UNTVERSTTY COLLEGE LONDON DEPARTMENT OF CHEMISTRY /M\ UCL UNIVERSITY OF LONDON CHIRAL DIAMINES IN ASYMMETRIC SYNTHESIS by ALEXANDER J A COBB A THESIS PRESENTED TOWARDS TFIE DEGREE OF DOCTOR OF PHILOSOPHY 2001 ProQuest Number: U643308 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest. ProQuest U643308 Published by ProQuest LLC(2016). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code. Microform Edition © ProQuest LLC. ProQuest LLC 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106-1346 Felix qui potuit rerum cognoscere causas Virgil, Georgies no, 2 ,1 490 To my Mother and Father, Contents _____________________________________________________________________________ Table of Contents Abstract vit Abbreviations viii Acknowledgements x Chapter 1 - Introduction 1.1 On the significance of asymmetric synthesis 1 1.2 On concepts within asymmetric synthesis 2 1.3 Asymmetric 1,2-addition of nucleophiles to prochiral carbonyl 5 compounds 1.3.1 Asymmetric addition of dialkylzinc to aldehydes 6 1.3.2 Tridentate ligands for the enantioselective addition of 13 diethylzinc to benzaldehyde 1.3.3 Ci-symmetric ligands in the enantioselective addition 15 of diethylzinc to benzaldehyde 1.3.4 Enantioselective hydrocyanation of carbonyl compounds 17 1.4 Asymmetric 1,4-conjugate addition - The Michael addition 22 1.4.1 Enantiopure crown ethers in the asymmetric Michael 23 addition. 1.4.2 Other Michael additions using alakali metal-catalysed systems. 25 1.4.3 Enantiopure p-aminoalcohols in the asymmetric Michael 27 addition. 1.4.4 Cz-symmetric ligands in the catalytic enantioselective 32 Michael addition. 1.5 Asymmetric epoxidations 35 1.5.1 The Katsuki-Sharpless asymmetric epoxidation 35 1.5.2 The Oxone® asymmetric epoxidation 38 1.5.3 The Julia-Colonna asymmetric epoxidation 41 Contents _____________________________________________________________________________v _ 1.6 Asymmetric lithium-mediated reactions 43 1.6.1 Asymmetric desymmetrisation of achiral epoxides by 43 deprotonation 1.6.2 Enantioselective deprotonation of ketones 46 Chapter 2 - Synthesis of ligands with two stereogenic centres derived from 1,2-diaminocyclohexane 2.1 Ligands with 1,2-vicinal stereogenic nitrogen atoms in 50 asymmetric synthesis 2.2 Synthesis of simple secondary amides 53 2.2.1 Synthesis of secondary amides with two stereogenic centres 53 2.3 Synthesis of tertiary amides with two stereogenic centres 61 2.4 Reduction of amides 65 2.4.1 Reductions with lithium aluminium hydride 65 2.4.2 Reductions with borane 68 2.43 In situ generation of diborane 70 2.4.4 Metal-alcohol reductions 72 2.4.5 Lewis acid assisted reductions 74 2.5 Synthesis of further ligands with two stereogenic centres 79 2.6 Synthesis of A-aryl ligands 82 2.7 Synthesis of chiral ketones 85 Chapter 3 - Synthesis of ligands with more than two stereogenic centres derived from 1,2-diaminocyclohexane 3.1 Chiral ligands with multiple stereogenic centres by acylation 90 3.2 Synthesis of tertiary amides with multiple stereogenicity 90 3.3 Synthesis of secondary amides with multiple stereogenicity 98 3.4 Reduction of amides with multiple stereogenic centres 102 3.5 Other p-aminoalcohols with multiple stereogenic centres 104 3.6 A-Alkylation of secondary amines with multiple stereogenic 106 centres Contents_____________________________________________________________________________vj__ Chapter 4 - Enantioselective additions of diethylzinc to aldehydes 4.1 Use of ligands in the asymmetric addition of diethylzinc to 111 aldehydes 4.2 Other ligands used in the asymmetric addition of diethylzinc to 123 benzaldehyde 4.3 Conclusions 124 Chapter 5 - Enantioselective 1,4-conjugate additions 5.1 Use of chiral amides in the asymmetric Michael addition 126 5.2 Chiral amine as a crown ether substitute 128 5.3 Nickel-catalysed asymmetric Michael additions 129 5.4 Other ligands used for the asymmetric Michael addition 134 5.5 Conclusions 135 Chapter 6 - Other asymmetric processes using ligands derived from 1,2- diaminocyclohexane 6.1 Asymmetric epoxidation 137 6.2 Asymmetric deprotonations 139 6.3 Asymmetric hydrocyanations 141 Chapter 7 - Experimental 142 References 200 Appendix A X-ray crystallographic data set 209 Appendix B Published Paper 221 Abstract _____________________________________________________________________________vii Abstract The synthesis of a range of novel enantiomerically pure vicinal 1,2- diamines is described as has their subsequent use as asymmetric catalysts. Most of the amines are of a C 2 symmetric nature and are derivatives of (l/?,2i?)