesis of cyclopentenone fragment 8 began with the preparation of racemic acetate by reduction of commercially available 2-cyclopentenone followed by acetylation. The C8 stereocenter was introduced by asymmetric Tsuji–Trost allylic alkylation of racemic acetate 5 with dimethyl malonate in the presence of [(η3-C3H5)PdCl]2 (0.5 mol%) and (S,S)-DACH-phenyl Trost ligand (1.5 mol%). The enantio-enriched dimethyl ester 6 was obtained in 71% yield and 97% ee. Upon a 4-step process, aldehyde 7 can undergo Wittig reaction with 2.5 equivalents of IPh3P(CH2)5OPMB in the presence of NaHMDS at –78 ºC, furnished the desired Z-alkene in high yield (79%) and good Z-selectivity (Z/E ≥ 10:1), which was converted to enone fragment 8 by PCC oxidation. To construct the ω-chain aldehyde, Mukaiyama aldol reaction with hex-3-ynal (10) and TMS-protected acetal 11, in the presence of (R)-NOBIN catalyst developed by Carreira and coworkers13 could afford homopropargylic alcohol 12 in 72% yield and 95% ee. Protection of the Scheme 1.2.1. Nicolaou’s 1st Generation Synthesis of ∆12 Prostaglandin J3 1. DIBAL-H O 2. Ac O 2 OAc [η3-C3H5PdCl]2 (S,S)-DACH dimethyl malonate 1. IPh3P(CH2)5OPMB CHO NaHMDS (79%) 2. PCC (93%) COOMe 4 steps COOMe (62%) (71%, 97% ee) asymmetric Tsuji-Trost 5 Wittig Olefination HO 6 7 Z:E = 10:1 OPMB OPMB 12 + O 8 O Me 14 Alkyne hydrogenation OTBS TBSCl (88%) 12: R = H 13: R = TBS O OTBS 15 Me OH Δ12-PGJ3 (3) OTMS 11 BnO (R)-NOBIN cat. OR O Aldol/dehydration 1. Pd/CaCO3/Pb quinoline, H2 (99%) 2. DIBAL-H (89%) BnOOC Me Me then MsCl, Et3N Al2O3 (62%) COOH 3 steps LDA (79%) (72%, 95% ee) Mukaiyama aldol O t-Bu DMP HO Me Me (95%) 9 10 N O Ti O Br O O O NH O O HN t-Bu PPh2 Ph2P (S,S)-DACH (R)-NOBIN t-Bu Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 6 secondary alcohol with TBS group, semi-hydrogenation of the alkyne (H2, Lindlar catalyst, quinoline) followed by DIBAL-H reduction provided ω-chain aldehyde 14 as the only geometrical isomer. At this stage, regioselective deprotonation of cyclopentenone 8 at the C12 position was achieved with LDA at –78 ºC, then ω-chain aldehyde 14 was added, and the aldol product was generated (79%) as a pair of C13 epimers (ca. 3:1 d.r.). Treatment of the aldol product with a mixture of MsCl and Et3N gave the corresponding mesylate, which did not undergo β-elimination even with excess amount of Et3N. By adding activated commercial neutral alumina, the crossconjugated dienone intermediate 15 can be formed when while leaving the OTBS group intact. ∆12-PGJ3 (3) can be prepared in three additional steps. In 2016, Nicolaou and co-workers reported a streamlined synthesis of ∆12-PGJ3 (Scheme 1.2.2).14 The synthesis commenced with the preparation of ω-chain aldehyde 14 in a modified route. Ring-opening of chiral epoxide 16 with lithium acetylide under Lewis acidic conditions, and TBS protection of secondary alcohol formed 17. Reduction of alkyne in 17 with nickel acetate furnished the desired Z-alkene. Deprotection of the primary alcohol with DDQ, followed by DMP oxidation furnished the ω-chain aldehyde 14. The α-chain fragment was prepared from terminal alkyne 18, which was alkylated with formaldehyde to produce propargyl alcohol 19. Then, the alkyne was reduced to the Z-alkene in the same conditions with nickel acetate. The allylic alcohol was subjected to Appel conditions to provide allylic bromide 20. Chiral induction of C8 was achieved by introducing L-menthol to cyclopentanedione 21 to form the vinyl ether 22. Alkylation of 22 with allyl bromide 20 formed two diastereomers (23:24 ca. 1:2.2) favored the β-H at C8 position. The undesired diastereomer 23 could be epimerized to 24 when subjected to KOt-Bu, which resulted in 1:1 ratio of two epimers. DIBAL-H reduction and hydrolysis elaborated enone 25, which can undergo aldol reaction with ω-chain aldehyde 14 in the presence of LDA. MsCl Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 7 and excess amount of DMAP can eliminate the secondary alcohol of aldol product to form intermediate 26. Global deprotection under aqueous HBF4 gave ∆12-PGJ3 (3) in excellent yield (92%, Scheme 1.2.2). A number of ∆12-PGJ3 analogues were also accessible via this streamlined route by Nicolaou and co-workers in 2016, which enabled a comprehensive structural-activity relationship (SAR) study of their anti-cancer activities.15 Scheme 1.2.2. Nicolaou’s 2nd Generation Synthesis of ∆12 Prostaglandin J3 1. Li-acetylide, BF3•OEt2 PMBO O 16 CO2t-Bu 1. Ni(OAc)4•4H2O NaBH4, H2 PMBO 2. TBSCl (80% over 2 steps) OTBS Zn(OTf)2, (CH2O)n CO2t-Bu 17 (80%) OH 18 Me 1. Ni(OAc)4•4H2O NaBH4, H2 8 TsOH (23:24 ca. 1:2.2) Me CO2t-Bu 20 CO2t-Bu Me Me Me Me Me 22 CO2H Me O Br O O O 21 14 LDA; then 20 L-menthol (81%) OTBS O O O Me 2. DDQ 3. DMP (83% over 3 steps) 2. CBr4, PPh3 (80% over 2 steps) 19 O OH Δ12-PGJ3 (3) KOt-Bu (23:24 ca. 1:1) aq. HBF4 23: 8α-H 24: 8β-H DIBAL-H, then TsOH (76%) CO2t-Bu 1. LDA; then 14 (92%) Me O OTBS 26 CO2t-Bu 2. MsCl, DMAP (43% over 2 steps) O 25 In 2018, the Aggarwal group reported a synthesis of ∆12-PGJ3 features an L-Proline catalyzed homodimerization of succinaldehyde to form a key intermediate 27 in high enantioselectivity (99:1 e.r., Scheme 1.2.3).16 Upon a six-step process, 27 was converted into the previously reported enone fragment 25. The ω-chain aldehyde was prepared from asymmetric conjugate addition of α,β-unsaturated ester 28 with B2pin2, followed by reduction with DIBAL-H Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 8 in good yield and enantioselectivity (79% over 2 steps, 93:7 e.r.). Similar to the previous approaches by Nicolaou and co-workers, an aldol reaction was performed with enone fragment 25 and aldehyde 29 in the presence of 2.0 equivalent of LDA. Then the crude reaction mixture from the aldol reaction was treated with MsCl and Et3N to give the corresponding mesylate, and subsequent elimination upon reaction with DBU produced exclusively the E-configured elimination product. Subsequent oxidation with NaBO3•4H2O gave the late stage intermediate 31. Finally, treatment of 31 with aqueous HBF4 gave ∆12-PGJ3 (3) in 75 % yield. Scheme 1.2.3. Aggarwal’s Synthesis of ∆12 Prostaglandin J3 HO PhI(OAc)2 cat. TEMPO Me EtO then Ph3P=CHCO2Et 1. CuCl, (R)-(S)-Josiphos NaOt-Bu, B2pin2 Me H O 28 (63%) Me O 2. DIBAL-H, THF Bpin 29 (79% over 2 steps, 93:7 er) OH O O 1. L-Proline (2 mol%), EtOAc 23 ºC, 40 h 2. O S O O CF3 O COOH Me O OH ∆12-PGJ3 (3) O 6 steps 65 ºC, 2 h O O 27 (29%, 99:1 e.r.) N H2 CO2t-Bu HBF4 (75%) Me O CO2t-Bu OH 31 1.LDA 25 2. MsCl, Et3N then DBU 3.NaBO3•4H2O THF/H2O (23% over 3 steps) CO2t-Bu Me O HO Bpin 30 Synthetic efforts toward ∆12-PGJ2 and 15d-PGJ2 compounds began in 2003, with a number of syntheses reported through various approaches.17 In 2019, the synthesis of ∆12-PGJ2 was enabled by a concise approach using Z-selective cross-metathesis by Nicolaou and coworkers (Scheme 1.2.4).18 Stereoselective conjugate addition of enantiomerically pure enone (+)-33 with the allyl cuprate reagent generated from allyl magnesium bromide, CuI and LiCl in the presence of TMSCl, followed by thermally induced retro-Diels−Alder reaction, furnished the Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 9 enantiopure intermediate 34 in 77% yield over the two steps. Chiral epoxide 16 was reacted with n-BuMgBr in the presence of CuI to form the secondary alcohol 35 (72% yield). Protection of 35 with TBS group furnished the TBS-ether 36 (90% yield). Removal of the PMB group of 36 with DDQ followed by oxidation with DMP elaborated the ω-chain aldehyde 37 in 76% over 2 steps. Then the dienone intermediate 38 was obtained by aldol reaction of 34 and aldehyde 37 with LDA, followed by the treatment with MsCl and DMAP. Subjecting 38 with to an excess amount of tert-butyl ester 39 with 10 mol% loading of Z-selective metathesis catalyst Ru-2, furnished the protected ∆12-PGJ2 derivative 40 in 42% yield (>95:5 Z/E, 52% recovered starting material 38, 90% yield based on recovered enone 38), which was exposed to aqueous HBF4 to reveal ∆12-PGJ2 (1) in 71% yield. This work presented a shorter synthetic sequence to ∆12-PGJ2 and its analogs, and the dimeric, trimeric, and tetrameric macrocyclic lactones consisting of ∆12PGJ2 units were prepared for the biological evaluation of those compounds. Scheme 1.2.4. Nicolaou’s Synthesis of ∆12 Prostaglandin J2 CuI BrMg PMBO O Me Me PMBO (72%) 16 TBSCl,imidazole CH2Cl2 (90%) 1. DDQ 2. DMP H (76% over 2 steps) OR 35: R = H 36: R = TBS Me O OTBS 37 H 1. 37, LDA 2. MsCl, DMAP 1. CuI, LiCl allylMgBr, TMSCl H Me 2. 1,2-dichlorobenzene 160 ºC (77% over 2 steps) O (+)-33 O (40% over 2 steps) 34 O 38 OTBS iPr CO2t-Bu COOH Me O OH ∆12-PGJ2 (1) CO2t-Bu HBF4 Me (71%) O OTBS 40 N N 39 iPr Ru-2 (10 mol%) O (42%, 52% sm recovered) O N Ru O O iPr Ru-2 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 1.3 10 INTRODUCTION OF STEREORETENTIVE METATHESIS Olefin cross-metathesis is a convergent method for building C–C double bonds in natural product syntheses.19 Most importantly, conventional metathesis catalysts typically gave imperfect control of alkene geometry. Previous syntheses relied on the semi-hydrogenation of alkynes or Wittig reactions, requiring multi-step functional group manipulation with concomitant waste generation. From a strategic perspective, chemoselectivity among multiple alkenes has also been another concern, especially in the later stages. Stereo- and chemoselective metathesis catalysts are in demand to realize a convergent synthesis from simple alkene building blocks. However, it has seldom been applied in the previous syntheses of ∆12-PGJ family. Figure 1.3.1. Structures of Z-selective and Stereoretentive Metathesis Catalysts Z-selective metathesis catalysts: Stereoretentive metathesis catalysts: iPr Me N N N N Me Ru O O N O O iPr Ru-1 O O N Ru O Cl Me S O iPr Ru-2 N N Me iPr Me Me Me Me Cl Cl Ru-3 iPr iPr S O iPr N N Ru S iPr iPr Me Ru S Cl O iPr Ru-4 A series of cyclometallated ruthenium-based catalysts (e.g. Ru-1, Ru-2, Figure 1.3.1) were recently developed by Grubbs and co-workers, which enable Z-selective metathesis through a favored syn-metallacyclobutane intermediate (Figure 1.3.2, Path A).20 More recently, catechodithiolate-based catalyst Ru-3 and its dithiolate variants were developed by Hoveyda group and showed high Z-selectivity in ring-opening metathesis polymerizations, ring-opening crossmetathesis, and cross-metathesis with Z-olefins.21 In fact, high kinetic E-selectivity in cross- metathesis with E-starting materials was also observed with Ru-3, the sIPr analogue Ru-4, and other less bulky fast-initiating analogues developed by Materia, Inc. and the Grubbs group, that defined these catalysts as stereoretentive.22 The origin of the stereoretention was attributed to the Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 11 formation of a side-bound metallacyclobutane intermediate, of which the α-substituents are forced down to minimize steric interactions with the bulky N-aryl groups of the NHC. As a result, when starting with Z-alkenes, the α-substituent points down to generate Z-alkene products (Figure 1.3.2, Path B). When starting with E-alkenes, however, the β-substituent has to point up into the open space between two N-aryl groups, leading to the generation of E-alkene products, albeit with slower rates (Figure 1.3.2, Path C). Cross-metathesis between two terminal alkenes is not possible with stereoretentive metathesis catalysts, however, because the intermediate methylidene species are unstable and lead to catalyst decomposition. A methylene capping strategy was recently reported as a remedy to this problem, enabling the cross-metathesis of two terminal alkenes. 23 Despite the unique properties of these stereoretentive catalysts, to date, limited synthetic evaluation has been conducted with Ru-based stereoretentive catalysts,24 as well as with Mo, Wbased catalysts.25 Total synthesis of the olefin-enriched Δ12-prostaglandin J natural products 1–4 sets a perfect test ground to evaluate the reactivity, chemoselectivity, and functional group compatibility of these newly developed metathesis catalysts. Figure 1.3.2. Models of Z-and E-selectivity Model of Z-selectivity: N N Ru O O N Ar N Ar Ru O Path A O N N Ar O Model of Stereoretention: N Ar O N Z-selective S Ru Ar N N Cl S Ar a Path B a S b Ru Ar Ar N N S S Ru Cl Path C a S b a E-selective Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 1.4 12 RESULTS AND DISCUSSIONS 1.4.1 Total Synthesis of ∆12-PGJ2, 15d-PGJ2, ∆12-PGJ3, and 15d-PGJ3 Retrosynthetically, ∆12-PGJ3 (3) for example can be simplified into a truncated prostaglandin structure 56 by use of stereoretentive metathesis (Scheme 1.4.1). A three- component coupling strategy26 can be applied toward the synthesis of 56, using a relatively simple and commercially available allyl Grignard reagent, ω-chain aldehyde 14, and a chiral cyclopentenone (R)-43. The O-Boc group of (R)-43 can be used as a traceless stereoinductive group to set the C8 stereocenter and give the desired enone moiety.27 Scheme 1.4.1. Retrosynthetic Analysis Three-component coupling Stereoretentive metathesis COOH Me O Me O OH ∆12-PGJ (3) 3 BocO kinetic resolution OTBS 56 BocO BrMg + O + Me O O (±)-43 (R)-43 OTBS 14 To construct chiral 4-hydroxyl-cyclopentenone (R)-42, asymmetric reduction with (R)BINAL-H reagent developed by Noyori and co-workers28 was firstly investigated. However, this reaction resulted in low yield of the alcohol product (R)-42, and required tedious cryogenic conditions. Alternatively, Boc-protected chiral cyclopentenone (R)-43 was prepared from furfuryl alcohol in a three-step process. Kinetic resolution in the presence of Pd2(dba)3 and (R,R)-DACH phenyl Trost ligand furnished the enantiopure product (R)-43 (99% ee) in 2.0 gram scale (Scheme 1.4.2).29 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 13 Scheme 1.4.2. Synthesis of (R)-43 O Al O H Li OEt O O HO (R)-42 H 2O HO microwave 180 ºC, 15 min O OH furfuryl alcohol (R,R)-DACH O (<10% yield) 41 HN PPh2 Ph2P (R)-BINAL-H THF, –100 ºC O O NH (82%) (Boc)2O Et3N, THF BocO (95%) Pd2(dba)3•CHCl3 Cs2CO3 (R,R)-DACH p-methoxyphenol CH2Cl2 BocO (41%, > 99% ee) O O O (±)-42 (±)-43 (R)-43 Then, CuBr•Me2S and LiCl facilitated the diastereoselective conjugate addition of the allyl magnesium bromide. The enolate formed can then be trapped by the subsequently added commercially available trans-2-octenal, and the O-Boc group was eliminated in the course of the aldol reaction to form the desired cyclopentenone motif. The enal functionality of the aldehyde was well tolerated in the aldol step. Elimination with MsCl and DMAP favored 12E-product 44 as the major product in reasonable yield (41% over 2 steps, Scheme 1.4.3). Scheme 1.4.3. Synthesis of 44 by Three-component Coupling BocO O (R)-43 1. CuBr.Me2S, LiCl, allylMgBr THF, –78 ºC then trans-2-octenal, THF, –78 ºC 2. MsCl, DMAP, CH2Cl2 (41% over 2 steps) Me O 44 (88% ee) Stereoretentive metathesis was then evaluated on 44. Since 44 cannot react with another terminal alkene using stereoretentive metathesis catalysts, we considered a symmetric Z-alkene 46 as the coupling partner, which could also be made by homodimerization of readily available 45 through stereoretentive metathesis. However, the homodimerization reaction only gave 50% conversion in the ambient pressure because of the thermodynamic equilibrium (Table 1.4.1, entry 1), and vacuum can be applied to remove the cis-3-hexene (b.p. 66–68 ºC) from the reaction Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 14 mixture. Performing the reaction under static vacuum gave 62% conversion, in which conditions cis-3-hexene still cannot be effectively removed (Table 1.4.1, entry 2). Decreasing the pressure will result in higher conversion (Table 1.4.1, entry 3–5), and using high boiling solvent such as toluene could ensure full conversion. With 1 mol% loading of Ru-4 as the catalyst, 98% conversion could be achieved by applying dynamic vacuum to remove the by-product, cis-3hexene (Table 1.4.1, entry 6). Next, 44 with an additional 5 mol% catalyst Ru-4 were added into the reaction mixture, and the alcohol product 47 could be isolated in 95% yield in high Z-selectivity (>99% Z). This result established the efficacy of an efficient one-pot, stereoretentive homodimerization/cross-metathesis strategy to build the C5 Z-alkene. In contrast, synthesis of PGE2 and PGF2α using stereoretentive metathesis catalyst Ru-3 required a large excess of gaseous butene and more complicated operations in the previously reported methylene capping strategy. The full conversion of first homodimerization step is necessary to avoid the formation of byproducts such as 48. Under standard cross-metathesis conditions with alcohol 45, the major Table 1.4.1. Optimization of Homodimerization Reaction Ru-4 (2 mol%) HO Me 45 HO OH toluene + Me Me 46 Entry starting material solvent temperature pressure conversiona yield 1 0.1 mmol THF 23 ºC 760 torr 50% 25% 2 0.1 mmol toluene 40 ºC static vacuumc 62% 31% 3 0.1 mmol toluene 40 ºC dynamic vacuumd 107 torr 60% 30% 4 0.1 mmol toluene 40 ºC dynamic vacuumd 45 torr 90% 45% 5 6 mmol toluene 40 ºC dynamic vacuumd 45 torr 96% 48% 6b 6 mmol toluene 23 ºC dynamic vacuume (ca. 2 torr) >98% 49% a Conversion was measured by GC analysis b 1 mol% of catalyst was added c Static vacuum was applied after one freeze-pump-thaw cycle of the reaction mixture in the Schlenk tube. d Dynamic vacuum was performed by attaching the Schlenk tube to a vacuum regulator. e The Schlenk tube was directly connected to high vacuum. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 15 product is 48 from the reaction with propylidene (Scheme 1.4.4), which is hard to be converted further into the desired product 47 by a second cross-metathesis with alcohol 45, unless dynamic vacuum is applied to effectively remove cis-3-hexene from the reaction system. The C14 E-alkene tolerated the reaction, consistent with the much slower reaction of Ealkenes with Ru-4 as seen previously.22 The enantiopurity of intermediates 44 and 47 was also assessed. Three-component coupling product 44 proceeded with a small loss in enantiopurity (88% ee) from (R)-43 (>99% ee), but the metathesis product 47 was obtained without significant erosion of enantiopurity (87% ee, Scheme 1.4.4). This result demonstrates that stereoretentive metathesis with catalyst Ru-4 also retained the stereochemistry of the C8 stereocenter. Finally, Ley oxidation30 of 47 with TPAP and NMO•H2O gave 15-deoxy-D12,14-prostaglandin J2 (2) in 68% yield (Scheme 1.4.5). Scheme 1.4.4. Stereoretentive Metathesis with 44 A. Cross-metathesis with stereoretentive catalyst Ru-4 OH 45 Me OH Ru-4 (1 mol%) Me O Me THF, 40 ºC static vacuum 44 48 (53%, >99:1 Z/E) Ru O S Cl O 47 (47%, >99:1 Z/E) iPr iPr S Me N N Cl O iPr iPr Me + iPr Ru-4 B. One-pot homodimerization/stereoretentive metathesis OH 45 Me Ru-4 (1 mol%) toluene, 23 ºC ca. 2 torr Me O Ru-4 (5 mol%) THF, 40 ºC 44 (88% ee) OH OH 46 HO Me O 47 (93%, >99:1 Z/E, 87% ee) Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 16 SCHEME 1.4.5. Completion of Synthesis of 15d-PGJ2 OH TPAP, NMO•H2O MeCN Me O COOH Me (68%) O 47 15d-PGJ2 (2) To synthesize ∆12-PGJ2, the ω-chain aldehyde 37 was firstly prepared from 5-hexenal (49) through asymmetric Keck allylation,31 TBS protection, and ozonolysis (Scheme 1.4.6). With all the starting materials in hand, the same three-component coupling sequence was performed to obtain 38 in good yield (45% over 2 steps). 38 was then subjected to the standard one-pot stereoretentive homodimerization/cross-metathesis conditions, and alcohol 52 was obtained in excellent yield (95% yield, Scheme 1.4.6) with high Z-selectivity (>99% Z). Ley oxidation and deprotection of the TBS group of 52 in aqueous HF furnished the natural product ∆12-PGJ2 (1) in 89% yield over the last two steps. Scheme 1.4.6. Synthesis of ∆12-PGJ2 A. O Me TiCl4, Ti(OiPr)4 (R)-BINOL allyl stannane Ag2O, CH2Cl2 Me (55%, > 95% ee) 49 O3 Me2S/Et3N CH2Cl2/MeOH OR TBSCl,imidazole CH2Cl2 (79%) (93%) O cis-5-octen-1-ol Ru-4 (1 mol%) toluene, 23 ºC ca. 2 torr Me 2. MsCl, DMAP, CH2Cl2 (45% over 2 steps) O (R)-43 OTBS COOH Me ∆12-PGJ2 (1) then 38 Ru-4 (5 mol%) THF, 40 ºC (95%, >99:1 Z:E) 38 OH 37 50: R = H 51: R = TBS 1. CuBr.Me2S, LiCl, allylMgBr THF, –78 ºC then 37, THF, –78 ºC O Me OTBS B. BocO O 1. TPAP, NMO•H2O MeCN 2. HF, MeCN (89% over 2 steps) OH Me O OTBS 52 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 17 Synthesis of ∆12-PGJ3 (3) began with the preparation of the ω-chain aldehyde 14. We envisioned the Z-alkene in 14 could also be generated from stereoretentive metathesis. First, we obtained chiral alcohol 53 through a reported chiral pool strategy with (R)-epichlorohydrin as the starting material (Scheme 1.4.7A).32 TBS protection of the alcohol and subsequent removal of the 1,3-dithiol gave aldehyde 55. Stereoretentive metathesis of 55 with an excess amount of cis3-hexene using catalyst Ru-4 (4 mol%) afforded ω-chain aldehyde 14 in good yield (88%) with high Z-selectivity (>99% Z). The short synthesis of aldehyde 14 proved that a broad range of functional groups, including aldehydes, can be tolerated without protecting group manipulations using stereoretentive catalysts. Then, 56 was synthesized through the standard three-component coupling sequence from (R)-43 (40% yield over 2 steps, Scheme 1.4.7B). Scheme 1.4.7. Synthesis of ∆12-PGJ3 A. cis-3-hexene n-BuLi, (R)-epichlorohydrin, THF S S S (58%) MeI, CaCO3 S then CuBr•Me2S vinylMgBr, THF OR TBSCl,imidazole CH2Cl2 (95%) Ru-4 (4 mol%) THF O MeCN/H2O 53: R = H 54: R = TBS Me (88%, >99:1 Z/E) OTBS (94%) O OTBS 14 55 B. iPr 1. CuBr.Me2S, LiCl, allylMgBr THF, –78 ºC then 14, THF, –78 ºC BocO 2. MsCl, DMAP, CH2Cl2 (40% over 2 steps) O 5-hexen-1-ol iPr Ru-2 (20 mol%) THF, 40 ºC Me O O O iPr Ru-2 OH 1.TPAP, NMO•H2O MeCN + 2. HF (aq.), MeCN O ∆12-PGJ3 (3) Me 56 OTBS OTBS 58 (<2%) D. trisubstituted metallacyclobutane cis-5-octen-1-ol Ru-4 (1 mol%) toluene, 23 ºC ca. 2 torr OTBS O 57 (52%) C. O OH Me (60% over 2 steps) OH then 56 Ru-4 (5 mol%) THF, 40 ºC O O N 56 Me Ru O OTBS (R)-43 COOH N N intermediate with Ru-2: OH O OTBS 57 (44%, > 99:1 Z/E) N N + Me Ar OTBS O O 59 (31%) O N Ru O highly unfavorable Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 18 Surprisingly, fast ring-closing metathesis (RCM) with Ru-4 yielded 59 as a by-product (31% yield) bearing an unusual 9-membered ring, and the desired alcohol product 57 was obtained in only 44% yield (Scheme 1.4.7C). Alternatively, we chose to use cyclometallated catalyst Ru-2 to circumvent the crossover of alkene reactivity. Because tri-substituted metallacyclobutane intermediates are highly unfavorable with this cyclometallated catalyst, this pathway can be easily avoided (Scheme 1.4.7D). 33 Chemoselective cross-metathesis of 5-hexen-1-ol with the allyl group of 56 furnished the desired product 57 in good yield (52%) with a trace amount of by-product 58 (less than 2%, Scheme 1.4.7B). The RCM product 59 was not observed under these conditions. The side-reaction of C17 internal Z-alkene could be attributed to ethylene produced or the residual ruthenium methylidene species in the solution. Then, Ley oxidation of 57 and deprotection of the TBS group with aqueous HF provided ∆12-prostaglandin J3 (3) in 8 linear steps. Scheme 1.4.8. Synthesis of 15d-PGJ3 cis-5-octen-1-ol Ru-4 (1 mol%) toluene, 23 ºC ca. 2 torr 1. CuBr.Me2S, LiCl, allylMgBr THF, –78 ºC then 60, THF, –78 ºC BocO 2. MsCl, DMAP, CH2Cl2 (36% over 2 steps) O Me O 61 then 61 Ru-4 (5 mol%) THF, 40 ºC (R)-43 OH 1. PCC, CH2Cl2 COOH 2. NaClO2, NaH2PO4, 2-methyl-2-butene t-BuOH/H2O (12% from 61) Me O 15d-PGJ3 (4) O Me 62 (36%, > 99:1 Z/E) + 63 (~12%), 64 (yield n.d.) OH O Me 60 OH OH O O 63 64 Finally, in the synthesis of 15d-PGJ3 (4), crossover of metathesis reactivity between the allyl group and the C17 Z-alkene of 61 could also be expected. Standard stereoretentive metathesis conditions with Ru-4 provided desired product 62 in 36% yield and by-products 63 and 64 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 19 (Scheme 1.4.8). Compared to ∆12-PGJ3 (3) synthesis, where the steric bulk of the OTBS group may be beneficial to achieving good chemoselectivity, 61 has no such steric hindrance. However, no RCM of 61 was observed, possibly due to the ring strain of RCM product. Though 62 could not be separated from 63, the mixture was subjected to PCC oxidation and Pinnick oxidation conditions, allowing us to isolate 15-deoxy-∆12,14-prostaglandin J3 (4) (12% yield from 61). 1.4.2 Improved Synthesis of Enantiopure 15d-PGJ2 In the previous synthesis, erosion of enantioselectivity was observed in compound 44 after three-component coupling reaction (Scheme 1.4.3, 88% ee), due to the racemization of the relative acidic C8 stereocenter in the reactive 2-alkylidene cyclopentenone moiety. Previous approaches toward these types of cross-conjugated dienone prostaglandins utilized masked forms of this structural motif, and the enone was unmasked in the final step of the syntheses. For example, through retro-Diels–Alder reaction, 34 Saegusa–Ito oxidation,17g bisallylic alcohol oxidation17b (Scheme 1.4.9). We hypothesize that racemization could be attenuated in the masked enone motif above. Retro-Diels-Alder reaction is an appealing approach since the 3-oxodicyclopentadiene starting material is readily available, which was also utilized in Nicolaou’s recent synthesis of ∆12PGJ2 (Scheme 1.2.4).18 The C8 stereocenter was introduced by stereoselective conjugate addition of enantiomerically pure enone (+)-33 with allyl magnesium bromide, CuI and LiCl in the presence of TMSCl. Then, it was directly unmasked with thermally induced retro-Diels−Alder reaction, furnished enantiopure intermediate 34 in 77% yield over the two steps. We proposed that this unmasking step could be performed after the three-component coupling step, to have a better strategic efficiency and avoid the relatively volatile intermediate 34. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 20 Scheme 1.4.9. Reported Synthetic Strategies to Cross-Conjugated Dienone R1 R2 O cross-conjugated dienone bisallylic alcohol oxidation retro-Diels–Alder Saegusa–Ito oxidation H R1 R1 R2 R2 H O R1 O R2 HO Several approaches have been reported to access chiral 3-oxodicyclopentadiene moiety, including enzymatic resolution by lipase, 35 and keto reductases, 36 Co-catalyzed asymmetric intermolecular Pauson−Khand reaction (PKR) of norbornadiene and alkynes, 37 and kinetic resolution via Cu-catalyzed 1,3-dipolar cycloaddition reactions. 38 Lipase-mediated enzymatic resolution was performed to synthesize enantiomerically pure 33, since racemic endo-3oxodicyclopentadiene (±)-33 can be readily obtained through one-pot allylic photooxidation of dicyclopentadiene catalyzed by tetraphenylporphyrin (TPP).39 Then, the endo-alcohol (±)-65 was obtained from DIBAL-H reduction in excellent yield. Kinetic resolution was successfully performed on 4.0 gram scale when (±)-65 was treated with vinyl acetate (0.6 equivalent) in tertbutyl methyl ether in the presence of commercially available lipase PS-on-celite (10% w/w of the substrate). The endo-acetate (–)-66 was isolated in 48% yield, leaving the endo-alcohol (+)-65 in 49% yield after 48 h at 37 ºC. The endo-acetate (–)-66 was treated with 1 equivalent of K2CO3 in methanol, which liberated the endo-alcohol (–)-65. Both enantiopure (+)- and (–)-65 can be obtained (>99% ee) by oxidation of endo-alcohol enantiomers by TPAP and NMO, in the presence of 4 Å molecular sieves in CH2Cl2/MeCN.40 Alternatively, (+)-65 could also be oxidized in the reaction conditions reported by Stahl and coworkers,41 which resulted in higher yield to obtain (–)33 (97% yield, Scheme 1.4.10). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 21 Scheme 1.4.10. Enzymatic Resolution 1. K2CO3, MeOH (98%) 2. TPAP, NMO, 4Å MS MeCN/CH2Cl2 H H H DIBAL-H THF H O (±)-33 H (81%) OH H (63%, >99% ee) OAc lipase PS (10 wt%) vinyl acetate (0.6 equiv) (–)-66 (48%) MTBE, 37 ºC, 48 h + H H (71%, >99% ee) OH (+)-65(49%) H O (+)-33 TPAP, NMO, 4Å MS MeCN/CH2Cl2 (±)-65 H Cu(MeObpy)OTf (5 mol%) ABNO (1 mol%) NMI (10 mol%) MeCN, air, 23 ºC H H O (–)-33 (97%, >99% ee) In previous reports by Nicolaou and others,12,14,16,18 aldol reaction in the presence of LDA usually resulted in moderate yield (30–40%), although the first deprotonation step is selective at cyclopentenone to form the enolate. In our improved route, the overall yields were largely improved in the three-component coupling step. In the presence of CuI and Me2S, allyl Gringard reagent firstly can form allyl cuprate, which undergoes regio- and stereoselective conjugate addition to the enone to form an enolate. Then, the resulting enolate can be trapped by the subsequent addition of an aldehyde, which could ensure the full conversion of starting material and reduce the by-product formation that occurred in previously reported aldol reactions with LDA. The reaction gave a mixture of aldol diastereomers, with adduct 68 identified as the major diastereomer, indicating an anti-aldol process. After elimination with MsCl and excess amount of DMAP, the mixture of diastereomers can be converted to the thermodynamically favored E-alkene in good yield (77% yield for (+)-67, 75% yield for (–)-67). Then, both enantiomers of 44 can be readily obtained in high enantioselectivity (>99% ee, Scheme 1.4.11), by Lewis acid-catalyzed retro-Diels-Alder reaction developed by Grieco,42 using EtAlCl2 and stoichiometric amount of maleic anhydride at a lower temperature (80 ºC) than the thermally induced conditions (> 160 ºC). In the previous synthesis with (R)-43, racemization was observed because the C8 position is Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 22 adjacent to enone and C8-H presents certain acidity, which is prone to racemize in the presence of base. However, when the enone was masked with the cyclopentadiene motif, the proton in the corresponding stereocenter is less prone to deprotonation. In addition, this reaction sequence was performed on a larger scale (1.6 gram starting material), and enantio-enriched enone (+)-33 was used as the limiting reagent. Excess amount of (R)-43 was required in the previous report of threecomponent coupling reactions because the O-Boc group is labile and (R)-43 was converted to undesired by-products, and the reaction scale was limited (up to 200 mg starting material). Scheme 1.4.11. Stereodivergent Three-component Coupling H H Maleic anhydride EtAlCl2 1. CuI, Me2S, allylMgBr, THF, –78 ºC H then trans-2-octenal, THF, –78 ºC 2. MsCl, DMAP, CH2Cl2 O Me H Me DCE, 80 ºC O O (+)-44 (68%, >99% ee) (+)-67 (+)-33 (77% yield over 2 steps) H Me H O H OH 68 H H as above H (–)-33 as above Me H O Me O O (–)-67 (–)-44 (70%, >99% ee) (75% yield over 2 steps) Finally, (+)-44 was carried on to the one-pot homodimerization/steroretentive metathesis reaction, and the primary alcohol product 47 was obtained in 99% yield and >99% ee with high Zselectivity (>99:1 Z/E, Scheme 1.4.12). Then, oxidation of 47 with PCC, and then Pinnick oxidation gave rise to the enantiopure 15d-PGJ2 (2) in 41.0 mg scale (65% yield over 2 steps). The enantiopurity was confirmed by synthesizing the methyl ester derivative of 2 with (trimethylsilyl)diazomethane, which 69 was obtained in 72% yield and 99% ee. This route presents a robust and scalable strategy to synthesize 15d-PGJ2 and the enantioselectivity was Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 23 retained throughout the synthesis. In principle, this strategy can be applied to the synthesis of other ∆12-PGJ analogs to obtain those compounds with high enantiopurity for biological studies. Scheme 1.4.12. Synthesis of Enantiopure 15d-PGJ2 cis-5-octen-1-ol Ru-4 (1 mol%) toluene, 23 ºC ca. 2 torr Me O (+)-44 OH Me then (+)-44 Ru-4 (5 mol%) THF, 40 ºC O 47 (>99% ee) (99%, >99:1 Z/E, >99% ee) OH COOR 1. PCC, CH2Cl2 Me O 47 (>99% ee) 1.5 2. NaClO2, NaH2PO4•H2O 2-methyl-2-butene Me O (65% yield over 2 steps) R = H, 2 R = Me, 69 (72%, >99% ee) TMSCH2N2 CONCLUSIONS In conclusion, a concise and convergent synthesis of four ∆12-prostaglandin J natural products in shorter sequences (7–8 steps in the longest linear sequences) was developed, empowered by stereoretentive and stereoselective metathesis. Furthermore, the reactivity, chemoselectivity, and functional group compatibility of stereoretentive metathesis was evaluated. This study should inspire further practical applications of stereoselective metathesis, such as a facile one-pot stereoretentive homodimerization/cross-metathesis strategy to introduce Z-alkenes with excellent geometric control. An improved synthesis was also developed starting with enzymatic resolution of 3-oxodicyclopendadiene. Racemization can be avoided in the threecomponent coupling step using the chiral 3-oxodicyclopendadiene starting material and enantiopure 15d-PGJ2 (>99% ee) was obtained. The modularity and expediency of this chemistry opens the synthesis of other prostaglandins and analogues to enable SAR studies in cancer treatment. With the well-defined kinetically Z/E-selective catalysts that have been developed to overcome the inherent thermodynamic preference of alkene product geometry, olefin metathesis can play a pivotal role in the synthesis design. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 1.6 EXPERIMENTAL METHODS AND ANALYTICAL DATA 1.6.1 Materials and Methods 24 Unless noted in the specific procedure, reactions were performed in flame-dried glassware under argon atmosphere. All metathesis reactions were carried out under air-free conditions in dry glassware in a Vacuum Atmospheres Glovebox filled with N2. General solvents were purified by passing through solvent purification columns. Commercially available substrates were used as received. All solvents and substrates were sparged with Ar before bringing into the glovebox and filtered over basic alumina (Brockmann I) prior to use. Reaction progress was monitored by thinlayer chromatography (TLC) using E. Merck silica gel 60 F254 precoated plates (0.25 mm) and visualized by UV fluorescence quenching, potassium permanganate, or p-anisaldehyde staining. Silicycle SiliaFlash P60 Academic Silica gel (particle size 0.040-0.063 mm) was used for flash chromatography. Analytical chiral HPLC was performed with an Agilent 1100 Series HPLC utilizing a Chiralcel OD-H column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. with visualization at 254 nm. Analytical SFC was performed with a Mettler SFC supercritical CO2 analytical chromatography system utilizing Chiralcel (IC) column (4.6 mm x 25 cm) obtained from Daicel Chemical Industries, Ltd. with visualization at 210 nm. GC conversion data was obtained using an HP-5 capillary column with an Agilent 6850 FID gas chromatograph. 1H and 13 C NMR spectra were recorded on a Varian Inova 500 spectrometer (500 MHz and 126 MHz, respectively), a Bruker AV III HD spectrometer equipped with a Prodigy liquid nitrogen temperature cryoprobe (400 MHz and 101 MHz, respectively), or a Varian Mercury 300 spectrometer (300 MHz and 75 MHz, respectively) and are reported in terms of chemical shift relative to residual CHCl3 (δ 7.26 and δ 77.16 ppm, respectively). Data for 1H NMR spectra are reported as follows: chemical shift (δ ppm) (multiplicity, coupling constant (Hz), integration). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 25 Abbreviations are used as follows: s = singlet, bs = broad singlet, d = doublet, t = triplet, q = quartet, quint = quintet, m = complex multiplet. Infrared (IR) spectra were recorded on a Perkin Elmer Paragon 1000 spectrometer using neat samples on ATR diamond, and are reported in frequency of absorption (cm–1). High-resolution mass spectra HRMS were acquired from the Caltech Mass Spectral Facility using fast-atom bombardment (FAB+), electrospray ionization (TOF ES+) or electron impact (EI+). Optical rotations were measured on a Jasco P-2000 polarimeter using a 100 mm path-length cell at 589 nm. 1.6.2 Experimental Procedures Preparation of enone (R)-43: BocO O (±)-43 Pd2(dba)3•CHCl3 Cs2CO3 (R,R)-DACH p-methoxyphenol CH2Cl2 (41% yield, > 99% ee) BocO O O NH HN O PPh2 Ph2P (R)-43 (R,R)-DACH Under argon atmosphere, a 500 mL flask was charged with (±)-43 (prepared through procedures by Reiser and co-workers27) (5.02 g, 25.4 mmol, 2.0 equiv) in CH2Cl2 (100 mL), p-methoxyphenol (1.57 g, 12.7 mmol, 1.0 equiv) and Cs2CO3 (1.22 g, 3.75 mmol, 0.296 equiv) was added and the solution was cooled to 0 ºC. In another 100 mL flask, Pd2(dba)3•CHCl3 (131 mg, 0.127 mmol, 0.01 equiv) and ligand (R,R)-DACH (306 mg, 0.44 mmol, 0.035 equiv) in CH2Cl2 (50 mL) was stirred until the initially purple solution turned yellow brown (4–5 min), and the catalyst solution was transferred to the 500 mL flask through a cannula. The solvent was removed under reduced pressure after 2.5 h stirring at 0 ºC. The residue was purified by flash chromatography (hexanes/EtOAc 9:1 to 6:1) to give (R)-43 (2.06 g, 41%, > 99% ee confirmed by chiral SFC analysis). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 26 TLC (4:1 hexanes/EtOAc): Rf= 0.4 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 7.59 (dd, J = 5.7, 2.4 Hz, 1H), 6.32 (dd, J = 5.7, 1.3 Hz, 1H), 5.70 (dtd, J = 6.2, 2.3, 1.3 Hz, 1H), 2.82 (dd, J = 18.7, 6.4 Hz, 1H), 2.39 (dd, J = 18.7, 2.3 Hz, 1H), 1.49 (s, 9H). 13 C NMR (101 MHz, CDCl3): δ 204.7, 158.7, 152.8, 137.2, 83.4, 74.3, 41.1, 27.8. FTIR (ATR): 2981, 2937, 1722, 1591, 1475, 1459, 1395, 1369, 1334, 1272, 1253, 1152, 1104, 994, 840, 791 cm–1. HRMS (FAB+, m/z): calc’d for C10H15O4 [M+H]+ 199.0965, found: 199.0986. [𝜶]𝟐𝟑 𝑫 : +78.7° (c = 1.0, CHCl3). SFC Conditions: 3% IPA, 4.0 mL/min, Chiralcel IC column, λ = 210 nm, tR (min): major = 2.36, minor = 3.16 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 27 Preparation of 44: BocO 1. CuBr•Me2S, LiCl, allylMgBr THF, –78 ºC then trans-2-octenal O 2. MsCl, DMAP, CH2Cl2 –10 ºC to 23 ºC (R)-43 (41% yield over 2 steps, 88% ee) Me O 44 A 25 mL flask was flame dried and charged with CuBr•Me2S (195 mg, 0.95 mmol, 3.0 equiv) and LiCl (42 mg, 1 mmol, 3.2 equiv) in a nitrogen-filled glove box. The flask was sealed with septum and brought out of glove box, and was heated under vacuum to remove residue water. Anhydrous THF (10 mL) was added, and the solution was vigorously stirred for 10 minute at 23 ºC until a yellow homogeneous solution was formed. At –78ºC, allylmagnesium bromide (0.9 mL, 1.0 M solution in THF, 0.9 mmol, 2.8 equiv) was added slowly. The reaction mixture was stirred at –78 ºC for 1 hour and a solution of (R)-43 (188 mg, 0.95 mmol, 3.0 equiv) in THF (1 mL) was added slowly. After 30 minutes stirring at the same temperature, a solution of trans-2-octenal (40 mg, 0.32 mmol, 1.0 equiv) in THF (1 mL) was added slowly. The reaction was stirred for additional 2 hours at –78 ºC before a solution of saturated NH4Cl and NH3•H2O (10 mL, 9:1 NH4Cl/NH3•H2O) was added. The biphasic solution was vigorously stirred until a homogeneous dark blue solution was formed in aqueous phase. The phases were separated and the organic phase was washed with 10 mL saturated NH4Cl solution. The combined aqueous phase was extracted with Et2O (2 × 30 mL). The combined organic phase was dried with anhydrous magnesium sulfate, and was concentrated in vacuo. The residue was purified by flash chromatography (SiO2, hexanes/EtOAc 15:1) to give a mixture of diasteromers of the aldol products (57 mg, 0.23 mmol). In a 25 mL flask, the crude aldol product was dissolved in CH2Cl2 (6 mL) and cooled to –10 ºC. DMAP (421 mg, 3.45 mmol, 15.0 equiv) and MsCl (53 μL, 0.69 mmol, 3.0 equiv) was added sequentially. The reaction mixture was slowly warmed to 23 ºC and stirred for 2 h before diluted Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 28 with 10 mL EtOAc and washed with 1 M HCl (10 mL). The aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic phase was dried with anhydrous magnesium sulfate, and was concentrated in vacuo. The residue was purified by flash chromatography (SiO2, hexanes/EtOAc 15:1) to give 44 (30 mg, 41% yield over 2 steps, 88% ee by chiral HPLC analysis) as a colorless liquid. TLC (4:1 hexanes/EtOAc): Rf= 0.56 (UV). 