Transannular Claisen Rearrangements of α-Sulfonyl Lactones Sophie Gore Julia Laboratory, Department of Chemistry, Imperial College London, South Kensington Campus, London SW7 2AZ, United Kingdom June 2009 A thesis submitted in partial fulfilment of the requirements for the degree of Doctor of Philosophy, Imperial College London Abstract This thesis is divided into three sections. Section one is a review of transannular pericyclic reactions. It covers the four main types of pericyclic reaction and major contributions in the field to date. Recent applications of these reactions to natural product synthesis are also included. Section two discusses the results of research efforts into transannular Claisen rearrangements of α-sulfonyl lactones. The background to the project is discussed along with initial investigations into the transannular Claisen and decarboxylative Claisen rearrangements (dCr) of the 7-membered α-tosyl lactone to form vinyl cyclopropanes. Stereoselectivity from within the pericyclic array, by substitution at the lactone C7 position is examined. Efforts towards stereoinduction from outside of the pericyclic array are also detailed, along with aryl substitution at the lactone C5 position to form highly substituted vinyl cyclopropanes. Extension of this methodology to the unprecedented transannular Claisen rearrangement and dCr reaction of 8-membered α- tosyl lactones to give vinyl cyclobutanes is reported. Finally, efforts towards a novel synthetic route to (±)-grandisol utilising the transannular Claisen rearrangement chemistry is described. Section three details the experimental procedures and spectroscopic data for the compounds described in section two. 2 Table of Contents Abstract 2 Table of Contents 3 Declaration 5 Acknowledgments 6 List of Abbreviations 7 Stereochemical Notation 10 Transannular Pericyclic Reactions 11 1.1 Introduction 12 1.2 Transannular Cycloadditions 14 1.2.1 Transannular Diels–Alder Reaction 14 1.2.2 The TADA Reaction as a General Approach to the Synthesis of Steroids 21 1.2.3 An Example of the TADA Reaction in Total Synthesis; (±)-Strychnine 25 1.2.4 Asymmetric Catalysis of the TADA Reaction 26 1.2.5 Alternative Transannular Cycloadditions 28 1.3 Transannular Electrocyclic Reactions 32 1.3.1 The Endiandric Acid Cascade 33 1.4 Transannular Sigmatropic Rearrangements 37 1.4.1 Transannular Cope Rearrangements 37 1.4.2 Transannular Claisen Rearrangements 39 1.5 Transannular Ene Reactions 46 1.5.1 The Tandem Oxy-Cope–Transannular Ene Reaction 46 1.5.2 The Oxy-Cope–Ene–Claisen Cascade 49 1.5.3 The Oxy-Cope–Claisen–Ene Cascade 50 1.6 Conclusion 53 Results and Discussion 54 2.1 Background 55 2.1.1 Historical Background 55 2.1.2 Transannular Claisen Rearrangements 57 2.1.3 The Decarboxylative Claisen Rearrangement 59 2.1.4 Prior Transannular Claisen Rearrangement Work within the Craig Group 60 2.1.5 Focus of the Current Work 62 2.2 The Transannular Claisen Rearrangement 63 2.2.1 The Transannular Decarboxylative Claisen Rearrangement 64 2.2.2 Alternative Lactonisation Strategies 65 2.3 Stereoinduction from Within the Pericyclic Array 70 2.3.1 Background 70 2.3.2 Model Racemic C-7 Substituted Lactone 71 2.3.3 Enantiomeric System 73 2.4 Stereoinduction from Outside of the Pericyclic Array 77 2.4.1 Background 77 2.4.2 Sulfoximine Approach 79 2.4.3 2,4,6-Triisopropylphenylsulfonyl Approach 82 2.5 Aryl-Substitution at the Lactone C-5 Position 84 2.5.1 Synthesis of the Aryl-Substituted Allylic Alcohol 85 2.5.2 The Tosyl Series 93 3 2.5.3 The Sulfoximine Series 96 2.6 Cyclobutane Synthesis 100 2.6.1 Synthesis of the 8-Membered Lactone 100 2.6.2 Transannular Claisen Rearrangements of 8-Membered Lactones 103 2.7 (±)-Grandisol 104 2.7.1 Background 104 2.7.2 Gueldner’s Synthesis 104 2.7.3 Siddall’s Synthesis 105 2.7.4 Billups’ Synthesis 105 2.7.5 Clark’s Synthesis 106 2.7.6 Mori’s Synthesis 106 2.7.7 A Novel Approach 107 2.7.8 Proposed Improvements to the Approach 111 2.8 Conclusion 112 Experimental 113 3.1 General Laboratory Procedures 114 3.2 General Synthetic Procedures 115 3.3 Individual Procedures 118 3.3.1 Compounds Relevant to Section 2.2 118 3.3.2 Compounds Relevant to Section 2.3 127 3.3.3 Compounds Relevant to Section 2.4 141 3.3.4 Compounds Relevant to Section 2.4 157 3.3.5 Compounds Relevant to Section 2.6 194 3.3.6 Compounds Relevant to Section 2.7 202 Appendix 212 4.1 Crystallographic Data for 488a 213 References 218 4 Declaration I certify that all work in this thesis is solely my own, except where explicitly stated and appropriately referenced. No part of the thesis has been submitted previously for a degree at this, or any other, university. 