-(-)-1,2- diaminocyclohexane, although several disymmetric ligands have been prepared. The preparation of these ligand systems is described including the synthesis of those with just the two stereogenic centres of the diaminocyclohexane as well as those with additional stereogenicity. The addition of a secondary chiral centre gives rise to the possibility of having several diastereomers which have all been synthesised where relevant. Furthermore, most of these ligands have been prepared as both secondary and tertiary amines. The amine ligands have been tested on a variety of reactions such as the asymmetric addition of diethylzinc to benzaldehyde, the asymmetric 1,4-conjugate Michael addition and to a lesser extent the asymmetric lithium mediated deprotonation and asymmetric epoxidations. The effects of varying from secondary to tertiary amines, and from having two stereogenic centres to having four has been recorded for the first two mentioned processes. From these results, catalytic models have been proposed to explain the enantioselectivity of the systems. A large majority of the intermediates required for the synthesis of the amines have also been tested to varying success and this is also described. Finally, full experimental data has been given as well as a full list of references. Abbreviations vin Abbreviations acac acetonylacetonate DBU Diazabicycloundecene DCC 1,3-Dicyclohexylcarbodiimide DCM Dichloromethane D.e. Diastereomeric excess DEPT Distortionless enhancement by polarisation transfer DIPA Diisopropylamine DMAP Dimethylaminopyridine DNA Deoxyribonucleic acid E.e. Enantiomeric excess El Electron impact FAB Fast atom bombardment HMPA Hexamethylphoshoramide HOBT 1 -hydroxybenzotriazole h.p.l.c High performance liquid chromatography HRMS High resolution mass spectrometry IR Infrared LAH Lithium aluminium hydride LDA Lithium diisopropylamide LRMS Low resolution mass spectrometry M.p. Melting point (in degrees celcius) NMR Nuclear magnetic resonance Nu Nucleophile rBHP tert-h\x\y\ hydroperoxide TFAT Trifluoroacetyl triflate THF Tetrahydrofuran tlx . Thin layer chromatography UHP Urea-hydrogen peroxide UV Ultraviolet Abbreviations_________________________________________________________________________ix Notation Stereochemistry is represented in the following ways; An even-shaped bar refers to relative stereochemistry H l.NH, %' Q I (±)-/rû«5-1,2-diaminocyclohexane. H A wedge-shaped bar refers to absolute stereochemistry. H ^ ^ 2 (l/?,27?^-(-)-/ra«5-1,2-diaminocyclohexane Acknowled gements Acknowledgements I would like to thank the following people for their help and contribution; My supervisor, Dr Charles M. Marson for his help over the past few years. Also, the many other academic staff whose help has been invaluable especially Dr Jason Eames, Dr Peter Wyatt and Dr Jon Steed. My colleagues that have added colour and/or inspired me with ideas throughout; Dr Robert Melling, Anthony Thacker, William Suthers, Dr Richard Decreau, Dr Ido Schwarz, Steven Wright and lastly, but by no means least, Alf Rioja. However, most of my thanks lies with the tireless efforts of the technical staff; Greg Combriades, Stuart Adams, Alvin Roachford, Alan Bradshaw, Steve Corker, Jorge Gonzalez, Dr Abil Aliev, Mike Cocksedge, Jill Maxwell and Alan Stones amongst many. My mother, father and sister for their love and support, moral and financial. Heather for her patience, love and encouragement without whom, the research would have been immeasurably more difficult. Finally, I would like to thank the EPSRC (Engineering and Physical Sciences Research Council) for their funding of this work. Chapter 1 Introduction Chapter 1 Introduction 1.1 The significance of asymmetric synthesis Until relatively recently, the concept of the world being either left or right handed at the molecular level was mainly limited to mathematical and physical models. With the advent of medicine and the advancement of analytical techniques the importance of molecular symmetry in biological contexts has become paramount. The discovery that DNA and amino acids were chiral (having a mirror image incapable of superimposition, figure 1.1a), introduced the importance of stereochemistry. However, the biological implications were less clear until the 1960’s when the consequences of adverse stereochemistry came to light in the unfortunate case of thalidomide (figure 1.1 b). One of the enantiomeric forms of the racemic drug had the sedative effects that were desired. However, the opposite enantiomer had devastating teratogenic effects. The racemic drug was administered to pregnant women to relieve pain but caused irreparable