1 H NMR (300 MHz, CDCl3): δ 7.50 (ddd, J = 6.0, 2.6, 1.0 Hz, 1H), 6.95 (dt, J = 10.7, 1.2 Hz, 1H), 6.35 (dd, J = 6.0, 1.8 Hz, 1H), 6.33 – 6.15 (m, 2H), 5.81 – 5.64 (m, 1H), 5.11 – 5.01 (m, 2H), 3.60 (ddq, J = 8.5, 4.1, 1.9 Hz, 1H), 2.73 – 2.58 (m, 1H), 2.24 (dddd, J = 13.4, 9.7, 6.8, 1.5 Hz, 3H), 1.54 – 1.37 (m, 2H), 1.38 – 1.22 (m, 4H), 0.89 (t, 3H, J = 6.9 Hz). 13 C NMR (75 MHz, CDCl3): δ 197.5, 160.6, 147.1, 135.4, 134.9, 134.3, 131.8, 125.7, 117.8, 43.2, 37.4, 33.6, 31.5, 28.6, 22.6, 14.1. FTIR (ATR): 2954, 2928, 2859, 1699, 1642, 1581, 1458, 1344, 1194, 994, 918, 829, 734 cm–1. HRMS (FAB+, m/z): calc’d for C16H21O [M+H–H2]+ 229.1586, found: 229.1581. [𝜶]𝟐𝟑 𝑫 : +65.4° (c = 1.0, CHCl3). HPLC Conditions: 10% IPA, 1.0 mL/min, Chiralcel OD-H column, λ = 254 nm, tR (min): major = 5.37, minor = 6.44 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 29 Preparation of 47: A. One-pot homodimerization/stereoretentive metathesis method cis-5-octen-1-ol Ru-4 (1 mol%) toluene, 23 ºC, 2 torr Me O 44 then 44, Ru-4 (5 mol%) THF, 40 ºC, 16 h OH Me O 47 (93% yield, > 99:1 Z/E, 87% ee) In a nitrogen-filled glovebox, cis-5-octen-1-ol (113 mg, 0.88 mmol, 8.0 equiv) was dissolved in toluene (1 mL) in a 50 mL Schlenk flask and a solution of catalyst Ru-4 (7.5 mg, 8.8 μmol, 1 mol%) in THF (0.6 mL) was added. The Schlenk flask was sealed and brought out of the glovebox, and then connected to high vacuum. The valve was gradually opened (Caution: open slowly and stir well to avoid splashing). After 15 minutes stirring, the flask was refilled with argon and sealed, and was brought back into the glovebox. The residue was diluted with THF (0.5 mL), and an aliquot was taken for GC analysis (conversion of homodimerization step was >98% by GC analysis). A solution of 44 (25 mg, 0.11 mmol, 1.0 equiv) in THF (0.5 mL) was added into the Schlenk flask and an additional portion of catalyst Ru-4 (4.6 mg, 5.5 μmol, 5 mol%) solution in THF (0.2 mL) was added. The Schlenk flask was sealed and brought out of glovebox. The reaction was stirred for 24 h at 40 ºC before a few drops of ethyl vinyl ether were added. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO2, hexanes/EtOAc 2:1) to give 47 (31 mg, 93%, >99:1 Z/E, 87% ee by chiral HPLC analysis). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 30 TLC (4:1 hexanes/EtOAc): Rf= 0.2 (UV). 1 H NMR (400 MHz, CDCl3) δ 7.48 (ddd, J = 6.0, 2.6, 1.0 Hz, 1H), 6.95 (dt, J = 11.0, 1.3 Hz, 1H), 6.35 (dd, J = 6.0, 1.8 Hz, 1H), 6.34 – 6.19 (m, 2H), 5.52 – 5.44 (m, 1H), 5.38 – 5.30 (m, 1H), 3.63 (t, J = 6.5 Hz, 2H), 3.60 – 3.55 (m, 1H), 2.60 (dddd, J = 14.0, 6.2, 4.3, 1.4 Hz, 1H), 2.30 (dtd, J = 14.4, 8.6, 1.2 Hz, 1H), 2.25 – 2.17 (m, 2H), 2.01 (qd, J = 7.3, 1.4 Hz, 2H), 1.59 – 1.49 (m, 2H), 1.48 – 1.37 (m, 5H), 1.34 – 1.29 (m, 4H), 0.89 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 197.6, 160.9, 147.0, 135.4, 135.3, 132.6, 131.8, 125.8, 125.3, 62.9, 43.7, 33.6, 32.5, 31.5, 30.9, 28.6, 27.2, 25.8, 22.6, 14.2. FTIR (ATR): 3445, 2960, 2930, 2862, 1690, 1629, 1580, 1447, 1264, 1207, 1054, 979, 732 cm– 1 . HRMS (TOF, ES+, m/z): calc’d for C20H31O2 [M+H]+ 303.2319, found: 303.2320. [𝜶]𝟐𝟑 𝑫 : +115.8° (c = 0.5, CHCl3). HPLC Conditions: 10% IPA, 1.0 mL/min, Chiralcel OD-H column, λ = 254 nm, tR (min): major = 10.12, minor = 13.57 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 31 B. Cross-metathesis method OH cis-5-octen-1-ol Ru-4 (5 mol%) Me O THF, 40 ºC, 24 h static vacuum Me Me + Me O O 47 48 (47% yield, >99:1 Z/E) (53% yield, >99:1 Z/E) 44 In a nitrogen-filled glovebox, 44 (49 mg, 0.21 mmol, 1.0 equiv) and cis-5-octen-1-ol (205 mg, 1.6 mmol, 7.6 equiv) was dissolved in THF (0.5 mL) in a 1-dram vial, and the solution was transferred to a 50 mL Schlenk flask. A solution of catalyst Ru-4 (8.5 mg, 10 µmol, 5 mol%) in THF (0.5 mL) was added. The Schlenk flask was sealed and brought out of the glovebox, and freeze-pumpthaw for one time to keep it under static vacuum. The reaction was stirred for 16 h at 40 ºC before quenched with a few drops of ethyl vinyl ether. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexanes/EtOAc 10:1 to 2:1) to give 47 (29 mg, 53%, >99:1 Z/E) and 48 (30 mg, 47%, >99:1 Z/E) as two major products. Me Me O 48 TLC (4:1 hexanes/EtOAc): Rf= 0.6 (UV). 1 H NMR (400 MHz, CDCl3) δ 7.48 (ddd, J = 5.9, 2.6, 1.0 Hz, 1H), 6.95 (dt, J = 11.2, 1.2 Hz, 1H), 6.39 – 6.17 (m, 3H), 5.53 – 5.43 (m, 1H), 5.34 – 5.24 (m, 1H), 3.56 (ddq, J = 8.6, 4.1, 2.0 Hz, 1H), 2.70 – 2.47 (m, 1H), 2.34 – 2.17 (m, 3H), 1.99 (pd, J = 7.5, 1.6 Hz, 2H), 1.46 (p, J = 7.3 Hz, 2H), 1.31 (tt, J = 5.6, 2.8 Hz, 4H), 0.93 (t, J = 7.6 Hz, 3H), 0.89 (t, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 197.6, 160.9, 146.8, 135.4, 134.6, 131.7, 125.8, 124.3, 43.8, 33.6, 31.5, 30.8, 28.6, 22.6, 20.8, 14.3, 14.1. FTIR (ATR): 2959, 2927, 2856, 2360, 1693, 1632, 1579, 1459, 1376, 1337, 1294, 1203, 1100, 1069, 1020, 976, 923, 867, 834, 805, 728, 668 cm–1. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 32 HRMS (TOF, ES+, m/z): calc’d for C20H31O2 [M+H]+ 259.2056, found: 259.2207. [𝜶]𝟐𝟑 𝑫 : +210.8° (c = 1.0, CHCl3). Preparation of 15-deoxy-∆12,14-prostaglandin J2 (2): OH COOH TPAP, NMO•H2O Me O Me MeCN (68% yield) O 47 2 To a stirred solution of 47 (14 mg, 0.046 mmol, 1.0 equiv) in MeCN (0.5 mL) was added NMO•H2O (65 mg, 0.46 mmol, 10.0 equiv). Tetrapropylammonium perruthenate (1.7 mg, 4.6 μmol, 0.1 equiv) was added until NMO•H2O was fully dissolved and the reaction was stirred at 23 ºC for 3 hours. The reaction mixture was stirred for 3 hours and the solvent was removed in vacuo. The residue was loaded onto a silica gel column, flushed with CH2Cl2 then CH2Cl2/MeOH (20:1). 15-deoxy-∆12,14-prostaglandin J2 (2) was obtained as a colorless oil (10 mg, 68% yield). TLC (100% EtOAc): Rf= 0.70 (UV). 1 H NMR (400 MHz, CDCl3): δ 7.47 (ddd, J = 6.0, 2.6, 1.0 Hz, 1H), 6.95 (d, J = 11.0 Hz, 1H), 6.38 – 6.35 (m, 1H), 6.33 – 6.20 (m, 2H), 5.50 – 5.33 (m, 2H), 3.59 (ddd, J = 8.4, 4.1, 2.2 Hz, 1H), 2.59 (m, 1H), 2.36 – 2.19 (m, 5H), 2.05 (q, J = 7.3 Hz, 2H), 1.68 (quint, J = 7.5 Hz, 2H), 1.50 – 1.41 (m, 2H), 1.34 – 1.28 (m, 4H), 0.90 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 197.6, 177.9, 160.8, 147.2, 135.5, 135.1, 131.9, 131.5, 126.2, 125.8, 43.6, 33.6, 33.2, 31.6, 30.8, 28.6, 26.7, 24.6, 22.6, 14.2. FTIR (ATR): 2960, 2928, 2850, 1708, 1692, 1629, 1456, 1265, 1207, 978, 734, 703 cm–1. HRMS (TOF, ES+, m/z): calc’d for C20H29O3 [M+H]+ 317.2111, found: 317.2127. [𝜶]𝟐𝟑 𝑫 : +106.2° (c = 0.2, CHCl3). Spectral data (1H NMR, 13C NMR, HRMS) matched with the published data.17b,d,g,h Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 33 Preparation of (S)-non-1-en-4-ol (50): O Me TiCl4 Ti(Oi-Pr)4 Ag2O (R)-BINOL allyltributyltin CH2Cl2 49 (55% yield, >95% ee) Me OH 50 Following the procedure by Yadav and co-workers43, to a stirred solution of TiCl4 (1.0 M solution in CH2Cl2, 2.5 mL, 2.5 mmol) in CH2Cl2 (50 mL) was added dried Ti(Oi-Pr)4 (2.24 mL,7.5 mmol) at 0 °C under argon. The solution was warmed to 23 ºC and stirred for 1 h, then Ag2O (1.15 g, 5.0 mmol) was added, and the mixture was stirred for 5 h with the exclusion of direct light by aluminum foil. The reaction mixture was diluted with CH2Cl2 (80 mL) and (R)-binaphthol (2.86 g, 10 mmol) was added at 23 ºC. After 2 h, the reaction mixture was cooled to –15 °C and hexanal (5.0 g, 50 mmol) and allyltributyltin (17 mL, 55 mmol) was added sequentially, then the reaction mixture was warmed to 0 °C. After 8 h, saturated NaHCO3 (50 mL) was added. The aqueous phase was extracted with diethyl ether (2 × 250 mL). The combined organic phases were washed with brine (1 × 200 mL), dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (SiO2, 15:1 hexanes/EtOAc) afforded compound 50 as a colorless oil (3.94 g, 55% yield, > 95% ee by Mosherester analysis). TLC (10:1 hexanes/EtOAc): Rf= 0.22 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 5.81 (dddd, J = 17.6, 9.4, 7.8, 6.5 Hz, 1H), 5.17 – 5.03 (m, 2H), 3.62 (dtd, J = 8.0, 4.0, 2.4 Hz, 1H), 2.28 (dddt, J = 13.7, 6.8, 4.3, 1.3 Hz, 1H), 2.18 – 2.05 (m, 1H), 1.74 (d, J = 3.6 Hz, 1H), 1.50 – 1.35 (m, 3H), 1.35 – 1.21 (m, 5H), 0.87 (t, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 135.1, 118.1, 70.8, 42.0, 36.9, 32.0, 25.5, 22.7, 14.1. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 34 FTIR (ATR): 3355, 3077, 2956, 2929, 2859, 1641, 1467, 1435, 1378, 1124, 1027, 994, 911, 865, 725 cm–1. HRMS (EI+, m/z): calc’d for C9H18O [M]+ 142.1352, found: 142.1372. [𝜶]𝟐𝟑 𝑫 : –7.2° (c = 1.0, CHCl3). Mosher-ester analysis of 50: 2 1 4 6 5 3 O O CF3 MeO Ph 7 8 Me 9 50a Me O O CF3 Ph OMe 50b To a stirred solution of 50 (21 mg, 0.15 mmol, 1.0 equiv) in CH2Cl2 (1.5 mL) in a 4 mL vial was added pyridine (0.1 mL, 1.24 mmol, 8.0 equiv) and (S)-(+)-Mosher chloride (100 mg, 0.40 mmol, 2.7 equiv) at 25 °C. After stirring for 2 h at the same temperature, the reaction mixture was diluted with CH2Cl2 (3 mL) and saturated NH4Cl solution (3 mL) was added. The phases were separated, and the aqueous layer was extracted with CH2Cl2 (2 × 5 mL). The combined organic extracts were concentrated after drying over magnesium sulfate. (R)-MTPA ester 50a was obtained through column chromatography (SiO2, 20:1 hexanes/EtOAc) as a colorless oil (50 mg, 94 %). Compound 50b was prepared in the same manner and on the same scale as above using (R)-(−)Mosher chloride. (S)-MTPA ester 50b was obtained through column chromatography (SiO2, hexanes/EtOAc, 20:1) as a colorless oil (51 mg, 96 %). (R)-MTPA ester 50a: TLC (10:1 hexanes/EtOAc): Rf= 0.57 (UV). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 1 35 H NMR (400 MHz, CDCl3): δ 7.57 – 7.50 (m, 2H), 7.43 – 7.31 (m, 3H), 5.73 – 5.56 (m, 1H), 5.14 (dq, J = 7.2, 5.7 Hz, 1H), 5.06 – 4.98 (m, 2H), 3.55 (q, J = 1.3 Hz, 3H), 2.35 (dddd, J = 6.2, 5.0, 2.5, 1.3 Hz, 2H), 1.71 – 1.54 (m, 2H), 1.39 – 1.22 (m, 6H), 0.88 (t, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 166.4, 133.0, 132.5, 129.7, 128.4, 127.6, 123.5 (q, J = 288.6 Hz), 118.4, 84.7 (q, J = 27.5 Hz), 76.7, 55.6, 38.2, 33.4, 31.6, 25.0, 22.6, 14.1. 19 F NMR (282 MHz, CDCl3): δ –71.3. FTIR (ATR): 2955, 2934, 2861, 1743, 1643, 1612, 1506, 1451, 1258, 1166, 1121, 1081, 1020, 993, 912, 823, 764, 732, 716, 696, 648 cm–1. HRMS (FAB+, m/z): calc’d for C19H26O3F3 [M+H]+ 359.1829, found: 359.1839. (S)-MTPA ester 50b: TLC (10:1 hexanes/EtOAc): Rf= 0.57 (UV). 1 H NMR (400 MHz, CDCl3): δ 7.58 – 7.52 (m, 2H), 7.43 – 7.34 (m, 3H), 5.76 (ddt, J = 16.1, 10.4, 7.0 Hz, 1H), 5.16 (dt, J = 10.8, 5.2 Hz, 1H), 5.13 – 5.08 (m, 2H), 3.56 (q, J = 1.3 Hz, 3H), 2.42 (ddt, J = 7.3, 6.1, 1.3 Hz, 2H), 1.65 – 1.49 (m, 2H), 1.27 – 1.10 (m, 6H), 0.84 (t, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 166.4, 133.4, 132.6, 129.6, 128.4, 127.5, 123.5 (q, J = 288.6 Hz), 118.5, 84.6 (q, J = 27.5 Hz), 76.7, 55.7, 38.5, 33.3, 31.6, 24.6, 22.6, 14.1. 19 F NMR (282 MHz, CDCl3): δ –71.3. FTIR (ATR): 2960, 2934, 2861, 1742, 1643, 1498, 1451, 1257, 1167, 1121, 1081, 1019, 992, 912, 824, 764, 732, 717, 696, 648 cm–1. HRMS (FAB+, m/z): calc’d for C19H26O3F3 [M+H]+ 359.1829, found: 359.1845. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 36 Table 1.6.1. Comparison of 1H NMR Data for (R)- and (S)-MTPA Esters Proton 1 2 3 4 5 6-8 9 (S)-MTPA ester 50b 5.01 5.64 2.35 5.14 1.62 1.28 0.88 (R)-MTPA ester 50a 5.11 5.76 2.42 5.16 1.57 1.20 0.84 ∆δ: (S)-(R) 0.1 0.12 0.07 0.02 –0.05 –0.08 –0.04 Preparation of 51: TBSCl Me imidazole Me OH CH2Cl2 OTBS 50 (79% yield) 51 To a stirred solution of 50 (2.0 g, 14 mmol) in CH2Cl2 (60 mL) was added imidazole (2.86 g, 42 mmol, 3.0 equiv) and TBSCl (4.22 g, 28 mmol, 2.0 equiv). Saturated NH4Cl solution (50 mL) was added after stirring overnight. The aqueous layer was extracted with CH2Cl2 (2 × 30 mL) and the combined organic phases were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, 20:1 hexanes/EtOAc) gave 51 as a colorless oil (2.85 g, 79% yield). TLC (10:1 hexanes/EtOAc): Rf= 0.85 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 5.82 (ddt, J = 17.5, 10.4, 7.1 Hz, 1H), 5.08 – 4.99 (m, 2H), 3.68 (quint, J = 5.7 Hz, 1H), 2.21 (dddt, J = 6.8, 5.3, 3.9, 1.3 Hz, 2H), 1.48 – 1.22 (m, 8H), 0.94 – 0.85 (m, 12H), 0.05 (s, 3H), 0.05 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 135.7, 116.7, 72.2, 42.1, 37.0, 32.2, 26.1, 25.2, 22.8, 18.3, 14.2, –4.2, –4.4. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 37 FTIR (ATR): 2956, 2929, 2857, 1641, 1472, 1463, 1361, 1255, 1127, 1049, 1005, 939, 910, 834, 807, 772, 664 cm–1. HRMS (EI+, m/z): calc’d for C15H31OSi [M+H–H2]+ 255.2138, found: 255.2174. [𝜶]𝟐𝟑 𝑫 : –15.7° (c = 1.0, CHCl3). Preparation of aldehyde 37: Me O3, Me2S, Et3N O Me OTBS CH2Cl2/MeOH OTBS 51 (93% yield) 37 To a stirred solution of 51 (1.6 g, 6.25 mmol) in CH2Cl2 (30 mL) and MeOH (30 mL) was bubbled with O3 through a gas dispersion tube. When the color of the solution turned blue, dimethyl sulfide (13.2 mL) and triethylamine (1.2 mL) was added. The solution was stirred overnight and was concentrated under reduced pressure. Column chromatography (SiO2, 20:1 hexenes/EtOAc) afforded 37 as a colorless oil (1.5 g, 93%) TLC (4:1 hexanes/EtOAc): Rf= 0.77 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 9.81 (td, J = 2.6, 0.7 Hz, 1H), 4.17 (quint, J = 5.8 Hz, 1H), 2.51 (ddd, J = 5.7, 2.6, 0.7 Hz, 2H), 1.56 – 1.41 (m, 2H), 1.37 – 1.22 (m, 6H), 0.96 – 0.83 (m, 12H), 0.07 (s, 3H), 0.05 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 202.7, 68.4, 51.0, 38.0, 31.9, 25.9, 25.0, 22.7, 18.1, 14.2, –4.3, – 4.5. FTIR (ATR): 2956, 2929, 2857, 1713, 1472, 1361, 1253, 1096, 1050, 1005, 939, 834, 810, 774 cm–1. HRMS (FAB+, m/z): calc’d for C14H31O2Si [M+H]+ 259.2088, found: 259.2088. [𝜶]𝟐𝟑 𝑫 : –3.0° (c = 1.0, CHCl3). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 38 Preparation of 38: 1. CuBr•Me2S, LiCl, allylMgBr THF, –78 ºC then 37, THF, –78 ºC BocO O Me OTBS 37 Me O 2. MsCl, DMAP, CH2Cl2 –10 ºC to 23 ºC (R)-43 (45% yield over 2 steps) O OTBS 38 A 25 mL flask was flame dried and charged with CuBr•Me2S (144 mg, 0.70 mmol, 2.8 equiv) and LiCl (32 mg, 0.75 mmol, 3.0 equiv) in a nitrogen-filled glove box. The flask was sealed with septum and brought out of glove box, and was heated under vacuum to remove residue water. Anhydrous THF (5 mL) was added, and the solution was vigorously stirred for 10 minutes at 23 ºC until a yellow solution was formed. At –78 ºC, allylmagnesium bromide (0.68 mL, 1.0 M solution in THF, 0.68 mmol, 2.7 equiv) was added slowly. The reaction mixture was stirred at – 78 ºC for 1 hour and a solution of (R)-43 (149 mg, 0.75 mmol, 3.0 equiv) in THF (1 mL) was added slowly. After 30 minutes stirring at the same temperature, a solution of 37 (65 mg, 0.25 mmol, 1.0 equiv) in THF (1 mL) was added slowly. The reaction was stirred for an additional 2 hours at –78 ºC before a solution of saturated NH4Cl and NH3•H2O (10 mL, 9:1 NH4Cl/NH3•H2O) was added. The biphasic solution was vigorously stirred until a homogeneous dark blue solution was formed in aqueous phase. The phases were separated and the organic phase was washed with 10 mL saturated NH4Cl solution. The combined aqueous phase was extracted with Et2O (2 × 30 mL). The combined organic phase was dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, hexanes/EtOAc 18:1) to give a mixture of diasteromers of the aldol product (82 mg, 0.22 mmol). In a 25 mL flask, the crude aldol product was dissolved in CH2Cl2 (6 mL) and cooled to –10 ºC. DMAP (403 mg, 3.3 mmol, 15.0 equiv) and MsCl (51 μL, 0.66 mmol, 3.0 equiv) were added Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 39 sequentially. The reaction mixture was slowly warmed to 23 ºC and was stirred for 12 h before diluted with 10 mL EtOAc and washed with 1 M HCl (10 mL). The aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic phase was dried with anhydrous magnesium sulfate, and was concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc 15:1) to give 38 (41 mg, 45% yield over 2 steps) as colorless liquid. TLC (9:1 hexanes/EtOAc): Rf= 0.25 (UV). 1 H NMR (400 MHz, CDCl3): δ 7.52 (ddd, J = 6.0, 2.6, 1.0 Hz, 1H), 6.60 (ddt, J = 8.3, 7.0, 1.3 Hz, 1H), 6.33 (dd, J = 6.0, 1.8 Hz, 1H), 5.79 – 5.65 (m, 1H), 5.11 – 5.01 (m, 2H), 3.83 (quint, J = 5.8 Hz, 1H), 3.50 (ddq, J = 8.4, 4.0, 2.0 Hz, 1H), 2.72 – 2.61 (m, 1H), 2.51 – 2.31 (m, 2H), 2.18 (dddt, J = 14.3, 9.0, 7.9, 1.1 Hz, 1H), 1.53 – 1.11 (m, 8H), 0.96 – 0.79 (m, 12H), 0.05 (s, 3H), 0.05 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 196.5, 161.4, 138.5, 135.1, 134.3, 132.8, 117.8, 71.7, 43.1, 37.4, 37.1, 32.0, 26.0, 25.1, 22.8, 18.2, 14.2, –4.2, –4.5. FTIR (ATR): 2955, 2928, 2856, 1705, 1656, 1582, 1472, 1360, 1252, 1207, 1127, 1050, 1005, 915, 863, 834, 806, 773, 726, 663 cm–1. HRMS (TOF, ES+, m/z): calc’d for C22H39O2Si [M+H]+ 363.2714, found: 363.2711. [𝜶]𝟐𝟑 𝑫 : +85.3° (c = 1.0, CHCl3). Preparation of 52: Me O OTBS 38 cis-5-octen-1-ol Ru-4 (1 mol%) toluene, 23 ºC, 2 torr then 38, Ru-4 (5 mol%) THF, 40 ºC OH Me O OTBS 52 (95% yield, >99:1 Z/E) Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 40 In a nitrogen-filled glovebox, cis-5-octen-1-ol (150 mg, 1.17 mmol, 8.0 equiv) was dissolved in toluene (2 mL) in a 50 mL Schlenk flask, and a solution of catalyst Ru-4 (9.9 mg, 11.7 μmol, 1 mol%) in THF (0.7 mL) was added. The Schlenk flask was sealed and brought out of the glovebox, and then connected to high vacuum. The valve was gradually opened (Caution: open slowly and stir well to avoid splashing). After 15 minutes stirring, the flask was refilled with argon and sealed, and was brought back into the glovebox. The residue was diluted with THF (0.5 mL), and an aliquot was taken for GC analysis (conversion of homodimerization step was >98% by GC analysis). A solution of 38 (53 mg, 0.146 mmol, 1.0 equiv) in THF (0.5 mL) was added into the Schlenk flask and an additional portion of catalyst Ru-4 (6.2 mg, 7.3 μmol, 5 mol%) solution in THF (0.3 mL) was added. The Schlenk flask was sealed and brought out of glovebox. The reaction was stirred for 24 h at 40 ºC before a few drops of ethyl vinyl ether were added. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (SiO2, hexanes/EtOAc 2:1) to give 52 (60 mg, 95%, >99:1 Z/E). TLC (3:1 hexanes/EtOAc): Rf= 0.23 (UV). 1 H NMR (400 MHz, CDCl3): δ 7.50 (ddd, J = 6.0, 2.6, 1.0 Hz, 1H), 6.59 (ddt, J = 8.3, 7.0, 1.3 Hz, 1H), 6.33 (dd, J = 6.0, 1.8 Hz, 1H), 5.49 (dddt, J = 8.6, 7.2, 5.5, 1.5 Hz, 1H), 5.35 (dtt, J = 11.0, 8.4, 1.6 Hz, 1H), 3.84 (quint, J = 5.9 Hz, 1H), 3.63 (t, J = 6.5 Hz, 2H), 3.46 (ddt, J = 11.0, 4.2, 2.2 Hz, 1H), 2.63 (dddd, J = 13.8, 6.5, 4.2, 1.5 Hz, 1H), 2.50 – 2.34 (m, 2H), 2.17 (dddd, J = 14.5, 9.4, 8.0, 1.3 Hz, 1H), 2.07 – 1.97 (m, 2H), 1.60 – 1.51 (m, 2H), 1.47 – 1.34 (m, 6H), 1.32 – 1.19 (m, 5H), 0.95 – 0.81 (m, 12H), 0.05 (s, 3H), 0.05 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 196.5, 161.8, 138.8, 135.0, 132.7, 132.5, 125.4, 71.7, 62.9, 43.6, 37.5, 37.5, 32.5, 32.0, 30.7, 27.2, 26.0, 25.8, 25.1, 22.8, 18.2, 14.2, –4.2, –4.5. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 41 FTIR (ATR): 3443, 2956, 2928, 2856, 1703, 1652, 1580, 1472, 1360, 1251, 1206, 1127, 1048, 1005, 975, 866, 834, 806, 773, 726, 664 cm–1. HRMS (TOF, ES+, m/z): calc’d for C26H47O3Si [M+H]+ 435.3289, found: 435.3298. [𝜶]𝟐𝟑 𝑫 : +83.5° (c = 1.0, CHCl3). Preparation of ∆12-prostaglandin J2 (1): OH Me O OTBS COOH 1. TPAP, NMO•H2O MeCN 2. HF (aq.), MeCN Me O (89% yield over 2 steps) 52 OH 1 To a stirred solution of 52 (26 mg, 0.06 mmol, 1.0 equiv) in MeCN (0.3 mL) was added NMO•H2O (81 mg, 6 mmol, 10.0 equiv). Tetrapropylammonium perruthenate (2.1 mg, 6 μmol, 0.1 equiv) was added until NMO•H2O was fully dissolved, and the reaction was stirred at 23 ºC for 3 hours. The solution was diluted with Et2O (5 mL), passed through a short pad of silica gel, concentrated, and subjected to the next reaction without further purification. The residue was dissolved in MeCN (1.0 mL) and cooled to 0 ºC. A solution of hydrofluoric acid (48 wt. % in H2O, 0.2 mL) in MeCN (0.4 mL) was added dropwisely. The solution was stirred in the same temperature for 30 min before saturated NaHCO3 solution (1.5 mL) and brine (1.5 mL) were added. The aqueous phase was extracted with EtOAc (5 × 5 mL). The combined organic phases were dried over magnesium sulfate, filtered, and concentrated (not to dryness). The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH 20:1) to give 1 (18 mg, 89% over 2 steps) as a colorless liquid. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 42 TLC (20:1 CH2Cl2/MeOH): Rf= 0.14 (UV). 1 H NMR (500 MHz, CDCl3): δ 7.57 (ddd, J = 6.0, 2.6, 1.0 Hz, 1H), 6.58 (ddt, J = 8.4, 7.2, 1.3 Hz, 1H), 6.36 (dd, J = 6.0, 1.8 Hz, 1H), 5.54 – 5.38 (m, 2H), 3.86 (dtt, J = 7.9, 6.4, 4.0 Hz, 1H), 3.47 (ddt, J = 9.5, 4.0, 2.1 Hz, 1H), 2.78 – 2.68 (m, 1H), 2.57 (dt, J = 14.8, 6.8 Hz, 1H), 2.52 – 2.42 (m, 1H), 2.40 – 2.33 (m, 2H), 2.20 – 2.02 (m, 3H), 1.77 – 1.64 (m, 2H), 1.61 – 1.41 (m, 3H), 1.40 – 1.24 (m, 5H), 0.90 (t, J = 6.8 Hz, 3H). 13 C NMR (126 MHz, CDCl3): δ 196.6, 177.3, 162.0, 139.8, 135.0, 131.8, 131.7, 126.2, 71.5, 43.9, 37.3, 36.7, 33.1, 31.9, 30.6, 26.6, 25.4, 24.6, 22.8, 14.2. FTIR (ATR): 3445, 2960, 2929, 2858, 1699, 1646, 1579, 1463, 1406, 1265, 1237, 1135, 1084, 1033, 842, 810, 734, 702 cm–1. HRMS (TOF, ES+, m/z): calc’d for C20H31O4 [M+H]+ 335.2217, found: 335.2223. [𝜶]𝟐𝟑 𝑫 : +99.5° (c = 0.2, CHCl3). Spectral data (1H NMR, 13C NMR, HRMS) matched with the published data.17e Preparation of 53: n-BuLi, (R)-epichlorohydrin, THF S S then CuBr•Me2S vinylmagnesium bromide, THF S S OH 53 (58% yield) Procedures are same as Dai and co-workers.32 1,3-dithiane (1.2 g, 10 mmol, 1.0 equiv) was dissolved in THF (15 mL) and cooled to –78 ºC. n-BuLi (2.5 M solution in hexanes, 4.4 mL, 11 mmol, 1.1 equiv) was added and the solution was stirred at the same temperature for 15 min, then warmed up to –20 °C and stirred for 1 h. The reaction mixture was cooled down to –78 °C and (R)-epichlorohydrin (1.1 mL, 14 mmol, 1.4 equiv) was added dropwisely. The reaction mixture was stirred at –78 °C for 1 h, then slowly warmed to 23 ºC and stirred overnight and then cooled Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 43 to –40 ºC. In another flame-dried flask, vinyl magnesium bromide (28 mL, 1.0 M in THF, 28 mmol, 2.8 equiv) was added to a stirred solution of CuBr•Me2S (124 mg, 0.6 mmol, 0.06 equiv) in THF (20 mL), and the resulting solution was transferred into the reaction mixture through a cannula at –40 ºC. The reaction mixture was slowly warmed to 23 ºC and stirred overnight before 1 M HCl (50 mL) was added. The biphasic mixture was extracted with EtOAc (3 × 50 mL). The combined organic extract was washed with brine, dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (SiO2, hexanes/EtOAc = 9:1) to afford 53 (1.20 g, 58% yield) as colorless liquid. TLC (4:1 hexanes/EtOAc): Rf= 0.27 (UV). 1 H NMR (400 MHz, CDCl3): δ 5.89 – 5.72 (m, 1H), 5.14 (m, 2H), 4.26 (dd, J = 7.8, 6.6 Hz, 1H), 4.02 – 3.94 (m, 1H), 2.96 – 2.78 (m, 4H), 2.33 – 2.24 (m, 1H), 2.24 – 2.16 (m, 1H), 2.16 – 2.06 (m, 1H), 2.01 (d, J = 4.2 Hz, 1H), 1.95 – 1.82 (m, 3H). 13 C NMR (101 MHz, CDCl3): δ 134.2, 118.7, 67.6, 44.3, 42.2, 42.1, 30.5, 30.2, 26.0. FTIR (ATR): 3413, 3073, 2930, 2900, 2851, 2827, 1640, 1422, 1275, 1242, 1172, 1123, 1062, 1027, 993, 908, 866, 770, 664 cm–1. HRMS (FAB+, m/z): calc’d for C9H16OS2 [M]+ 204.0637, found: 204.0657. [𝜶]𝟐𝟑 𝑫 : +22.2° (c = 1.0, CHCl3). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 44 Preparation of 54: TBSCl imidazole S S OH 53 CH2Cl2 (95% yield) S S OTBS 54 To a stirred solution of 53 (0.70 g, 3.43 mmol) in CH2Cl2 (20 mL) was added imidazole (0.70 g, 10.29 mmol, 3.0 equiv) and TBSCl (1.03 g, 6.86 mmol, 2.0 equiv). Saturated NH4Cl solution (20 mL) was added after stirring overnight. The aqueous layer was extracted with CH2Cl2 (3 × 20 mL) and the combined organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Column chromatography (SiO2, 20:1 hexanes/EtOAc) gave 54 as a colorless oil (1.04 g, 95% yield). TLC (10:1 hexanes/EtOAc): Rf= 0.54 (UV). 1 H NMR (400 MHz, CDCl3): δ 5.83 – 5.71 (m, 1H), 5.07 – 5.00 (m, 2H), 4.08 (dd, J = 7.8, 6.9 Hz, 1H), 4.00 (qd, J = 6.2, 4.9 Hz, 1H), 2.92 – 2.75 (m, 4H), 2.23 (dtt, J = 7.5, 5.1, 1.3 Hz, 2H), 2.09 (dddt, J = 10.6, 5.0, 4.2, 2.8 Hz, 1H), 1.93 – 1.83 (m, 1H), 1.83 – 1.78 (m, 2H), 0.88 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 134.3, 117.6, 68.1, 44.1, 42.3, 42.3, 30.7, 30.1, 26.2, 26.0, 18.2, –4.3, –4.5. FTIR (ATR): 2952, 2928, 2896, 2855, 1640, 1472, 1423, 1360, 1254, 1185, 1070, 1004, 940, 915, 834, 808, 773, 666 cm–1. HRMS (FAB+, m/z): calc’d for C15H31OS2Si [M+H]+ 319.1580, found: 319.1583. [𝜶]𝟐𝟑 𝑫 : +41.1° (c = 1.0, CHCl3). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 45 Preparation of aldehyde 55: MeI, CaCO3 S S OTBS 54 MeCN/H2O (94% yield) O OTBS 55 To a solution of 54 (636 mg, 2 mmol, 1.0 equiv) in MeCN/H2O (20 mL, 9:1) was added CaCO3 (1.0 g, 10 mmol, 5.0 equiv) and MeI (1.87 mL, 30 mmol, 15.0 equiv). The reaction mixture was stirred at 50 ºC for 6 h, then diluted with water (20 mL) and extracted with EtOAc (3 × 20 mL). The combined organic extract was dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by column chromatography (SiO2, 20:1 hexanes/EtOAc) to afford 55 (430 mg, 94%) as a colorless liquid. TLC (10:1 hexanes/EtOAc): Rf= 0.45 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 9.80 (td, J = 2.4, 0.8 Hz, 1H), 5.78 (ddt, J = 16.5, 10.8, 7.2 Hz, 1H), 5.12 – 5.03 (m, 2H), 4.26 (quint, J = 5.9 Hz, 1H), 2.55 – 2.52 (m, 2H), 2.30 (ddt, J = 7.1, 6.0, 1.2 Hz, 2H), 0.87 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 202.3, 133.9, 118.3, 67.9, 50.5, 42.5, 25.9, 18.1, –4.2, –4.7. FTIR (ATR): 2955, 2929, 2890, 2857, 1726, 1641, 1472, 1361, 1254, 1098, 1041, 1005, 915, 834, 810, 774, 680 cm–1. HRMS (FAB+, m/z): calc’d for C12H25O2Si [M+H]+ 229.1618, found: 229.1629. [𝜶]𝟐𝟑 𝑫 : +22.0° (c = 1.0, CHCl3). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 46 Preparation of aldehyde 14: cis-3-hexene O Ru-4 (4 mol%) OTBS 55 O THF (88% yield, >99:1 Z/E) Me OTBS 14 In a nitrogen-filled glovebox, 55 (146 mg, 0.64 mmol, 1 equiv) and cis-3-hexene (215 mg, 2.56 mmol, 4 equiv) were weighed into a 4 mL vial. A solution of catalyst Ru-4 (22 mg, 25.6 μmol, 4 mol%) in THF (1.5 mL) was transferred into the vial. The reaction mixture was stirred for 1 h at 23 ºC. An aliquot was taken for GC analysis to monitor the conversion. Then the vial was brought out of the glovebox, and concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/EtOAc 20:1) to afford 14 (145 mg, 88%) as a colorless liquid. TLC (10:1 hexanes/EtOAc): Rf= 0.45 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3): δ 9.80 (t, J = 2.4 Hz, 1H), 5.54 – 5.41 (m, 1H), 5.32 (dtt, J = 10.8, 7.5, 1.6 Hz, 1H), 4.22 (dq, J = 7.1, 5.7 Hz, 1H), 2.51 (dd, J = 5.8, 2.4 Hz, 2H), 2.38 – 2.17 (m, 2H), 2.10 – 1.92 (m, 2H), 0.96 (t, J = 7.5 Hz, 3H), 0.87 (s, 9H), 0.08 (s, 3H), 0.06 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 202.4, 134.8, 123.7, 68.3, 50.6, 35.7, 25.9, 20.9, 18.1, 14.3, –4.2, –4.7. FTIR (ATR): 2957, 2930, 2890, 2857, 1726, 1472, 1361, 1253, 1096, 1005, 938, 834, 811, 774, 680 cm–1. HRMS (FAB+, m/z): calc’d for C14H27O2Si [M+H-H2]+ 255.1774, found: 255.1780. [𝜶]𝟐𝟑 𝑫 : +22.0° (c = 0.4, C6H6). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 47 Preparation of 56: BocO 1. CuBr•Me2S, LiCl, allylMgBr THF, –78 ºC then 14, THF, –78 ºC O Me OTBS O (R)-43 14 2. MsCl, DMAP, CH2Cl2 –10 ºC to 23 ºC (40% yield over 2 steps) Me O OTBS 56 A 25 mL flask was flame dried and charged with CuBr•Me2S (142 mg, 0.69 mmol, 3.0 equiv) and LiCl (31 mg, 0.74 mmol, 3.2 equiv) in a nitrogen-filled glove box. The flask was sealed with a septum and brought out of the glove box, and heated under vacuum to remove residue water. Anhydrous THF (5 mL) was added, and the solution was vigorously stirred for 10 minute at 23 ºC until a yellow solution was formed. At –78ºC, allylmagnesium bromide (0.65 mL, 1.0 M solution in THF, 0.65 mmol, 2.8 equiv) was added slowly. The reaction mixture was stirred at –78 ºC for 1 hour and a solution of (R)-43 (137 mg, 0.69 mmol, 3.0 equiv) in THF (1 mL) was added slowly. After 30 minutes stirring at the same temperature, a solution of 14 (59 mg, 0.23 mmol, 1.0 equiv) in THF (1 mL) was added slowly. The reaction was stirred for an additional 2 hours at –78 ºC before a solution of saturated NH4Cl and NH3•H2O (10 mL, 9:1 NH4Cl/NH3•H2O) was added. The biphasic solution was vigorously stirred until a homogeneous dark blue solution was formed in the aqueous phase. The phases were separated and the organic phase was washed with 10 mL saturated NH4Cl solution. The combined aqueous phase was extracted with Et2O (2 × 30 mL). The combined organic phase was dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, hexanes/EtOAc 18:1) to give a mixture of diasteromers of the aldol products (50 mg, 0.13 mmol). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 48 In a 25 mL flask, the crude aldol product was dissolved in CH2Cl2 (5 mL) and cooled to –10 ºC. DMAP (242 mg, 2.0 mmol, 15.0 equiv) and MsCl (31 μL, 0.4 mmol, 3.0 equiv) was added sequentially. The reaction mixture was slowly warmed to 23 ºC and was stirred for 12 h before diluted with 10 mL EtOAc and washed with 1 M HCl (5 mL). The aqueous phase was extracted with EtOAc (2 × 10 mL). The combined organic phase was dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc 15:1) to give 56 (33 mg, 40% yield over 2 steps) as a colorless liquid. TLC (4:1 hexenes/EtOAc): Rf= 0.67 (UV). 1 H NMR (400 MHz, CDCl3): δ 7.51 (ddd, J = 6.1, 2.6, 1.0 Hz, 1H), 6.61 (ddt, J = 9.0, 8.0, 1.3 Hz, 1H), 6.33 (dd, J = 6.0, 1.8 Hz, 1H), 5.79 – 5.64 (m, 1H), 5.52 – 5.41 (m, 1H), 5.42 – 5.30 (m, 1H), 5.10 – 5.01 (m, 2H), 3.88 (quint, J = 6.0 Hz, 1H), 3.48 (ddd, J = 8.8, 4.0, 2.0 Hz, 1H), 2.72 – 2.61 (m, 1H), 2.46 – 2.38 (m, 2H), 2.30 – 2.11 (m, 3H), 2.05 – 1.95 (m, 2H), 0.93 (t, J = 7.5 Hz, 3H), 0.87 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 196.4, 161.4, 138.6, 135.1, 134.4, 134.1, 132.7, 124.4, 117.7, 71.7, 43.1, 37.1, 36.9, 35.3, 26.0, 20.9, 18.2, 14.3, –4.4, –4.4. FTIR (ATR): 2957, 2929, 2894, 2856, 1706, 1657, 1582, 1472, 1366, 1253, 1148, 1083, 1005, 966, 915, 835, 808, 775 cm–1. HRMS (FAB+, m/z): calc’d for C22H37O2Si [M+H]+ 361.2557, found: 361.2576. [𝜶]𝟐𝟑 𝑫 : +122.3° (c = 1.0, CHCl3). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 49 Preparation of 57: A. Stereoretentive metathesis using Ru-4: Me O OTBS 56 cis-5-octen-1-ol Ru-4 (1 mol%) toluene, 23 ºC, 2 torr OH then 56, Ru-4 (5 mol%) THF, 23 ºC Me + O OTBS 57 (44% yield) OTBS O 59 (31% yield) In a nitrogen-filled glovebox, cis-5-octen-1-ol (72 mg, 0.55 mmol, 6.7 equiv) was dissolved in toluene (1 mL) in a 50 mL Schlenk flask and a solution of catalyst Ru-4 (4.7 mg, 5.6 μmol, 1 mol%) in THF (0.6 mL) was added. The Schlenk flask was sealed and brought out of the glovebox, and then connected to high vacuum. The valve was gradually opened (Caution: open slowly and stir well to avoid splashing). After 15 minutes stirring, the flask was refilled with argon and sealed, and was brought back into the glovebox. The residue was diluted with 0.5 mL THF, and an aliquot was taken for GC analysis (conversion of homodimerization step was >98% by GC analysis). A solution of 56 (30 mg, 0.083 mmol, 1 equiv) in 0.5 mL THF was added into the Schlenk flask and an additional 0.4 mL of catalyst solution with Ru-4 (2.9 mg, 3.5 μmol, 5 mol%) was added. The Schlenk flask was sealed and brought out of glovebox. The reaction was stirred for 12 h at 23 ºC before a few drops of ethyl vinyl ether were added. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexanes/EtOAc 10:1 to 2:1). 57 (16 mg, 44%) and 59 (8 mg, 31%) was isolated as two products. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 50 Compound 57: TLC (2:1 hexanes/EtOAc): Rf= 0.28 (UV). 1 H NMR (400 MHz, CDCl3) δ 7.50 (ddd, J = 6.0, 2.7, 1.0 Hz, 1H), 6.60 (ddt, J = 8.2, 7.0, 1.3 Hz, 1H), 6.32 (dd, J = 6.0, 1.8 Hz, 1H), 5.53 – 5.43 (m, 2H), 5.41 – 5.31 (m, 2H), 3.89 (quint, J = 6.1 Hz, 1H), 3.64 (t, J = 6.5 Hz, 2H), 3.45 (ddq, J = 8.4, 4.3, 2.2 Hz, 1H), 2.68 – 2.55 (m, 1H), 2.43 (ddd, J = 7.7, 6.4, 2.3 Hz, 2H), 2.29 – 2.11 (m, 3H), 2.08 – 1.91 (m, 4H), 1.62 – 1.51 (m, 2H), 1.48 – 1.36 (m, 2H), 0.94 (t, J = 7.6 Hz, 3H), 0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 196.5, 161.8, 138.9, 135.0, 134.2, 132.7, 132.5, 125.5, 124.4, 71.7, 62.9, 43.6, 37.0, 35.3, 32.5, 30.8, 27.2, 26.0, 25.9, 20.9, 18.2, 14.3, –4.4, –4.4. FTIR (ATR): 3429, 2956, 2928, 2856, 2361, 2327, 1702, 1652, 1580, 1472, 1360, 1251, 1213, 1066, 1005, 968, 834, 807, 774, 721, 668 cm–1. HRMS (FAB+, m/z): calc’d for C26H45O3Si [M+H]+ 433.3132, found: 433.3121. [𝜶]𝟐𝟑 𝑫 : +136.3° (c = 1.0, C6H6). Compound 59: TLC (2:1 hexanes/EtOAc): Rf= 0.6 (UV). 1 H NMR (400 MHz, CDCl3): δ 7.43 (ddd, J = 5.9, 2.8, 1.0 Hz, 1H), 6.80 (ddt, J = 10.8, 8.8, 1.3 Hz, 1H), 6.31 (dd, J = 5.9, 1.7 Hz, 1H), 5.76 (q, J = 9.1 Hz, 1H), 5.61 (dddd, J = 11.9, 10.7, 5.2, 1.2 Hz, 1H), 4.08 – 4.02 (m, 1H), 3.27 (d, J = 9.6 Hz, 1H), 2.38 (dd, J = 9.5, 3.0 Hz, 2H), 2.24 (q, J = 11.6 Hz, 2H), 2.17 – 1.95 (m, 2H), 0.91 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H). 13 C NMR (101 MHz, CDCl3): δ 196.4, 162.3, 141.3, 134.0, 132.4, 130.6, 129.6, 73.1, 44.2, 34.7, 34.5, 32.6, 26.0, 18.3, –4.6, –4.7. FTIR (ATR): 2952, 2926, 2886, 2855, 2359, 2339, 1705, 1654, 1586, 1471, 1369, 1251, 1190, 1077, 1039, 997, 980, 938, 855, 835, 808, 790, 774, 727, 668 cm–1. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 51 HRMS (FAB+, m/z): calc’d for C18H29O2Si [M+H]+ 305.1931, found: 305.1942. [𝜶]𝟐𝟑 𝑫 : –27.8° (c = 0.8, CHCl3) B. Z-selective cross-metathesis using Ru-2: OH 5-hexen-1-ol Ru-2 (20 mol%) + Me O OTBS THF, 40 ºC 56 Me O OH O OTBS OTBS 57 58 (52% yield) (<2% yield) In a nitrogen-filled glovebox, 56 (64 mg, 0.18 mmol, 1.0 equiv) and 5-hexen-1-ol (142 mg, 1.42 mmol, 8.0 equiv) were weighed into a 4 mL vial. THF (0.3 mL) was added to dissolve the mixture. Catalyst Ru-2 (24 mg, 20 mol%) was dissolved in THF (0.4 mL) and 0.1 mL of this catalyst solution was transferred into the vial. The vial was sealed with a 14/20 septum and brought out of the glovebox. The reaction was stirred at 40 ºC with a stream of argon (saturated with anhydrous THF) bubbling through a needle. A portion of the catalyst solution (0.1 mL) was added into the vial in each 1 hour. After all the catalyst was added, the reaction mixture was continued to stir for 4 h with argon bubbling. A few drops of ethyl vinyl ether were added, and the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/EtOAc 2:1) to afford 57 (40 mg, 52%) as a colorless liquid. Compund 58 was the proposed by-product (molar ratio of 57:58 was 32:1 as determined by crude NMR analysis). Compound 57: Characterization data were in agreement with previously obtained data. Compound 58: Characterization data not available due to the difficulty in separation; mass data was obtained by LC-MS (TOF, ES+, m/z): calc’d for C24H41O3Si [M+H]+ 405.2819, found: 405.2801. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 52 Preparation of ∆12-prostaglandin J3 (3): OH Me O OTBS 57 COOH 1.TPAP, NMO•H2O MeCN 2. HF (aq.), MeCN (60% over 2 steps) Me O OH 3 To a stirred solution of 57 (21.6 mg, 0.05 mmol, 1.0 equiv) in MeCN (0.5 mL) was added NMO•H2O (67.5 mg, 0.5 mmol, 10.0 equiv). Tetrapropylammonium perruthenate (1.8 mg, 5 μmol, 0.1 equiv) was added until NMO•H2O was fully dissolved and the reaction was stirred at 23 ºC for 3 hours. The solution was diluted with Et2O (5 mL), passed through a short pad of silica gel, concentrated, and subjected to the next reaction without further purification. The residue was dissolved in MeCN (1.0 mL) and cooled to 0 ºC. A solution of hydrofluoric acid (48 wt. % in H2O, 0.2 mL) in MeCN (0.4 mL) was added dropwisely. The solution was stirred in the same temperature for 30 min before saturated NaHCO3 solution (1.5 mL) and brine (1.5 mL) were added. The aqueous phase was extracted with EtOAc (5 × 5 mL). The combined organic phase was dried over magnesium sulfate, filtered, and concentrated (not to dryness). The residue was purified by flash chromatography (SiO2, CH2Cl2/MeOH 20:1) and through Biotage® SNAP Ultra C18 column (H2O/MeOH) to give 3 (10 mg, 60% over 2 steps) as a colorless liquid. TLC (100% EtOAc): Rf= 0.55 (UV). 1 H NMR (400 MHz, CDCl3): δ 7.58 (ddd, J = 6.0, 2.6, 1.0 Hz, 1H), 6.57 (ddt, J = 8.4, 7.0, 1.2 Hz, 1H), 6.36 (dd, J = 6.0, 1.8 Hz, 1H), 5.69 – 5.60 (m, 1H), 5.60 – 5.45 (m, 2H), 5.45 – 5.35 (m, 1H), 3.91 (quint, J = 6.8 Hz, 1H), 3.50 – 3.44 (m, 1H), 2.75 (ddd, J = 13.9, 6.9, 4.4 Hz, 1H), 2.68 – 2.58 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 53 (m, 1H), 2.49 (ddd, J = 15.2, 8.4, 7.0 Hz, 1H), 2.36 (t, J = 6.8 Hz, 2H), 2.33 – 2.28 (m, 2H), 2.20 – 1.98 (m, 5H), 1.68 (quint, J = 7.0 Hz, 2H), 0.96 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 196.4, 175.8, 161.8, 139.9, 136.4, 135.1, 131.7, 131.2, 126.3, 123.6, 71.1, 44.0, 36.3, 34.5, 32.9, 30.7, 26.6, 24.7, 20.9, 14.4. FTIR (ATR): 3449, 3010, 2956, 2919, 2850, 1728, 1703, 1650, 1579, 1455, 1375, 1222, 1182, 1046, 959, 838, 809, 721 cm–1. HRMS (FAB+, m/z): calc’d for C20H29O4 [M+H]+ 333.2060, found: 333.2060. [𝜶]𝟐𝟑 𝑫 : +122.6° (c = 0.5, C6H6). