Asymmetric Synthesis Using a Camphene-Derived Chiral Auxiliary Paul Thorburn B.Sc. Thesis presented for the degree of Doctor of Philosophy The University of Edinburgh 1997 Declaration I declare that this thesis is my own composition, that the work of which it is a record has been carried out by myself, and that it has not been submitted in any previous application for a higher degree. The thesis describes the results of research carried out in the Department of Chemistry of The University of Edinburgh, under the supervision of Dr. I. Gosney since the 14th of January 1992, the date of my admission as a reseach student. Paul Thorburn To Malcolm and both lans Acknowledgements I would like to thank Dr. Ian Gosney for his supervision and encouragement, Dr. Malcolm Banks for his advice and expertise, and Dr Ian Dawson for the inspiration to carry on. I would also like to thank all the departmental technical staff for the services that - they have provided over the years. Particular thanks must go to John R. Miller for his patience and provision of a working NMR service despite the pressure on it. And finally, I must thank my comrades who have accompanied me on this odyssey, Suneel Gaur, Keith Grant, Derek Kilgour, Douglas McDougall, Allan Doyle, Laurence Joly, Jamie Mayo and last and least Stuart Gebbie. Courses Attended The following is a statement of the courses attended during the period of research:- 1 Current Topics in Organic Chemistry, various speakers, Department of Chemistry, University of Edinburgh, 3 years attendance. 2 Organic Research Seminars, various speakers, Department of Chemistry, University of Edinburgh, 3 years attendance. 3 Royal- Society oLChemistry, Perkin Division (ScottishSection), annua1_ --- -- -- meetings, various speakers, 3 years attendance. 4 Merck, Sharp and Dohme, Medicinal Chemistry Lectures, Prof R. Baker and Dr. P. Leeson, Department of Chemistry, University of Edinburgh, three years attendance 5 NMR of Biological Molecules, Dr. J. Parkinson and Dr. I. Sadler, Department of Chemistry, University of Edinburgh, 1993. 6 Chemical Development in the Pharmaceutical Industry, Smith-Kline Beecham, various speakers, Department of Chemistry, University of Edinburgh, 1993. 7 Industrial Fine Organic Chemistry, Prof. A. McKillop (University of East Anglia), Department of Chemistry, University of Edinburgh, 1993. 8 Industrial Biocatalysts, Smith-Kline Beecham, various speakers, Department of Chemistry, University of Edinburgh, 1994. 9 25th Sheffield Stereochemical Meeting, various speakers, Sheffield, 1991. 10 Royal Society of Chemistry, Heterocyclic Group, 2 years attendance. Abstract The synthesis of a novel spiro-oxazolidin-2-one chiral auxiliary from both enantiomers of the common terpene camphene is described. The compound is formed via nitrene insertion and its structure has been determined by both NMR spectroscopy and X-ray diffraction studies. Evaluation of the functional isation conditions for this hindered oxazolidin-2-one have been carried out and it has been observed that zinc salts give superior yields of N-acyl products compared to the use of the orthodox lithium or halomagnesium salts. It has been demonstrated that using suitable conditions the auxiliary is capable of inducing high degrees of stereoselectivity in a variety of enolate reactions including alkylation, acylation and aldol condensation. Unsaturated acyl derivatives undergo Diels-Alder cycloaddition with cyclopentadiene in the presence of diethylaluminium chloride to give adducts with very high diastereomeric excess. Michael additions of aluminium reagents to these acyl derivatives also give high diastereomeric excesses where the possibility of formation of a cationic intermediate exists. When such intermediates cannot be formed, in particular addition of trialkyl aluminium reagents, very low diastereomeric excesses are observed. 1,4-Conjugate addition of magnesium reagents is dependent on the presence of copper catalysts but the reactions proceed with high stereoselectivity and the intermediate enolates may be readily alkylated with equal selectivity. In many cases the so formed adducts have been cleaved to give the newly created chiral fragments in high optical purity and chemical yield with almost complete recovery of the auxiliary (>90%). The application of a combination of stereoselective 1,4 conjugate addition and aldol condensation reactions has been applied to the synthesis of a number of substituted 3- carboxy-7-lactones (paraconic acids). The stereochemistry of these target molecules has been readily created with a high degree of specificity in very good chemical yield. In one attempted synthesis use of a surprisingly stereoselective lithium enolate aldol condensation is described. The origins of this selectivity