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Stereoselective Conjugate Addition of Cyanide

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Stereoselective Conjugate Addition of Cyanide Stereoselective Conjugate Addition of Cyanide A thesis presented by Nicola Jane Con vine In partial fulfilment of the requirements for the degree of Doctor of Philosophy and the award of the Diploma of Imperial College London 1630442 Heilbron Laboratory Department of Chemistry Imperial College London SW7 2AY Abstract This thesis describes the development of a diastereoselective conjugate addition of cyanide. Chapter One contains a critical review of reported asymmetric conjugate additions of cyanide and a brief summary of non-asymmetric conjugate additions of cyanide to enones. Chapter Two summarises the initial research objective of this project; namely development of an enantioselective conjugate addition of cyanide to enones. Chapter Three presents the research undertaken to achieve this objective and the evolution of the project to the successful diastereoselective hydrocyanation employing an oxazolidinone as a chiral auxiliary. In Chapter Three, investigation into the ZnI2 and YbCb catalysed addition of TMSCN to cyclohexenone and other carbonyl compounds is detailed. Since enantioselective adaptation of this methodology proved unsuccessful, further research into the hydrocyanation of a,p- unsaturated carbonyl compounds under Sm(O'Pr)3 catalysis with the cheap cyanide source, acetone cyanohydrin, is detailed. This is followed by adaptation of the Sm(O'Pr)3 methodology to chiral a,|3-unsaturated W-acyl oxazolidinones to provide a diastereoselective conjugate addition of cyanide. This section includes a review of reported asymmetric conjugate additions to chiral a,(3-unsaturated 7V-acyl oxazolidinones and continues with a discussion of the substrate scope and possible mechanism of the hydrocyanation. Chapter Three concludes with the application of this stereoselective hydrocyanation to the synthesis of three drug molecules, Pregabalin, Baclofen and Rolipram, and includes a brief review of previously reported syntheses of these molecules. Chapter Four summarises the findings in this thesis and offers suggestions for future development of this work. Chapter Five gives full experimental details along with spectroscopic and physical data for all new compounds. Acknowledgements Firstly I have to thank Prof. Alan Armstrong for giving me the opportunity to undertake this project and for all his help and guidance throughout. I would also like to thank Dr. Matt Popkin for his support and suggestions for the project, especially during my time at GSK. I would also like to acknowledge EPSRC and GSK for their financial support. My thanks go to the Armstrong group members (Tom, lan, Jenna, Graham, Fred, Rich C, Chris, Steve, James, Richie, Lizzie, Hans, Nigel, Dave, Nat, Carol, Teika, Rich K, Jamie) for making the whole experience more enjoyable and for their ideas. Special thanks go to Tom and Nigel for their computer support and Dave for proof-reading this thesis. Thanks also to my lab colleagues at GSK Tonbridge for making me welcome during my placement. I would also like to acknowledge the technical support given by the NMR, MS and X- ray departments at 1C and from the NMR and MS departments at GSK Tonbridge. Finally I would like to thank my family for all their support throughout. Contents Abstract.......................... .................................................................................... ............2 Acknowledgements................ ........................................................................................ 3 Abbreviations.................................................................................................................? 1 Introduction-Stereoselective conjugate addition of carbon nucleophiles....................9 1.1 Enantioselective conjugate addition to enones.............................................9 1.2 Enantioselective conjugate addition of cyanide.. .................................. .....14 1.3 Diastereoselective conjugate addition of cyanide............................ .......... 18 1.4 Non-asymmetric conjugate addition of cyanide to enones...................... .20 2 Research Objectives..... .............................................................................. ...............24 3 Results and Discussion................................................. ............... ..............................25 3.1 Metal-catalysed cyanide addition to enones........ ...................................... .25 3.1.1 Zinc iodide catalysed reaction.. ....................................................... ..25 3.1.1.1 Isomerisation of 1,2-adductto l,4-adduct................................28 3.1.1.1.1 Investigation of stereospecificity of isomerisation..........3 1 3.1.1.2 Addition of asymmetric ligands.................. ....... ......................33 3.1.1.3 Znl2 catalysed conjugate addition of TMSCN to other substrates............... .............................................................. .....35 3.1.1.3.1 Synthesis of substrates.....................................................35 3.1.1.3.2 Results of Znb catalysed addition of TMSCN to other 3.1.2 Ytterbium trichloride catalysed reaction.................. ................... ......42 3.1.2.1 Comparison with other lanthanide catalysts...................... .......46 3.1.2.2 YbCl3 catalysis of TMSCN addition to other substrates.......... 48 3.1.2.3 Yb-catalysed reaction in presence of asymmetric ligands....... 49 3.1.3 Samarium isopropoxide catalysed conjugate addition with acetone cyanohydrin................. ...................................... ............ .......53 3.2 Development of auxiliary-controlled cyanide conjugate addition... ...... ....56 3.2.1 Introduction: Diastereoselective conjugate addition with oxazolidinone auxiliaries...................................................................56 3.2.2 Diastereoselective conjugate addition of cyanide with Evans' auxiliary.............................................................................................60 3.2.2.1 Initial test reactions..................................................................60 3.2.2.2 Relative stereochemistry of product.........................................63 3.2.2.3 Investigation of the Sm-catalysed reaction conditions.............64 3.2.2.4 Chiral oxazolidinone substrates in other hydrocyanating systems.....................................................................................68 3.2.2.5 Effect of auxiliary on stereoselectivity.....................................70 3.2.2.6 Scope of substitution of the alkene...........................................73 3.2.2.6.1 Synthesis of substrates.....................................................73 3.2.2.6.2 Hydrocyanation...............................................................78 3.2.2.7 Mechanistic possibilities..........................................................82 3.2.2.8 Auxiliary cleavage and product manipulation..........................85 3.2.2.8.1 Hydrolytic auxiliary cleavage.........................................85 3.2.2.8.2 Reductive auxiliary cleavage...........................................86 3.2.2.8.3 Nitrile reduction with concomitant auxilary cleavage....87 3.3 Application of methodology to drug molecule syntheses..........................90 3.3.1 Introduction.......................................................................................90 3.3.1.1 Pregabalin.................................................................................90 3.3.1.2 Baclofen....................................................................................92 3.3.1.3 Rolipram...................................................................................94 3.3.2 e«/-Pregabalinsynthesis....................................................................98 3.3.3 (5)-Baclofen synthesis.....................................................................101 3.3.4 (5)-Rolipram synthesis.................................................................... 104 4 Conclusions.............................................................................................................107 5 Experimental........................................................................................................... 109 5.1 Znh catalysed conjugate addition of TMSCN.........................................111 5.1.1 Preparation of authentic samples of cyclohexenone derived products...........................................................................................! 11 5.1.2 Investigation into Znl2 catalysed cyanations...................................! 15 5.1.2.1 Znl2 catalysed cyanation in the presence of chiral additives.... .............................................................................. 119 5.1.2.2 Znl2 catalysed cyanation of other substrates.......................... 121 5.1.2.2.1 Synthesis of a,p-unsaturated compounds.. .................... 121 5.1.2.2.2 Cyanation of substrates.... ............................................. 125 5.2 YbCls catalysed cyanation... ..................................................................... 129 5.2.1 Cyanation in the presence of pybox Iigands....................................l35 5.3 Non-asymmetric Sm(O'Pr)3 catalysed reaction.... .................................... 138 5.4 Diastereoselective conjugate addition of cyanide...................... .............. 140 5.4.1 Synthesis of initial test substrates.................................................... 140 5.4.2 Asymmetric hydrocyanation of a,p-unsaturated N-acyl 5.4.3 Hydrocyanation of chiral a,p-unsaturated TV-acyl oxazolidinones under
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