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 54 Spectral data (1H NMR, 13C NMR, HRMS) matched with the published data.12,14,16 Comparisons of 1H NMR data of natural and synthetic ∆12-prostaglandin J3 (3) are listed in Table 1.6.2. Table 1.6.2. Comparison of 1H NMR Data for ∆12-prostaglandin J3 (3) 9 10 8 7 12 6 14 11 O 4 5 15 3 2 16 13 1 COOH 19 17 18 OH Me 20 Δ12 -PGJ3 (3) Proton Number 1 2 3 4 5 6 7α 7β 8 9 10 11 12 13 14α 14β 15 16 17 18 19α 19β 20 Natural ∆12-PGJ3 1H NMR12 600 MHz, CDCl3 1H [δ, multi, J (Hz)] n.d. 2.35 (t, J = 7.0 Hz) hidden 2.02 (m) 5.42 (m) hidden 2.64 (m) 2.08 (m) 3.47 (ddd, J = 10.0, 4.0, 2.0 Hz) 7.56 (ddd, J = 6.0, 2.0, 1.0 Hz) 6.35 (dd, J = 6.0, 2.0 Hz) n.d. n.d. 6.58 (m) 2.55 (dt, J = 15.0, 7.0 Hz) 2.47 (ddd, J = 15.0, 8.0, 6.0 Hz) 3.88 (quint, J = 6.0 Hz) 2.28 (m) hidden 5.51 (m) 2.00 (m) 1.98 (m) 0.96 (t, J = 7.0 Hz) This Work, Synthetic ∆12-PGJ3 1H NMR 400 MHz, CDCl3 1H [δ, multi, J (Hz)] 2.36 (t, J = 6.8 Hz) 1.78 – 1.66 (m) 2.20 – 2.10 (m) 5.60 – 5.51 (m) 5.51 – 5.45 (m) 2.75 (ddd, J = 13.9, 6.9, 4.4 Hz) 2.20 – 2.10 (m) 3.50 – 3.44 (m) 7.58 (ddd, J = 6.0, 2.6, 1.0 Hz) 6.36 (dd, J = 6.0, 1.8 Hz) 6.57 (ddt, J = 8.4, 7.0, 1.2 Hz) 2.68 – 2.57 (m) 2.49 (ddd, J = 15.2, 8.4, 7.0 Hz) 3.91 (quint, J = 6.8 Hz) 2.33 – 2.28 (m) 5.45 – 5.35 (m) 5.69 – 5.60 (m) 2.10 – 1.98 (m) 2.10 – 1.98 (m) 0.96 (t, J = 7.5 Hz) Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 55 Preparation of 61: 1. CuBr•Me2S, LiCl, allylMgBr THF, –78 ºC then 60, THF, –78 ºC BocO O 60 O 2. MsCl, DMAP, CH2Cl2 –10 ºC to 23 ºC (R)-43 (36 % yield over 2 steps) Me Me O 61 A 25 mL flask was flame dried and charged with CuBr•Me2S (195 mg, 0.95 mmol, 1.9 equiv) and LiCl (42 mg, 1.0 mmol, 2.0 equiv) in a nitrogen-filled glove box. The flask was sealed with septum and brought out of glove box, and was heated under vacuum to remove residue water. Anhydrous THF (10 mL) was added, and the solution was vigorously stirred for 10 minute at 23 ºC until a yellow homogeneous solution was formed. At –78ºC, allyl magnesium bromide (0.9 mL, 1.0 M solution in THF, 0.9 mmol, 1.8 equiv) was added slowly. The reaction mixture was stirred at –78 ºC for 1 hour and a solution of (R)-43 (198 mg, 1.0 mmol, 2.0 equiv) in THF (1 mL) was added slowly. After 30 minutes of stirring at the same temperature, a solution of known compound 60 (prepared according to Honda and co-workers44) (62 mg, 0.5 mmol, 1.0 equiv) in THF (1 mL) was added slowly. The reaction was stirred for an additional 2 hours at –78 ºC before a solution of saturated NH4Cl and NH3•H2O (10 mL, 9:1 NH4Cl/NH3•H2O) was added. The biphasic solution was vigorously stirred until a homogeneous dark blue solution formed in aqueous phase. The phases were separated and the organic phase was washed with 10 mL saturated NH4Cl solution. The combined aqueous phase was extracted with Et2O (2 × 30 mL). The combined organic phase was dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (SiO2, hexanes/EtOAc 15:1) to give a mixture of diasteromers of the aldol products (51 mg, 0.21 mmol). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 56 In a 25 mL flask, the crude aldol product was dissolved in CH2Cl2 (6 mL) and cooled to –10 ºC. DMAP (384 mg, 3.15 mmol, 15.0 equiv) and MsCl (49 μL, 0.63 mmol, 3.0 equiv) was added sequentially. The reaction mixture was slowly warmed to 23 ºC and was stirred for 2 h before diluted with 10 mL EtOAc and washed with 1 M HCl (10 mL). The aqueous phase was extracted with EtOAc (2 × 20 mL). The combined organic phase was dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc 15:1) to give 61 (41 mg, 36% yield over 2 steps) as a colorless liquid. TLC (4:1 hexanes/EtOAc): Rf= 0.56 (UV). 1 H NMR (400 MHz, CDCl3): δ 7.50 (ddd, J = 5.9, 2.6, 1.0 Hz, 1H), 7.03 – 6.90 (m, 1H), 6.36 (dd, J = 6.1, 1.8 Hz, 1H), 6.34 – 6.29 (m, 1H), 6.21 (dt, J = 15.1, 6.3 Hz, 1H), 5.79 – 5.66 (m, 1H), 5.54 (dtt, J = 10.2, 7.2, 1.5 Hz, 1H), 5.37 (dtt, J = 10.5, 7.3, 1.6 Hz, 1H), 5.10 – 5.02 (m, 2H), 3.60 (ddq, J = 8.5, 4.0, 1.9 Hz, 1H), 3.00 – 2.95 (m, 2H), 2.65 (dddt, J = 13.7, 6.8, 4.2, 1.4 Hz, 1H), 2.25 (dddt, J = 14.2, 8.8, 7.7, 1.1 Hz, 1H), 2.07 (dquint, J = 7.5, 1.5 Hz, 2H), 0.98 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 197.5, 160.7, 144.5, 135.4, 135.4, 134.2, 134.1, 131.6, 125.8, 124.6, 117.9, 43.3, 37.4, 31.2, 20.7, 14.3. FTIR (ATR): 3011, 2963, 2931, 2874, 2361, 2335, 1692, 1629, 1579, 1440, 1339, 1280, 1207, 1100, 989, 915, 872, 839, 729, 668 cm–1. HRMS (FAB+, m/z): calc’d for C16H21O [M+H]+ 229.1587, found: 229.1588. [𝜶]𝟐𝟑 𝑫 : +117.7° (c = 0.5, CHCl3). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 57 Preparation of 62: A. Stereoretentive metathesis using Ru-4: cis-5-octen-1-ol Ru-4 (1 mol%) toluene, 23 ºC, 2 torr Me O 61 then 61, Ru-4 (5 mol%) THF, 23 ºC OH + OH Me O 62 O 63 In a nitrogen-filled glovebox, cis-5-octen-1-ol (205 mg, 1.6 mmol, 8.0 equiv) was dissolved in toluene (1 mL) in a 50 mL Schlenk flask and a solution of catalyst Ru-4 (13.6 mg, 16 μmol, 1 mol%) in THF (0.6 mL) was added. The Schlenk flask was sealed and brought out of the glovebox, and then connected to high vacuum. The valve was gradually opened (Caution: open slowly and stir well to avoid splashing). After 15 minutes stirring, the flask was refilled with argon and sealed, and was brought back into the glovebox. The residue was diluted with 0.5 mL THF, and an aliquot was taken for GC analysis (conversion of homodimerization step was >98% by GC analysis). A solution of 61 (46 mg, 0.2 mmol, 1.0 equiv) in 0.5 mL THF was added into the Schlenk flask and an additional 0.4 mL of catalyst solution with Ru-4 (8.5 mg, 10 μmol, 5 mol%) was added. The Schlenk flask was sealed and brought out of glovebox. The reaction was stirred for 12 h at 23 ºC before a few drops of ethyl vinyl ether were added. The solvent was removed under reduced pressure. The residue was purified by column chromatography (SiO2, hexanes/EtOAc 2:1). Compounds 62 (22 mg, 36%) and 63 were separated as a mixture (28 mg, molar ratio of 62:63 was 3:1 as determined by crude NMR analysis). Compound 62: Characterization data not available due to the difficulty in separation. Mass data was obtained by LC-MS (TOF, ES+, m/z): calc’d for C20H29O2 [M+H]+ 301.2162, found: 301.2080. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 58 Compound 63: Characterization data not available due to the difficulty in separation, mass data was obtained by LC-MS (TOF, ES+, m/z): calc’d for C18H25O2 [M+H]+ 273.1849, found: 273.1759. B. Z-selective cross-metathesis using Ru-2: OH 5-hexen-1-ol Ru-2 (20 mol%) Me O + THF, 40 ºC 61 OH Me O 62 O 63 In a nitrogen-filled glovebox, 61 (23 mg, 0.1 mmol, 1.0 equiv) and 5-hexen-1-ol (80 mg, 0.8 mmol, 8.0 equiv) were weighed into a 4 mL vial. THF (0.1 mL) was added to dissolve the mixture. Catalyst Ru-2 (13.6 mg, 20 mol%) was dissolved in THF (0.4 mL) and 0.1 mL of this catalyst solution was transferred into the vial. The vial was sealed with a 14/20 septum and brought out of the glovebox. The reaction was stirred at 40 ºC with a stream of argon (saturated with anhydrous THF) bubbling through a needle. A portion of the catalyst solution (0.1 mL) was added into the vial in each 1 hour. After all the catalyst was added, the reaction mixture was continued to stir for 2 h with argon bubbling. A few drops of ethyl vinyl ether was added, and the reaction mixture was concentrated in vacuo. The residue was purified by column chromatography (SiO2, hexanes/EtOAc 2:1). Compounds 62 (9.2 mg, 31%) and 63 were separated as a mixture (12 mg, molar ratio of 62:63 was 3:1 as determined by crude NMR analysis). Compound 62: Characterization data not available due to the difficulty in separation. Mass data was obtained by LC-MS (TOF, ES+, m/z): calc’d for C20H29O2 [M+H]+ 301.2162, found: 301.2166. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 59 Compound 63: Characterization data not available due to the difficulty in separation, mass data was obtained by LC-MS (TOF, ES+, m/z): calc’d for C18H25O2 [M+H]+ 273.1849, found: 273.1855. Preparation of 15-deoxy-∆12,14-prostaglandin J3 (4): OH Me O 62 COOH 1. PCC, CH2Cl2 2. NaClO2, NaH2PO4 2-methyl-2-butene t-BuOH (12% yield over 3 steps) Me O 4 Pyridinium chlorochromate (22 mg, 0.1 mmol, 3.0 equiv) was added to a solution of 62 (mixed with by-product 63) (10 mg, 0.033 mmol, 1.0 equiv) in CH2Cl2 (0.5 mL) at 23 ºC. The reaction was monitored by TLC and was diluted with Et2O (3 mL) after stirring for 3 h. The resulting solution was filtered through a short pad of silica gel, and was subjected to the next step without further purification. The residue was dissolved in t-BuOH (0.5 mL) at 23 ºC, and 2-methyl-2-butene (35 μL, 0.33 mmol, 10 equiv), a solution of NaH2PO4•H2O (6.9 mg, 0.05 mmol, 1.5 equiv) in H2O (0.12 mL) and a solution of NaClO2 (80 %, 5.6 mg, 0.05 mmol, 1.5 equiv) in H2O (0.12 mL) was added sequentially. After stirring at 23 ºC for 30 minutes, the reaction mixture was diluted with a solution of NaH2PO4•H2O (108 mg) in H2O (2 mL) and extracted with EtOAc (5 × 5 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Flash column chromatography (SiO2, CH2Cl2/MeOH 20:1) and purification through Biotage® SNAP Ultra C18 column (H2O/MeOH) afforded pure compound 4 (4 mg, 0.013 mmol, 12% yield from 61) as a colorless oil. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 60 TLC (10:1 CH2Cl2/MeOH): Rf= 0.44 (UV). 1 H NMR (500 MHz, CDCl3): δ 7.48 (ddd, J = 6.1, 2.6, 1.0 Hz, 1H), 6.96 (d, J = 11.5 Hz, 1H), 6.42 – 6.31 (m, 2H), 6.22 (dt, J = 14.9, 6.3 Hz, 1H), 5.57 – 5.51 (m, 1H), 5.50 – 5.43 (m, 1H), 5.37 (dtt, J = 10.1, 6.8, 1.7 Hz, 2H), 3.64 – 3.55 (m, 1H), 2.98 (t, J = 6.8 Hz, 2H), 2.60 (dt, J = 12.3, 5.9 Hz, 1H), 2.43 – 2.25 (m, 3H), 2.12 – 2.00 (m, 4H), 1.69 (quint, J = 7.4 Hz, 2H), 0.99 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3): δ 197.6, 176.6, 160.9, 144.5, 135.5, 135.5, 134.2, 131.6, 131.5, 126.1, 125.8, 124.6, 43.6, 33.0, 31.2, 30.9, 26.7, 24.6, 20.7, 14.3. FTIR (ATR): 3010, 2960, 2926, 2874, 2854, 1710, 1693, 1626, 1578, 1512, 1455, 1208, 1154, 1087, 1024, 977, 817, 728 cm–1. HRMS (FAB+, m/z): calc’d for C20H27O3 [M+H]+ 315.1955, found: 315.1968. [𝜶]𝟐𝟑 𝑫 : +129.6° (c = 0.07, C6H6). Spectral data (1H NMR, 13C NMR, HRMS) matched with the published data.15 Preparation of (±)-65: H DIBAL-H O (±)-33 THF (81%) H H OH (±)-65 Racemic enone (±)-33 was obtained from photooxygenation of dicyclopentadiene catalyzed by tetraphenylporphyrin (TPP) according to Mihelich-Eickhoff’s procedure.39 In a 500 mL round bottom flask, (±)-33 (13.2 g, 8.9 mmol) was dissolved in anhydrous toluene (150 mL) under argon atmosphere. The solution was cooled to –78 ºC, and a solution of DIBAL-H (1.0 M solution in toluene, 13.4 mL, 13.4 mmol, 1.5 equiv) was added dropwisely. After 1.5 h, MeOH (50 mL) was added (dropwisely at beginning to avoid splashing). The reaction mixture was warmed to ambient Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 61 temperature and poured into a saturated Na-K tartrate solution (150 mL) and the biphasic solution was stirred overnight. The aqueous phase was extracted with CH2Cl2 (3 × 200 mL). The combined organic phases were dried with anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Purification by flash column chromatography on silica gel (SiO2, 10:1 to 4:1 hexanes/EtOAc) afforded compound (±)-65 as a white solid (10.9 g, 81% yield). TLC (4:1 hexanes/EtOAc): Rf= 0.3 (KMnO4). 1 H NMR (400 MHz, CDCl3) δ 6.15 (dd, J = 5.7, 2.6 Hz, 1H), 5.81 (dd, J = 5.7, 3.2 Hz, 1H), 5.59 (s, 2H), 4.67 (t, J = 9.0 Hz, 1H), 3.29 (dd, J = 7.6, 4.1 Hz, 1H), 2.99 – 2.87 (m, 3H), 1.51 (ddt, J = 46.0, 8.0, 1.6 Hz, 2H), 1.23 (d, J = 9.6 Hz, 1H) Enzymatic Kinetic resolution: H lipase PS (10 wt%) vinyl acetate(0.6 equiv) H H + MTBE, 37 ºC, 48 h HH (±)-65 OH OAc H H OH (–)-66 (48%) (+)-65 (49%) HH In a 250 mL round bottom flask, (±)-65 (4.8 g, 32.4 mmol) was dissolved in MTBE (100 mL, 0.33M), and vinyl acetate (1.78 mL, 0.6 equiv) was added via syringe. Lipase PS (10% on celite, 480 mg, 10 wt%) was added to the flask. The flask was sealed with septum and kept under argon atmosphere, and placed in 37 ºC oil bath. After 48 h, the reaction mixture was filtered through celite and concentrated. Column chromatography (SiO2, 10:1to 4:1 hexanes/EtOAc) afforded white solids (–)-66 (2.93 g, 48% yield) and (+)-65 (2.36 g, 49% yield). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 62 (–)-66: TLC (10:1 hexanes/EtOAc): Rf= 0.68 (KMnO4). 1 H NMR (400 MHz, CDCl3) δ 5.98 (dd, J = 5.7, 2.9 Hz, 1H), 5.76 (dd, J = 5.6, 3.1 Hz, 1H), 5.70 (dt, J = 5.8, 2.0 Hz, 1H), 5.55 (dt, J = 5.8, 1.9 Hz, 1H), 5.44 (dq, J = 9.0, 1.7 Hz, 1H), 3.28 (ddt, J = 7.6, 3.5, 1.7 Hz, 1H), 3.08 (ddd, J = 8.9, 7.7, 4.1 Hz, 1H), 2.89 (ddp, J = 4.3, 2.9, 1.3 Hz, 1H), 2.76 (s, 1H), 2.07 (s, 3H), 1.46 (ddt, J = 39.3, 8.2, 1.7 Hz, 2H). (+)-65: TLC (10:1 hexanes/EtOAc): Rf= 0.28 (KMnO4). 1 H NMR spectrum data matches (±)-65 [𝜶]𝟐𝟑 𝑫 : +117.9° (c = 1.0, CHCl3). Preparation of (+)-33: H H K2CO3MeOH H H OAc (–)-66 H TPAP, NMO H H OH 4Å MS MeCN/CH2Cl2 (–)-65 (98%) H O (+)-33 (63%, >99% ee) To a stirred solution of (–)-66 (2.8 g, 14.7 mmol) in MeOH (50 mL) was added K2CO3 (2.03 g, 1 equiv). The solution was stirred for 12 h and concentrated, then dissolved in water (30 mL) and extracted by Et2O (30 mL). Column chromatography (SiO2, 4:1 hexenes/EtOAc) afforded (–)-65 as a white solid (2.04 g, 98%). Spectrum data matches (±)-65. [𝜶]𝟐𝟑 𝑫 : –138.1° (c = 1.0, CHCl3). A 100 mL round bottom flask containing 4Å molecular sieves (9.0 g) was flame dried under vacuum. After the flask cooled down to room temperature, (–)-65 (2.01 g, 13.6 mmol), NMO (3.19 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 63 g, 27.2 mmol, 2 equiv) was added and dissolved in MeCN (3 mL) and CH2Cl2 (27 mL). TPAP (150 mg, 0.42 mmol, 0.03 equiv) and the reaction was stirred under argon for 1 hour, and the reaction progress was monitored by GC. The reaction mixture was filtered over celite and concentrated. Column chromatography (SiO2, 4:1 hexenes/EtOAc) afforded (+)-33 as a white solid (1.24 g, 63%). NMR spectrum data matches (±)-33. TLC (4:1 hexanes/EtOAc): Rf= 0.35 (UV). 1 H NMR (400 MHz, CDCl3) δ 7.38 (dd, J = 5.7, 2.6 Hz, 1H), 5.95 (ddd, J = 7.8, 5.6, 2.3 Hz, 2H), 5.78 (dd, J = 5.7, 3.0 Hz, 1H), 3.42 (dddd, J = 5.6, 4.2, 2.6, 1.6 Hz, 1H), 3.22 (dt, J = 4.1, 1.8 Hz, 1H), 2.97 (ddt, J = 4.2, 2.7, 1.4 Hz, 1H), 2.80 (t, J = 5.1 Hz, 1H), 1.78 – 1.60 (m, 2H). 13 C NMR (101 MHz, CDCl3) δ 210.9, 164.7, 137.1, 132.7, 52.9, 50.4, 48.4, 45.1, 44.2. FTIR (ATR): 2990. 2972, 1683, 1576, 1347, 1333, 1294, 1251, 1224, 1194, 1178, 1120, 1091, 1018, 959, 853, 817, 784, 739, 721, 652 cm–1. HRMS (FAB+, m/z): calc’d for C10H11O [M+H]+ 147.0810, found: 147.0809. [𝜶]𝟐𝟑 𝑫 : +136.6° (c = 1.0, CHCl3). Preparation of enone (–)-33: A. Oxidation using TPAP, NMO: H H TPAP, NMO H H OH (+)-65 4Å MS MeCN/CH2Cl2 H O (–)-33 (71%, >99% ee) A 100 mL round bottom flask containing 4Å molecular sieves (9.0 g) was flame dried under vacuum. After the flask cooled down to room temperature, (+)-65 (2.00 g, 13.5 mmol), NMO (3.16 g, 27 mmol, 2 equiv) was added and dissolved in MeCN (3 mL) and CH2Cl2 (27 mL). TPAP (142 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 64 mg, 0.41 mmol, 0.03 equiv) was addedand the reaction was stirred under argon for 1 hour, and the reaction progress was monitored by GC. The reaction mixture was filtered over celite and concentrated. Column chromatography (SiO2, 4:1 hexenes/EtOAc) afforded (–)-33 as a white solid (1.41 g, 71%). B. Oxidation using Stahl’s conditions: H H H OH Cu(MeObpy)OTf (5 mol%) ABNO (1 mol%) NMI (10 mol%) MeCN, air, 23 ºC (+)-65 H H O (–)-33 (97%, >99% ee) An oven-dried, 200 mL round-bottomed flask was charged with alcohol (+)-65 (2.01 g, 13.6 mmol, 1.0 equiv) and anhydrous MeCN (100 mL). The solution was vigorously stirred (>700 rpm) open to air while being treated with MeObpy (147 mg, 0.68 mmol, 0.05 equiv), Cu(MeCN)4OTf (256 mg, 0.68 mmol, 0.05 equiv), ABNO (0.04 M in MeCN, 3.4 mL, 135.6 µmol, 0.01 equiv), and then NMI (110 µL, 1.36 mmol, 0.10 equiv) via microsyringe. The resulting brick-red reaction mixture was vigorously stirred exposed to air at ambient temperature until the reaction mixture turned a blue-green in an hour, at which point TLC analysis indicated the complete consumption of starting material. The reaction mixture was diluted with Et2O (50 mL), and filtered through Celite, washing with 50% EtOAc/hexanes. The filtrate was concentrated in vacuo and the crude residue was directly purified by flash chromatography (SiO2, 4:1 hexenes/EtOAc) to afford (–)-33 (1.92 g, 97% yield) as a white solid. TLC (4:1 hexanes/EtOAc): Rf= 0.35 (UV). 1 H NMR spectrum data matches (+)-33 [𝛼])* ( : –121.9° (c = 1.0, CHCl3). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis HPLC Conditions: 5% IPA, 1.0 mL/min, Chiralcel OJ-H column, λ = 254 nm, tR (min) = 7.78, 8.30 (±)-33: (+)-33: (–)-33: 65 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 66 Preparation of (+)-67: 1. CuI, Me2S allylmagnesium bromide then trans-2-octenal, THF, -78 ºC H H O (+)-33 2. MsCl, DMAP, CH2Cl2 - 10 ºC to 23 ºC H Me H O (+)-67 (77% yield over 2 steps) A 250 mL flask was charged with CuI (2.56 g, 13.44 mmol, 1.2 equiv) and flame dried under vacuum. After cooling to room temperature, anhydrous THF (100 mL) and Me2S (5 mL) was added, and the solution was vigorously stirred for 5 minutes at room temperature until a yellow homogeneous solution was formed. At –78ºC, allylmagnesium bromide (12.3 mL, 1.0 M solution in THF, 12.3 mmol, 1.1 equiv) was added slowly. The reaction mixture was stirred at –78 ºC for 1 hour and a solution of (+)-33 (1.637 g, 11.2 mmol, 1.0 equiv) in THF (5 mL) was added slowly. After 30 minutes stirring at the same temperature, a solution of trans-2-octenal (2.826 g, 22.4 mmol, 2.0 equiv) in THF (3 mL) was added slowly. The reaction was stirred for additional 1 hour at –78 ºC, and a solution of saturated NH4Cl and NH3•H2O (100 mL, 9:1 NH4Cl/NH3•H2O) was added. The biphasic solution was warmed to room temperature and was vigorously stirred until a homogeneous dark blue solution was formed in the aqueous phase. The phases were separated and the organic phase was washed with 20 mL saturated NH4Cl solution. The combined aqueous phase was extracted with Et2O (3 × 100 mL). The combined organic phase was dried with anhydrous magnesium sulfate, and was concentrated in vacuo. The residue was purified by flash chromatography (SiO2, hexanes/EtOAc 15:1) to give a mixture of diastereomers of the aldol products (3.6g). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 67 A portion of reaction mixture was taken out and the major diastereomer 68 was isolated as follow: H Me H O Ha H OH b 3J Ha-Hb = 8.2 Hz 68 TLC (4:1 hexanes/EtOAc): Rf= 0.33 (p-anisaldehyde). 1 H NMR (400 MHz, CDCl3) δ 6.18 (dd, J = 5.7, 2.9 Hz, 1H), 6.10 (dd, J = 5.8, 3.0 Hz, 1H), 5.80 (dddd, J = 15.7, 11.0, 8.1, 6.1 Hz, 1H), 5.63 (dt, J = 15.3, 6.7 Hz, 1H), 5.30 (ddt, J = 15.3, 8.0, 1.6 Hz, 1H), 5.13 – 5.06 (m, 2H), 4.18 (d, J = 1.9 Hz, 1H), 4.04 (td, J = 8.2, 1.9 Hz, 1H), 3.19 (ddt, J = 4.5, 3.0, 1.4 Hz, 1H), 3.09 (ddd, J = 10.2, 4.7, 2.4 Hz, 1H), 2.98 (tt, J = 2.9, 1.6 Hz, 1H), 2.64 (ddd, J = 9.9, 5.6, 4.1 Hz, 1H), 2.40 (dddd, J = 13.3, 5.5, 3.8, 1.7 Hz, 1H), 2.12 – 1.97 (m, 4H), 1.57 (dt, J = 8.4, 1.8 Hz, 1H), 1.51 – 1.42 (m, 2H), 1.41 – 1.22 (m, 6H), 0.87 (t, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 136.3, 135.8, 134.0, 129.8, 117.2, 73.1, 61.8, 56.6, 52.5, 47.2, 45.9, 45.5, 40.9, 40.4, 32.3, 31.6, 28.8, 22.6, 14.1. (Carbonyl peak not observed below 219 ppm) FTIR (ATR): 3465, 3073, 2957, 2925, 2857, 1709, 1640, 1600, 1439, 1413, 1338, 1249, 1224, 1090, 973, 911, 836, 733 cm–1. HRMS (FAB+, m/z): calc’d for C21H29O2 [M+H–H2]+ 313.2168, found: 313.2158. [𝜶]𝟐𝟑 𝑫 : +28.1° (c = 1.0, CHCl3). Kobayashi et al. established that for compounds 68 (anti-aldols) 3JHa-Hb is in the range of 8.4 to 9.7 Hz, while for the corresponding syn-aldols 3JHa-Hb is around 3 Hz.45 Without further separation, the crude aldol product was dissolved in CH2Cl2 (200 mL) and cooled to 0 ºC. DMAP (20.5 g, 168 mmol, 15.0 equiv) and MsCl (2.6 mL, 33.6 mmol, 3.0 equiv) was added sequentially. The reaction mixture was slowly warmed to room temperature and stirred for 16 h before washed with 1 M HCl (100 mL). The aqueous phase was extracted with EtOAc (3 × Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 68 100 mL). The combined organic phase was dried with anhydrous magnesium sulfate, and was concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc 20:1) to give (+)-67 (2.55 g, 77% yield over 2 steps) as a yellow liquid. H Me H O (+)-67 TLC (10:1 hexanes/EtOAc): Rf= 0.48 (UV). 1 H NMR (400 MHz, CDCl3) δ 6.70 (dd, J = 10.7, 2.1 Hz, 1H), 6.20 – 6.04 (m, 2H), 5.97 (qd, J = 5.6, 2.7 Hz, 2H), 5.79 (ddt, J = 17.1, 10.2, 6.9 Hz, 1H), 5.14 – 5.05 (m, 2H), 3.24 (tq, J = 2.8, 1.4 Hz, 1H), 3.01 (dp, J = 4.4, 1.4 Hz, 1H), 2.97 (dd, J = 8.6, 4.8 Hz, 1H), 2.64 – 2.56 (m, 2H), 2.35 – 2.26 (m, 1H), 2.22 – 2.07 (m, 3H), 1.49 – 1.37 (m, 4H), 1.35 – 1.23 (m, 4H), 0.89 (t, J = 6.8 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 209.8, 146.8, 141.1, 136.1, 136.0, 133.5, 132.7, 126.3, 117.1, 54.0, 51.5, 47.4, 47.2, 43.7, 41.2, 40.3, 33.5, 31.4, 28.5, 22.5, 14.0. FTIR (ATR): 3062, 2957, 2928, 2858, 1701, 1625, 1600, 1438, 1341, 1293, 1202, 1178, 1122, 973, 912, 727, 698 cm–1. HRMS (FAB+, m/z): calc’d for C21H29O [M+H]+ 297.2218, found: 297.2214. [𝜶]𝟐𝟑 𝑫 : +150.4° (c = 1.0, CHCl3). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 69 Preparation of (–)-67: 1. CuI, Me2S allylmagnesium bromide then trans-2-octenal, THF, -78 ºC H H O (–)-33 2. MsCl, DMAP, CH2Cl2 - 10 ºC to 23 ºC H Me H O (–)-67 (75% yield over 2 steps) A 250 mL flask was charged with CuI (571 mg, 3 mmol, 1.2 equiv) and flame dried under vacuum. After cooling to room temperature, anhydrous THF (25 mL) and Me2S (1 mL) was added, and the solution was vigorously stirred for 5 minutes at room temperature until a yellow homogeneous solution was formed. At –78ºC, allylmagnesium bromide (2.75 mL, 1.0 M solution in THF, 2.75 mmol, 1.1 equiv) was added slowly. The reaction mixture was stirred at –78 ºC for 1 hour and a solution of (–)-33 (365 mg, 2.5 mmol, 1.0 equiv) in THF (2 mL) was added slowly. After 30 minutes stirring at the same temperature, a solution of trans-2-octenal (631 mg, 5.0 mmol, 2.0 equiv) in THF (1 mL) was added slowly. The reaction was stirred for additional 1 hour at –78 ºC, and a solution of saturated NH4Cl and NH3•H2O (25 mL, 9:1 NH4Cl/NH3•H2O) was added. The biphasic solution was warmed to room temperature and vigorously stirred until a homogeneous dark blue solution was formed in the aqueous phase. The phases were separated and the organic phase was washed with 10 mL saturated NH4Cl solution. The combined aqueous phase was extracted with Et2O (3 × 30 mL). The combined organic phase was dried with anhydrous magnesium sulfate, and was concentrated in vacuo. The residue was purified by flash chromatography (SiO2, hexanes/EtOAc 15:1) to give a mixture of diasteromers of the aldol products (790 mg). Without further separation, the crude aldol product was dissolved in CH2Cl2 (40 mL) and cooled to 0 ºC. DMAP (4.58 g, 37.5 mmol, 15.0 equiv) and MsCl (0.58 mL, 7.5 mmol, 3.0 equiv) was added sequentially. The reaction mixture was slowly warmed to room temperature and stirred for Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 70 16 h before being washed with 1 M HCl (40 mL). The aqueous phase was extracted with EtOAc (3 × 40 mL). The combined organic phase was dried with anhydrous magnesium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography (hexanes/EtOAc 20:1) to give (–)-67 (559 mg, 75% yield over 2 steps) as a yellow liquid. Characterization data matches (+)-67. [𝜶]𝟐𝟑 𝑫 : –193.4° (c = 1.0, CHCl3). Preparation of (+)-44: H Maleic anhydride EtAlCl2 Me H O (+)-67 DCE 80 ºC, 2 h Me O (+)-44 (60%, >99% ee) In a 100 mL round bottom flask, (+)-67 (1.64 g, 5.54 mmol, 1.0 equiv) was dissolved in DCE (50 mL) and maleic anhydride (5.4 g, 55.4 mmol, 10.0 equiv) and EtAlCl2 (6.0 mL, 1.0 M solution in hexanes, 6.0 mmol, 1.1 equiv) were added sequentially. A reflux condenser was attached and the reaction mixture was warmed to reflux under argon. After 2 hours, the reaction mixture was cooled down, concentrated, and directly loaded on silica gel. Purification by flash chromatography (hexanes/EtOAc 15:1) afforded (+)-44 (760 mg, 60% yield, >99% ee by chiral HPLC analysis) as a colorless liquid. TLC (4:1 hexanes/EtOAc): Rf= 0.56 (UV). 1 H NMR (300 MHz, CDCl3): δ 7.50 (ddd, J = 6.0, 2.6, 1.0 Hz, 1H), 6.95 (dt, J = 10.7, 1.2 Hz, 1H), 6.35 (dd, J = 6.0, 1.8 Hz, 1H), 6.33 – 6.15 (m, 2H), 5.81 – 5.64 (m, 1H), 5.11 – 5.01 (m, 2H), 3.60 (ddq, J = 8.5, 4.1, 1.9 Hz, 1H), 2.73 – 2.58 (m, 1H), 2.24 (dddd, J = 13.4, 9.7, 6.8, 1.5 Hz, 3H), 1.54 – 1.37 (m, 2H), 1.38 – 1.22 (m, 4H), 0.96 – 0.84 (t, 3H, J = 6.9 Hz). 13 C NMR (75 MHz, CDCl3): δ 197.5, 160.6, 147.1, 135.4, 134.9, 134.3, 131.8, 125.7, 117.8, 43.2, 37.4, 33.6, 31.5, 28.6, 22.6, 14.1. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 71 FTIR (ATR): 2956, 2926, 2856, 1692, 1631, 1580, 1440, 1338, 1280, 1207, 1102, 977, 915, 871, 839, 801, 753, 730, 666 cm–1. HRMS (FAB+, m/z): calc’d for C16H21O [M+H–H2]+ 229.1586, found: 229.1581. [𝜶]𝟐𝟑 𝑫 : +150.4° (c = 1.0, CHCl3). Preparation of (–)-44: H Maleic anhydride EtAlCl2 Me H O (–)-67 DCE 80 ºC, 2 h Me O (–)-44 (70%, >99% ee) In a 50 mL round bottom flask, (–)-67 (667 mg, 2.25 mmol, 1.0 equiv) was dissolved in DCE (20 mL) and maleic anhydride (2.2 g, 22.5 mmol, 10.0 equiv) and EtAlCl2 (2.5 mL, 1.0 M solution in hexanes, 2.5 mmol, 1.1 equiv) were added sequentially. A reflux condenser was attached and the reaction mixture was warmed to reflux under argon. After 2 hours, the reaction mixture was cooled down, concentrated, and directly loaded on silica gel. Purification by flash chromatography (hexanes/EtOAc 15:1) afforded (–)-44 (361 mg, 70% yield, >99% ee by chiral HPLC analysis) as a colorless liquid. Characterization data matches (+)-44. [𝜶]𝟐𝟑 𝑫 : –122.9° (c = 1.0, CHCl3). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis HPLC Conditions: 5% IPA, 1.0 mL/min, Chiralcel OD-H column, λ = 254 nm, tR (min) = 5.94, 8.23 (±)-44: (+)-44: (–)-44: 72 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 73 Preparation of 47: cis-5-octen-1-ol Ru-4 (1 mol%) toluene, 23 ºC, 2 torr Me O (+)-44 then (+)-44, Ru-4 (5 mol%) THF, 40 ºC, 16 h OH Me O 47 (99% yield, >99:1 Z/E, >99% ee) In a nitrogen-filled glovebox, cis-5-octen-1-ol (205 mg, 1.6 mmol, 8.0 equiv) was dissolved in toluene (2 mL) in a 50 mL Schlenk flask and a solution of catalyst Ru-4 (13.5 mg, 16 µmol, 1 mol%) in THF (0.8 mL) was added. The Schlenk flask was sealed and brought out of the glovebox, and then connected to high vacuum. The valve was gradually opened (Caution: open slowly and stir well to avoid splashing). After 15 minutes stirring, the flask was refilled with argon and sealed, and was brought back into the glovebox. The residue was diluted with THF (0.5 mL), and an aliquot was taken for GC analysis (conversion of homodimerization step was >98% by GC analysis). A solution of (+)-44 (46 mg, 0.2 mmol, 1.0 equiv) in THF (0.5 mL) was added into the Schlenk flask and an additional portion of catalyst Ru-4 (8.5 mg, 10 µmol, 5 mol%) solution in THF (0.5 mL) was added. The Schlenk flask was sealed and brought out of glovebox. The reaction was stirred for 16 h at 40 ºC before quenched with a few drops of ethyl vinyl ether. The solvent was removed under reduced pressure. The residue was purified by flash chromatography (hexanes/EtOAc 2:1) to give 47 (60 mg, 99%, >99:1 Z/E, >99% ee by chiral HPLC analysis). Spectral data (1H NMR, 13C NMR, HRMS, IR) matched with the published data.46 [𝜶]𝟐𝟑 𝑫 : +142.6° (c = 0.5, CHCl3). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 74 HPLC Conditions: 10% IPA, 1.0 mL/min, Chiralcel OD-H column, λ = 210 nm, tR (min): major = 9.64, minor = 13.83 Preparation of 15-deoxy-∆12,14-prostaglandin J2 (2): OH COOH 1. PCC, CH2Cl2 Me O 47 2. NaClO2, NaH2PO4•H2O 2-methyl-2-butene t-BuOH, H2O Me O 15d-PGJ2 (2) (65% yield over 2 steps) Pyridinium chlorochromate (129 mg, 0.6 mmol, 3.0 equiv) was added to a solution of 47 (60 mg, 0.2 mmol, 1.0 equiv) in CH2Cl2 (2 mL) at room temperature. The reaction progress was monitored by TLC and diluted with Et2O (2 mL) after stirring for 1 h. The resulting solution was filtered Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 75 through a short pad of celite, and was concentrated and subjected to the next step without further purification. The residue was dissolved in t-BuOH (3 mL) at room temperature, and 2-methyl-2-butene (210 μL, 2.0 mmol, 10 equiv), a solution of NaH2PO4•H2O (41.4 mg, 0.3 mmol, 1.5 equiv) in H2O (0.72 mL) and a solution of NaClO2 (80 %, 33.6 mg, 0.3 mmol, 1.5 equiv) in H2O (0.72 mL) was added sequentially. After stirring at room temperature for 30 minutes, the reaction mixture was diluted with a solution of NaH2PO4•H2O (648 mg) in H2O (12 mL) and extracted with EtOAc (5 × 10 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. Flash column chromatography (SiO2, CH2Cl2/MeOH 20:1) afforded pure compound 2 (41 mg, 65% yield over 2 steps) as a colorless oil. Spectral data (1H NMR, 13C NMR, HRMS, IR) matched with the published data.46 [𝜶]𝟐𝟑 𝑫 : +154.4° (c = 1.0, CHCl3). Preparation of 15-deoxy-∆12,14-prostaglandin J2 methyl ester(69): COOH Me O 15d-PGJ2 (2) COOMe TMSCH2N2 benzene/MeOH 23 ºC, 2 h Me O 69 (72% yield, >99% ee) In a 1-dram vial, 15d-PGJ2 (2) (8.0 mg, 25 µmol, 1.0 equiv) was dissolved in C6H6/MeOH (3:2, 0.75 mL) at 23 °C. A solution of trimethylsilyldiazomethane (20 µL, 2.0 M in hexanes, 40 µmol, 1.5 equiv) (yellow color persists). After stirring for 2 hours, the reaction mixture was concentrated Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 76 under vacuum. The residue was purified by flash column chromatography (SiO2, hexanes/EtOAc, 4:1) to give 69 (6.0 mg, 72% yield, >99% ee) as a colorless oil. TLC (4:1 hexanes/EtOAc): Rf= 0.28 (UV). 1 H NMR (400 MHz, CDCl3) δ 7.47 (ddd, J = 6.0, 2.6, 1.0 Hz, 1H), 6.95 (dt, J = 11.0, 1.2 Hz, 1H), 6.37 – 6.17 (m, 3H), 5.50 – 5.31 (m, 2H), 3.66 (s, 3H), 3.57 (ddt, J = 8.7, 3.8, 2.0 Hz, 1H), 2.64 – 2.56 (m, 1H), 2.33 – 2.18 (m, 5H), 2.03 (q, J = 7.3 Hz, 2H), 1.66 (p, J = 7.5 Hz, 2H), 1.46 (p, J = 7.2 Hz, 2H), 1.31 (ddt, J = 9.3, 5.3, 3.6 Hz, 4H), 0.89 (t, J = 6.9 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 197.5, 174.0, 160.8, 147.1, 135.5, 135.2, 131.8, 131.6, 126.1, 125.8, 51.7, 43.6, 33.6, 33.5, 31.6, 30.9, 28.6, 26.8, 24.8, 22.6, 14.1. FTIR (ATR): 2953, 2927, 2856, 2360, 2342, 1736, 1694, 1632, 1579, 1436, 1364, 1205, 1090, 979, 836, 729, 668 cm–1. HRMS (TOF, ES+, m/z): calc’d for C20H29O3 [M+H]+ 331.2268, found: 331.2720. [𝜶]𝟐𝟑 𝑫 : +72.1° (c = 0.2, CHCl3). Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis SFC Conditions: 10% IPA, 4.0 mL/min, Chiralcel OD-H column, λ = 254 nm, tR (min)= 6.27, 7.09 77 Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 1.7 78 NOTES AND REFERENCES 1. (a) Marks, F. and Fürstenberger, G. Prostaglandins, Laukotrienes and Other Eicosanoids; Wiley-Blackwell, 1999. (b) Funk, C. D. Science 2001, 294, 1871–1875. 2. Straus, D. S.; Glass, C. K. Med. Res. Rev. 2001, 21, 185–210. 3. (a) Fitzpatrick, F. A.; Wynalda, M. A. J. Biol. Chem. 1983, 258, 11713–11718. (b) Shibata, T.; Kondo, M.; Osawa, T.; Shibata, N.; Kobayashi, M.; Uchida, K. J. Biol. Chem. 2002, 277, 10459– 10466. 4. Hegde, S.; Kaushal, N.; Ravindra, K. C.; Chiaro, C.; Hafer, K. T.; Gandhi, U. H.; Thompson, J. T.; van den Heuvel, J. P.; Kennett, M. J.; Hankey, P.; Paulson, R. F.; Prabhu, K. S. Blood 2011, 118, 6909–6919. 5. Forman, B. M., Tontonoz, P., Chen, J., Brun, R. P., Spiegelman, B. M., and Evans, R. M. Cell, 1995, 83, 803−812. 6. Kim, E.-H.; Surh, Y.-J. Biochemical Pharmacology 2006, 72, 1516–1528. 7. Gou, Q.; Gong, X.; Jin, J.; Shi, J.; Hou, Y. Oncotarget 2017, 8, 60704–60709. 8. (a) Soares, A. F.; Nosjean, O.; Cozzone, D.; D’Orazio, D.; Becchi, M.; Guichardant, M.; Ferry, G.; Boutin, J. A.; Lagarde, M.; Géloën, A. Biochem. and Biophys. Res. Commun. 2005, 337, 521– 525. (b) Waku, T.; Shiraki, T.; Oyama, T.; Fujimoto, Y.; Maebara, K.; Kamiya, N.; Jingami, H.; Morikawa, K. J. Mol. Biol. 2009, 385, 188–199. (c) Reddy, A. T.; Lakshmi, S. P.; Banno, A.; Reddy, R. C. ACS Chem. Biol. 2018, 13, 3269–3278. 9. Figure was adapted from RCSB Protein Data Bank website: https://www.rcsb.org/3dview/2ZK1?preset=ligandInteraction&sele=PTG 10. Kudva, A. K.; Kaushal, N.; Mohinta, S.; Kennett, M. J.; August, A.; Paulson, R. F.; Prabhu, K. S. PLOS ONE 2013, 8, e80622. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 79 11. (a) Corey, E. J.; Weinshenker, N. M.; Schaaf, T. K.; Huber, W. J. Am. Chem. Soc. 1969, 91, 5675–5677. (b) Das, S.; Chandrasekhar, S.; Yadav, J. S.; Grée, R. Chem. Rev. 2007, 107, 3286– 3337. (c) Peng, H.; Chen, F.-E. Org. Biomol. Chem. 2017, 15, 6281–6301. 12. Nicolaou, K. C.; Heretsch, P.; ElMarrouni, A.; Hale, C. R. H.; Pulukuri, K. K.; Kudva, A. K.; Narayan, V.; Prabhu, K. S. Angew. Chem. Int. Ed. 2014, 53, 10443–10447. 13. Carreira, E. M.; Singer, R. A.; Lee, W.; J. Am. Chem. Soc. 1994, 116, 8837–8838. 14. Nicolaou, K. C.; Pulukuri, K. K.; Yu, R.; Rigol, S.; Heretsch, P.; Grove, C. I.; Hale, C. R. H.; El Marrouni, A. Chem. - Eur. J. 2016, 22, 8559–8570. 15. Nicolaou, K. C.; Pulukuri, K. K.; Rigol, S.; Heretsch, P.; Yu, R.; Grove, C. I.; Hale, C. R. H.; ElMarrouni, A.; Fetz, V.; Brönstrup, M.; Aujay M.; Sandoval J.; Gavrilyuk J. J. Am. Chem. Soc. 2016, 138, 6550–6560. 16. Pelšs, A.; Gandhamsetty, N.; Smith, J. R.; Mailhol, D.; Silvi, M.; Watson, A. J. A.; PerezPowell, I.; Prévost, S.; Schützenmeister, N.; Moore, P. R.; Aggarwal V. K. Chem.-Eur. J. 2018, 24, 9542–9545. 17. (a) Bickley, J. F.; Jadhav, V.; Roberts, S. M.; Santoro, M. G.; Steiner, A.; Sutton, P. W. Synlett 2003, 1170–1174. (b) Brummond, K. M.; Sill, P. C.; Chen, H. Org. Lett. 2004, 6, 149–152. (c) Iqbal, M.; Li, Y.; Evans, P. Tetrahedron 2004, 60, 2531–2538. (d) Acharya, H. P.; Kobayashi, Y. Tetrahedron Lett. 2004, 45, 1199–1202. (e) Acharya, H. P.; Kobayashi, Y. Tetrahedron 2006, 62, 3329–3343. (f) Tanaka, H.; Hasegawa, T.; Kita, N.; Nakahara, H.; Shibata, T.; Oe, S.; Ojika, M.; Uchida, K.; Takahashi, T. Chem. Asian J. 2006, 1, 669–677. (g) Kim, N.-J.; Moon, H.; Park, T.; Yun, H.; Jung, J.-W.; Chang, D.-J.; Kim, D.-D.; Suh, Y.-G. J. Org. Chem. 2010, 75, 7458–7460. (h) Egger, J.; Fischer, S.; Bretscher, P.; Freigang, S.; Kopf, M.; Carreira, E. M. Org. Lett. 2015, 17, 4340–4343. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 80 18. Nicolaou, K. C.; Pulukuri, K. K.; Rigol, S.; Peitsinis, Z.; Yu, R.; Kishigami, S.; Cen, N.; Aujay, M.; Sandoval, J.; Zepeda, N.; et al. J. Org. Chem. 2019, 84 , 365–378. 19. (a) Cheng-Sánchez, I.; Sarabia, F. Synthesis 2018, 50, 3749–3786. (b) Fürstner, A. Chem. Commun. 2011, 47, 6505. (c) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4490–4527. 20. (a) Endo, K.; Grubbs, R. H. J. Am. Chem. Soc. 2011, 133, 8525–8527. (b) Keitz, B. K.; Endo, K.; Patel, P. R.; Herbert, M. B.; Grubbs, R. H. J. Am. Chem. Soc. 2012, 134, 693–699. 21 (a) Khan, R. K. M.; Torker, S.; Hoveyda, A. H. J. Am. Chem. Soc. 2013, 135, 10258–10261. (b) Hoveyda, A. H. J. Org. Chem. 2014, 79, 4763–4792. (c) Koh, M. J.; Khan, R. K. M.; Torker, S.; Hoveyda, A. H. Angew. Chem. Int. Ed. 2014, 53, 1968–1972. (d) Koh, M. J.; Khan, R. K. M.; Torker, S.; Yu, M.; Mikus, M. S.; Hoveyda, A. H. Nature 2015, 517, 181–186. 22. (a) Johns, A. M.; Ahmed, T. S.; Jackson, B. W.; Grubbs, R. H.; Pederson, R. L. Org. Lett. 2016, 18, 772–775. (b) Ahmed, T. S.; Grubbs, R. H. J. Am. Chem. Soc. 2017, 139, 1532–1537. 23. Xu, C.; Shen, X.; Hoveyda, A. H. J. Am. Chem. Soc. 2017, 139, 10919–10928. 24. (a) Montgomery, T. P.; Ahmed, T. S.; Grubbs, R. H. Angew. Chem. Int. Ed. 2017, 56, 11024– 11036. (b) Ahmed, T. S.; Grubbs, R. H. Angew. Chem. Int. Ed. 2017, 56, 11213–11216. (c) Ahmed, T. S.; Montgomery, T. P.; Grubbs, R. H. Chem. Sci. 2018, 9, 3580–3583. (d) Jung, K.; Kim, K.; Sung, J.-C.; Ahmed, T. S.; Hong, S. H.; Grubbs, R. H.; Choi, T.-L. Macromolecules 2018, 51, 4564–4571. (e) Müller, D. S.; Curbet, I.; Raoul, Y.; Le Nôtre, J.; Baslé, O.; Mauduit, M. Org. Lett. 2018, 20, 6822–6826. 25. (a) Couturier, J.-L.; Paillet, C.; Leconte, M.; Basset, J.-M.; Weiss, K. Angew. Chem. Int. Ed. 1992, 31, 628–631. (b) Lam, J. K.; Zhu, C.; Bukhryakov, K. V.; Müller, P.; Hoveyda, A.; Schrock, R. R. J. Am. Chem. Soc. 2016, 138, 15774–15783. (c) Nguyen, T. T.; Koh, M. J.; Shen, X.; Romiti, Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 81 F.; Schrock, R. R.; Hoveyda, A. H. Science 2016, 352, 569–575. (d) Shen, X.; Nguyen, T. T.; Koh, M. J.; Xu, D.; Speed, A. W. H.; Schrock, R. R.; Hoveyda, A. H. Nature 2017, 541, 380–385. (e) Koh, M. J.; Nguyen, T. T.; Lam, J. K.; Torker, S.; Hyvl, J.; Schrock, R. R.; Hoveyda, A. H. Nature 2017, 542, 80–85. 26. Noyori, R.; Suzuki, M. Angew. Chem. Int. Ed. 1984, 23, 847–876. 27. Arisetti, N.; Reiser, O. Org. Lett. 2015, 17, 94–97. 28. (a) Noyori, R.; Tomino, I.; Nishizawa, M. J. Am. Chem. Soc. 1979, 101, 5843–5844. (b) Suzuki, M.; Kawagishi, T.; Suzuki, T.; Noyori, R. Tetrahedron Lett. 1982, 23, 4057–4060. 29. Ulbrich, K.; Kreitmeier, P.; Vilaivan, T.; Reiser, O. J. Org. Chem. 2013, 78, 4202–4206. 30. Schmidt, A.-K. C.; Stark, C. B. W. Org. Lett. 2011, 13, 4164–4167. 31. Yadav, J. S.; Suresh, B.; Srihari, P. Eur. J. Org. Chem. 2015, 2015, 5856–5863. 32. Bai, Y.; Shen, X.; Li, Y.; Dai, M. J. Am. Chem. Soc. 2016, 138, 10838–10841. 33. Herbert, M. B.; Grubbs, R. H. Angew. Chem. Int. Ed. 2015, 54, 5018–5024. 34. (a) Iqbal, M.; Evans, P. Tetrahedron Lett. 2003, 44, 5741–5745. (b) Eddolls, J. P.; Iqbal, M.; Roberts, S. M.; Santoro, M. G. Tetrahedron 2004, 60, 2539–2550. 35. Tanaka, K.; Ogasawara, K. Synthesis 1995, 1995, 1237–1239. 36. Kärki, K.; Siitonen, J.; Kortet, S.; Cederström, M.; Pihko, P. Synlett 2018, 29, 1723–1728. 37. (a) Orgué, S.; León, T.; Riera, A.; Verdaguer, X. Org. Lett. 2015, 17, 250–253. (b) Verdaguer, X.; Lledó, A.; López-Mosquera, C.; Maestro, M. A.; Pericàs, M. A.; Riera, A. J. Org. Chem. 2004, 69, 8053–8061. 38. Chang, X.; Sun, X.-S.; Che, C.; Hu, Y.-Z.; Tao, H.-Y.; Wang, C.-J. Org. Lett. 2019, 21, 1191– 1196. 39. Mihelich, E. D.; Eickhoff, D. J. J. Org. Chem. 1983, 48, 4135–4137. Chapter 1 – Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis 82 40. Mehta, G.; Reddy, D. S. Tetrahedron Lett. 1999, 40, 991–994. 41. Hoover, J. M.; Stahl, S. S. J. Am. Chem. Soc. 2011, 133, 16901–16910. 42. Grieco, P. A.; Abood, N. J. Org. Chem. 1989, 54, 6008–6010. 43. Yadav, J. S.; Suresh, B.; Srihari, P. Eur. J. Org. Chem. 2015, 2015, 5856–5863. 44. Honda, T.; Ohta, M.; Mizutani, H. J. Chem. Soc., Perkin Trans. 1 1999, 23–29. 45. Kobayashi, Y.; Murugesh, M. G.; Nakano, M.; Takahisa, E.; Usmani, S. B.; Ainai, T. J. Org. Chem. 2002, 67, 7110–7123. 46. Li, J.; Ahmed, T. S.; Xu, C.; Stoltz, B. M.; Grubbs, R. H. J. Am. Chem. Soc., 2019, 141, 154– 158 Appendix 1 – Spectra Relevant to Chapter 1 83 APPENDIX 1 Spectra Relevant to Chapter 1: Concise Total Syntheses of ∆12-Prostaglandin J Natural Products Via Stereoretentive Metathesis  (R)-43 O BocO        1                               H NMR (400 MHz, CDCl3) of compound (R)-43.                 
 Appendix 1 – Spectra Relevant to Chapter 1 84 


