Alkylations, Rearangements, and Cyclizations of Oxidized Organosulfur Compounds
Total Page：16
File Type：pdf, Size：1020Kb
Alkylations, Rearangements, and Cyclizations of Oxidized Organosulfur Compounds by Stefan Charles Soderman A Thesis Presented To The University of Guelph In partial fulfillment of requirements for the degree of Doctor of Philosophy in Chemistry Guelph, Ontario, Canada © Stefan C. Soderman, August, 2013 ABSTRACT ALKYLATIONS, REARRANGEMENTS, AND CYCLIZATIONS OF OXIDIZED ORGANOSULFUR COMPOUNDS Stefan C. Soderman Advisor: University of Guelph, 2013 Dr. Adrian Schwan Organosulfur compounds have been used by humans for centuries and played a pivotal role in shaping our history. The chemistry presented herein deals primarily with three distinct organic transformations involving organosulfur species. The three transformations are used in tandem to complete the synthesis of natural products. The first chapter examines a new diastereoselective alkylation reaction of sulfenate anions with stereoinduction provided by chiral amino iodides. A series of β-amino sulfoxides are accessed in good yields and selectivities from alkylations with the corresponding lithium arene- and E-1-alkenesulfenate anions. The relative reactivity of different electrophiles towards a selection of lithium sulfenate anions was also evaluated by performing competition experiments. In the second chapter 1,2-dibromotetrachloroethane (C2Br2Cl4) was evaluated as a more economical halogenating agent for the in-situ Ramberg-Bäcklund rearrangement (RBR). A series of trans-stilbenoids were successfully synthesized using this protocol in excellent yields. The new RBR system also worked well for dialkyl and cyclic substrates, but the reaction was plagued by polyhalogenation for hexyl benzyl sulfone. The methodology was extended to the formal total synthesis of natural polyphenol E-resveratrol. Chapter three investigates asymmetric aza-Michael reactions of chiral β-amino sulfoxides/sulfones to synthesize thiomorpholine S-oxides and S,S-dioxides, respectively. Remarkably, cyclizations of the β-amino sulfoxides provide the trans- 3,5-substituted heterocycles, while the β-amino sulfones provide the complementary cis-3,5-substituted heterocycles. The aza-Michael chemistry was exploited along with the sulfenate and RBR protocols to access two ant venom alkaloids. Acknowledgements After nearly five years in the Schwan lab it is time for me to express my gratitude for those that have helped me complete my PhD. I would like to thank NSERC, the Ontario government, and the Petroleum Research Fund for subsidizing the chemistry research I have achieved. The staff in the chemistry department was crucial in helping me achieve my goals. I thank Steve Wilson of the machine shop and Steve Seifried of the electronics shop. Many thanks go to Uwe Oehler for helping with all my computer issues. The staff at the NMR centre has been excellent and I express my sincere thanks to Valerie Robertson, Andy Lo, Pete Scheffer and Joe Meissner. Rob Reed was a great help in many of the practical aspects of the practical challenges I faced in setting up experiments. I have had the pleasure of working with an excellent group of students at (GWC)2 which make it a great environment to be part of. A special thanks goes out to my lab mates in MACN 238 including Selim Hossain, Mary McKee, Jamie Haner, Tom Malig and Alex Michaelides. All of you have made my time here very memorable and sometimes downright ridiculous. A very special thanks goes out to my wife Vanesse for her ongoing patience, love, and support throughout this process. I truly could not have done it without you. Lastly, my sincere gratitude goes out to Adrian for giving a psychology major a chance to do chemistry. Your support, encouragement and knowledge about chemistry/sports made my time here very enjoyable. You are a true friend and I look forward to keeping in touch with you in years to come. iv Table of Contents Acknowledgements……………………………………………………………………………………………..iv List of Abbreviations………..………………………………………………………………………………..viii List of Tables……………………………………………………………………………………………………….xi List of Figures……………………………………………………………………………………………………xiii 1.0 Diastereoselective Alkylations of Lithium Sulfenate Anions……………………………..2 1.1 Introduction………………………………………………………………………………………..2 1.1.1 Forward on Organosulfur Chemistry………………………………………….2 1.1.2 Sulfenate Anion Background Information…………………………………..3 1.1.3 Recent Progress in Sulfenate Anion Chemistry…………………………...5 1.1.4 Proposed Diastereoselective Sulfenate Alkylations with Chiral Iodides…………………………………………………………………………………...29 1.2 Results and Discussion………………………………………………………………………33 1.2.1 Diastereoselective Alkylations of Arenesulfente Anions……………33 1.2.2 Diastereoselective Alkylations of Alkanesulfenate Anions…..