have been proposed after considering the selectivities of a number of different substrates. However removal of the chiral product fragment from the auxiliary leaving both intact has been found to be highly dependant on both the functionality and stereochemistry of the adduct. Further applications of the auxiliary to short natural product synthesis and the potential of these routes is also briefly described. Contents 1. Introduction 1 1.1 Chirality 2 1.1.1 The Importance of Chirality 2 1.1.2 Methods of Obtaining Single Enantiomers 4 1.2 Methods of Asymmetric Synthesis 7 1.2.1 Auxiliary Controlled Asymmetric Synthesis 8 1.2.1.1 Oxazolidin-2-one Chiral Auxiliaries 9 1.2.1.2 Oppoizer's Camphor Sultam 18 1.2.1.3 Asymmetric Alkylation of Chiral Hydrazones 20 1.2.1.4 Conjugate Addition to Chiral Oxazoline Substituted Naphthalenes 23 1.2.1.5 Chiral Suiphoxides 25 1.2.1.6 Chiral Induction Without Chelation via 8-Phenylmenthol 26 1.2.1.7 Chiral Bicyclic Lactams 28 1.2.2 Reagent Controlled Asymmetric synthesis 29 1.2.2.1 Reduction using a Binaphthol-Modified Aluminium Hydride Reagent 30 1.2.2.2 Asymmetric Oxidation using an Enantiomericaly Pure Oxaziridine 31 1.2.2.3 Homochiral Lithium Amide Bases (HCLAs) 33 1.2.2.4 Allylation using Diisopropyltartrate-modified Allylborinate Reagents 35 1.2.3 Catalyst Controlled Asymmetric Synthesis 38 1.2.3.1 Asymmetric Hydrogenations using a Chiral Transition Metal Complex 39 1.2.3.2 Asymmetric Oxidation of Alkenes 41 1.2.3.3 Catalytic Asymmetric Diels-Alder Cycloaddition 45 1.2.3.4 Catalytic Asymmetric Aldol Condensation 46 1.3 Asymmetric Synthesis of y'-Lactones 49 1.3.1 Asymmetric Synthesis of y-Lactones Possessing One Chiral Centre 49 1.3.1.1 Synthesis of a Simple 3-Substituted y-Lactone 49 1.3.1.2 Synthesis of a Simple y-Substituted y-Lactone, a Precursor to Rubrenolide 51 1.3.1.3 A Divergent Synthesis of Either Enantiomer of Simple a- or - Substituted y-Lactones 52 1.3.1.4 Synthesis of cc-Methylene 7-Substituted 7-Lactones 55 1.3.2 Asymmetric Synthesis of y-Lactones Possessing Two Chiral Centres 56 1.3.2.1 A 'Chiral Pool' Approach to trans-Whisky Lactone 56 1.3.2.2 Synthesis of Lignan Lactones via a Chiral Michael Acceptor 57 1.3.2.3 Synthesis of an cc-Methylene 3,y-Di-substituted y-Lactone via HCLA Methodology 58 1.3.2.4 Synthesis of a-Methylene—,y-Di-substituted 7-Lactones via Halocyclisation 60 1.3.3 Asymmetric Synthesis of y-Lactones Possessing Three Chiral Centres 61 1.3.3.1 Total Synthesis of Blastmycinone 61 1.3.3.2 Chiral Recognition in the Synthesis of Tr-substituted y-Lactones 63 1.3.3.3 Tr-substituted y-Lactones via a Chiral Butenolide Synthon 65 2 Discussion 67 2.1 The Conception and Synthesis of a Camphene-Derived Chiral Auxiliary 68 2.1.1 Chiral Auxiliaries Derived From Chiral Alcohols via Nitrene Insertion 68 2.1.2 Synthesis of Chiracamphox 75 2.2 Functionalisation of Chiracamphox 92 2.2.1 Synthesis of the Propionyl Imide of Chiracamphox - 92 2.2.2 Synthesis of the N-Acryloyl Imide of Chiracamphox 98 2.2.3 Synthesis of Substituted Acryloyl Imides of Chiracamphox 101 2.3 Alkylation and Acylation of Metal Enolates of Acyl Imides of Chiracamphox 105 2.3.1 Stereospecific Metal Enolate Formation 105 2.3.2 Alkylation Reactions 106 2.3.3 Acylation Reactions 114 2.4 Asymmetric Aldol Condensation Reactions 119 2.4.1 Aldol Condensation of Lithium Enolates 119 2.4.2 Aldol Condensation of Dialkylboron Enolates -123 2.5 Asymmetric Diels-Alder Cycloaddition Reactions 128 2.5.1 Lewis Acid Catalysts in the Diels-Alder Cycloaddition Reaction 128 2.5.2 Asymmetric Diets-Alder Reaction of Unsaturated Imides of Chiracamphox 131 2.6 Asymmetric 1,4-Conjugate Addition to Unsaturated Imides of 207 and Related Reactions 136 2.6.1 Auxiliary Controlled 1,4-Conjugate Addition Reactions 136 2.6.2 1,4-Conjugate Addition of Diethylaluminium Chloride to Unsaturated Imides of Chiracamphox 140 2.6.3 Reaction of Unsaturated Imides of Chiracamphox with Aluminium Vinyl Reagents 144 2.6.4 1,4-Addition of Grignard Reagents to Unsaturated Imides 146 2.6.5 Electrophilic Quenching of Intermediate Enolates 153 2.6.6 Attempted Stereocontrol of Enolate Protonations 156 2.7. Enatioselective Synthesis of a Class of Di- and Tr- Substituted y-Lactones: the Paraconic Acids 158 2.7.1. The Nature and Biological Properties of the Paraconic Acids 158 2.7.2 Asymmetric Synthesis of Paraconic Fatty Acids 162 2.7.3 Choice of Target and Retrosynthesis 167 2.7.4 Michael Addition Reactions with Sorbyl Imide 301 171 2.7.5 Enatioselective Synthesis of Dihyroprotolichesterinic Acid (-)-278 182 2.7.6 Synthesis of the (+)-Dihydroprotolichesterinic Acid Using Phenyl as a Carboxyl Equivalent. 197 2.7.7 Synthesis of a 5- Substituted Paraconic Acid a Formal Synthesis of (-)-Protolichesterinic Acid 298 202 2.7.8 Attempted Synthesis