13 


 
   
C NMR (101 MHz, CDCl3) of compound (R)-43.  
      
  


Appendix 1 – Spectra Relevant to Chapter 1 85     
 O  44 Me     1       H NMR (400 MHz, CDCl3) of compound 44.           
                                                                      Appendix 1 – Spectra Relevant to Chapter 1 86 


 
 



C NMR (101 MHz, CDCl3) of compound 44.   13   
         
    


         

Appendix 1 – Spectra Relevant to Chapter 1 87   O  47 Me OH     1        H NMR (400 MHz, CDCl3) of compound 47.               
                                                                     Appendix 1 – Spectra Relevant to Chapter 1 88 


13 

 

 C NMR (101 MHz, CDCl3) of compound 47. 
          
     


   
        

Appendix 1 – Spectra Relevant to Chapter 1 89   
O 

48 CDCl3 – 7.26  Me 
 Me    1 
    H NMR (400 MHz, CDCl3) of compound 48. 
 
 
           
          
     
               
  
   
      
             
     
  
    
   

        
 

          
           
 
  
         










 Appendix 1 – Spectra Relevant to Chapter 1 90 

  
 

   
13 

 

C NMR (101 MHz, CDCl3) of compound 48. 
      
     
 CDCl3 – 77.16   

 

     
     
Appendix 1 – Spectra Relevant to Chapter 1 91 O  2 Me COOH     1       H NMR (400 MHz, CDCl3) of compound 2.              
                                                                         Appendix 1 – Spectra Relevant to Chapter 1 92 

 
13 

 

C NMR (101 MHz, CDCl3) of compound 2. 
           
      


  
          

Appendix 1 – Spectra Relevant to Chapter 1 93      50 OH Me  
1     H NMR (400 MHz, CDCl3) of compound 50.            
                                                                            Appendix 1 – Spectra Relevant to Chapter 1 94 




 

 
C NMR (101 MHz, CDCl3) of compound 50.  13 

      

 
  


Appendix 1 – Spectra Relevant to Chapter 1 95   Ph CF3 MeO  O O 50a Me     1     H NMR (400 MHz, CDCl3) of compound 50a.            
                                                                  Appendix 1 – Spectra Relevant to Chapter 1 96      
             97 
                  Appendix 1 – Spectra Relevant to Chapter 1 






 







 C NMR (101 MHz, CDCl3) of compound 50a.
 13 
 

 19

 

 F NMR (282 MHz, CDCl3) of compound 50a.  CF3 Ph O OMe O 50b Me     1     H NMR (400 MHz, CDCl3) of compound 50b.           
                                                                      Appendix 1 – Spectra Relevant to Chapter 1 98       
           99                    Appendix 1 – Spectra Relevant to Chapter 1 







 







 C NMR (101 MHz, CDCl3) of compound 50b.
 13  

 19

 

 F NMR (282 MHz, CDCl3) of compound 50b.  51 OTBS Me   1     H NMR (400 MHz, CDCl3) of compound 51.            
                                                                       Appendix 1 – Spectra Relevant to Chapter 1 100 



13  

 
 
C NMR (101 MHz, CDCl3) of compound 51. 
    

 
          
 
Appendix 1 – Spectra Relevant to Chapter 1 101 O   37 OTBS Me   1     H NMR (400 MHz, CDCl3) of compound 37.          
                                                                             Appendix 1 – Spectra Relevant to Chapter 1 102 


13 

 


  C NMR (101 MHz, CDCl3) of compound 37. 
   
 



   
     
 
Appendix 1 – Spectra Relevant to Chapter 1 103  O 38 OTBS Me     1      H NMR (400 MHz, CDCl3) of compound 38.             
                                                                     Appendix 1 – Spectra Relevant to Chapter 1 104 
  
13   


 
 
C NMR (101 MHz, CDCl3) of compound 38.         
    


    

        
 
Appendix 1 – Spectra Relevant to Chapter 1 105 O  OTBS 52 Me OH     1      H NMR (400 MHz, CDCl3) of compound 52.                 
                                                                  Appendix 1 – Spectra Relevant to Chapter 1 106 

 

13 
  

 
 
C NMR (101 MHz, CDCl3) of compound 52.   
      
       
 

  
          

  Appendix 1 – Spectra Relevant to Chapter 1 107  O 1 OH Me COOH     1     H NMR (500 MHz, CDCl3) of compound 1.                  
                                                                        Appendix 1 – Spectra Relevant to Chapter 1 108  


  
      13 


 
 
C NMR (126 MHz, CDCl3) of compound 1. 
     