…….40 1.2.3 Diastereoselective Alkylations of 1-Alkenesulfenate Anions..........42 1.2.4 Sulfenate Anion Alkylation Competition Experiments………………46 1.2.5 Proposed Model for Observed Stereoinduction………………………...48 1.2.6 Sulfenate Alkylation as a Method for accessing β-Amino Sulfoxides……………………………………………………………………………….51 1.3 Conclusion………………………………………………………………………………………...55 1.4 Experimental…………………………………………………………………………………….57 1.4.1 General Experimental…………………………………………………………57 1.4.2 Synthesis of Sulfenate Anion Precursors and Amino Iodide Electrophiles……………………………………………………………………...58 v 1.4.3 Synthesis of Aryl β-Amino Sulfoxides…………………………………..58 1.4.4 Synthesis of 2-(carboethoxyl)ethyl Alkyl Sulfoxides…………….70 1.4.5 Synthesis of Alkyl β-Amino Sulfoxides…………………………………73 1.4.6 Synthesis of 1-Alkenyl β-Amino Sulfoxides………………………….77 1.4.7 Sulfenate Alkylation Competition Experiments……………………87 1.5 References………………………………………………………………………………………...90 2.0 A New Halogenating Reagent for the Ramberg-Bäcklund Rearrangement…………………………………………………………………………………………….99 2.1 Introduction……………………………………………………………………………………...99 2.1.1 Background Information…………………………………………………….99 2.1.2 Proposed Reagent for RBR………………………………………………..119 2.2 Results and Discussion…………………………………………………………………….121 2.2.1 Sulfone Precursor Synthesis and RBR Optimization Experiments…………………………………………………………………….121 2.2.2 Expansion of RBR Substrate Scope……………………………………123 2.2.3 Formal Total Synthesis of Resveratrol……………………………….128 2.3 Conclusion………………………………………………………………………………………129 2.4 Experimental…………………………………………………………………………………..130 2.4.1 Synthesis of Sulfones………………………………………………………..130 2.4.2 RBR Experiments……………………………………………………………..143 2.5 References………………………………………………………………………………………151 3.0 Cyclization Chemistry of β-Aminoalkyl Alkenyl Sulfoxides/Sulfones…………….156 3.1 Introduction……………………………………………………………………………………156 3.1.1 Background Information…………………………………………………..156 vi 3.1.2 Proposed Cyclization Chemistry………………………………………..175 3.2 Results and Discussion…………………………………………………………………….177 3.2.1 Optimization and Scope of Cyclization Reaction………………...177 3.2.2 Ant Venom Alkaloid Synthesis…………………………………………..191 3.2.3 Discussion of Cyclization Stereochemistry…………………………203 3.3 Conclusion………………………………………………………………………………………208 3.4 Experimental…………………………………………………………………………………..209 3.4.1 Synthesis of sulfones 83…………………………………………………...209 3.4.2 Deprotection Protocols of β-Amino Sulfones/Sulfoxides……213 3.4.3 Cyclization Reaction Experiments……………………………………..222 3.4.4 Synthesis of Venom Alkaloids 89 & 90………………………………229 3.4.5 Cyclization Chemistry of Minor Diastereomer 113…………….240 3.5 References………………………………………………………………………………………243 4.0 Future Work………………………………………………………………………………………………249 4.1 Proposed Research Projects……………………………………………………………..249 4.2 References………………………………………………………………………………………253 APPENDIX……………………………………………………………………………………………………….254 vii List of Abbreviations 12-c-4 = 12-crown-4 Ac = acetyl AIBN = azobisisobutyronitrile An = 1-anthraquinoyl Ar = aryl Bn = benzyl Boc = tert-butyloxycarbonyl Bu = butyl c = cyclo- Cbz = benzyloxycarbonyl CI = chemical ionization DBU = 1,8-diazabicyclo[5.4.0]undec-7-ene DCE = 1,2-dichloroethane DCM = dichloromethane DMF = N, N-dimethylformamide DMSO = dimethyl sulfoxide DNA = deoxyribonucleic acid dppe = 1,2-bis(diphenylphosphino)ethane dr = diastereomeric ratio ee = enantiomeric excess ent = enantiomer er = enantiomeric ratio viii ESI = electrospray ionization Et = ethyl GCMS = gas chromatography-mass spectrometry HPLC = high-performance liquid chromatography HRMS = high-resolution mass spectrometry i = iso- Imid-H = imidazole IR = infrared KHMDS = potassium hexamethyldisilazide LA = Lewis acid LDA = lithium diisopropylamide LG = leaving group LiHMDS = lithium hexamethyldisilazide mCPBA = meta-chloroperoxybenzoic acid Me = methyl Ms = mesyl n = normal NaHMDS = sodium hexamethyldisilazide Napht = naphthyl NMR = nuclear magnetic resonance NOE = nuclear Overhauser effect NOESY = nuclear Overhauser effect spectroscopy Nuc = nucleophile ix ODS = ozone-depleting substance p = para PDC = pyridinium dichromate PG = protecting group Ph = phenyl Pr = propyl rt = room temperature s = sec t = tert TBAF = tetrabutylammonium fluoride TBDPS = tert-butyldiphenylsilyl TEA = triethylamine TFA = trifluoroacetic acid TFAA = trifluoroacetic anhydride THF = tetrahydrofuran TLC = thin layer chormatography TMEDA = N,N,N’,N’-tetramethylethylenediamine TMSCl = trimethylsilyl chloride TOF = time of flight Tol = para-tolyl Ts = tosyl TSA = toluenesulfonic acid UV = ultraviolet x List of Tables Chapter 1 Table 1.1: Synthesis of Benzyl Sulfoxides via Sulfenates…………………………………………6 Table 1.2: Alkylation of Sulfenate 15……………………………………………………………………..8 Table 1.3: Sulfenate Anions via a Retro-Michael Addition Protocol……………………….11 Table 1.4: Palladium-Catalyzed Arylations of Sulfenate Anions………………………….…16