5 Acknowledgments First and foremost I would like to thank Professor Donald Craig. Your support and constant enthusiasm over the years are hugely appreciated. I have enjoyed and learned so much through the opportunity to work in your group. Secondly, massive thanks go to Dr Alexander Mayweg. Your encouragement, support and input to my PhD have gone far beyond the job description. The Craig group, in all their guises over the years, have been a fantastic bunch to work with. Dr Jason Camp, you are an absolute star for the amount of time and effort you put into my proof-reading. Federica, Steve, Pengfei, Alex, Niels, Kiyo, Jasprit, Claire, Simon and Shu; it’s been a pleasure. Finally, Mum, Dad, Kathryn, Alice, Rob; collectively you are my rock. I am so lucky to have you all. 6 List of Abbreviations Ac acetyl Ar aryl aq aqueous br broad Bu butyl BSA N,O -bis(trimethylsilyl)acetamide cat. catalytic CI chemical ionisation COD cyclooctadiene conc. concentrated conv. conversion CSA camphorsulfonic acid Cy cyclohexane d doublet dr diastereomeric ratio DBU 1,8-diazobicyclo[5.4.0]undec-7-ene DCC N,N’-dicyclohexylcarbodiimide dCr decarboxylative Claisen rearrangement DHP dihydropyran DIBAL-H diisobutylaluminium hydride DIC N,N’-diisopropylcarbodiimide DIPEA diisopropylethylamine DMAP 4-dimethylaminopyridine DMSO dimethylsulfoxide DMF dimethylformamide EDCI 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide ee enantiomeric excess EI electron ionisation equiv equivalents Et ethyl EWG electron-withdrawing group 7 FAB fast atom bombardment Grubbs II Grubbs’ second generation catalyst h hours HATU O-(7-azabenzotriazol-1-yl)-N,N,N', N'-tetramethyluronium hexafluorophosphate Hex hexyl HMPA hexamethylphosphorictriamide IBX 2-iodoxybenzoic acid LDA Lithium diisopropylamine m- meta- m multiplet M molar m/w microwave Me methyl min minutes MNBA 2-methyl-6-nitrobenzoic acid MOM methoxymethyl mp melting point Ms methanesulfonyl MS mass spectrum Na - naphthalide NOESY nuclear Overhauser effect spectroscopy NMR nuclear magnetic resonance o- ortho- p- para- Ph phenyl ppm parts per million PPTS pyridinium para -toluenesulfonate iPr iso -propyl PTSA para -toluene sulfonic acid q quartet RCM ring closing metathesis Red-Al sodium dihydridobis(2-methoxyethoxy)aluminate rt room temperature 8 s singlet sat. saturated sept septet soln. solution t triplet TADA transannular Diels–Alder TBDMS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl Tf trifluoroacetyl TFA trifluoroacetic acid THF tetrahydrofuran THP tetrahydropyran TLC thin layer chromatography TMS trimethylsilyl Tol tolyl Tris 2,4,6-triisopropylphenylsulfonyl Ts para -toluenesulfonyl TS transition state wt. weight 9 Stereochemical Notation It should be noted that the Maehr convention for indicating relative and absolute stereochemistry has been used throughout this report. 1 Therefore, solid and broken lines are used to denote racemates, and solid and broken wedges denote absolute configuration. Narrowing of the wedges implies increasing distance from the reader in the latter case. It should also be noted that in the case of the cyclopropanes with a sulfoximine appendage, the stereochemistry at the carbon centre is implied by the dashed bond to COOH or H. The bond to the sulfoximine is kept as a single line, allowing the stereochemistry at the sulfur centre to remain unchanged to save confusion. 10 Chapter 1 Transannular Pericyclic Reactions 11 Transannular Pericyclic Reactions 1.1 Introduction Pericyclic reactions are concerted, single-step processes with no intermediates. The transition state is always cyclic, and as such the stereochemistry of the product is highly predictable. They are highly versatile and some of the most efficient known reactions in terms of atom economy.2 Pericyclic reactions can broadly be divided into four major categories (Figure 1): • Cycloadditions: the formation of two new σ-bonds between the termini of two conjugated π systems to form a ring 1 → 2. • Electrocyclic reactions: the formation of one new σ bond, often the cyclisation of a linear conjugated system 3 → 4 . • Sigmatropic rearrangements: the simultaneous formation and breaking of a σ bond 5 → 6 . These are further classified by the distance migrated by each end of the σ bond along the conjugated system. • Group transfer reactions: the cleavage and formation of unequal numbers of σ bonds to form an acyclic product, for example, the ene reaction 7 → 8 . Figure 1: Major classes of pericyclic reaction Transannular reactions occur across a ring, presenting both an enthalpic and entropic advantage due to the proximity of the reacting sites. Sterically congested systems which are inert to inter- and intra-molecular strategies may also react. Conformational restrictions lead to marked chemo-, regio- and diastereoselectivities. When these attributes are combined with those of pericyclic reactions, the rapid establishment of high levels of cyclic complexity and enhanced stereocontrol are predicted. Transannular reactions can also be divided into the four major classes of pericyclic reaction (Figure 2): 12 Transannular Pericyclic Reactions • Transannular cycloaddition: the formation of a tricycle from an alkene- containing macrocycle with establishment of four new contiguous stereocentres 9 → 10 . • Transannular electrocyclic reactions: the formation of a bicycle containing two new stereogenic centres in the forward sense 11 → 12 .