  
           

Appendix 1 – Spectra Relevant to Chapter 1 109  S  S 53 OH   1     H NMR (400 MHz, CDCl3) of compound 53.              
                                                                                 Appendix 1 – Spectra Relevant to Chapter 1 110 





  
C NMR (101 MHz, CDCl3) of compound 53.   13 

      
     


Appendix 1 – Spectra Relevant to Chapter 1 111

 
 S S 54 OTBS   1     H NMR (400 MHz, CDCl3) of compound 54.               
                                                                                   Appendix 1 – Spectra Relevant to Chapter 1 112 





  
C NMR (101 MHz, CDCl3) of compound 54.   13 

      
    
 

   

 
Appendix 1 – Spectra Relevant to Chapter 1 113 O  55 OTBS    1     H NMR (400 MHz, CDCl3) of compound 55.           
                                                                              Appendix 1 – Spectra Relevant to Chapter 1 114 

  


 


 C NMR (101 MHz, CDCl3) of compound 55.  13 
  
  

 
  
 
Appendix 1 – Spectra Relevant to Chapter 1 115  O    14 OTBS Me   1     H NMR (400 MHz, CDCl3) of compound 14.                
                                                                     Appendix 1 – Spectra Relevant to Chapter 1 116 




 


  C NMR (101 MHz, CDCl3) of compound 14.   13  
   
  


 
   
 
Appendix 1 – Spectra Relevant to Chapter 1 117  O  56 OTBS Me     1      H NMR (400 MHz, CDCl3) of compound 56.                  
                                                                      Appendix 1 – Spectra Relevant to Chapter 1 118 

  

  13 



 

C NMR (101 MHz, CDCl3) of compound 56.                    
    


  
  Appendix 1 – Spectra Relevant to Chapter 1 119  O 57 OTBS Me OH     1      H NMR (400 MHz, CDCl3) of compound 57.                   
                                                                     Appendix 1 – Spectra Relevant to Chapter 1 120 

  

  
13 

 

C NMR (101 MHz, CDCl3) of compound 57. 
  
               
  


   
 
  
 Appendix 1 – Spectra Relevant to Chapter 1 121  O 59 OTBS      1      H NMR (400 MHz, CDCl3) of compound 59.               
                                                                        Appendix 1 – Spectra Relevant to Chapter 1 122 
 
13 


 
 
C NMR (101 MHz, CDCl3) of compound 59.   
  
   
     


 
 
Appendix 1 – Spectra Relevant to Chapter 1 123    
  O  3 OH Me COOH    1      H NMR (400 MHz, CDCl3) of compound 3.                    
                                                                             Appendix 1 – Spectra Relevant to Chapter 1 124   
  
13 

 
 
C NMR (101 MHz, CDCl3) of compound 3. 
            
     


  
   
  

Appendix 1 – Spectra Relevant to Chapter 1 125 
 O 61 Me     1     H NMR (400 MHz, CDCl3) of compound 61.                        
                                                                       Appendix 1 – Spectra Relevant to Chapter 1 126 


13 

 

C NMR (101 MHz, CDCl3) of compound 61. 
               
    

   



Appendix 1 – Spectra Relevant to Chapter 1 127   O  4 Me COOH     1      H NMR (400 MHz, CDCl3) of compound 4.               
                                                                     Appendix 1 – Spectra Relevant to Chapter 1 128   


13 

 

C NMR (101 MHz, CDCl3) of compound 4. 
               
     




   
 

Appendix 1 – Spectra Relevant to Chapter 1 129    H (+)-33 H O
CDCl3 – 7.26           1
  
  H NMR (400 MHz, CDCl3) of compound (+)-33.                                   
 
 
             


              
 



















Appendix 1 – Spectra Relevant to Chapter 1 130 


 CDCl3 – 77.16 

 


 


 
       C NMR (101 MHz, CDCl3) of compound (+)-33.   13  


Appendix 1 – Spectra Relevant to Chapter 1 131 
 H O H H 68 OH CDCl3 – 7.26  Me  


 
 
 
1    H NMR (400 MHz, CDCl3) of compound 68. 


 
 
 
 
 
    
       
 
       

              



   
 
           



 
 
 
 
 
 
 
 
 

                          
 
        


 Appendix 1 – Spectra Relevant to Chapter 1 132 



13      
    


 
 CDCl3 – 77.16 C NMR (101 MHz, CDCl3) of compound 68. 

            

 
       

Appendix 1 – Spectra Relevant to Chapter 1 133   Appendix 1 – Spectra Relevant to Chapter 1 134



 
 
   
 
 
 
 

 1      
1 H– H COSY NMR (400 MHz, CDCl3) of compound 68. 















 1  13     
H– C HSQC NMR (400 MHz, CDCl3) of compound 68. 
  
Appendix 1 – Spectra Relevant to Chapter 1 135 







  








 1      

13 H– C HMBC NMR (400 MHz, CDCl3) of compound 68. 
      
 
 
 
 
   
 
 
NOESY NMR (400 MHz, CDCl3) of compound 68.


   H O H (+)-67 CDCl3 – 7.26  

Me      
 1    H NMR (400 MHz, CDCl3) of compound (+)-67.  
 
 
 
  
 
      
              

           





 
 
 
         
 
 
 

          
 
 
                                  
   



 Appendix 1 – Spectra Relevant to Chapter 1 136 
 




13 


 

C NMR (101 MHz, CDCl3) of compound (+)-67.   
         
CDCl3 – 77.16 
         

      


Appendix 1 – Spectra Relevant to Chapter 1 137 O 69 

CDCl3 – 7.26  
 Me COOMe    1    H NMR (400 MHz, CDCl3) of compound 69.  
  
 
            
         
            
                             
  
  
   
 
                
 

   
 
       
       
 
             

 
 
      



 Appendix 1 – Spectra Relevant to Chapter 1 138 

  

 
  

 13 


 

C NMR (101 MHz, CDCl3) of compound 69. 
          

 
  CDCl3 – 77.16 
      
   
   
 
     
  
Appendix 1 – Spectra Relevant to Chapter 1 139 Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 140 CHAPTER 2 Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate† ABSTRACT Palladium-catalyzed aminoacetoxylation of alkenes has been applied as an efficient strategy in the synthesis of nitrogen-containing heterocycles. The aminoacetoxylation products are generated from the reductive elimination of high-valent palladium intermediates and stoichiometric amount of strong oxidants are typically required to oxidize Pd(II) intermediates. A mild aerobic intramolecular aminoacetoxylation method for the synthesis of pyrrolidine and indoline derivatives was achieved using molecular oxygen as oxidant. A catalytic NOx species acts as an electron transfer mediator to access a high-valent palladium intermediate as the presumed active oxidant. 2.1 INTRODUCTION Numerous alkene difunctionalization reactions enabled by palladium catalysts have been developed as efficient transformations for the construction of useful organic building blocks.1 For example, palladium-catalyzed amination of alkenes has been applied as a new strategy to † Adapted with permission from Li, J.; Grubbs, R. H.; Stoltz, B. M. Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate. Org. Lett. 2016, 18, 5449–5451. Copyright © 2019, American Chemical Society Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 141 synthesize nitrogen-containing heterocycles. 2 Arising from a key aminopalladation step, an alkylpalladium(II) intermediate can undergo versatile pathways to generate different structural motifs (Scheme 2.1.1).2a From the mechanistic view, to realize the aminooxygenation of alkene, a rapid β-hydride elimination process 3 should be avoided after forming the aminopalladation intermediate in the initial step. Oxidation of aminopalladation intermediate could form a Pd(IV) intermediate, which could readily undergo reductive elimination to obtain the difunctionalization product (Scheme 2.1.1). So, the key determinant to get the aminooxygenation product is the competition between two pathways, which relies on various reaction conditions, especially the choice of oxidants.4 Scheme 2.1.1. Aminopalladation and Subsequent Transformations NHPG PdII – H+ PG β-H elimination N aminopalladation PG N PdII Oxidation PG reductive PdIV elimination N PG OAc N OAc– "Wacker-type" product Aminooxygenation product In the past decade, aminooxygenation has been achieved by oxidizing the alkylpalladium(II) intermediate into high-valent palladium (PdIV or PdIII) followed by C–O bond-forming reductive elimination. However, a stoichiometric amount of a strong oxidant, such as PhI(OAc)2 or NFSI, is typically required to access the high-valent palladium intermediate. PhI(OAc)2 is widely applied as a strong oxidant to generate the Pd(IV) intermediate to realize alkene difunctionalization and other reactions such as C–H functionalization, which have been reported by Sorensen5, Stahl,6 Sanford,7 Muñiz,8 Dong,9 and Liu and co-workers10. For example, in Sorensen’s pioneer study in 2005, N-tosyl carbamates can be obtained as diamination products from internal or terminal alkenes (Scheme 2.1.2A).6 In this method, palladium acetate was applied as catalyst, which can Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 142 be oxidized to Pd(IV) species in the presence of 2 equivalents of PhI(OAc)2. Muñiz and coworkers in the same year achieved the aminoacetoxylation in similar conditions (Scheme 2.1.2A).9a Liu, Stahl, and co-workers also developed various aminooxygen reactions using PhI(OAc)2 as oxidant, and one impressive example is the intermolecular aminoacetoxylation by reacting terminal alkenes with phthalimide, to obtain protected amino alcohol products (Scheme 2.1.2B).11 Scheme 2.1.2. Examples of Alkene Difunctionalization Using PhI(OAc)2 A. Intramolecular aminoacetoxylation/diamination (2005): O TsHN Ph Pd(OAc)2 (10 mol%), PhI(OAc)2 (2 equiv) O O TsN OAc O HN O Ph Bu4NOAc (1 equiv) CH3CN O Pd(OAc)2 (5 mol%), PhI(OAc)2 (2.2 equiv) NHTs N DCM NTs B. Intermolecular aminoacetoxylation (2006): O C6H13 + HN PdCl2(MeCN)2 PhI(OAc)2 (2 equiv) DCE NPhth C6H13 OAc O Another approach to generate high-valent palladium intermediate is to use NFluorobenzenesulfonimide (NFSI) as oxidant, and several palladium-catalyzed alkene difunctionalization examples has been reported by Michael group. NFSI, a bystanding F+ oxidant, 11 is strong enough to oxidize Pd(II) to Pd(IV), thus facilitate the difunctionalization reaction happening through reductive elimination. Such as the example shown in Scheme 2.1.2A, where 2 equivalents of NFSI were used to convert the Cbz-protected amino alkene into the pyrrolidine product catalyzed by PdCl2(MeCN)2, and the vicinal position is attached with methoxy group which is from the methanol solvent (Scheme 2.1.3A).12 Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 143 An enantioselective diamination reaction was developed in 2013. In the highly oxidative conditions in the presence of NFSI, most phosphine ligands that can be successfully used in many enantioselective processes, are incompatible in such conditions and subjected to be oxidized. So, introduction of chiral elements becomes very challenging. In this example, Ph-quinox was used as a chiral ligands and 82-98 % ee can be achieved (Scheme 2.1.3B).13 The key Pd(II) intermediate was isolated and the absolute structure was unambiguously determined by X-ray crystallography. This work shows very promising result that the challenging difunctionalization of alkene could be achieved by ligand design that could tolerate oxidative conditions, and new types of chiral ligands are anticipated by further research in this field. Scheme 2.1.3. Examples of Alkene Difunctionalization Using NFSI A. SO2Ph PdCl2(MeCN)2 SO2Ph 3Å MS, MeOH F N + NH Cbz N Cbz (2 equiv.) B. 10 mol% Pd(TFA)2 12 mol% Ph-quinox 20 mol% TEMPO SO2Ph F N + NH O OMe 1,4-dioxane SO2Ph R (2 equiv.) N(SO2Ph)2 N O R 82-99 ee % O N O PdII Me N Ph N H Me Me However, stoichiometric amount of wasteful high-energy oxidants, such as PhI(OAc)2, are typically required to access high-valent palladium centers and large quantities of by-products are generated. Recently, milder conditions have also been developed using H2O2 as an environmentally tractable and inexpensive oxidant. In 2014, the Liu group first reported a Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 144 palladium-catalyzed aminohydroxylation reaction with 3 equivalents of H2O2 as oxidant. Alkene tethered with N-tosyl carbamates can be converted to the aminohydroxylation product with a free hydroxyl group in high yield at room temperate (Scheme 2.1.4A).14 In 2015, another example showed the ability of hydrogen peroxide of oxidizing Pd(II) to achieve aminoacetoxylation reaction with similar aminoalkene substrates as previous examples.15 However, in this report, a six-membered piperidine derivative was formed as the major product over five-membered ring product, which is ascribed to the kinetic difference of 5-exo and 6-endo attack as they suggested. Bis-nitrogen ligands are very suitable to this reaction because they were proved to potentially suppress β-H elimination of palladium complex.16 Scheme 2.1.4. Examples of Alkene Difunctionalization by Using H2O2 A. NHTs O O Pd(OAc)2 (5 mol%) 35% aq. H2O2 (3 equiv) CF3CO2Li (2 eq.) Acetone, 23 ºC, 10 h Ts N O OH O 85% Pd(OAc)2 (5 mol%) bipyridine (7.5 mol%) 35% aq. H2O2 (3 equiv) B. NHTs 2.2 HOAc, 23 ºC, 24 h OAc + N Ts N Ts 93% trace OAc PALLADIUM-CATALYZED AEROBIC TRANSFORMATIONS H2O2 was utilized as an environmentally tractable and inexpensive oxidant, but aerobic conditions are still in high demand from a sustainable perspective. A classic and well-studied example of a palladium-catalyzed aerobic homogeneous transformation is the Wacker process. This transformation was developed in the 1950s using O2 as the terminal oxidant in combination with a Cu salt as a redox co-catalyst to facilite the reoxidation of Pd0 to PdII.17 In contrast, reports of alkene difunctionalizations under aerobic conditions are rare, presumably because the oxidation Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 145 of the intermediate alkylpalladium(II) species using O2 as the sole oxidant is kinetically challenging; 18 hence, care must be taken to avoid facile β-hydride elimination immediately (Scheme 2.1.1). Recently, NOx species have been shown to be effective electron transfer mediators capable of facilitating the aerobic oxidation of alkylpalladium(II) intermediates to their high-valent counterparts.19 Sanford and co-workers reported that nitrate/nitrite could serve as a redox cocatalyst in the aerobic acetoxylation of unactivated C(sp3)–H bonds via C–O bond reductive elimination of a high-valent palladacycle directed by oxime ether or pyridine-type directing groups (Scheme 2.2.1).20 Pd(OAc)2 was used as a catalyst, with NaNO3 as a co-catalyst, under 1 atm O2 as the terminal oxidant. NaNO2 can also play a similar activating role though the reactivity was lower than NaNO3. Scheme 2.2.1. Aerobic Palladium-catalyzed C(sp3)–H Acetoxylation with NOx Co-catalyst OAc N Pd(OAc)2, NaNO3 or NaNO2 OMe AcOH/ Ac2O, O2, 100oC N OMe Grubbs and co-workers recently reported a nitrite-modified Wacker oxidation that shows anti-Markovnikov selectivity.21 In the presence of nitrite from AgNO2, aldehyde was obtained as the major product, which is catalyst-controlled. A [Pd]-NO2 complex was proposed to be formed in situ and nitrite could be a donor of oxygen to form a [Pd]-NO complex, which could be reoxidized by O2 (Scheme 2.2.2). The oxygen atom in aldehyde product was proved to be donated from nitrite by 18O-labeled study. Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 146 Scheme 2.2.2. Nitrite-modified Aldehyde-selective Wacker Oxidation PdCl2(PhCN)2 (1 equiv) CuCl2 (1 equiv) Na15N18O2 (1 equiv) Ph Ph 18O t-BuOH/MeNO2 (15:1) rt, 12 min, dry box 1/2 O2 O [Pd] N O R O [Pd] [Pd] NO N O R H β-hydride elimination O R Very recently, the Grubbs group reported a palladium-catalyzed aerobic alkene diacetoxylation method mediated by a catalytic amount of silver nitrite. By simply changing the solvent from t-BuOH to AcOH, along with other slightly variations of reaction conditions, diacetoxylation of unbiased terminal alkenes was achieved by Grubbs and co-workers in 2014 (Scheme 2.2.3A).22 NO2 was released in situ in these acidic conditions, and served as an ETM to oxidize Pd(II) to higher oxidation states such as Pd(III) or Pd(IV), which was suggested by the mechanistic studies by reacting with NO2 gas in the reaction conditions (Scheme 2.2.3B). Scheme 2.2.3. Diacetoxylation of Unbiased Terminal Alkenes A. OAc PdCl2(PhCN)2, CuCl2, AgNO2 R AcOH/Ac2O/MeNO2, O2, 35oC, 16 h OAc R [stoichiometric] B. OAc PdCl2(PhCN)2, CuCl2, AgNO2 or NO2 R AcOH/Ac2O/MeNO2, 35oC R OAc Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 147 However, the ligand sets coordinating with Pd were not defined in those methods, and palladium-nitrite ligands could be present as suggested by previous studies. The possible formation of [Pd]-NOx complexes is supported by previous work by Cámpora, Palma, and coworkers.23 A [Pd]-NO complex was synthesized by the reaction of an in situ generated anionic Pd(II) salt with diazald (N-nitroso-N-methyl-p-toluenesulfonamide). Oxidation of [Pd]-NO complex with O2 in toluene gave [Pd]-NO3 complex. Although no direct evidence was gained for [Pd]-NO2 being formed as an intermediate in the reaction, its independent synthesis was accomplished by treating Pd(II) starting material with NO2 (Scheme 2.2.4). This study suggests the redox conversions of [Pd]-NOx complexes in the presence of O2, which may provide some mechanistic evidences to the aerobic transformations mediated by Pd/NOx catalysts. Scheme 2.2.4. Evidence of [Pd]-NOx Complexes K+ N – N N NO2 N Pd N Pd NO2 N 'N~N~N-Pd-NO2' PdIV nitro complex Diazald N N N Pd N N N=O O2 'N~N~N-Pd-NO' PdIV nitrosyl complex N Pd ONO2 'N~N~N-Pd-NO3' PdIV nitrato complex (N ~ N ~ N = tris(pyrazolyl)borate ligand) Based on the literature precedent of those aerobic transformations, we reasoned that a palladium-catalyzed aerobic aminooxygenation reaction might be possible using this electron transfer mediator strategy, as NOx species could be a kinetically suitable mediator in the aerobic oxidation of the alkylpalladium(II) intermediate formed after aminopalladation. This aerobic Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 148 reaction can be an environmentally tractable alternative to current methods using wasteful high energy oxidants. 2.3 OPTIMIZATION OF PALLADIUM-CATALYZED AMINOOXYGENATION REACTIONS We started our investigation by subjecting acetyl-protected aminoalkene substrate 1a to our previously published intermolecular diacetoxylation reaction conditions. 11% of cyclized product 2a was obtained, which is identical to the authentic product sample directly synthesized from pyrrolidin-2-ylmethanol. Scheme 2.3.1. Initial Trial and Synthesis of Authentic Product Sample OAc PdCl2(PhCN)2, CuCl2.2H2O, AgNO2 (10 mol%) NHAc N Ac AcOH/Ac2O/MeNO2 (10:5:3) O2, 35oC, 16h, dark 1a OH N H 2a (11%) OAc Ac2O (2.5 equiv.) TEA, DMAP, DCM, 23oC N Ac 2a At the initial point of optimization, a control experiment was conducted to verify if all components are required for the conversion. We were delighted to find that removing nitromethane from the reaction system could boost the yield to 50% as measured by GC analysis (Table 2.3.1). However, AcOH and Ac2O are both necessary for the transformation. In the solvent screen and solvent/co-solvent ratio experiments, the yield obtained in AcOH/Ac2O was significantly above other solvents/Ac2O tested, and removal of Ac2O co-solvent dropped the yield. The role of the Ac2O was not discussed in previous diacetoxylation conditions, but similar to Sanford’s C–H acetoxylation example19, it can potentially serve to sequester H2O in the reaction conditions. In another set of reactions shown in Table 2.3.2, both AgNO2 and the O2 atmosphere are proved to be necessary for the product formation. Although the role of Cu still remains elusive, it could potentially make the reaction more efficient, because less product could still be obtained Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 149 in 34% yield without CuCl2 (Table 2.3.2, entry 3). Methyl ketone was the major byproduct, which was generated from the competing b-hydride elimination pathway. Possible alkene isomerization products were also detected. Table 2.3.1. Initial Control Experiment of Solvent PdCl2(PhCN)2 (10 mol %) CuCl2•2H2O (10 mol %) AgNO2 (10 mol%) a NHAc Ac OAc N AcOH/Ac2O (8:1), O2, 35 ºC, 16 h 1a 2a entry conditions conversion (%) yield (%)a 1 no change 99 11 2 no Ac2O 96 1 3 no AcOH, Ac2O 99 1 no MeNO2 100 50 4 Table 2.3.2. Initial Control Experiment of Catalysts PdCl2(PhCN)2 (10 mol %) CuCl2•2H2O (10 mol %) AgNO2 (10 mol%) NHAc Ac OAc N AcOH/Ac2O (8:1), O2, 35 ºC, 16 h 1a 2a entry conditions conversion (%) yield (%)a 1 no change 100 50 2 no AgNO2 99 0 3 no CuCl2 97 34 4 no CuCl2, AgNO2 86 0 15 2 5 Observed by-products: no O2 Me O NHAc Me NHAc Next, different source of nitrates/nitrites were tested. To our delight, most of metal nitrates/nitrites and alkyl nitrites have shown decent reactivity, including very cheap source of sodium nitrate, sodium nitrite and iso-butylnitrite, the cheapest commercially available alkyl nitrite. Among them, cupric nitrate gave the highest yield of product (56%, Table 2.3.3 Entry 6). So, it was used as the optimized source of NOx in the following optimization experiment, and a third Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 150 catalyst component CuCl2 was not required anymore. Furthermore, reactions could be performed without shielding from light because light-sensitive silver nitrite was replaced. Table 2.3.3. Nitrate/nitrite Sources Screening Ac PdCl2(PhCN)2 (10 mol%) CuCl2•2H2O (10 mol%), MNOx (10 mol%) NHAc OAc N AcOH/Ac2O (8:1) 35oC, O2 (1 atm), 16 h 1a Entry MNOx yield (%) 1 AgNO2 50 2 NaNO2 32 3* TBANO2 41 4 iBuONO 48 5 NaNO3 35 6 Cu(NO3)2 56 7 Fe(NO3)3 48 8 AgNO3 40 0 9 NO+BF4- 17 C 2a 10 no MNOx 0 60 50 30 20 4 N O O+ B N no aN N O 2 3 3 O aN N x F - 2 O gN A Fe ( O 2 O gN A u( N N O 3) 3 iB uO N O TB A N O 10 3) 2 Yield (%) 40 *TBANO2 = tetrabutylammonium nitrite A series of Pd(II) sources with different counterions were tested. It was found that chloride ion gave the highest yield (Table 2.3.4, Entry 6) over the other counterions commonly used in palladium-catalyzed reactions. Additionally, reaction could be performed at room temperature to get higher yield. The following screening of ligands showed distinct results among different ligands (Table 2.3.5). Only benzonitrile, triphenylphosphine, and norbornadiene ligands showed decent yield, but other ligands tested showed no conversion, including the previously used bipyridine and di(2-pyridyl) ketone ligands in Liu’s aminooxygenation example.16 Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 151 Table 2.3.4. Palladium Counterions Screen NHAc Ac PdCl2(PhCN)2 (10 mol%), Cu(NO3)2•3H2O (10 mol%) N OAc AcOH/Ac2O (8:1) 23oC, O2 (1 atm), 16 h 1a 2a Entry Pd sources conversion (%)yield (%) 1 Pd(OAc)2 48 10 2 Pd(TFA)2 73 17 3 Pd(PhCN)2Br2 100 54 4 Pd(MeCN)4(BF4)2 37 14 5 Pd(PhCN)2Cl2 100 56 6* Pd(PhCN)2Cl2 100 62 *Entry 6 was conducted in 23oC Table 2.3.5. Ligand Screen Entry Pd sources 1 Pd(PhCN)2Cl2 100 2 Pd(PPh3)2Cl2 100 63 3 Pd(nbd)Cl2 100 66 4 Pd(COD)Cl2 9 0 5 Pd(bipy)Cl2 0 0 6 Pd(dppe)Cl2 0 0 7 Pd(quinox)Cl2 0 0 8 PdCl2, bipy 0 0 9 PdCl2, dpk 0 0 10 PdCl2 100 20 conversion (%)yield (%) N 66 N bipy O N N dpk O a N N quinox a After the determination of best catalysts, the loading and ratio of those two catalysts were studied. When decreasing the loading of Pd and Cu catalysts from 10 mol % to 5 mol%, acceptable yield of 51% could still be obtained, and there was no significant increase of yield when increasing the loading of Cu(NO3)2 while keeping PdCl2(MeCN)2 as 5 mol%. However, when the loading of Cu(NO3)2 was lower than PdCl2(MeCN)2, decreased yield was obtained (Table 2.3.6 Entry 4). Similar result can be obtained by controlling Pd/Cu/nitrite ratio by adding PdCl2(MeCN)2, CuCl2 and AgNO2, that the optimal ratio of Pd/Cu/nitrite was 1:1:2 (Table 2.3.6, Entry 6), which suggested that a sufficient amount of nitrite/nitrate was required to get high catalytic turnover. Keeping the loading of PdCl2(PhCN)2 and Cu(NO3)2 as 5 mol%, further screening was conducted by tuning the solvent ratio, concentration, reaction time, temperature, and additives. For additives, Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 152 common acidic and basic additives, including the previous effective trifluoroacetate salts in Liu’s work15 have been tried, but none of them showed increased yield. Table 2.3.6. Studies of Catalyst Loading and Ratio NHAc OAc N AcOH/Ac2O (8:1) O2 (1 atm balloon), 35 ºC, 16 h 1a entry Ac PdCl2(PhCN)2, Cu(NO3)2•3H2O 2a PdCl2(PhCN)2 (mol%) Cu(NO3)2•3H2O (mol%) yield (%)a 1 5 5 51 2 5 7.5 52 3 5 10 52 4 10 5 NHAc 17 Ac PdCl2(PhCN)2, CuCl2•2H2O, AgNO2 OAc N AcOH/Ac2O (8:1) O2 (1 atm balloon), 35 ºC, 16 h 1a 2a AgNO2 (mol%) yield (%)a entry PdCl2(PhCN)2 (mol%) CuCl2•2H2O (mol%) 5 5 5 5 26 6 5 5 10 52 By switching the counterions between Pd and Cu, we found that the combination of Pd(NO3)2•2H2O and CuCl2•2H2O also gave similar yield. Surprisingly, by replacing CuCl2 into some simple chloride salts, such as sodium chloride or zinc chloride, decent yield could still be obtained, which suggests that Cu may not be necessary in this reaction (Table 2.3.7). But chloride anion was very important in this reaction, since low yield was obtained if adding no chloride in the reaction conditions. However, the reactions using Pd(NO3)2 as catalyst were less reproducible, and Pd(NO3)2 is a more expensive source of palladium. Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 153 Table 2.3.7. Reaction Conditions Using Pd(NO3)2 as Catalyst without Cu Salts Ac NHAc Pd(NO3)2•2H2O (5 mol%), MCln•xH2O (15 mol%) OAc N AcOH/Ac2O (6:1) 23oC, O2 (1 atm), 16 h Entry 2.4 Cl- source yield(%) a 1 CuCl2 2 3 4 5 6 7 8 LiCl NaCl KCl ZnCl2 NBu4Cl Cu(NO3)2 no Cl- 48 55 60 54 64 5 11 10 SUBSTRATE SCOPE Next, we evaluated substrate scope and functional group tolerance under our optimized conditions. First, several linear aliphatic acetyl-protected amino alkenes were tested in the optimized conditions (Scheme 2.4.1). The gem-diphenyl substrate 1b has been tried and gave a higher yield of 75%, which was expected to have the Thorpe-Ingold effect that could facilitate the cyclization processes. And gem-dibenzyl substrate also gave the corresponding pyrrolidine product 2c in 83% yield. Different amine protecting groups were also tested at the initial stage. However, acetyl group is the best among different amine protecting groups that have been tested (Table 2.4.1, Entry 1). Scheme 2.4.1. Optimized Reaction Conditions NHAc PdCl2(PhCN)2 (5 mol%), Cu(NO3)2•3H2O (5 mol%) Ac N AcOH/Ac2O (6:1), O2, 23 oC, 16 h 1a 2a OAc Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 154 Table 2.4.1. Reactions with Aliphatic Amino Alkenes R PdCl2(PhCN)2 (5 mol %) Cu(NO3)2•3H2O (5 mol %) R R NHAc OAc R AcOH/Ac2O (6:1) 23 °C, O2 (1 atm, balloon), 16 h N Ac 1 entry 2 product amine substrate yield OAc NHR 1 N R 1a 2a Ph Ph Ph R = Ac 69% Cbz 34% Boc 20% Ns 0% Bz 0% Me 0% H 0% OAc Ph NHAc 2 75 % N Ac 1b 2b Bn Bn 3 OAc Bn Bn 83 % NHAc N Ac 1c 2c Acetyl-protected aromatic amine substrates have been tried and we were delighted to find 87% yield could be obtained from o-allyl aniline substrate 3a. Based on the good result obtained from o-allyl aniline substrate, we tested a series of o-allylaniline derivatives, obtaining a variety of indoline derivatives 4b-i in moderate to excellent yields (Table 2.4.2, 30-95% yield). A variety of substituents and functional groups were well tolerated, including fluoro, chloro, methyl ester, and trifluoromethyl groups. A lesser extent nitro, and cyano groups gave lower yields due to the electronic effect. Notably, we also tested the reaction under air and product 4a can also be obtained in good yield (Table 2.4.2, entry 2; 80% yield). Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 155 Table 2.4.2. Reactions with Aromatic Substrates R2 PdCl2(PhCN)2 (5 mol %) Cu(NO3)2•3H2O (5 mol %) R2 AcOH/Ac2O (6:1) 23 °C, O2 (1 atm, balloon), 16 h R1 NHAc R1 Ac N 3 OAc 4 entry product R1 R2 yield (%)b 1 4a H H 87 2c 4a H H 80 3 4b Me H 89 4 4c H Me 95 5 4d F H 88 6 4e Cl H 80 7 4f COOMe H 65 8 4g CF3 H 58 9 4h NO2 H 30 10 4i CN H 32 Efforts have been made to investigate whether this method can be applied to other types of substrates, but the substrates shown in Scheme 2.4.2 showed no reactivity. For example, alternation of the substrate structure gave no product, such as 2,2-disubstituted alkene 5, o-vinyl benzylamine substrates 6, and o-allylaniline with allylic substitution 7 (Scheme 2.4.2A), which may be ascribed to the steric bulk at the 2- or 3- positions of alkenes. Internal olefins are also synthesized but the reactivity was much lower, that trace amount of product can be detected by LC-MS from the reaction with substrate 8. A series of amide 9 were also synthesized, which would expect the similar electronic property to the well-reacted o-allylaniline substrates 3. However, those substrates with different amide acidity all showed no reactivity. Six-membered ring product 12 was not observed in the standard condition with substrate 10. However, the diacetoxylation product 11 was observed in trace amount (Scheme 2.4.2B). In all, this method is very restricted to o-allylaniline and other linear terminal alkenes. The current reaction conditions are under optimized to be applied to a broader range of substrates. Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 156 Scheme 2.4.2. Substrates with Low Reactivity A. Substrates with no products formed NHAc NHAc NHAc Me 6 5 NHAc Me 7 R O Me N H 9 8 R = H, OMe, CF3 B. Six-membered ring product was not observed NHAc AcO NHAc 10 PdCl2(PhCN)2 (5 mol%) Cu(NO3)2•2H2O (5 mol%) AcOH/Ac2O (6:1), 23 ºC, O2 (1 atm, balloon), 16 h OAc N Ac 11 (trace) OAc 12 (not observed) Based on our observations and previous mechanistic studies, we propose the catalytic cycle shown in Scheme 2.4.3. Aminopalladation of the substrate 1a likely forms Pd(II) intermediate I, which can be oxidized to high-valent palladium intermediate II by an NOx species (possibly be NO2) and molecular oxygen acts as the terminal oxidant. We envision that high-valent palladium intermediate II can then undergo the C–O bond-forming reductive elimination to release a cationic intermediate III, which forms the aminoacetoxylation product 2a upon acetolysis. The source of additional oxygen atoms in the product is not verified, but a previous 18O labeling study showed that the oxygen came from the AcOH solvent. Although the role of copper still remains elusive, the presence of copper is clearly advantageous as a decrease in yield was observed when no source of Cu was added.24 Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 157 Scheme 2.4.3. Proposed Mechanism NHAc NHAc Pd(II) 1a Me Pd(II) Me O N + N (I) O Me N OAc NO 2 O (III) Ac N Pd(II) Pd(IV) (II) NO 1/ O 2 2 2a 2.5 CONCLUSIONS In summary, this chapter presented a mild, aerobic intramolecular aminoacetoxylation method, which provides another example that catalytic nitrite/nitrate is capable of mediating the aerobic oxidation from Pd(II) to high-valent Pd(IV) intermediate after aminopalladation process, forming the desired aminoacetoxylation products in good to high yield (30-95%) from a variety of substrates. However, the amine protecting group is currently restricted to acetyl group. Internal olefins and steric hindered terminal olefins always showed low reactivity. Continuous efforts will be on the optimization of reaction conditions to fit in a larger range of substrates including the currently unreactive internal olefins. In addition, it would be worth introducing chiral ligands which may influence the stereoselectivity in the initial aminopalladation step and form the pyrrolidine or indolines with high enantioselectivity. Ongoing mechanistic studies, including a full stereochemical analysis, of this unique catalytic system would be beneficial to the development of novel stereoselective methods. Finally, in today’s renaissance of NOx redox chemistry, we anticipate efficient utilization of the oxidation potential of O2 will enable access to even more environmentally benign processes rather than consuming other high-energy/high-cost stoichiometric oxidants. Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 2.6 EXPERIMENTAL METHODS AND ANALYTICAL DATA 2.6.1 Materials and Methods 158 Commercial reagents and metal salts were obtained from Sigma-Aldrich, TCI, Combi-Blocks, Alfa Aesar and used without further purification. 1H and 13C NMR spectra were recorded on a Varian 500 MHz, Varian 400 MHz, or a Varian 300 MHz spectrometer. High-resolution mass spectra were provided by the California Institute of Technology Mass Spectrometry Facility, using JEOL JMS-600H High Resolution Mass Spectrometer. Gas chromatography data was obtained using an Agilent 6850 FID gas chromatograph equipped with a HP-5 (5%phenyl)-methylpolysiloxane capillary column (Agilent). Response factors relative to the internal standard tridecane were collected for the substrate N-(pent-4-en-1-yl)acetamide (1a), and the product (1-acetylpyrrolidin-2-yl)methyl acetate (2a) following literature procedures.25 2.6.2 Experimental Procedures General procedure A for isolation scale (0.5 mmol) aminoacetoxylation of alkenes: PdCl2(PhCN)2 (0.025 mmol, 9.6 mg), Cu(NO3)2•3H2O (0.025 mmol, 6.0 mg) and alkene substrate (0.5 mmol) were weighed into a 50 mL flame-dried round bottom flask (14/20 neck) with a stir bar. The flask was sparged with oxygen (1 atm) from an oxygen balloon, through a vacuum adapter (14/20). AcOH (9.0 mL) and Ac2O (1.5 mL) were premixed in a separated vial and sparged with oxygen (through needle and oxygen balloon) for 2 minutes. The oxygenated solvent mixture was then transferred into the flask via syringe. The reaction was then allowed to stir at 23 °C for 16 h under an atmosphere of oxygen (1 atm balloon). The solvent was removed Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 159 under reduced pressure. Dichloromethane (20 mL) was then added and the resulting mixture was washed with saturated NaHCO3 (20 mL). The aqueous layer was extracted with dichloromethane (2 × 20 mL) and the combined organic layer was dried over MgSO4. The solvent was removed under reduced pressure and the crude mixture was purified by silica gel chromatography. General procedure B for analytical scale (0.2 mmol) aminoacetoxylation of 1a: PdCl2(PhCN)2 (0.01 mmol, 3.8 mg), Cu(NO3)2•3H2O (0.01 mmol, 2.4 mg) and alkene substrate (0.5 mmol) were weighed into a 2-dram screw-cap vial charged with a stir bar. The vial was sparged with oxygen (1 atm balloon) for 45 seconds. AcOH (3.6 mL), Ac2O (0.6 mL) and tridecane (0.00246 mmol, 6 µL) were subsequently added via syringe. The solution was saturated with oxygen by an additional 45 seconds of sparging. The reaction was then allowed to stir at 23 °C for 16 h under an atmosphere of oxygen (balloon). Next, an aliquot (ca. 0.2 mL) was injected into a 2 mL vial containing an estimated 1 mL of premixed EtOAc/pyridine solution (3:1) to quench the reaction. The resulting solution was subjected to GC analysis to determine yield. Substrate Synthesis and Characterization Data LiAlH4 CN Et2O NH2 Ac2O Et2O NHAc 1a N-(pent-4-en-1-yl)acetamide (1a): Prepared according to the literature procedure from 4pentenitrile26 as a colorless oil (1.34 g, 52% yield over 2 steps). Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 1 160 H NMR (500 MHz, CDCl3) δ 6.59 (bs, 1H), 5.73 (ddt, J = 16.9, 10.1, 6.6 Hz, 1H), 5.10 – 4.82 (m, 2H), 3.17 (td, J = 7.3, 5.8 Hz, 2H), 2.02 (m, 2H), 1.91 (s, 3H), 1.54 (ddd, J = 14.7, 7.9, 6.8 Hz, 2H); 13 C NMR (126 MHz, CDCl3) δ 170.4, 137.7, 115.0, 39.1, 31.0, 28.6, 23.1; HRMS (FAB+) m/z calc’d for C7H14NO [M+H]+: 128.1075, found: 128.1077. CN Ph allylbromide, LDA Ph Ac2O Ph NH2 LiAlH4 CN THF, –78 ºC to 23 ºC Ph Ph Ph Ph Et2O Ph NHAc Et2O 1b N-(2,2-diphenylpent-4-enyl)acetamide (1b): Synthesized according to literature procedure27 as a white solid (3.03 g, 54% yield over 3 steps). 1 H NMR (500 MHz, CDCl3) δ 7.33 (dd, J = 8.2, 7.0 Hz, 4H), 7.28 – 7.24 (m, 2H), 7.22 – 7.19 (m, 4H), 5.45 (ddt, J = 16.7, 10.4, 7.1 Hz, 1H), 5.06 (bs, 1H), 5.03 – 4.96 (m, 2H), 3.99 (d, J = 5.8 Hz, 2H), 2.87 (dt, J = 7.2, 1.2 Hz, 2H), 1.87 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 169.9, 145.2, 133.6, 128.3, 128.0, 126.6, 118.7, 50.2, 46.0, 42.1, 23.4; HRMS (FAB+) m/z calc’d for C19H22NO [M+H]+: 280.1701, found 280.1702. O NC K2CO3 DMF O LiAlH4 NC Bn BnBr Bn Et2O O NC Bn rac-BINAP, Pd2(dba)3 O toluene, 90 ºC Bn Ac2O Bn Bn NH2 Bn Bn NHAc Et2O 1c Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 161 N-(2,2-dibenzylpent-4-en-1-yl)acetamide (1c): 2,2-dibenzyl-4-pentenenitrile could be prepared from allyl 2-cyanoacetate according to the literature procedure28 as a colorless liquid (1.13 g, 72% yield). Then, LiAlH4 (0.9 g, 23 mmol) was weighed into a flame-dried flask, and the flask was exchanged with vacuum/argon 3 times. 100 mL Et2O was added to flask through cannula transfer. 2,2-dibenzyl-4-pentenenitrile (1.13 g, 4.3 mmol) was dissolved into 10 mL Et2O and added via syringe. The reaction was stirred overnight and quenched with water and 1M NaOH solution. After the grey color of suspension turned white completely, the reaction mixture was filtered through celite. The filtrate was dried over Na2SO4 and concentrated in vacuo without purification. Then the crude 2,2-dibenzylpent-4-en-1-amine was dissolved into 50 mL Et2O and acetic anhydride (1.2 mL, 12.9 mmol) was added. After 3 h, the reaction mixture was washed with saturate NaHCO3 solution (20 mL), and then the aqueous layer was extracted with EtOAc (2 × 20 mL). The combined organic layers were concentrated in vacuo and purified by silica gel chromatography (50% EtOAc in hexanes). Product 1c was obtained as a colorless oil (976 mg, 74% yield over last two steps). 1 H NMR (500 MHz, CDCl3) δ 7.35 – 7.30 (m, 4H), 7.30 – 7.25 (m, 2H), 7.23 – 7.20 (m, 4H), 6.01 (ddt, J = 17.3, 10.2, 7.2 Hz, 1H), 5.24 – 5.13 (m, 2H), 5.02 (bs, 1H), 3.27 (d, J = 5.9 Hz, 2H), 2.76 – 2.66 (m, 4H), 2.16 (dt, J = 7.2, 1.4 Hz, 2H), 1.74 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 169.8, 137.8, 134.5, 130.6, 128.3, 126.6, 118.8, 45.7, 43.4, 41.4, 39.4, 23.3 (one quaternary carbon signal unresolved); HRMS (FAB+) m/z calc’d for C21H26NO [M+H] +: 308.2014, found 308.2013. Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 162 General procedure C: synthesis of o-allylaniline derivatives 3a, 3b, 3d, 3e NH2 allylbromide HN BF3•OEt2 xylenes 180 ºC, 2 h microwave K2CO3 DMF NH2 NHAc Ac2O DCM 3a N-allylanilines can be prepared from the literature procedure.29 In a 5 mL microwave tube, a solution of N-allylaniline (665 mg, 5 mmol) in 4 mL xylenes was added boron trifluoride etherate (0.7 mL, 5,5 mmol) under an argon atmosphere. Then the microwave tubes was sealed and heated to 180 °C in the microwave reactor for 2 h. After cooling down to room temperature, the reaction mixture was poured into 2 M NaOH solution (10 mL), and extracted with EtOAc (10 mL × 2). The combined organic layers were dried over MgSO4, and concentrated in vacuo. The crude o-allylaniline was dissolved in DCM (30 mL) and acetic anhydride (1.4 mL, 15 mmol) was added dropwise. After reacting 2 h in room temperature, the reaction mixture was poured into saturated NaHCO3 and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over MgSO4. The solvent was removed by rotary evaporation, and the residue was purified by column chromatography (30% EtOAc in hexanes). NHAc 3a N-(2-allylphenyl)acetamide (3a): Prepared according to General Procedure C as a white solid (257 mg, 44% yield over 2 steps). Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 1 163 H NMR (500 MHz, CDCl3) δ 7.86 (dd, J = 8.3, 4.0 Hz, 1H), 7.32 – 7.26 (m, 1H), 7.20 (dd, J = 7.7, 1.6 Hz, 1H), 7.14 (t, J = 7.4 Hz, 1H), 6.00 (ddt, J = 16.6, 11.4, 6.2 Hz, 1H), 5.25 – 5.08 (m, 2H), 3.41 (d, J = 6.0, 2H), 2.17 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 168.4, 136.4, 136.0, 130.2, 130.0, 127.5, 125.4, 123.9, 116.6, 37.0, 24.3; HRMS (FAB+) m/z calc’d for C11H14NO [M+H]+: 176.1075, found: 176.1083. NHAc Me 3b N-(2-allyl-4-methylphenyl)acetamide (3b): Prepared according to General Procedure C from the corresponding N-allyl-4-methylaniline as a white solid (342 mg, 36% yield over 2 steps). 1 H NMR (500 MHz, CDCl3) δ 7.66 (d, J = 8.1 Hz, 1H), 7.18 (bs, 1H), 7.08 (dd, J = 8.2, 2.1 Hz, 1H), 7.01 (d, J = 2.0 Hz, 1H), 5.98 (ddt, J = 16.5, 10.1, 6.1 Hz, 1H), 5.23 – 5.07 (m, 2H), 3.36 (dd, J = 6.2, 1.8 Hz, 2H), 2.33 (s, 3H), 2.16 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 168.3, 136.5, 135.2, 133.3, 130.8, 130.3, 128.0, 124.2, 116.3, 36.9, 24.2, 20.9; HRMS (FAB+) m/z calc’d for C12H16NO [M+H]+: 190.1232, found 190.1233. NHAc F 3d N-(2-allyl-4-fluorophenyl)acetamide (3d): Prepared according to General Procedure C from the corresponding N-allyl-4-fluoroaniline as a white solid (425 mg, 44% yield over 2 steps). Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 1 164 H NMR (500 MHz, CDCl3) δ 7.72 (dd, J = 8.9, 5.4 Hz, 1H), 7.12 (bs, 1H), 6.97 (td, J = 8.4, 3.0 Hz, 1H), 6.93 (dd, J = 9.1, 3.0 Hz, 1H), 5.97 (ddt, J = 17.2, 10.1, 6.1 Hz, 1H), 5.26 – 5.08 (m, 2H), 3.37 (dt, J = 6.1, 1.7 Hz, 2H), 2.18 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 168.4, 160.1 (d, J = 244.7 Hz), 135.5, 133.2 (d, J = 7.4 Hz), 131.7 (d, J = 2.6 Hz), 126.1 (d, J = 8.4 Hz), 117.1, 116.7 (d, J = 22.8 Hz), 114.0 (d, J = 22.1 Hz), 36.7, 24.1; HRMS (FAB+) m/z calc’d for C11H13NOF [M+H]+: 194.0981, found 194.0977. NHAc Cl 3e N-(2-allyl-4-chlorophenyl)acetamide (3e): Prepared according to General Procedure C from the corresponding N-allyl-4-chloroaniline as a white solid (442 mg, 42% yield over 2 steps). 1 H NMR (500 MHz, CDCl3) δ 7.90 – 7.73 (m, 1H), 7.28 (bs, 1H), 7.25 – 7.22 (m, 1H), 7.18 (m, 1H), 6.00 – 5.90 (m, 1H), 5.26 – 5.09 (m, 2H), 3.36 (dt, J = 6.4, 1.9 Hz, 2H), 2.16 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 168.3, 135.4, 134.6, 131.7, 130.3, 130.0, 127.4, 125.0, 117.2, 36.6, 24.3; HRMS (FAB+) m/z calc’d for C11H13NOCl [M+H]+: 210.0686, found 210.0683. Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 165 General procedure D: synthesis of o-allyl aniline derivatives30 NH2 NH2 Br SnBu3 NHAc Ac2O Pd(PPh3)4 DMF, 85 ºC, 16 h CH2Cl2 CF3 CF3 3g CF3 4-Amino-3-bromobenzotrifluoride (960 mg, 4 mmol) dissolved in dry DMF (10 mL) was added allyltributyltin (1.50 mL, 4.8 mmol) under argon at room temperature. Pd(PPh3)4 (457 mg, 0.39 mmol) was then added and the reaction mixture was stirred at 85 °C for 16 h. The reaction mixture was then cooled down to room temperature and diluted with water (10 mL). The aqueous layer was extracted with Et2O (3 × 10 mL). The combined organic layers were dried over MgSO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography gave 2-allyl-4-(trifluoromethyl)aniline (685 mg, 85% yield) as yellow oil. Then 2-allyl-4-(trifluoromethyl)aniline was dissolved in DCM (30 mL) and acetic anhydride (1.0 mL, 10.2 mmol) was added dropwise. After reacting 2 h in room temperature, the reaction mixture was poured into saturated NaHCO3 and extracted with EtOAc (2 × 30 mL). The combined organic layers were dried over MgSO4. The solvent was removed by rotary evaporation, and the residue was purified by column chromatography (30% EtOAc in hexanes). Me NHAc 3c N-(2-allyl-5-methylphenyl)acetamide (3c): Prepared according to General Procedure D from the corresponding 2-bromo-5-methylaniline as a white solid (605 mg, 80% yield over 2 steps). 1 H NMR (500 MHz, CDCl3) δ 7.68 (m, 1H), 7.23 (bs, 1H), 7.08 (d, J = 7.7 Hz, 1H), 6.96 – 6.94 (m, 1H), 5.98 (ddt, J = 16.5, 10.1, 6.1 Hz, 1H), 5.21 – 5.07 (m, 2H), 3.36 (dt, J = 6.3, 1.7 Hz, 2H), 2.35 (s, 3H), 2.16 (s, 3H); Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 13 166 C NMR (126 MHz, CDCl3) δ 168.4, 137.2, 136.7, 135.8, 130.0, 127.1, 126.2, 124.5, 116.3, 36.6, 24.3, 21.2; HRMS (FAB+) m/z calc’d for C12H16NO [M+H]+: 190.1232, found 190.1237. NHAc MeOOC 3f Methyl 4-acetamido-3-allylbenzoate (3f): Prepared according to General Procedure D from the corresponding methyl 4-amino-3-bromobenzoate as a white solid (451 mg, 48% yield over 2 steps). 1 H NMR (500 MHz, CDCl3) δ 8.15 – 8.09 (m, 1H), 7.95 – 7.91 (m, 1H), 7.87 (bs, 1H), 7.57 – 7.50 (m, 1H), 5.97 (tdt, J = 11.1, 10.1, 6.0 Hz, 1H), 5.28 – 5.10 (m, 2H), 3.90 (s, 3H), 3.45 – 3.43 (m, 2H), 2.17 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 168.3, 166.7, 140.6, 135.6, 131.7, 129.2, 128.1, 126.0, 121.9, 117.3, 52.1, 36.9, 24.6; HRMS (FAB+) m/z calc’d for C13H16NO3 [M+H]+: 234.1130, found 234.1122. NHAc CF3 3g N-(2-allyl-4-(trifluoromethyl)phenyl)acetamide (3g): Prepared according to General Procedure D as a white solid (583 mg, 60% yield over 2 steps). 1 H NMR (500 MHz, CDCl3) δ 8.10 (d, J = 8.5 Hz, 1H), 7.51 (dd, J = 8.5, 2.2 Hz, 1H), 7.44 (d, J = 2.2 Hz, 1H), 5.97 (ddt, J = 17.3, 10.1, 6.1 Hz, 1H), 5.29 – 5.12 (m, 2H), 3.44 (dt, J = 6.1, 1.7 Hz, 2H), 2.18 (s, 3H); Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 13 167 C NMR (126 MHz, CDCl3) δ 168.5, 139.3, 135.2, 129.4, 127.1 (q, J = 4.2 Hz), 126.7 (q, J = 32.6 Hz), 124.6 (q, J = 3.8 Hz), 124.0 (q, J = 272 Hz), 122.9, 117.6, 36.7, 24.4; HRMS (FAB+) m/z calc’d for C12H13NOF3 [M+H]+: 244.0949, found 244.0952. NHAc O2N 3h N-(2-allyl-4-nitrophenyl)acetamide (3h): Prepared according to General Procedure D from the corresponding 2-bromo-4-nitroaniline as a white solid (183 mg, 21% yield over 2 steps). 1 H NMR (500 MHz, CDCl3) δ 8.35 (d, J = 9.1 Hz, 1H), 8.16 (dd, J = 9.0, 2.7 Hz, 1H), 8.10 (d, J = 2.7 Hz, 1H), 7.57 (bs, 1H), 6.00 (ddt, J = 16.5, 10.1, 6.1 Hz, 1H), 5.42 – 5.08 (m, 2H), 3.51 (dt, J = 6.1, 1.8 Hz, 2H), 2.22 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 168.3, 143.6, 142.3, 134.5, 128.4, 125.6, 123.5, 121.6, 118.3, 36.8, 24.8; HRMS (FAB+) m/z calc’d for C11H13N2O3 [M+H]+: 221.0926, found 221.0919. NHAc NC 3i N-(2-allyl-4-cyanophenyl)acetamide (3i): Prepared according to General Procedure D from the corresponding 4-amino-3-bromobenzonitrile as a white solid (460 mg, 58% yield over 2 steps). 1 H NMR (500 MHz, CDCl3) δ 8.23 (d, J = 8.5 Hz, 1H), 7.56 (dd, J = 8.5, 1.9 Hz, 1H), 7.51 (bs, 1H), 7.48 (d, J = 1.9 Hz, 1H), 5.97 (ddt, J = 16.8, 10.1, 6.1 Hz, 1H), 5.40 – 5.03 (m, 2H), 3.43 (dt, J = 6.1, 1.8 Hz, 2H), 2.20 (s, 3H); Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 13 168 C NMR (126 MHz, CDCl3) δ 168.3, 140.5, 134.7, 133.9, 131.8, 128.9, 122.4, 118.8, 118.1, 107.6, 36.5, 24.7; HRMS (FAB+) m/z calc’d for C12H13N2O [M+H]+: 201.1028, found 201.1022. Product characterization Mixture of rotamer may occur in most products. A representative VT-NMR experiment was conducted on the product 4a. At 75 °C in DMSO solvent, only one rotamer is predominantly appeared in 1H NMR and the characterization data is shown below. Ac N OAc 4a (1-acetylindolin-2-yl)methyl acetate (4a): Prepared according to the general procedure A to provide 4a (102 mg, 87% yield) as a colorless oil. When the reaction was conducted under air (Table 3, entry 2), an air balloon was used instead of an oxygen balloon, which provided 4a (94 mg, 80% yield) as a colorless oil. 1 H NMR (400 MHz, DMSO, 75 °C) δ 7.77 (bs, 1H), 7.23 (d, J = 7.4 Hz, 1H), 7.14 (t, J = 7.8 Hz, 1H), 6.99 (t, J = 7.4 Hz, 1H), 4.82 – 4.74 (m, 1H), 4.08 (d, J = 5.7 Hz, 2H), 3.33 (dd, J = 16.3, 9.2 Hz, 1H), 2.83 (d, J = 16.3 Hz, 1H), 2.26 (s, 3H), 1.87 (s, 3H); 13 C NMR (126 MHz, CDCl3) mixture of rotamers, chemical shifts reported are from major rotamer δ 170.7, 168.7, 141.9, 129.7, 127.7, 124.8, 124.2, 118.1, 64.9, 58.5, 32.1, 23.4, 20.7; HRMS (FAB+) m/z calc’d for C13H16NO3 [M+H]+: 234.1130, found 234.1127. Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 169 For 1H and 13C NMR characterization of the rest of compounds, chemical shifts of only the major rotamer are reported. In 1H and 13C NMR spectra of products, only the major rotamer peaks are integrated. OAc N Ac 2a (1-acetylpyrrolidin-2-yl)methyl acetate (2a) : Prepared according to the general procedure A to provide 2a (64 mg, 69% yield) as a colorless liquid. 1 H NMR (500 MHz, CDCl3) mixture of rotamers, chemical shifts reported are from the major rotamer δ 4.32 (tt, J = 7.4, 3.7 Hz, 1H), 4.15 (dd, J = 10.8, 3.9 Hz, 1H) 4.09 (dd, J = 10.8, 6.8 Hz, 1H), 3.50 – 3.37 (m, 2H), 2.03 (s, 3H), 2.03 (s, 3H) (two overlapped singlets), 1.96 – 1.88 (m, 3H) 1.86 – 1.81 (m, 1H); 13 C NMR (126 MHz, CDCl3) δ 170.8, 169.7, 63.8, 55.2, 47.9, 27.5, 24.0, 21.9, 20.9; HRMS (FAB+) m/z calc’d for C9H16NO3 [M+H]+: 186.1130, found 186.1134. Ph Ph OAc N Ac 2b (1-acetyl-4,4-diphenylpyrrolidin-2-yl)methyl acetate (2b): Prepared according to the general procedure A to provide 2b (126 mg, 75% yield) as a white solid. 1 H NMR (500 MHz, DMSO, 23 °C) mixture of rotamers, chemical shifts reported are from major rotamer δ 7.46 – 7.43 (m, 2H), 7.38 – 7.35 (m, 2H), 7.33 – 7.28 (m, 4H), 7.19 (ddt, J = 9.0, 7.9, 1.4 Hz, 2H), 4.68 (dd, J = 11.2, 2.0 Hz, 1H), 4.23 (dd, J = 10.6, 3.5 Hz, 1H), 4.06 (dd, J = 10.6, 6.3 Hz, 1H), 3.92 (dd, J = 10.0, 6.7, 1H), 3.82 (d, J = 11.2 Hz, 1H), 3.12 (ddd, J = 13.0, 7.1, 1.9 Hz, 1H), 2.30 (dd, J = 13.0, 9.2 Hz, 1H), 2.03 (s, 3H), 2.00 (s, 3H); Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 13 170 C NMR (126 MHz, CDCl3) δ 170.8, 169.3, 145.2, 144.6, 128.8, 128.7, 126.8, 126.8, 126.6, 126.2, 64.1, 58.5, 55.0, 53.2, 40.1, 23.1, 20.9; HRMS (FAB+) m/z calc’d for C21H24NO3 [M+H]+: 338.1756, found 338.1757. Bn Bn OAc N Ac 2c (1-acetyl-4,4-dibenzylpyrrolidin-2-yl)methyl acetate (2c): Prepared according to the general procedure A to provide 2c (152 mg, 83% yield) as a white solid. 1 H NMR (500 MHz, CDCl3) mixture of rotamers, chemical shifts reported are from major rotamer δ 7.38 – 7.22 (m, 6H), 7.19 – 7.09 (m, 4H), 4.33 (dd, J = 11.1, 4.1 Hz, 1H), 4.29 – 4.20 (m, 1H), 4.17 (dd, J = 11.1, 2.5 Hz, 1H), 3.31 (dd, J = 10.5, 1.6 Hz, 1H), 3.18 (d, J = 10.5 Hz, 1H), 2.80 (s, 2H), 2.69 (s, 2H), 2.03 (s, 3H), 1.93 – 1.89 (m, 1H), 1.79 (dd, J = 13.1, 9.1 Hz, 1H), 1.72 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 170.8, 169.3, 137.5, 137.1, 130.8, 130.3, 128.4, 128.3, 126.9, 126.6, 63.6, 55.0, 54.6, 45.7, 43.9, 41.8, 35.0, 23.2, 20.6; HRMS (FAB+) m/z calc’d for C23H28NO3 [M+H]+: 366.2069, found 366.2053. Ac N OAc Me 4b (1-acetyl-5-methylindolin-2-yl)methyl acetate (4b): Prepared according to the general procedure A to provide 4b (110 mg, 89% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3) mixture of rotamers, chemical shifts reported are from major rotamer δ 7.98 (d, J = 8.1 Hz, 1H), 7.01 (m, 2H), 4.61 (m, 1H), 4.25 – 4.08 (m, 2H), 3.35 (dd, J = 16.1, 8.8 Hz, 1H), 2.83 (d, J = 16.0 Hz, 1H), 2.35 (s, 3H), 2.32 (s, 3H), 2.06 (s, 3H); Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 13 171 C NMR (126 MHz, CDCl3) δ 170.7, 168.4, 139.6, 133.8, 129.8, 128.1, 125.4, 117.8, 64.8, 58.6, 32.0, 23.3, 21.0, 20.8; HRMS (FAB+) m/z calc’d for C14H18NO3 [M+H]+: 248.1287, found 248.1280. Ac Me N OAc 4c (1-acetyl-6-methylindolin-2-yl)methyl acetate (4c): Prepared according to the general procedure A to provide 4c (118 mg, 95% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3) mixture of rotamers, chemical shifts reported are from major rotamer δ 7.95 (s, 1H), 7.06 (d, J = 7.6 Hz, 1H), 6.85 (d, J = 7.5 Hz, 1H), 4.60 (m, 1H), 4.19 (dd, J = 11.8, 6.2 Hz, 2H), 3.31 (dd, J = 16.1, 8.8 Hz, 1H), 2.81 (d, J = 15.9 Hz, 1H), 2.35 (s, 3H), 2.34 (s, 3H), 2.04 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 170.7, 168.6, 142.0, 137.6, 126.8, 124.9, 124.4, 118.8, 64.8, 58.8, 31.7, 23.4, 21.6, 20.7; HRMS (FAB+) m/z calc’d for C14H18NO3 [M+H]+: 248.1287, found 248.1280. Ac N OAc F 4d (1-acetyl-5-fluoroindolin-2-yl)methyl acetate (4d). Prepared according to the general procedure A to provide 4d (110 mg, 88% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3) mixture of rotamers, chemical shifts reported are from major rotamer δ 8.05 (dd, J = 8.4, 4.9 Hz, 1H), 6.97 – 6.83 (m, 2H), 4.63 (m, 1H), 4.20 (dd, J = 11.2, 5.9 Hz, 2H), 3.37 (dd, J = 16.4, 8.9 Hz, 1H), 2.86 (d, J = 16.3 Hz, 1H), 2.34 (s, 3H), 2.03 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 170.6, 168.4, 159.5 (d, J = 243.0 Hz), 134.2 (d, J = 2.7 Hz), Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 172 131.8 (d, J = 8.5 Hz), 121.7 (d, J = 7.8 Hz), 115.5 (d, J = 22.3 Hz), 112.0 (d, J = 24.8 Hz), 64.7, 58.8, 32.0, 23.1, 20.7; HRMS (FAB+) m/z calc’d for C13H15NO3F [M+H]+: 252.1036, found 252.1037. Ac OAc N Cl 4e (1-acetyl-5-chloroindolin-2-yl)methyl acetate (4e). Prepared according to the general procedure A to provide 4e (107 mg, 80% yield) as a yellow oil. 1 H NMR (500 MHz, CDCl3) mixture of rotamers, chemical shifts reported are from major rotamer δ 8.03 (d, J = 8.5 Hz, 1H), 7.18 – 7.15 (m, 2H), 4.63 (m, 1H), 4.19 (dd, J = 11.4, 5.8 Hz, 2H), 3.35 (dd, J = 16.4, 8.9 Hz, 1H), 2.86 (d, J = 16.3 Hz, 1H), 2.35 (s, 3H), 2.03 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 170.6, 168.7, 140.7, 131.7, 129.0, 127.6, 124.9, 118.9, 64.7, 58.7, 31.9, 23.2, 20.7; HRMS (FAB+) m/z calc’d for C13H15NO3Cl [M+H]+: 268.0740, found 268.0738. Ac N OAc MeOOC 4f methyl 2-(acetoxymethyl)-1-acetylindoline-5-carboxylate (4f). Prepared according to the general procedure A to provide 4f (95 mg, 65% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3) mixture of rotamers, chemical shifts reported are from major rotamer δ 8.13 (s, 1H), 7.93 – 7.90 (m, 1H), 7.86 (s, 1H), 4.67 (m, 1H), 4.18 (m, 2H), 3.88 (s, 3H), 3.37 (m, 1H), 2.92 (d, J = 16.1 Hz, 1H), 2.39 (s, 3H), 2.00 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 170.6, 169.0, 166.6, 146.0, 130.1, 126.2, 125.8, 117.2, 114.0, 64.7, 58.9, 52.0, 31.8, 23.5, 20.6; Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 173 HRMS (FAB+) m/z calc’d for C15H18NO5 [M+H]+: 292.1185, found 292.1183. Ac N OAc CF3 4g (1-acetyl-5-(trifluoromethyl)indolin-2-yl)methyl acetate (4g). Prepared according to the general procedure A to provide 4g (88 mg, 58% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3) mixture of rotamers, chemical shifts reported are from major rotamer δ 8.21 (s, 1H), 7.58 – 7.39 (m, 2H), 4.69 (m, J = 8.5 Hz, 1H), 4.23 (m, 2H), 3.41 (m, 1H), 2.96 (d, J = 16.3 Hz, 1H), 2.41 (s, 3H), 2.04 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 170.6, 169.0, 144.8, 130.5, 125.4, 123.1, 121.8, 117.7, 64.6, 58.8, 31.9, 23.4, 20.6 (C–F coupling constants unresolved and one quaternary carbon signal unresolved); HRMS (FAB+) m/z calc’d for C14H15NO3F3 [M+H]+: 302.1004, found 302.1011. Ac N OAc O2N 4h (1-acetyl-5-nitroindolin-2-yl)methyl acetate (4h). Prepared according to the general procedure A to provide 4h (41 mg, 30% yield) as a yellow oil. 1 H NMR (500 MHz, CDCl3) mixture of rotamers, chemical shifts reported are from major rotamer δ 8.24 (s, 1H), 8.17 (dd, J = 8.8, 2.4 Hz, 1H), 8.09 (m, 1H), 4.78 (s, 1H), 4.24 (dd, J = 11.8, 5.1 Hz, 2H), 3.46 (dd, J = 16.5, 9.2 Hz, 1H), 3.03 (d, J = 16.5 Hz, 1H), 2.44 (s, 3H), 2.02 (s, 3H); Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 13 174 C NMR (126 MHz, CDCl3) δ 170.6, 169.2, 147.4, 143.9, 124.7, 120.6, 117.3, 64.6, 59.2, 31.6, 23.5, 20.6 (one quaternary carbon signal unresolved); HRMS (FAB+) m/z calc’d for C13H15N2O5 [M+H]+: 279.0981, found 279.0975. Ac N OAc NC 4i (1-acetyl-5-cyanoindolin-2-yl)methyl acetate (4i). Prepared according to the general procedure A to provide 4i (41 mg, 32% yield) as a colorless oil. 1 H NMR (500 MHz, CDCl3) mixture of rotamers, chemical shifts reported are from major rotamer δ 8.22 (s, 1H), 7.59 – 7.52 (m, 1H), 7.48 (s, 1H), 4.71 (m, 1H), 4.22 (d, J = 9.1 Hz, 2H), 3.42 (d, J = 15.1 Hz, 1H), 2.97 (d, J = 16.4 Hz, 1H), 2.41 (s, 3H), 2.02 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 170.6, 169.2, 145.8, 132.8, 128.4, 119.0, 118.1, 107.0, 64.6, 58.7, 31.7, 23.6, 20.6 (one quaternary carbon signal unresolved); HRMS (FAB+) m/z calc’d for C14H15N2O3 [M+H]+: 259.1083, found 259.1089. Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 2.7 175 NOTES AND REFERENCES 1. Selected reviews for Pd-catalyzed alkene difunctionalization reactions: (a) Muñiz, K. Angew. Chem. Int. Ed. 2009, 48, 9412–9423. (b) Xu, L.-M.; Li, B.-J.; Yang, Z.; Shi, Z.-J. Chem. Soc. Rev. 2010, 39, 712–733. (c) Sehnal, P.; Taylor, R. J. K.; Fairlamb, I. J. S. Chem. Rev. 2010, 110, 824–889. (d) Hickman, A. J.; Sanford, M. S. Nature 2012, 484, 177–185. (e) Coombs, J. R.; Morken, J. P. Angew. Chem. Int. Ed. 2016, 55, 2636–2649. 2. For Pd-catalyzed amination reactions: (a) McDonald, R. I.; Liu, G.; Stahl, S. S. Chem. Rev. 2011, 111, 2981–3019. (b) Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2007, 129, 6328–6335. (c) Bertrand, M. B.; Neukom, J. D.; Wolfe, J. P. J. Org. Chem. 2008, 73, 8851–8860. (d) Muñiz, K.; Hövelmann, C. H.; Streuff, J. J. Am. Chem. Soc. 2008, 130, 763–773. (e) Ye, X.; Liu, G.; Popp, B. V.; Stahl, S. S. J. Org. Chem. 2011, 76, 1031–1044. 3. Brice, J. L.; Harang, J. E.; Timokhin, V. I.; Anastasi, N. R.; Stahl, S. S. J. Am. Chem. Soc. 2005, 127, 2868–2869. 4. For reviews, see: (a) Martínez, C.; Wu, Y.; Weinstein, A. B.; Stahl, S. S.; Liu, G.; Muñiz, K. J. Org. Chem. 2013, 78, 6309–6315. (b) Jensen, K. H.; Sigman, M. S. Org. Biomol. Chem. 2008, 6, 4083–4086. 5. Alexanian, E. J.; Lee, C.; Sorensen, E. J. J. Am. Chem. Soc. 2005, 127, 7690–7691. 6 Liu, G.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 7179–7181. 7. (a) Desai, L. V.; Sanford, M. S. Angew. Chem. Int. Ed. 2007, 46, 5737–5740. (b) Dick, A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300–2301. 8. (a) Streuff, J.; Hövelmann, C. H.; Nieger, M.; Muñiz, K. J. Am. Chem. Soc. 2005, 127, 14586– 14587. (b) Hövelmann, C. H.; Streuff, J.; Brelot, L.; Muñiz, K. Chem. Commun. 2008, 20, 2334– 2336. Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 176 9. Li, Y.; Song, D.; Dong, V. M. J. Am. Chem. Soc. 2008, 130, 2962–2964. 10. Chen, S.; Wu, T.; Liu, G.; Zhen, X. Synlett 2011, 2011, 891–894. 11. Engle, K. M.; Mei, T.-S.; Wang, X.; Yu, J.-Q. Angew. Chem. Int. Ed. 2011, 50, 1478–1491. 12. Liskin, D. V.; Sibbald, P. A.; Rosewall, C. F.; Michael, F. E. J. Org. Chem. 2010, 75, 6294– 6296. 13. Ingalls, E. L.; Sibbald, P. A.; Kaminsky, W.; Michael, F. E. J. Am. Chem. Soc. 2013, 135, 8854–8856. 14. Zhu, H.; Chen, P.; Liu, G. J. Am. Chem. Soc. 2014, 136, 1766–1769. 15. Zhu, H.; Chen, P.; Liu, G. Org. Lett. 2015, 17, 1485–1488. 16. (a) Zhang, Q.; Lu, X. J. Am. Chem. Soc. 2000, 122, 7604–7605. (b) Zhang, Q.; Lu, X.; Han, X. J. Org. Chem. 2001, 66, 7676–7684. 17. For reviews of Wacker oxidation and selected examples: (a) Takacs, J. M.; Jiang, X. Curr. Org. Chem. 2003, 7, 369–396. (b) Cornell, C. N.; Sigman, M. S. Inorg. Chem. 2007, 46, 1903–1909. (c) Keith, J. A.; Henry, P. M. Angew. Chem. Int. Ed. 2009, 48, 9038–9049. (d) Dong, J. J.; Browne, W. R.; Feringa, B. L. Angew. Chem. Int. Ed. 2015, 54, 734–744. (e) Trend, R. M.; Ramtohul, Y. K.; Stoltz, B. M. J. Am. Chem. Soc. 2005, 127, 17778–17788. (f) Trend, R. M.; Ramtohul, Y. K.; Ferreira, E. M.; Stoltz, B. M. Angew. Chem. Int. Ed. 2003, 42, 2892–2895. (g) Wickens, Z. K.; Morandi, B.; Grubbs, R. H. Angew. Chem. Int. Ed. 2013, 52, 11257–11260. (h) Wickens, Z. K.; Skakuj, K.; Morandi, B.; Grubbs, R. H. J. Am. Chem. Soc. 2014, 136, 890–893. 18. (a) Zhang, J.; Khaskin, E.; Anderson, N. P.; Zavalij, P. Y.; Vedernikov, A. N. Chem. Commun. 2008, 31, 3625–3627. (b) Wang, A.; Jiang, H.; Chen, H. J. Am. Chem. Soc. 2009, 131, 3846–3847. (c) Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 14654–14655. (d) Tang, Chapter 2 – Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 177 F.; Zhang, Y.; Rath, N. P.; Mirica, L. M. Organometallics 2012, 31, 6690–6696. (e) Khusnutdinova, J. R.; Rath, N. P.; Mirica, L. M. J. Am. Chem. Soc. 2012, 134, 2414–2422. 19. (a) Fairlamb, I. J. S. Angew. Chem. Int. Ed. 2015, 54, 10415–10427. (b) Gerken, J. B.; Stahl, S. S. ACS Cent. Sci. 2015, 1, 234−243. (c) Liang, Y.-F.; Li, X.; Wang, X.; Yan, Y.; Feng, P.; Jiao, N. ACS Catal. 2015, 5, 1956−1963. (d) Zultanski, S. L.; Stahl, S. S. J. Organomet. Chem. 2015, 793, 263-268. (e) For a review on NO2/NO redox cycle in transition-metal chemistry, see: Ford, P. C.; Lorkovic, I. M. Chem. Rev. 2002, 102, 993–1018. 20. Stowers, K. J.; Kubota, A.; Sanford, M. S. Chem. Sci. 2012, 3, 3192–3194. 21. Wickens, Z. K.; Morandi, B.; Grubbs, R. H. Angew. Chem. Int. Ed. 2013, 52, 11257–11260. 22. Wickens, Z. K.; Guzmán, P. E.; Grubbs, R. H. Angew. Chem. Int. Ed. 2014, 54, 236–240. 23. Cámpora, J.; Palma, P.; del Río, D.; Carmona, E.; Graiff, C.; Tiripicchio, A. Organometallics 2003, 22, 3345–3347. 24. Possible heterobimetallic Pd/Cu catalyst species were suggested by previous computational studies: Jiang, Y.-Y.; Zhang, Q.; Yu, H.-Z.; Fu, Y. ACS Catal. 2015, 5, 1414–1423. 25. Ritter, T.; Heil, A.; Wenzel, A. G.; Funk, T. W.; Grubbs, R. H. Organometallics 2006, 25, 5740–5745 26. Bertrand, M. B.; Wolfe, J. P. Tetrahedron 2005, 61, 6447–6459. 27. Liu, G.-Q.; Li, W.; Li, Y.-M. Adv. Synth. Catal. 2013, 355, 395–402. 28. Recio, A., III; Tunge, J. A. Org. Lett. 2009, 11, 5630–5633. 29. Yip, K.-T.; Yang, M.; Law, K.-L.; Zhu, N.-Y.; Yang, D. J. Am. Chem. Soc. 2006, 128, 3130– 3131. 30. Brucelle, F.; Renaud, P. Org. Lett. 2012, 14, 3048–3051. Appendix 2 – Spectra Relevant to Chapter 2 178 APPENDIX 2 Spectra Relevant to Chapter 2: Palladium-Catalyzed Aerobic Intramolecular Aminoacetoxylation of Alkenes Enabled by Catalytic Nitrate 179 1a NHAc 1 H NMR (500 MHz, CDCl3) of compound 1a. Appendix 2 – Spectra Relevant to Chapter 2 C NMR (126 MHz, CDCl3) of compound 1a. 180 13 Appendix 2 – Spectra Relevant to Chapter 2 1b Ph Ph NHAc 1 H NMR (500 MHz, CDCl3) of compound 1b. Appendix 2 – Spectra Relevant to Chapter 2 181 C NMR (126 MHz, CDCl3) of compound 1b. 182 13 Appendix 2 – Spectra Relevant to Chapter 2 1c Bn Bn NHAc 1 H NMR (500 MHz, CDCl3) of compound 1c. Appendix 2 – Spectra Relevant to Chapter 2 183 C NMR (126 MHz, CDCl3) of compound 1c. 184 13 Appendix 2 – Spectra Relevant to Chapter 2 185 3a NHAc 1 H NMR (500 MHz, CDCl3) of compound 3a. Appendix 2 – Spectra Relevant to Chapter 2 C NMR (126 MHz, CDCl3) of compound 3a. 186 13 Appendix 2 – Spectra Relevant to Chapter 2 Me 3b NHAc 1 H NMR (500 MHz, CDCl3) of compound 3b. Appendix 2 – Spectra Relevant to Chapter 2 187 C NMR (126 MHz, CDCl3) of compound 3b. 188 13 Appendix 2 – Spectra Relevant to Chapter 2 Me 3c NHAc 1 H NMR (500 MHz, CDCl3) of compound 3c Appendix 2 – Spectra Relevant to Chapter 2 189 C NMR (126 MHz, CDCl3) of compound 3c. 190 13 Appendix 2 – Spectra Relevant to Chapter 2 F 3d NHAc 1 H NMR (500 MHz, CDCl3) of compound 3d. Appendix 2 – Spectra Relevant to Chapter 2 191 C NMR (126 MHz, CDCl3) of compound 3d. 192 13 Appendix 2 – Spectra Relevant to Chapter 2 Cl 3e NHAc 1 H NMR (500 MHz, CDCl3) of compound 3e. Appendix 2 – Spectra Relevant to Chapter 2 193 C NMR (126 MHz, CDCl3) of compound 3e. 194 13 Appendix 2 – Spectra Relevant to Chapter 2 MeOOC 3f NHAc 1 H NMR (500 MHz, CDCl3) of compound 3f. Appendix 2 – Spectra Relevant to Chapter 2 195 C NMR (126 MHz, CDCl3) of compound 3f. 196 13 Appendix 2 – Spectra Relevant to Chapter 2 F 3C 3g NHAc 1 H NMR (500 MHz, CDCl3) of compound 3g. Appendix 2 – Spectra Relevant to Chapter 2 197 C NMR (126 MHz, CDCl3) of compound 3g. 198 13 Appendix 2 – Spectra Relevant to Chapter 2 O2N 3h NHAc 1 H NMR (500 MHz, CDCl3) of compound 3h. Appendix 2 – Spectra Relevant to Chapter 2 199 C NMR (126 MHz, CDCl3) of compound 3h. 200 13 Appendix 2 – Spectra Relevant to Chapter 2 NC 3i NHAc 1 H NMR (500 MHz, CDCl3) of compound 3i. Appendix 2 – Spectra Relevant to Chapter 2 201 C NMR (126 MHz, CDCl3) of compound 3i. 202 13 Appendix 2 – Spectra Relevant to Chapter 2 2a Ac N OAc 1 H NMR (500 MHz, CDCl3) of compound 2a. Appendix 2 – Spectra Relevant to Chapter 2 203 C NMR (126 MHz, CDCl3) of compound 2a. 204 13 Appendix 2 – Spectra Relevant to Chapter 2 Ph Ph Ac 2b N OAc 1 H NMR (500 MHz, DMSO) of compound 2b. Appendix 2 – Spectra Relevant to Chapter 2 205 C NMR (126 MHz, CDCl3) of compound 2b. 206 13 Appendix 2 – Spectra Relevant to Chapter 2 Bn Bn 2c Ac N OAc 1 H NMR (500 MHz, CDCl3) of compound 2c. Appendix 2 – Spectra Relevant to Chapter 2 207 C NMR (126 MHz, CDCl3) of compound 2c. 208 13 Appendix 2 – Spectra Relevant to Chapter 2 Appendix 2 – Spectra Relevant to Chapter 2 209 Appendix 2 – Spectra Relevant to Chapter 2 210 Appendix 2 – Spectra Relevant to Chapter 2 211 Me 4b Ac N OAc 1 H NMR (500 MHz, CDCl3) of compound 4b. Appendix 2 – Spectra Relevant to Chapter 2 212 C NMR (126 MHz, CDCl3) of compound 4b. 213 13 Appendix 2 – Spectra Relevant to Chapter 2 Me 4c N Ac OAc 1 H NMR (500 MHz, CDCl3) of compound 4c. Appendix 2 – Spectra Relevant to Chapter 2 214 C NMR (126 MHz, CDCl3) of compound 4c. 215 13 Appendix 2 – Spectra Relevant to Chapter 2 F Ac 4d N OAc 1 H NMR (500 MHz, CDCl3) of compound 4d. Appendix 2 – Spectra Relevant to Chapter 2 216 C NMR (126 MHz, CDCl3) of compound 4d. 217 13 Appendix 2 – Spectra Relevant to Chapter 2 Cl 4e N Ac OAc 1 H NMR (500 MHz, CDCl3) of compound 4e. Appendix 2 – Spectra Relevant to Chapter 2 218 C NMR (126 MHz, CDCl3) of compound 4e. 219 13 Appendix 2 – Spectra Relevant to Chapter 2 MeOOC 4f Ac N OAc 1 H NMR (500 MHz, CDCl3) of compound 4f. Appendix 2 – Spectra Relevant to Chapter 2 220 C NMR (126 MHz, CDCl3) of compound 4f. 221 13 Appendix 2 – Spectra Relevant to Chapter 2 F 3C 4g Ac N 1 H NMR (500 MHz, CDCl3) of compound 4g. OAc Appendix 2 – Spectra Relevant to Chapter 2 222 C NMR (126 MHz, CDCl3) of compound 4g. 223 13 Appendix 2 – Spectra Relevant to Chapter 2 O2N 4h N Ac OAc 1 H NMR (500 MHz, CDCl3) of compound 4h. Appendix 2 – Spectra Relevant to Chapter 2 224 C NMR (126 MHz, CDCl3) of compound 4h. 225 13 Appendix 2 – Spectra Relevant to Chapter 2 NC 4i N Ac OAc 1 H NMR (500 MHz, CDCl3) of compound 4i. Appendix 2 – Spectra Relevant to Chapter 2 226 C NMR (126 MHz, CDCl3) of compound 4i. 227 13 Appendix 2 – Spectra Relevant to Chapter 2 Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 228 CHAPTER 3 A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization ABSTRACT A new, robust synthesis of gem-dialkyl acyclic diene monomers has been developed. This route is scalable and flexible, allowing for the production of a wide range of diene monomers of different lengths and different gem-dialkyl substitution. The metathesis polymerization of these monomers and the hydrogenation of the resulting polyolefins leads to telechelic gem-dialkyl polyethylenes, which can be used as elastomers in the synthesis of polyurethanes and other block polymers. 3.1 INTRODUCTION Poly(isobutylene) (PIB, Scheme 3.1.1, equation 1) is a homopolymer of isobutylene that has a number of unique properties, among them being low permeability, and excellent chemical compatibility and oxidative stability. PIB is particularly useful as a component of elastomeric polyurethanes as these properties provide superior performance over other polyester and polyether based materials. Poly(ethylene)-co-isobutylene (PEIB, Scheme 3.1.1, equation 2) is a copolymer of ethylene and isobutylene that has shown promise as an alternative to PIB, especially telechelic PEIB. The gem-dimethyl groups along the polymer backbone act as defects to interfere with the crystallization of the polymer, and so amorphous material with low glass transition temperature can be produced that is especially attractive for use in thermoplastic polyurethanes. Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 229 Scheme 3.1.1. Poly(isobutylene) and Poly(ethylene)-co-isobutylene Me Me Me (1) n Me n PIB Me Me Me m H 2C CH2 + n (2) n Me m PEIB PEIB and its analogues have been difficult to produce due to the different reactivities of ethylene and isobutylene. Nevertheless, there are numerous examples of its synthesis using metallocene catalysts, 1 Lewis acid catalysts, 2 and olefin metathesis catalysts. Ring opening metathesis polymerization (ROMP) is well-suited for the production of these types of polymers, and it has been used by Grubbs (Scheme 3.1.2A),3 Buchmeiser (Scheme 3.1.2B),4 and the Hillmyer group (Scheme 3.1.2C) 5 to access PEIB and its related derivatives. Scheme 3.1.2. PEIB Synthesis by Olefin Metathesis Polymerization A. ROMP of 3,3-Dimethylcyclobutene (Grubbs 1995) Me Me ROMP Me Me Me reduction Me n n B. ROMP of 3,3-Dimethylcyclopropene (Buchmeiser 2008) Me Me ROMP Me Me Me reduction Me n n C. ROMP of (Z)-5,5-Dimethylcyclooctene (Hillmyer 2015) Me Me Me Me ROMP OAc AcO AcO n OAc reduction 5 Me Me OH HO n D. ADMET Polymerization of gem-dimethyl diene monomer (Wagener 2005) Me Me x x x = 3, 6, 9 ADMET Me Me x x x = 3, 6, 9 reduction n Me Me x x x = 3, 6, 9 n Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 230 Linear polyolefins with precisely spaced gem-dimethyl groups, analogous to PEIB, have been synthesized using Acyclic Diene Metathesis (ADMET) polymerization, as first reported by Schwendeman and Wagener (Scheme 3.1.2D).6,7 They showed that a higher frequency of gemdimethyl groups in the polymer backbone led to amorphous polymers.6 These “liquid rubbers” were incorporated into telechelic diols using Ru catalysis. Telechelic PEIB has also been synthesized using ring-opening metathesis polymerization (ROMP) from (Z)-5,5-dimethylcyclooct1-ene (5)5 and cis-1,4-diacetoxy-2-butene to afford polyolefins of different molecular weights (Scheme 3.1.2C). Hydrogenation of these polymers afforded the telechelic PEIB, which has been used in PEIBpolyurethane (PU) thermoplastic elastomers, which perform exceptionally well for biomedical applications.8 Due to the amorphous PEIB component, the oxidative, hydrolytic, thermal stability, and the barrier properties of these copolymers are much improved than conventional PUs containing polyesters and polyethers as soft segments.9 The synthesis of any polymer is predicated on the synthetic accessibility of the constituent monomers, which may be challenging to produce. For gem-dialkyl containing monomers, several different routes have previously been developed. Hillmyer and co-workers synthesized (Z)-5,5dimethylcyclooct-1-ene (5) in five steps.5 Starting from inexpensive 1,5-cyclooctadiene (1,5COD), the tert-butyl ester 1 was prepared through Pd-catalyzed alkoxycarbonylation in 84% yield. Methylation with LDA and iodomethane gave α-methyl tert-butyl ester 2 in 92% yield. Then 2 was reduced to the primary alcohol 3 by LiAlH4, and the alcohol was removed by tosylation and the subsequent reduction by LiAlH4, which gave the monomer 5 in 54% yield (Scheme 3.1.3). Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 231 Scheme 3.1.3. Synthesis of 5,5-gem-dimethyl Cyclooctene by Hillmyer O O Ot-Bu PdCl2, PPh3 1. LDA -78 ºC to 0 ºC t-BuOH/toluene CO,90 ºC (84%) 2. MeI, 0 ºC (92%) Me 1 Ot-Bu 2 LiAlH4 0 ºC to 23 ºC (98%) Me HO TsO Me LiAlH4 Me TsCl/DMAP Pyridine/DCM 0 ºC to 23 ºC (99%) THF, reflux (54%) 5 Me 3 4 As an alternative to ROMP, acyclic diene metathesis (ADMET) polymerization has also been used to prepare gem-dimethyl containing polymers. To prepare the monomer for ADMET polymerization, the Wagener group developed a synthetic route to diene monomers with different number of methylene units between the gem-dimethyl branch point and the terminal alkenes.6 Propionic acid was treated with LDA, and alkylated by the addition of two equivalents of an alkenyl bromide to form the carboxylic acid intermediate (7a-c). Reduction of carboxylic acid with LiAlH4 generates the primary alcohol (8a-c), which is deoxygenated through tosylation and reduction with LiAlH4 to give the requisite symmetrical gem-dimethyl substituted diene monomers possessing 3, 6, and 9 methylene “spacer” units (10a-c, Scheme 3.1.4). Scheme 3.1.4. Synthesis of Gem-dimethyl Diene Monomer by Wagener 1. LDA (3 equiv) O Me 2. OH 6 Br (2 equiv) x x = 3, 6, 9 Me CO2H LiAlH4 x x OH Me x x 7a-c 8a-c TsCl 10a, x = 3, 27% overall 10b, x = 6, 10% overall 10c, x = 9, 26% overall Me Me x 10a-c x LiAlH4 OTs Me x 9a-c x Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 232 However, these routes to this type of gem-dimethyl substituted diene monomers required long synthetic sequences and wasteful materials. Due to the need of large quantities of these monomers (kilogram scale) in biomedical device development, we aimed to optimize a synthetic route from inexpensive sources, with fewer steps and operations. In this work, we have developed a new synthetic route to gem-dialkyl diene monomers for ADMET polymerization using the Claisen condensation of an unsaturated ester as the key step. This approach offers several benefits in terms of cost and scalability as well as synthetic flexibility. In particular, the unsaturated ester can be sourced from seed oils enabling a biorenewable route to these polymers. Telechelic polymers with different gem-dialkyl substituted diene monomers were prepared using Rucatalyzed olefin metathesis, and the desired thermal properties (low glass transition temperature) has been accomplished. 3.2 DEVELOPMENT OF SYNTHETIC ROUTES TO GEM-DIALKYL DIENES In Hillmyer’s synthesis of gem-dimethyl cyclooctene monomers, the major disadvantage is the use of wasteful amount of tosyl chloride and dangerous LiAlH4 reductant in order to remove the oxygen atom to furnish the all-carbon structure. Our initial proposal is to directly oxidize 1,5COD to the ketone 11 in modified Wacker oxidation conditions with hydrogen peroxide as oxidant. Geminal-dimethylation through in situ formed TiMe2Cl2 reagent was reported by Reetz and coworkers in 1980,10 and has been applied in the syntheses of a variety of gem-dimethyl containing molecules.11 However, when the ketone 11 was subjected to the reaction conditions, a complex mixture of products was formed; the desired product 5 was never observed. We reasoned a fast transannular reaction caused the disappearance of alkenes after this reaction (Scheme 3.2.1). Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 233 Scheme 3.2.1. Gem-dimethylation of Ketone 11. O Pd(OAc)2 BQ TiCl4, Me2Zn 35% H2O2 30 ºC, 5 d (27%) THF, -50 ºC 11 5 TiCl4 Me2Zn HO Me Me + + After several attempts to convert the ketone 11 with various approaches, we found that αmethylation with 2.5 equivalents KOt-Bu and 5 equivalents iodomethane gave the α,α-gemdimethyl ketone 12 as the major product (dimethyl product 12:monomethyl product 13 > 50:1), which was used as a precursor to the gem-dimethyl cyclooctene monomer upon deoxygenation. Ketone 12 was first reduced to the secondary alcohol 14 by Red-Al, then the alcohol was converted to xanthate 15. Treatment of the crude xanthate 15 with BEt3, H2O and O2 bubbling according to a radical deoxygenation conditions developed by Wood and co-workers,12 finally provided the (Z)4,4-dimethylcyclooct-1-ene (16, Scheme 3.2.2). However, this route still requires 5 steps to synthesize the gem-dimethyl cyclooctene monomer from 1,5-COD, and the scaling up of those reactions could be challenging. Scheme 3.2.2. Synthesis of Gem-dimethylcyclooctene Monomer 16 O Pd(OAc)2 (1 mol%) BQ (2 mol%) O 1. KOt-Bu (2.5 equiv) THF, –40 ºC, 1 h O + 35% H2O2 (1.5 equiv) 30 ºC, 5 d (27%) 2. MeI (5 equiv) THF, 23 ºC, 12 h (42%) 11 13 12 1. Red-Al (1.2 equiv) THF –78 ºC – 23 ºC (12:13 > 50:1) S 3. BEt3 (5 equiv) H2O (5 equiv) O2 (0.8 equiv) 16 benzene (0.03 M) 23 ºC, 24 h (72% over 3 steps) O SMe 15 OH 2. NaH (4 equiv) CS2 (10 equiv) MeI (10 equiv) 14 Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 234 In light of these synthetic difficulties, we decided to focus on the preparation of linear diene monomers instead of cyclooctene-based monomers. We were initially drawn to the Claisen condensation as a key step. The Claisen condensation reaction has been an important synthetic reaction for more than 100 years.13 The b-ketoester intermediate from the Claisen condensation can be transformed into a symmetric linear ketone by hydrolysis and decarboxylation, and so the use of unsaturated esters provides linear dienes containing ketone groups, which are versatile intermediates upon further synthetic manipulations. Watson and Wagener used this transformation to synthesize diene monomers en route to ethylene/CO copolymers.14 These long chain ketones provided a convenient starting point for our synthesis. Importantly, established ethenolysis chemistry can provide methyl 9-decenoate (17) from methyl oleate from plant oils,15 providing an opportunity for a biorenewable synthesis of the ketone 18, which can be used to synthesize the subsequent gem-dimethyl containing diene monomers such as 21 (Scheme 3.2.3). Scheme 3.2.3. Claisen Condensation Route O Me 7 7 methyl oleate ethenolysis OMe O 7 17 O OMe 7 Me 7 18 Me 7 7 21 There are several reports of the direct transformation of ketones to the gem-dimethyl moiety. Unfortunately, TiCl2Me2,16 AlMe3,17 and AlMe3 in the presence of Me3SiOTf18 were all unsuccessful for the direct transformation of 18 to the desired monomer 21. Instead, either olefin polymerization by TiCl2Me2 or the addition of a methyl nucleophile to the ketone by AlMe3 was observed. The two methyl groups were installed sequentially: the first by a Grignard addition to 18, and the second by SN1 reaction of a subsequent tertiary alkyl halide with a nucleophilic alkylating reagent (Scheme 3.2.4). Precedent for the use of both alkyl zinc10 and alkyl aluminum19 nucleophiles to accomplish this transformation prompted us to explore these options. The addition of methylmagnesiumbromide to 18 proceeded in high yield and the resulting tertiary alcohol (19) Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 235 was easily transformed into the tertiary chloride 20 using SOCl2. Substitution of 20 using AlMe3 completed the sequence. The transformation of tertiary alcohol 19 to 21 can be achieved in a single pot procedure.20 Me2Zn was also a viable nucleophile, but AlMe3 gave higher yields and is more economically viable. Scheme 3.2.4. Synthesis of Gem-dimethyl Diene Monomer 21 1. NaH 2. NaOH O OMe 7 MeMgBr 7 7 Me THF, 0 °C Me OH 7 7 SOCl2 Me Cl 7 OH 7 18 (90%) 17 19 O 7 19 AlMe3 Me Me 7 7 7 20 21 (83% over 3 steps) Following this success, several other linear diene monomers were prepared from ketones of varying lengths. Ethyl pent-4-enoate (22) was easily converted to nona-1,8-dien-5-one (23)21 and the subsequent 9-carbon gem-dimethyl monomer 24. Alkylation of acetone dimethylhydrazone 25 with 5-bromo-1-pentene provided the medium length ketone 26 in good yield (Scheme 3.2.5), which was readily transformed into the 13-carbon monomer 27 in 58% yield over three steps. Longer linear diene monomers were also synthesized from long chain unsaturated esters. Ethyl 10-undecenoate 28, a precursor to Nylon,22 was readily transformed into the ketone 29, which was used to make the 21-carbon monomer 30 (Scheme 3.2.5). Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 236 Scheme 3.2.5. The Synthesis of Gem-dimethyl Diene Monomers with Different Lengths 1. NaH 2. NaOH O 2 OEt 2 22 Me 1. n-BuLi Me 2. HCl (aq.), CH2Cl2 4 4 1. NaOEt 2. NaOH O OEt 28 1. MeMgBr 2. SOCl2 3. AlMe3 O 8 8 29 (63%) Me 2 2 Me Me 4 4 27 (58%) 26 (90%) 25 8 O Me 24 (83%) 1. MeMgBr 2. SOCl2 3. AlMe3 Br THF, 0 ºC N Me 2 23 (75%) Me N 1. MeMgBr 2. SOCl2 3. AlMe3 O Me Me 8 8 30 (72%) The gem-dialkyl groups can easily be varied by using different Grignard and alkylzinc reagents or alkylaluminum reagents to provide both homo- and heterodialkyl substitution, as demonstrated by the preparation of 32, 33, 34, and 35 (Scheme 3.2.6). This route tolerates both terminal and internal olefins with no detectable olefin isomerization, as demonstrated by the synthesis of 36 from 31. Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 237 Scheme 3.2.6. Diene Monomers with Varying Alkyl Substitutions 1. MeMgBr 2. PBr3 3. Et2Zn O 2 2 23 1. EtMgBr 2. SOCl2 3. AlEt3 2 8 8 1. n-OctMgBr 2. SOCl2 3. AlEt3 8 Et 8 8 35 (71%) O 3.3 8 n-Oct 29 Me 31 Et 34 (60%) O 2 2 n-Bu 29 2 Et 2 1. n-BuMgBr 2. SOCl2 3. AlEt3 Me 2 33 (63%) O 8 2 Et 23 8 Me 32 (61%) O 2 Et 1. MeMgBr 2. SOCl2 3. AlMe3 Me Me 2 2 Me Me 36 (71%) ADMET POLYMERIZATION OF GEM-DIALKYL DIENES The two major types of metathesis polymerizations include ROMP and ADMET polymerization. ROMP is a chain-growth polymerization, whereas ADMET is a step-growth polymerization. The mechanism for ADMET polymerization is shown in Scheme 3.3.1. The olefin initially reacts with the metal alkylidene to form a metallacyclobutane intermediate by reversible [2+2] cycloaddition. Subsequent cycloreversion gives the growing polymer and a new alkylidene species, which undergoes further coordination, cycloaddition and cycloreversion. The productive pathway in ADMET polymerization of terminal olefins features the generation of the methylidene carbene catalyst and the condensate (e.g. ethylene). Note that each step in the mechanism is completely reversible. Therefore, the constant removal of condensate from the reaction mixture Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 238 is required to drive the equilibrium towards chain growth. ADMET polymerization was firstly observed in the late 1980s by Wagener and Lindmark-Hamburg23 while studying the condensation of unconjugated α,ω-dienes with the WCl6/EtAlCl2 catalyst system. The development of welldefined ruthenium-based catalyst allowed ADMET to become a feasible and useful method of polymerization.24 Scheme 3.3.1. Mechanism of ADMET Polymerization R’ [M] + [M] R’ R R [M] C 2H 4 R R Removal of ethylene drives the reaction [M] [M] ADMET R R R [M] R CH2 R R Represents a growing polymer chain The ADMET polymerization25 of 21, 24, 27, and 30 using the 2nd generation Ru catalyst (G2) produced the desired polyolefins with targeted molecular weights of 2000 g/mol. The polymerization of 24 was complicated by the formation of both polyolefin poly-24 and the 7membered cyclic olefin 37 (Scheme 3.3.2). ADMET polymerization is well-known to produce cyclic oligomers 26 as the reaction proceeds, but the gem-dimethyl substitution results in a pronounced Thorpe-Ingold effect27 that favors cyclization. The cyclic olefin 37 also possesses low ring-strain, and did not fully incorporate into the growing polymer chain; prolonged reaction times (up to 5 days) did not result in full consumption of 37 (equilibrium ratios of ~3:1 poly-24:37 were Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 239 observed, in both the ADMET polymerization of 24 and 36). However, once the desired molecular weight is achieved, 37 can easily be removed in vacuo and recycled in a subsequent ring-opening polymerization. The ROMP of 37 afforded the same distribution of poly-24 and 37 as was achieved in the ADMET of 24. Scheme 3.3.2. ADMET Polymerization of Short Chain Monomer 24 Me Me Me G2 (0.5 mol%) 2 50 °C, 60 mTorr 2 N Me N Me Me Cl + 2 2 Ph Cl poly-24 24 Ru PCy3 37 G2 The longer diene monomers (21, 27 and 30) did not suffer from the competing ring-closing metathesis and readily polymerized using G2 under static vacuum.30 We used the “polymerization/depolymerization” method developed by Wagener7 to produce the target telechelic diols. The chain transfer agent (CTA) 38 was added to the polyolefin mixture after sufficient reaction time to cleave the longer polyolefins and install the protected telechelic endgroups. Hydrogenation of the unsaturated polymers was accomplished using Pd/C under H2 and the resulting telechelic PEIB derivatives were isolated in high yield after filtration and concentration in vacuo (Scheme 3.3.3). Scheme 3.3.3. Synthesis of Gem-dimethyl Substituted Telechelic Polymers 1. G2 (0.5 mol%) CH2Cl2, static vacuum, 60 ºC Me Me x x 2. CbzO x = 2, 24 x = 4, 27 x = 7, 21 x = 8, 30 OCbz toluene, 60 ºC 38 x x x x = 2, poly-24a x = 4, poly-27a x = 7, poly-21a x = 8, poly-30a n OCbz toluene, 23 ºC x OCbz n x = 2, poly-24a x = 4, poly-27a x = 7, poly-21a x = 8, poly-30a Pd/C (10 mol%) H2 (1 atm) Me Me CbzO Me Me CbzO Me Me HO x x n x = 2, poly-24b x = 4, poly-27b x = 7, poly-21b x = 8, poly-30b OH Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 240 Differential scanning calorimetry (DSC) was used to determine the effects of substitution and molecular weight on the thermal behavior for the series of polymers (see DSC traces in Figure 3.5.1). The measured Tg values (Table 3.3.1) were in agreement with those for the PEIB analogues prepared by both Wagener6,7 and Hillmyer5, and a higher density of substitution (e.g. poly-24b) resulted in amorphous materials without melting points. Polymers derived from the longer monomers 21 and 30 displayed broad, multimodal melting points indicating the semicrystalline nature of the longer saturated segments of the polymer, as described by Wagener.7 Table 3.3.1. Molecular Weight, Polydistribution, and Thermal Properties of Telechelic Polymers Polymer Poly-21b Poly-24b Poly-27b Poly-30b-1 Poly-30b-2 Poly-30b-3 Poly-30b-4 Poly-32b Poly-34b Mn a 4200 2200 2000 3100 6300 17200 28700 3200 6800 PDIb 1.4 1.4 1.5 1.5 1.1 1.5 1.7 1.1 1.4 Tg No Tg observed –60 °C –60 °C –50 °C –60 °C –26 °C –30 °C –52 °C –59 °C Tm –50 – 8 °Cc –d –d –24 – 0 °Cc –14 – 10 °Cc –12 – 50 °Cc 30 °C –d –18 °Cc a Determined by 1H NMR b PDI = M /M (determined by GPC) c broad melting point d no melting point observed w n 3.4 CONCLUSIONS We have described a new synthetic route to gem-dialkyl diene monomers for ADMET polymerization. This route enables the use of unsaturated fatty acid esters as a raw material source, offers several benefits in terms of cost and scalability as well as synthetic flexibility. Several different diene monomers have been prepared and polymerized using Ru-catalyzed ADMET polymerization to access short (Mn ~2–7 kDa) amorphous telechelic polymers. These telechelic polymers are desirable as the soft segment of polyurethane elastomers for biomedical applications, and this work demonstrates a cost-effective and convenient route for their preparation. Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 241 3.5 EXPERIMENTAL METHODS AND ANALYTICAL DATA 3.5.1 Materials and Methods Unless otherwise stated, all reactions were performed under argon atmosphere using oven dried glassware. Anhydrous solvents were dried using activated alumina and stored in Schlenk flasks over activated 3 Å molecular sieves. All reagents were purchased from commercial suppliers and used as received. NMR spectra were collected using Varian 500 or 600 MHz spectrometers or a Bruker 400 MHz spectrometer. Mass spectrometry was performed at the Caltech Mass spectrometry facility. Differential Scanning Calorimetry was performed using a Mettler Toledo DSC 3+ Star System. Ethyl-(E)-hex-4-enoate,28 and nona-1,8-dien-5-one21 were synthesized according to literature precedent. 3.5.2 Experimental Procedures O Pd(OAc)2 (1 mol%) BQ (2 mol%) 35% H2O2 (1.5 equiv) 30 ºC, 5 d (27%) 11 (Z)-cyclooct-4-en-1-one (11): According to a known procedure, 29 to a solution of hydrogen peroxide (35% in water, 5 mL, 60 mmol) was added to a mixture of palladium acetate (90 mg, 0.4 mmol), benzoquinone (87 mg, 0.8 mmol) and 1,5-cyclooctadiene (5.4 mL, 40 mmol). The mixture was stirred for 5 days at 30° C. The mixture was poured into Et2O (100 mL) and water was added (100 mL) then the mixture was slowly basified with 1M NaOH solution while cooling with ice. The layers were separated and the aqueous layer was extracted with Et2O (2 × 100 mL). The combined organic layers were twice washed with 1M NaOH and dried over Na2SO4. Distillation under reduced pressure afforded ketone 11 (1.36 g, 27% yield) as a colorless oil. Spectral data matched those reported in the literature.30 Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization O 242 O 1. KOt-Bu (2.5 equiv) THF, –40 ºC, 1 h O + 2. MeI (5 equiv) THF, 23 ºC, 12 h (42%) 11 13 12 (12:13 > 50:1) (Z)-2,2-dimethylcyclooct-4-en-1-one (12): To a stirred solution of KOt-Bu (5.61 g, 2.5 equiv) in THF (100 mL) was added ketone 11 (2.48 g, 20.0 mmol) in THF (20 mL). The solution was stirred for 1 hour at –40 ºC, and MeI (6.3 mL, 5.0 equiv) was added. The reaction mixture was slowly warmed to 23 ºC and stirring was continues for 20 hours. Water (50 mL) was then added and the aqueous phase was extracted by Et2O (3 × 50 mL). GC analysis showed > 50:1 ratio of products 12 and 13, and pure compound 12 can be isolated by column chromatography (SiO2, 10:1 pentane/Et2O) as a colorless liquid (1.29 g, 42%). TLC (10:1 pentane/Et2O): Rf= 0.4 (KMnO4). 1 H NMR (400 MHz, CDCl3) δ 5.69 – 5.56 (m, 1H), 2.45 (dd, J = 8.0, 4.0 Hz, 1H), 2.25 (d, J = 7.2 Hz, 1H), 2.15 – 2.07 (m, 1H), 1.64 – 1.54 (m, 1H), 1.06 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 217.5, 131.9, 129.2, 52.6, 37.8, 36.5, 27.3, 26.3, 23.7. HRMS (FAB+, m/z): calc’d for C10H17O [M+H]+ 153.1279, found: 153.1276. O OH 1. Red-Al (1.2 equiv) THF –78 ºC – 23 ºC 12 S 2. NaH (4 equiv) CS2 (10 equiv) MeI (10 equiv) O SMe benzene (0.03 M) 23 ºC, 24 h (72% over 3 steps) THF 14 3. BEt3 (5 equiv) H2O (5 equiv) O2 (0.8 equiv) 15 16 (Z)-4,4-dimethylcyclooct-1-ene (16): Ketone 12 (2.10 g, 13.8 mmol) in THF (50 mL) was added to a solution of Red-Al (16.6 mmol, 1.2 equiv) in THF (40 mL) dropwise at –78 °C under argon atmosphere. After stirring at the same temperature for 3 hours, the solution was quenched with 0.1 M HCl (100 mL), and the aqueous layer was extracted with EtOAc (3 × 100 mL). The combined organic layers were then washed with saturated aqueous NaHCO3 (50 mL) and brine Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 243 (50 mL), dried over Na2SO4, and concentrated under reduced pressure. The residue was filtered through a plug of silica with Et2O wash. The crude alcohol product 14 was obtained as a colorless oil (2.23 g), which was used in the next step without further purification. To a suspension of NaH (60% in mineral oil, 2.24 g, 96 mmol, 4.0 equiv) in THF (100 mL) at 0 °C was added alcohol 14 (2.23 g, 14 mmol, 1.0 equiv) in THF (20 mL). The mixture was stirred for 30 min, at which point CS2 (8.4 mL, 140 mmol, 10.0 equiv) was added. The mixture was stirred for an additional 30 min, at which point iodomethane (8.7 mL, 140 mmol, 10.0 equiv) was added. The reaction mixture was allowed to warm to room temperature for 3 hours before being quenched with MeOH (50 mL) and evaporated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with water (50 mL) and brine (50 mL). The organic layer was dried over Na2SO4 and concentrated. Column chromatography (SiO2, hexanes) afforded crude xanthate 15 (4.42 g) as a yellow oil. Then, methyl xanthate 15 (733 mg, 3 mmol, 1.0 equiv) was dissolved in a flame-dried 500 mL flask with benzene (100 mL), combined with H2O (0.27 mL, 15 mmol, 5.0 equiv) and allowed to stir for 1 h. Argon gas was then bubbled through the solution for a period of 1 h, after which, a solution of BEt3 (1.0 M in THF, 15 mL, 15 mmol, 5.0 equiv) was added via syringe pump over 1 h. On completion of BEt3 addition, dry oxygen (54 mL, 2.4 mmol O2, 0.8 equiv) was introduced via syringe pump at a rate of 1.2 ml/hr through a stainless steel cannula positioned beneath the reaction surface. Upon completion of air addition, hydrogen peroxide (30 % in water, 50 mL) and sodium hydroxide (3.0 M in water, 50 mL) were introduced simultaneously into the reaction mixture (Caution: reaction is exothermic). After stirring for 10 min, the solution was diluted with brine (100 mL), and the aqueous layer was extracted with EtOAc (3 × 100 mL). Combined organic portions were dried over anhydrous sodium sulfate, filtered, and concentrated. Distillation under reduced pressure afforded 16 as a colorless oil (297 mg, 72%). Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 244 TLC (pentane): Rf= 0.9 (KMnO4). 1 H NMR (400 MHz, CDCl3) δ 5.85 – 5.48 (m, 2H), 2.17 – 2.04 (m, 2H), 1.92 (d, J = 8.2 Hz, 2H), 1.49 (dd, J = 6.0, 3.2 Hz, 4H), 1.33 – 1.23 (m, 2H), 0.89 (s, 6H). 13 C NMR (126 MHz, CDCl3) δ 131.4, 128.9, 39.7, 37.5, 36.1, 30.3, 29.0, 26.8, 23.5. HRMS (EI+, m/z): calc’d for C10H18 [M]+• 138.1409, found: 138.1408. O 7 NaH OMe 17 110 ºC PhMe O 7 NaOH 6 CO2Et 18a EtOHreflux O 7 7 18 (90%) Nonadeca-1,18-dien-10-one (18): A 100 mL three-necked round bottom flask was fitted with a dropping funnel and two ground glass stoppers and charged with a magnetic stirbar, NaH (60 wt% in mineral oil, 3.7 g, 92 mmol, 1.2 equiv), and toluene (25 mL). This suspension was heated to 100 °C and a solution of methyl 9-decenoate (14.3 g, 80 mmol, 1 equiv) in toluene (10 mL) was added dropwise over the course of 30 min. The reaction mixture was then heated to 110 °C with stirring for 24 h, cooled to ambient temperature and quenched by the slow addition of MeOH. The solvent was removed in vacuo and the residue was suspended in EtOH (50 mL) and water (25 mL). NaOH (1.6 g, 1.0 equiv) was added and the reaction mixture was heated to reflux for 2 h. After cooling to ambient temperature, the reaction mixture was extracted with Et2O (3 × 50 mL) and the combined organic layers were washed with water (3 × 50 mL), brine (30 mL), dried over anhydrous MgSO4, filtered, and concentrated. Crystallization with MeOH afforded 18 as a white solid (10.2 g, 90% yield over two steps) Spectral data matched those reported in the literature.31 Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 1. n-BuLi Me Me N Me Me 25 Br O THF, 0 ºC N 245 2. HCl (aq.), CH2Cl2 4 4 26 (90%) Trideca-1,12-dien-7-one (26): To a stirred solution of hydrazone 25 (4.0 g, 40 mmol, 1.0 equiv) in THF (80 mL) was added n-butyl lithium solution (16.8 mL, 2.5 M solution in hexanes, 42 mmol, 1.05 equiv). After stirring 30 minutes at 0 ºC, 5-bromo-1-pentene (4.8 mL, 40 mmol, 1.0 equiv) was added and the reaction mixture was stirred for 1 hour at 23 ºC. Then the reaction mixture was cooled to 0 ºC again and n-butyl lithium solution (16.8 mL, 2.5 M solution in hexanes, 42 mmol, 1.05 equiv) was added. After stirring 30 minutes at 0 ºC, 5-bromo-1-pentene (4.8 mL, 40 mmol, 1.0 equiv) was added again and the reaction mixture was stirred for 2 hours at 23 ºC before quenched by saturated NH4Cl solution (100 mL). The aqueous layer was extracted with Et2O (2 × 100 mL) and the combined organic phases were washed with brine (100 mL), dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The crude reaction mixture was dissolved in CH2Cl2 (40 mL), and HCl solution (16 mL, 3.0 M) was added. After 12 h, the phases were separated and the aqueous phase was extracted with CH2Cl2 (2 × 50 mL). The combined organic phases are washed with saturated NaHCO3 solution (100 mL). Column chromatography (SiO2, 10:1 hexanes/EtOAc) gave 26 as a colorless oil (7.0 g, 90% yield). 1 H NMR (400 MHz, CDCl3): δ 5.66 (ddt, J = 16.9, 10.2, 6.5 Hz, 2H), 4.94 – 4.77 (m, 4H), 2.32 – 2.23 (m, 4H), 1.97 – 1.88 (m, 4H), 1.46 (dt, J = 15.2, 7.3 Hz, 4H), 1.30 – 1.20 (m, 4H). 13 C NMR (101 MHz, CDCl3): δ 211.2, 138.5, 114.6, 42.6, 33.6, 28.5, 23.3. HRMS (EI+, m/z): calc’d for C13H22O [M]+• 194.1671, found: 194.1646. Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization O 8 NaOEt OEt 100 ºC 2 torr 28 O 8 246 O NaOH 7 CO2Et 8 EtOHreflux 29a 8 29 (63%) Henicosa-1,20-dien-11-one (29): A 500 mL flamed-dried round bottom flask charged with ethyl 10-undecenoate (21.0 g, 100 mmol, 1.0 equiv) and sodium ethoxide (3.4 g, 50 mmol, 0.5 equiv) was equipped with a reflux condenser and a vacuum adapter. The reaction was stirred at 100 ºC under a dynamic vacuum (2 torr) for 12 hours to remove the ethanol produced. After the reaction was cooled to 23 ºC, the crude b-keto ester 29a was dissolved in ethanol (50 mL) and 2 M NaOH solution (20 mL, 1.0 equiv) was added. The reaction mixture was warmed to reflux for 2 hours and cooled to 23 ºC. A white solid precipitated and was collected by filtration and recrystallized from refluxing methanol, to give ketone 29 as a white solid (7.47 g, 63% yield over two steps). 1 H NMR (400 MHz, CDCl3): δ 5.73 (ddt, J = 16.9, 10.1, 6.6 Hz, 2H), 4.97 – 4.82 (m, 4H), 2.31 (t, J = 7.5 Hz, 4H), 2.01 – 1.91 (m, 4H), 1.49 (q, J = 7.0 Hz, 4H), 1.34 – 1.25 (m, 4H), 1.24 – 1.17 (m, 16H). 13 C NMR (101 MHz, CDCl3): δ 211.7, 139.2, 114.2, 42.8, 33.8, 29.4, 29.3, 29.3, 29.1, 28.9, 23.9. HRMS (EI+, m/z): calc’d for C21H38O [M]+• 306.2923, found: 306.2927. 1. TiCl4, NBu3 toluene, -78 ºC 2. NaOH EtOH, 80 ºC O Me OEt O Me Me 31 An oven-dried 500 mL three-necked round bottom flask was equipped with a magnetic stirbar and fitted with two rubber septa and a ground glass flow adaptor to introduce inert atmosphere. This flask was charged with (E)-hex-4-enoate (20 g, 140 mmol) and NBu3 (17 mL, Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 247 140 mmol) via syringe. Anhydrous toluene (350 mL) was added by cannula, and the reaction mixture was cooled to –78 °C. TiCl4 (18.4 mL, 168 mmol) was added dropwise via syringe over twenty minutes, causing the reaction mixture to become deep red in color. The reaction mixture was stirred with warming to ambient temperature for 10 h, and saturated aqueous NaHCO3 was carefully added to quench the reaction. The organic layer was separated, the aqueous layer was extracted with Et2O (3 × 25 mL), and the combined organic layers were washed with water (20 mL), brine (2 × 20 mL), dried over MgSO4, and concentrated to a clear, yellow oil. The yellow oil was dissolved in EtOH (200 mL) and water (50 mL) and NaOH pellets were added (3 g). The reaction mixture was heated to 85 °C and monitored by TLC (5% Et2O in hexanes) until the starting material was fully consumed. The reaction mixture was concentrated and extracted with Et2O (3 × 50 mL), and the combined organic layers were washed with water (3 × 25 mL) and brine (25 mL), dried over MgSO4, filtered and concentrated. The product 31 was purified by column chromatography (SiO2, 5% Et2O in hexanes) to yield a clear, pale yellow oil (11 g, 60 mmol, 85 %) 1 H NMR (600 MHz, CDCl3) δ 5.49 – 5.34 (m, 4H), 2.43 (t, J = 7.4 Hz, 4H), 2.28 – 2.19 (m, 4H), 1.65 – 1.59 (m, 6H). 13 C NMR (101 MHz, CDCl3) δ 210.4, 129.7, 126.0, 42.8, 26.9, 18.0. HRMS (EI+) calc’d for C11H18O [M]+• 166.1358; found 166.1346 Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 248 O Ru-2 (0.1 mol%) OH THF, 35 ºC BnO HO OH 38a Cl pyridine, DMAP CH2Cl2, 0 ºC to 23 ºC CbzO OCbz 38 iPr N N iPr O O N Ru O O iPr Ru-2 (Z)-dibenzyl oct-4-ene-1,8-diyl bis(carbonate) (38): In a nitrogen-filled glovebox, 4-penten-1ol (1.72 g, 20 mmol) was dissolved in 6 mL THF in a 20 mL vial equipped with a stir bar, and Ru-2 (13.5 mg, 0.1 mol%) was added. The vial was placed on a 35 ºC stir plate without capping and stirring was continued for 4 hours. At that time the reaction progress was monitored by GC analysis to ensure full conversion, and the vial was brought outside the glovebox and the reaction mixture was quenched with a few drops of ethyl vinyl ether. Column chromatography (SiO2, 2:1 hexanes/EtOAc) gave 38a as a colorless oil (1.06 g, 74% yield). To the diol 38a (1.06 g, 7.35 mmol, 1.0 equiv) in 30 mL CH2Cl2 , pyridine (3.0 mL, 36.75 mmol, 5.0 equiv) and DMAP (180 mg, 1.47 mmol, 0.2 equiv) was added sequentially at 0 ºC. Then benzyl chloroformate (4.2 mL, 29.4 mmol, 4.0 equiv) was added dropwisely. The mixture was left to stir at 23 ºC for overnight before it was quenched with 1 M HCl (30 mL). The aqueous phase was extracted by Et2O three times. The combined organic phases were dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. Column chromatography (SiO2, 9:1 hexanes/EtOAc) gave 38 as a colorless oil (2.52 g, 83% yield). 1 H NMR (400 MHz, CDCl3) δ 7.43 – 7.30 (m, 10H), 5.38 (ddd, J = 5.6, 4.4, 1.1 Hz, 2H), 5.15 (s, 4H), 4.13 (t, J = 6.6 Hz, 4H), 2.18 – 2.03 (m, 4H), 1.72 (dq, J = 8.2, 6.7 Hz, 4H). 13 C NMR (101 MHz, CDCl3) δ 155.3, 135.4, 129.5, 128.7, 128.6, 128.5, 69.6, 67.7, 28.6, 23.4. Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 249 HRMS (FAB+, m/z): calc’d for C24H29O6 [M+H]+ 413.1964, found: 413.1961. General Procedure A for gem-dimethylation of ketones: O x MeMgBr x Me x OH SOCl2 x x = 2, 23 x = 4, 26 x = 7, 18 x = 8, 29 Me x Cl AlMe3 x Me Me x x x = 2, 24 x = 4, 27 x = 7, 21 x = 8, 30 In a flame-dried round-bottom flask, ketone (1.0 equiv) was dissolved in THF and the reaction mixture was cooled to 0 ºC. Methylmagnesium bromide solution (3.0 M solution in diethyl ether, 1.5 equiv) was added dropwise, and the reaction mixture was slowly warmed to 23 ºC. After 1 hour, the reaction mixture was cooled to 0 ºC, and quenched by saturated NH4Cl solution. The aqueous phase was extracted with Et2O twice, dried over anhydrous MgSO4, filtered over a short silica plug, and concentrated under reduced pressure. The crude tertiary alcohol was transferred into a Schlenk flask (with one side arm fitted with a glass stopcock) with dry CH2Cl2. The residual solvent was removed by connecting the side arm to vacuum. The flask was back-filled with argon and cooled to 0 ºC, and then SOCl2 (2.5 equiv) was added slowly. A minimal amount of CH2Cl2 can be added to aid with stirring. The reaction mixture was stirred at 0 ºC for 1 hour, and the reaction progress can be monitored by TLC (using Al2O3 plate). The side arm of the Schlenk flask was reconnected to vacuum and excess SOCl2 was removed at 0 ºC. Then the crude tertiary chloride product was dissolved in CH2Cl2 (0.3 M) and the reaction mixture was cooled to –78 ºC. Trimethylaluminum (2.0 M solution in hexanes, 2.0 equiv) was added dropwise. The reaction mixture was slowly warmed to 23 ºC and stirred for 4 Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 250 hours and then quenched with aqueous HCl solution (1.0 M) at 0 ºC. The aqueous layer was extracted with CH2Cl2, dried over anhydrous MgSO4, filtered, and concentrated under reduced pressure. The gem-dimethylation products were purified by column chromatography (SiO2, 100% hexanes) or distillation. Me Me 21 10,10-dimethylnonadeca-1,18-diene (21): Prepared according to General Procedure A from ketone 18 (10.2 g, 37 mmol) as a colorless liquid (9.1 g, 83% yield). 1 H NMR (600 MHz, CDCl3) δ 5.82 (ddt, J = 16.9, 10.1, 6.7 Hz, 2H), 5.00 (dq, J = 17.1, 1.7 Hz, 2H), 4.93 (ddt, J = 10.2, 2.4, 1.2 Hz, 2H), 2.07 – 2.00 (m, 4H), 1.42 – 1.09 (m, 24H), 0.81 (s, 6H). 13 C NMR (126 MHz, CDCl3) δ 139.3, 114.1, 42.0, 33.8, 32.6, 30.6, 29.6, 29.2, 29.0, 27.3, 24.0. HRMS (EI+, m/z): calc’d for C21H40 [M]+• 292.3130, found: 292.3144. Me Me 24 5,5-dimethylnona-1,8-diene (24): Prepared according to General Procedure A from ketone 23 (25 g, 181 mmol) as a colorless liquid (13 g, 58% yield). 1 H NMR (400 MHz, CDCl3) δ 5.81 (ddt, J = 16.9, 10.2, 6.6 Hz, 2H), 4.99 (dq, J = 17.1, 1.7 Hz, 2H), 4.94 – 4.86 (m, 2H), 2.02 – 1.93 (m, 4H), 1.30 – 1.22 (m, 4H), 0.86 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 139.80, 113.77, 41.06, 32.65, 28.58, 27.08. HRMS (EI+, m/z): calc’d for C11H20 [M]+• 152.1565, found: 152.1561. Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization Me 251 Me 27 7,7-dimethyltrideca-1,12-diene (27): Prepared according to General Procedure A from ketone 26 (1.94 g, 10 mmol) as a colorless liquid (1.2 g, 58% yield). 1 H NMR (400 MHz, CDCl3) δ 5.75 (ddt, J = 16.9, 10.1, 6.7 Hz, 2H), 4.98 – 4.81 (m, 4H), 2.03 – 1.94 (m, 4H), 1.32 – 1.23 (m, 4H), 1.19 – 1.05 (m, 8H), 0.75 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 139.3, 114.1, 41.8, 33.9, 32.7, 29.9, 27.3, 23.5. HRMS (EI+, m/z): calc’d for C15H28 [M]+• 208.2191, found: 208.2177. Me Me 30 11,11-dimethylhenicosa-1,20-diene (30): Prepared according to General Procedure A from ketone 29 (7.47 g, 24.4 mmol) as a colorless liquid (5.66 g, 72% yield). 1 H NMR (400 MHz, CDCl3) δ 5.84 (ddt, J = 16.9, 10.2, 6.7 Hz, 2H), 5.08 – 4.89 (m, 4H), 2.14 – 2.00 (m, 4H), 1.40 (q, J = 6.9 Hz, 4H), 1.35 – 1.12 (m, 24H), 0.84 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 139.4, 114.2, 42.1, 34.0, 32.7, 30.8, 29.8, 29.7, 29.3, 29.1, 27.5, 24.2. HRMS (EI+, m/z): calc’d for C23H44 [M]+• 320.3443, found: 320.3425. Et Et 33 5,5-diethylnona-1,8-diene (33): Prepared according to modified General Procedure A from ketone 23 (276 mg, 2.0 mmol), EtMgBr, and AlEt3 to afford 33 as a clear, colorless oil (230 mg, 63% yield). Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 1 252 H NMR (600 MHz, CDCl3) δ 5.82 (ddt, J = 16.9, 10.2, 6.6 Hz, 2H), 5.00 (dq, J = 17.1, 1.6 Hz, 2H), 4.91 (ddt, J = 10.0, 2.3, 1.2 Hz, 2H), 1.96 – 1.87 (m, 4H), 1.26 – 1.19 (m, 8H), 0.75 (t, J = 7.5, 1.0 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 139.9, 113.9, 37.3, 34.9, 28.0, 27.7, 7.6. HRMS (EI+) calc’d for C13H24 [M]+• 180.1878; found 180.1894. n-Bu Et 34 11-butyl-11-ethylhenicosa-1,20-diene (34): Prepared according to modified General Procedure A from ketone 29 (918 mg, 3 mmol) with n-butylmagnesium chloride solution (2.0 M solution in diethyl ether, 1.5 equiv) and triethylaluminum (2.0 equiv). 34 was obtained as a colorless liquid (680 mg, 60% yield). 1 H NMR (400 MHz, CDCl3) δ 5.74 (ddt, J = 17.0, 10.2, 6.7 Hz, 2H), 4.96 – 4.82 (m, 4H), 2.01 – 1.92 (m, 4H), 1.35 – 1.25 (m, 4H), 1.25 – 1.11 (m, 24H), 1.07 – 0.99 (m, 8H), 0.82 (td, J = 7.2, 2.0 Hz, 3H), 0.64 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 139.4, 114.2, 37.5, 37.1, 36.2, 35.9, 33.9, 33.9, 33.5, 30.8, 30.3, 29.8, 29.7, 29.7, 29.3, 29.1, 28.7, 26.8, 25.4, 23.8, 23.3, 23.1, 14.4, 14.4, 7.7. HRMS (EI+, m/z): calc’d for C27H52 [M]+• 376.4069, found: 376.4120. Et n-Oct 35 11-ethyl-11-octylhenicosa-1,20-diene (35): Prepared according to modified General Procedure A from ketone 29 (153 mg, 0.5 mmol) with n-octylmagnesium chloride solution (2.0 M solution in Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 253 THF, 1.5 equiv) and triethylaluminum (2.0 equiv). 35 was obtained as a colorless liquid (154 mg, 71% yield). 1 H NMR (400 MHz, CDCl3) δ 5.74 (ddt, J = 16.9, 10.2, 6.7 Hz, 2H), 4.99 – 4.80 (m, 4H), 2.04 – 1.90 (m, 4H), 1.34 – 1.26 (m, 4H), 1.25 – 1.10 (m, 34H), 1.05 – 1.00 (m, 6H), 0.83 – 0.78 (m, 3H), 0.64 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 139.4, 114.2, 37.5, 37.2, 36.2, 34.0, 33.8, 32.1, 30.8, 30.8, 30.5, 30.3, 30.3, 29.8, 29.8, 29.8, 29.7, 29.7, 29.6, 29.5, 29.3, 29.1, 28.7, 26.8, 23.1, 22.9, 14.3, 7.7. HRMS (EI+, m/z): calc’d for C31H60 [M]+• 432.4695, found: 432.4714. Me Me Me 36 Me (2E,9E)-6,6-dimethylundeca-2,9-diene (36): Prepared according to general procedure A from ketone 31 (258 mg, 1.6 mmol) as a colorless liquid (230 mg, 82%). 1 H NMR (500 MHz, CDCl3) δ 5.49 – 5.39 (m, 4H), 1.96 – 1.89 (m, 4H), 1.66 (dt, J = 4.8, 1.3 Hz, 6H), 1.27 – 1.21 (m, 4H), 0.86 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 132.3, 124.2, 41.8, 32.6, 27.3, 27.1, 18.0. HRMS (EI+) calc’d for C13H24 [M]+• 180.1878; found 180.1865. General Procedure B for gem-dialkylation of ketones: O n MeMgBr n n = 2, 23 Me OH n PBr3 n Me n Br Et2Zn, ZnCl2 n Et n Me n n = 2, 32 Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 254 In a flame-dried round-bottom flask, ketone (1.0 equiv) was dissolved in THF and the reaction mixture was cooled to 0 ºC. Methylmagnesium bromide solution (3.0 M solution in diethyl ether, 1.5 equiv) was added dropwise, and the reaction mixture was slowly warmed to 23 ºC. After 1 hour, the reaction mixture was cooled to 0 ºC, and quenched by saturated NH4Cl solution. The aqueous phase was extracted with Et2O twice, dried over anhydrous MgSO4, filtered over a short silica plug, and concentrated under reduced pressure. A 100 mL round bottom flask equipped with a magnetic stirbar was charged with the tertiary alcohol (1.0 equiv) and dissolved in anhydrous CH2Cl2 (1 M). This solution was cooled to 0 °C and PBr3 (0.35 equiv) was added dropwise. The reaction mixture was stirred for 2 h at 0 °C, and then concentrated in vacuo. The flask was fitted with a short path distillation head and the residue was distilled under vacuum to afford the tertiary bromide as a clear, colorless oil. A 250 mL round bottom flask equipped with a magnetic stirbar was charged with ZnCl2 (0.1 equiv) and the tertiary bromide (1 equiv) and dissolved in anhydrous CH2Cl2 (0.5 M). This solution was cooled to –40 °C and the dialkylzinc reagent (1.0 equiv) was added dropwise via syringe. The reaction mixture was stirred with warming to ambient temperature for 12 h, and then quenched by the dropwise addition of MeOH. The reaction mixture was washed with 1 M HCl, the organic layer was separated, washed with brine, dried over MgSO4, and concentrated in vacuo. The product was purified by distillation. Me Et 32 Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 255 5-ethyl-5-methylnona-1,8-diene (32): Prepared according to general procedure B from ketone 23 (5.86 g, 42.5 mmol) and Et2Zn to afford 32 as a clear, colorless oil (4.3 g, 61% yield). 1 H NMR (600 MHz, CDCl3) δ 5.79 (ddt, J = 16.9, 10.1, 6.6 Hz, 2H), 4.97 (dt, J = 17.0, 1.8 Hz, 2H), 4.92 – 4.86 (m, 2H), 1.96 – 1.88 (m, 4H), 1.27 – 1.18 (overlapping m, 6H), 0.79 (s, 3H), 0.76 (t, J = 7.5 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 139.8, 113.7, 38.1, 34.9, 31.4, 28.1, 24.4, 7.9. HRMS (EI+) calc’d for C12H22 [M]+• 166.1722; found 166.1700. General Procedure C for ADMET Polymerization: 1. G2 (0.5 mol%) CH2Cl2, static vacuum, 60 ºC Me Me x x x = 2, 24 x = 4, 27 x = 7, 21 x = 8, 30 Me Me CbzO 2. CbzO OCbz 38 toluene, 60 ºC x N x n x x = 2, poly-24a x = 4, poly-27a x = 7, poly-21a x = 8, poly-30a n OCbz toluene, 23 ºC N OCbz Cl Ru x = 2, poly-24a x = 4, poly-27a x = 7, poly-21a x = 8, poly-30a Pd/C (10 mol%) H2 (1 atm) Me Me CbzO x Ph Cl PCy3 G2 Me Me HO x x n OH x = 2, poly-24b x = 4, poly-27b x = 7, poly-21b x = 8, poly-30b In a nitrogen-filled glovebox, monomer 30 (320 mg, 1 mmol) in 0.5 mL CH2Cl2 was transferred into a 50 mL Schlenk flask equipped with a stir bar, followed by Grubbs 2nd Generation Catalyst (4.2 mg, 0.5 mol%) in 0.5 mL CH2Cl2. The Schlenk tube was sealed and removed from the glovebox and placed under static vacuum after one freeze-pump-thaw cycle. Then the Schlenk flask was placed in to a 60 ºC oil bath for 12 hours. The valve was opened to dynamic vacuum and stirring was continued for 2 hours until the mixture turned viscous and became difficult to stir. Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 256 The Schlenk tube was sealed and taken into the glovebox where the CTA 38 (20.6 mg, 0.05 mmol, 20:1 monomer: CTA ratio) in 2 mL toluene was added. The Schlenk tube was removed from the glovebox and the side arm was flame dried under vacuum and backfilled three times with argon. Then the Schlenk tube was opened to the argon line and placed in a 60 °C oil bath for 72 h. The reaction mixture was transferred into a flame-dried round bottom flask and the solvent was removed under reduced pressure to obtain crude polymer poly-30a. 1 H NMR (500 MHz, CDCl3) δ 7.47 – 7.14 (m, 5H), 5.47 – 5.32 (m, 11H), 5.16 (s, 1H), 4.21 – 4.10 (m, 1H), 2.08 – 1.91 (m, 21H), 1.46 – 1.06 (m, 131H), 0.82 (s, 29H). 1H NMR determined n = 22, Mn = 6800. GPC data: Mn = 5400; PDI (Mw/Mn) = 1.2. The crude polymer poly-30a was dissolved in toluene (10 mL) and 10% palladium on carbon (100 mg, 0.1 equiv) was added in a round-bottom flask with a stir bar. The flask was sealed with a septum and back-filled with argon for three times, and then back-filled with H2 using a balloon. The reaction was allowed to stir at 23 °C for 24 hours under an atmosphere of hydrogen (1 atm H2 balloon). After that time the reaction mixture was filtered through a short pad of Celite (caution: Palladium on carbon is highly flammable and the palladium waste must be collected separately and covered with water). The filtered solution was concentrated upon heating under high vacuum to obtain the hydroxyl telechelic polymer poly-30b (286 mg, 97% yield). 1H NMR (500 MHz, CDCl3) δ 3.65 (t, J = 6.6 Hz, 1H), 1.39 – 1.10 (m, 210H), 0.82 (s, 32H). 1H NMR determined n = 21, Mn = 6300. GPC data: Mn = 7600; PDI (Mw/Mn) = 1.1. Table 3.5.1. Summary of Telechelic Polymer Samples Prepared. Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization Polymer poly-21b poly-24b poly-27b poly-30b-1 poly-30b-2 poly-30b-3 poly-30b-4 poly-32b poly-34b Monomer/CTA ratio 10:1 22:1 12:1 8:1 20:1 50:1 100:1 22:1 20:1 Yield (%) 95 55 99 99 97 96 89 56 95 n 15 16 10 10 21 58 97 22 19 257 Mn(NMR)(Da) 4200 2200 2000 3100 6300 17200 28700 3200 6800 Me Me HO 7 7 n OH poly-21b Telechelic polymer poly-21b: 1H NMR (400 MHz, CDCl3) δ 3.57 (t, J = 6.6 Hz, 1H), 1.62 – 1.48 (m, 7H), 1.32 – 1.00 (m, 122H), 0.74 (s, 22H). 1H NMR determined n = 15, Mn = 4200. GPC data: Mn =2800; PDI (Mw/Mn) = 1.44. Me Me HO 2 2 n OH poly-24b Telechelic polymer poly-24b: 1H NMR (600 MHz, CDCl3) δ 3.63 (t, J = 6.7 Hz, 1H), 1.59 – 1.52 (m, 1H), 1.36 – 1.04 (m, 46H), 0.80 (s, 20H).1H NMR determined n = 16, Mn = 2200. GPC data: Mn =4000; PDI (Mw/Mn) = 1.4. Me Me HO 4 4 n OH poly-27b Telechelic polymer poly-27b: 1H NMR (500 MHz, CDCl3) δ 3.65 (t, J = 6.6 Hz, 1H), 1.43 – 1.09 (m, 58H), 0.82 (s, 13H).1H NMR determined n = 10, Mn = 2000. GPC data: Mn = 3800; PDI (Mw/Mn) = 1.5. Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 258 Me Me HO 8 8 n OH poly-30b poly-30b-1: 1H NMR (500 MHz, CDCl3) δ 3.65 (dt, J = 6.5, 4.8 Hz, 1H), 1.41 – 1.17 (m, 94H), 0.82 (s, 15H). 1H NMR determined n = 10, Mn = 3100. poly-30b-2: 1H NMR (500 MHz, CDCl3) δ 3.65 (t, J = 6.6 Hz, 1H), 1.34 – 1.11 (m, 208H), 0.82 (s, 32H). 1H NMR determined n = 21, Mn = 6300. poly-30b-3: 1H NMR (500 MHz, CDCl3) δ 3.65 (dt, J = 6.7, 5.6 Hz, 1H), 1.32 – 1.12 (m, 571H), 0.82 (s, 88H). 1H NMR determined n = 58, Mn = 17200. poly-30b-4: 1H NMR (500 MHz, CDCl3) δ 3.65 (dt, J = 6.6, 5.5 Hz, 1H), 1.35 – 1.11 (m, 943H), 0.82 (s, 146H). 1H NMR determined n = 97, Mn = 28700. Me HO Et 2 2 n OH poly-32b Telechelic polymer poly-32b: 1H NMR (600 MHz, CDCl3) δ 3.63 (t, J = 6.7 Hz, 1H), 1.55 (q, J = 6.9 Hz, 2H), 1.38 – 1.05 (m, 83H), 0.78 – 0.68 (m, 34H). 1H NMR determined n = 22, Mn = 3200. GPC data: Mn =6800; PDI (Mw/Mn) = 1.1. n-Bu HO 8 Et 8 n OH poly-34b poly-34b: 1H NMR (500 MHz, CDCl3) δ 3.65 (q, J = 6.4 Hz, 1H), 1.34 – 1.19 (m, 265H), 1.14 – 1.09 (m, 56H), 0.92 – 0.87 (m, 29H), 0.72 (t, J = 7.5 Hz, 14H). 1H NMR determined n = 19, Mn = 6800. Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization Me 259 Me 37 5,5-dimethylcyclohept-1-ene (37): After the polymerization of 24, the cyclic olefin was removed by vacuum distillation from the reaction mixture (23 °C, 100 mTorr). 1 H NMR (400 MHz, CDCl3) δ 5.60 (ddd, J = 3.8, 2.9, 0.8 Hz, 2H), 2.06 – 1.94 (m, 4H), 1.40 – 1.32 (m, 4H), 0.87 (s, 6H). 13 C NMR (101 MHz, CDCl3) δ 131.5, 40.3, 33.7, 29.3, 24.4. HRMS (EI+, m/z) calc’d for C9H16 [M]+• 124.1252, found: 124.1264. Me Et 39 5-ethyl-5-methylcyclohept-1-ene (39): After the polymerization of 32, the cyclic olefin was removed by vacuum distillation from the reaction mixture (23 °C, 100 mTorr). 1 H NMR (600 MHz, CDCl3) δ 5.63 (t, J = 3.2 Hz, 2H), 2.09 – 2.01 (m, 4H), 1.49 – 1.33 (m, 4H), 1.29 (q, J = 7.5 Hz, 2H), 0.83 (s, 3H), 0.80 (t, J = 7.5 Hz, 3H). 13 C NMR (126 MHz, CDCl3) δ 131.4, 38.3, 35.9, 33.6, 25.2, 24.1, 8.1. HRMS (EI+, m/z) calc’d for C10H18 [M]+• 138.1409, found: 138.1413. Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 260 Figure 3.5.1. DSC Traces for Different Gem-dimethyl Polymer Samples Me Me HO 7 n poly-21b OH HO 8 n OH HO n OH HO 8 Mn = 3100 Da Me 8 poly-30b-4 n OH Mn = 28700 Da HO 2 4 4 n poly-27b Mn = 2200 Da OH Mn = 2000 Da Me Me 8 n poly-30b-2 Me Me 8 2 Me Me 8 poly-30b-1 HO 2 poly-24b Mn = 4200 Da Me Me HO Me Me Me Me 7 OH HO 8 Mn = 6300 Da Et n-Bu 2 poly-32b n OH Mn = 3200 Da 8 n poly-30b-3 HO 8 OH Mn = 17200 Da Et 8 poly-34b n OH Mn = 6800 Da Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 3.6 261 NOTES AND REFERENCES 1. (a) Shaffer, T. D.; Canich, J. A. M.; Squire, K. R. Macromolecules 1998, 31, 5145–5147. (b) Li, H.; Li, L.; Marks, T. J.; Liable-Sands, L.; Rheingold, A. L. J. Am. Chem. Soc. 2003, 125, 10788–10789. (c) Nakayama, Y.; Sogo, Y.; Cai, Z.; Shiono, T. J. Polym. Sci. Part Polym. Chem. 2013, 51, 1223–1229. 2. Kostjuk, S. V.; Yeong, H. Y.; Voit, B. J. Polym. Sci. Part A: Polym. Chem. 2013, 51, 471–486 3. Wu, Z.; Grubbs, R. H. Macromolecules 1995, 28, 3502–3508. 4. Binder, W. H.; Kurzhals, S.; Pulamagatta, B.; Decker, U.; Manohar Pawar, G.; Wang, D.; Kühnel, C.; Buchmeiser, M. R. Macromolecules 2008, 41, 8405–8412. 5. Wang, Y.; Hillmyer, M. A. Polym. Chem. 2015, 6, 6806–6811. 6. Schwendeman, J. E.; Wagener, K. B. Macromol. Chem. Phys. 2005, 206, 1461–1471. 7. Schwendeman, J. E.; Wagener, K. B. Macromol. Chem. Phys. 2009, 210, 1818–1833. 8. Wang, Y.; Hillmyer, M. A. ACS Macro Lett. 2017, 6, 613–618. 9. Kang, J.; Erdodi, G.; Kennedy, J. P. J. Polym. Sci. Part A: Polym. Chem. 2011, 49, 3891– 3904. 10. (a) Reetz, M. T.; Wenderoth, B.; Peter, R.; Steinbach, R.; Westermann, J. J. Chem. Soc. Chem. Commun. 1980, 0 (24), 1202–1204. (b) Reetz, M. T.; Westermann, J.; Steinbach, R. J. Chem. Soc., Chem. Commun. 1981, 0 (5), 237–239. 11. (a) Reetz, M. T.; Westermann, J.; Kyung, S.-H. Chem. Ber. 1985, 118, 1050–1057. (b) Seebach, D. Angew. Chem. Int. Ed. 2011, 50, 96–101. 12. Spiegel, D. A.; Wiberg, K. B.; Schacherer, L. N.; Medeiros, M. R.; Wood, J. L. J. Am. Chem. Soc. 2005, 127, 12513–12515. 13. Briese, R. R.; McElvain, S. M. J. Am. Chem. Soc. 1933, 55, 1697–1700. Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 262 14. Watson, M. D.; Wagener, K. B. Macromolecules 2000, 33, 3196–3201 15. (a) Corma, A.; Iborra, S.; Velty, A. Chem. Rev. 2007, 107, 2411–2502. (b) Schrodi, Y.; Ung, T.; Vargas, A.; Mkrtumyan, G.; Lee, C. W.; Champagne, T. M.; Pederson, R. L.; Hong, S. H. CLEAN - Soil Air Water 2008, 36, 669–673. 16. Reetz, M. T.; Kyung, S.-H. Chem. Ber. 1987, 120, 123–123. 17. Meisters, A.; Mole, T. Aust. J. Chem. 1974, 27, 1655 18. Kim, C. U.; Misco, P. F.; Luh, B. Y.; Mansuri, M. M. Tetrahedron Lett. 1994, 35, 3017– 3020. 19. Kennedy, J. P. J. Org. Chem. 1970, 35, 532–536. 20. Hartsel, J. A.; Craft, D. T.; Chen, Q.-H.; Ma, M.; Carlier, P. R. J. Org. Chem. 2012, 77, 3127–3133. 21. Thommen, M.; Prevot, L.; Eberle, M. K.; Bigler, P.; Keese, R. Tetrahedron 2011, 67, 3868– 3873. 22. Ogunniyi, D. Bioresour. Technol. 2006, 97, 1086–1091. 23. Lindmark-Hamburg, M. and Wagener, K.B. Macromolecules, 1987, 20, 2949–2951. 24. (a) Trnka, T. M.; Grubbs, R. H. Acc. Chem. Res. 2001, 34, 18–29. (b) Vougioukalakis, G. C.; Grubbs, R. H. Chem. Rev. 2010, 110, 1746–1787. 25. Li, H.; Silva, L. C. da; Schulz, M. D.; Rojas, G.; Wagener, K. B. Polym. Int. 2017, 66, 7–12. 26. Caire da Silva, L.; Rojas, G.; Schulz, M. D.; Wagener, K. B. Prog. Polym. Sci. 2017, 69, 79– 107. 27. Forbes, M. D. E.; Patton, J. T.; Myers, T. L.; Maynard, H. D.; Smith, D. W.; Schulz, G. R.; Wagener, K. B. J. Am. Chem. Soc. 1992, 114, 10978–10980. 28. Noack, M.; Göttlich, R. Eur. J. Org. Chem. 2002, 2002 (18), 3171–3178. Chapter 3 – A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 263 29. Lub, J.; Ten, H. W.; Rossin, R.; Van, D. B. S. M.; Robillard, M. S. US2013189184 (A1), July 25, 2013. 30. Arrington, K. J.; Murray, C. B.; Smith, E. C.; Marand, H.; Matson, J. B. Macromolecules 2016, 49, 3655–3662. 31. Marx, V. M.; Herbert, M. B.; Keitz, B. K.; Grubbs, R. H. J. Am. Chem. Soc. 2013, 135, 94– 97. Appendix 3 – Spectra Relevant to Chapter 3 264 APPENDIX 3 Spectra Relevant to Chapter 3: A Convenient Synthesis of Geminal-Dialkyl Dienes for Olefin Metathesis Polymerization 12 O CDCl3 – 7.26            
 
 
            

1   H NMR (400 MHz, CDCl3) of compound 12.         
 
     
                                              

     
Appendix 3 – Spectra Relevant to Chapter 3 265 



13 


 
CDCl3 – 77.16     C NMR (101 MHz, CDCl3) of compound 12. 


      

Appendix 3 – Spectra Relevant to Chapter 3 266       Appendix 3 – Spectra Relevant to Chapter 3 267
          1      
1 H– H COSY NMR (400 MHz, CDCl3) of compound 12.














 1 13       H– C HSQC NMR (400 MHz, CDCl3) of compound 12.
 
 
16 CDCl3 – 7.26             
     
 
                 
               

1   H NMR (400 MHz, CDCl3) of compound 16.             

 
 
 
 
 
 
      
                
     



      

   

Appendix 3 – Spectra Relevant to Chapter 3 268 



  



 13   CDCl3 – 77.16   C NMR (101 MHz, CDCl3) of compound 16.
       

   

      
 Appendix 3 – Spectra Relevant to Chapter 3 269 Appendix 3 – Spectra Relevant to Chapter 3 270
          1      
1 H– H COSY NMR (400 MHz, CDCl3) of compound 16.












 1 13       H– C HSQC NMR (400 MHz, CDCl3) of compound 16.

 
 
4 26 O 4           
            
 
 
 
                                         CDCl3 – 7.26   

1   H NMR (400 MHz, CDCl3) of compound 26.  
     

 
 
 
 
 
 
  
        
              
Appendix 3 – Spectra Relevant to Chapter 3 271 



13   


 
CDCl3 – 77.16  C NMR (101 MHz, CDCl3) of compound 26. 

  


Appendix 3 – Spectra Relevant to Chapter 3 272   
    29 8 O 8 CDCl3 – 7.26                     
 



                     



1   H NMR (400 MHz, CDCl3) of compound 29.  
       
    
 
 
 
 
 
 
 



                           
Appendix 3 – Spectra Relevant to Chapter 3 273 



13   


 
CDCl3 – 77.16   C NMR (101 MHz, CDCl3) of compound 29. 


   
     

 



Appendix 3 – Spectra Relevant to Chapter 3 274   Me 31 2 O 2 Me CDCl3 – 7.26         
   
 
           
 

                      1    H NMR (600 MHz, CDCl3) of compound 31. 
      
       
   
                
Appendix 3 – Spectra Relevant to Chapter 3 275 



    


 
C NMR (101 MHz, CDCl3) of compound 31. 
CDCl3 – 77.16 13 

  



Appendix 3 – Spectra Relevant to Chapter 3 276 
CbzO   38 CDCl3 – 7.26  OCbz  

1    H NMR (600 MHz, CDCl3) of compound 38. 
 
  
 
 
                                                                       
 



           
 
 

 


Appendix 3 – Spectra Relevant to Chapter 3 277 



13           


 
CDCl3 – 77.16     C NMR (101 MHz, CDCl3) of compound 38. 




Appendix 3 – Spectra Relevant to Chapter 3 278       CDCl3 – 7.26  21 Me Me  

1   H NMR (600 MHz, CDCl3) of compound 21.  
                             
 
 
 
                    

 
 
 
       
         

       
Appendix 3 – Spectra Relevant to Chapter 3 279 



13   


 
CDCl3 – 77.16   C NMR (101 MHz, CDCl3) of compound 21. 

  

          

Appendix 3 – Spectra Relevant to Chapter 3 280 Me 24 Me CDCl3 – 7.26                
   

1 
 
 
 
 
 
                       


 
 
 







             
      
   H NMR (400 MHz, CDCl3) of compound 24.  
   
  

Appendix 3 – Spectra Relevant to Chapter 3 281 



13 

 
CDCl3 – 77.16   C NMR (101 MHz, CDCl3) of compound 24. 

 

  


Appendix 3 – Spectra Relevant to Chapter 3 282       Me 27 Me CDCl3 – 7.26   

1   H NMR (400 MHz, CDCl3) of compound 27.           
       
 
 
 
 
 
                           

 
 
 
 
 
 
 
 
 
                                        
 
                   
 Appendix 3 – Spectra Relevant to Chapter 3 283 



13  


 
CDCl3 – 77.16   C NMR (101 MHz, CDCl3) of compound 27. 

  




     

Appendix 3 – Spectra Relevant to Chapter 3 284 CDCl3 – 7.26  Me 30 Me  

1   H NMR (400 MHz, CDCl3) of compound 30.  
                          
 
 
 
 
 



                      





 
 
 
 
 
 
 
    
      

Appendix 3 – Spectra Relevant to Chapter 3 285 



13   


 
CDCl3 – 77.16   C NMR (101 MHz, CDCl3) of compound 30. 

  

             

Appendix 3 – Spectra Relevant to Chapter 3 286 Et 33 Et CDCl3 – 7.26   1 

  H NMR (600 MHz, CDCl3) of compound 33.  
 
       

 
  
  
 
   
              

           
 


         
          


 
                   
            
  

      




 

    
Appendix 3 – Spectra Relevant to Chapter 3 287 



 

 
C NMR (101 MHz, CDCl3) of compound 33. 
   
CDCl3 – 77.16 13 




Appendix 3 – Spectra Relevant to Chapter 3 288         
CDCl3 – 7.26  n-Bu 34 Et  

1   H NMR (400 MHz, CDCl3) of compound 34.  
               
    
 
 
 
                            
 
 
 
 
 
 
 
 
 
 
 
                 







   
     

Appendix 3 – Spectra Relevant to Chapter 3 289 



13   
 


   CDCl3 – 77.16   C NMR (101 MHz, CDCl3) of compound 34. 




  
                
    

Appendix 3 – Spectra Relevant to Chapter 3 290   CDCl3 – 7.26  n-Oct 35 Et  

1   H NMR (400 MHz, CDCl3) of compound 35.                
            
    
 
 
 
                        
 
 
 
 
 
 
 
 
 
 
 
  
                           








 Appendix 3 – Spectra Relevant to Chapter 3 291 



13  


 
C NMR (101 MHz, CDCl3) of compound 35. 
       CDCl3 – 77.16 


  





      
               
   
Appendix 3 – Spectra Relevant to Chapter 3 292 293
Appendix 3 – Spectra Relevant to Chapter 3    
  

 Me  1 H NMR (500 MHz, CDCl3) of compound 36.     
 Me Me 36 Me CDCl3 – 7.26 



13 

      

 
C NMR (101 MHz, CDCl3) of compound 36. 

 
  

Appendix 3 – Spectra Relevant to Chapter 3 294 CDCl3 – 77.16       Me 32 Et CDCl3 – 7.26   

1   H NMR (600 MHz, CDCl3) of compound 32.       
     
             
 
     


 
 
          
             
 
 
         
          
                         
  



 
 Appendix 3 – Spectra Relevant to Chapter 3 295 296
Appendix 3 – Spectra Relevant to Chapter 3 
   
   



 

13 

 
CDCl3 – 77.16 C NMR (101 MHz, CDCl3) of compound 32. 


 hexanes CDCl3 – 77.16   HO  7 poly-21b 7 Me Me CDCl3 – 7.26 n  OH 1   H NMR (400 MHz, CDCl3) of compound poly-21b.     
  

 
            
                
      

        
Appendix 3 – Spectra Relevant to Chapter 3 297 HO  2 poly-24b 2 Me Me CDCl3 – 7.26 n  OH 1   

 H NMR (600 MHz, CDCl3) of compound poly-24b.          

        
    
          
  
        
  
  

   
           
           
       
      
Appendix 3 – Spectra Relevant to Chapter 3 298 HO  4 poly-27b 4 Me Me CDCl3 – 7.26 n  OH 1    H NMR (500 MHz, CDCl3) of compound poly-27b.        

                             



   


Appendix 3 – Spectra Relevant to Chapter 3 299 HO  8 poly-30b-1 8 Me Me CDCl3 – 7.26 n  OH 1  

  H NMR (500 MHz, CDCl3) of compound poly-30b-1.                 
 
 
            
 
                     
     
Appendix 3 – Spectra Relevant to Chapter 3 300 HO  8 poly-30b-2 8 Me Me CDCl3 – 7.26 n  OH 1  

  H NMR (500 MHz, CDCl3) of compound poly-30b-2.             
 
                 
                           
 


 

Appendix 3 – Spectra Relevant to Chapter 3 301 HO CDCl3 – 7.26  8 poly-30b-3 8 Me Me n  1 OH  

  H NMR (500 MHz, CDCl3) of compound poly-30b-3.               
 
             
                      
   

Appendix 3 – Spectra Relevant to Chapter 3 302 HO  8 poly-30b-4 8 Me Me CDCl3 – 7.26 n  OH 1  

  H NMR (500 MHz, CDCl3) of compound poly-30b-4.             
              
                    
     
Appendix 3 – Spectra Relevant to Chapter 3 303 HO  Et 2 poly-32b 2 Me CDCl3 – 7.26 n  1 OH   H NMR (500 MHz, CDCl3) of compound poly-32b.        

      
       
                   
   
 
    

Appendix 3 – Spectra Relevant to Chapter 3 304 HO 8 Et 8 poly-34b n-Bu CDCl3 – 7.26  n OH  1  

  H NMR (500 MHz, CDCl3) of compound poly-34b.           
             














   


  
Appendix 3 – Spectra Relevant to Chapter 3 305 Me 37 Me CDCl3 – 7.26   1 

   H NMR (400 MHz, CDCl3) of compound 37.             







 
 
 
 
 
 
            
      

Appendix 3 – Spectra Relevant to Chapter 3 306 


  


 
C NMR (101 MHz, CDCl3) of compound 37. 
CDCl3 – 77.16 13 


     


Appendix 3 – Spectra Relevant to Chapter 3 307 Me 39 Et   1    H NMR (600 MHz, CDCl3) of compound 39.       






 
 
 
 
                               
 
       




      
 
 
Appendix 3 – Spectra Relevant to Chapter 3 308 


   


 
C NMR (101 MHz, CDCl3) of compound 39. 
CDCl3 – 77.16 13 

 

    

Appendix 3 – Spectra Relevant to Chapter 3 309    310 ABOUT THE AUTHOR Jiaming Li was born in Urumqi, Xinjiang, China on November 28th, 1991 to Yongfu Li and Jiange Tan. Jiaming was raised in Urumqi and hadn’t been to other provinces until he was 12, but he was always curious about the outside world. Jiaming was interested in many subjects including science, geography, and history. In high school, he spent most of the summers studying for the Chemistry Olympiad, and learned college level chemistry with his chemistry teacher Manli Jing. In 2010, Jiaming was admitted to Zhejiang University and spent 4 years in Hangzhou, Zhejiang. Fascinated by the teaching by Prof. Xiaogang Peng in Physical Chemistry and Prof. Ping Lu in Organic Chemistry, Jiaming changed his major from engineering to chemistry. In his sophomore year, he joined Prof. Ping Lu’s lab and worked on the synthesis of florescent sensors. In the summer of 2013, Jiaming had a chance to study abroad and spent two months in Prof. Xi Chen’s lab at UC Davis. During his time there, he synthesized a number of oligosaccharides using enzymes. It was a great experience for Jiaming to be immersed in chemical biology research, after taking biochemistry and molecular biology courses. This experience confirmed his goal to apply for graduate school in the U.S. After obtaining Bachelor’s degree in 2014, Jiaming moved to Pasadena, California to pursue his doctoral studies at the California Institute of Technology with Professor Robert Grubbs and Brian Stoltz. His doctoral research focused on the total synthesis of prostaglandins using newly developed olefin metathesis catalysts. Upon completion of his doctoral research in November, 2019, Jiaming will be a postdoc researcher in Prof. Brian Liau’s lab at Harvard University.