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Enantioselective Copper final version PDF

158 Pages·2010·7.24 MB·English
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Enantioselective Copper-Catalysed Reductive Michael Cyclisations Thesis Submitted in Accordance with the Requirement of The University of Edinburgh for the Degree of Doctor of Philosophy By Claire Louise Oswald MChem (Hons) Doctor of Philosophy – The University of Edinburgh – 2010 Declaration I hereby declare that, except where specific reference is made to other sources, the work contained within this thesis is the original work of my own research since the registration of the PhD degree in September 2006, and any collaboration is clearly indicated. This thesis has been composed by myself and has not been submitted, in whole or part, for any other degree, diploma or other qualification. Signed Claire Louise Oswald Doctor of Philosophy – The University of Edinburgh – 2010 Table of Contents Declaration...................................................................................................................2
 Acknowledgements.....................................................................................................iv
 Abstract.......................................................................................................................vi
 Abbreviations.............................................................................................................vii
 Ligands........................................................................................................................xi
 Ligands.......................................................................................................................xii
 1
 Copper-Mediated Conjugate Reduction...............................................................1
 1.1
 Introduction..................................................................................................1
 1.2
 Stryker’s Reagent.........................................................................................1
 1.3
 Copper-Catalysed Hydrosilylation...............................................................4
 1.4
 Copper-Catalysed Asymmetric 1,4-Reduction Reactions............................9
 1.4.1
 Introduction..............................................................................................9
 1.4.2
 Copper-Catalysed Asymmetric 1,4-Reductions of α,β-Unsaturated Esters, Ketones and Aldehydes............................................................................9
 1.4.3
 Copper-Catalysed Asymmetric 1,4-Reductions of α,β-Unsaturated Nitroalkenes.......................................................................................................27
 1.4.4
 Copper-Catalysed Asymmetric 1,4-Reductions of α,β-Unsaturated Nitriles ................................................................................................................30
 1.4.5
 Copper-Catalysed Asymmetric 1,4-Reductions of α,β-Unsaturated Sulfones..............................................................................................................35
 1.4.6
 Copper-Catalysed Asymmetric Reduction of Other Electron Deficient Alkenes...............................................................................................................38
 1.4.7
 Conclusion..............................................................................................39
 1.5
 Reductive Aldol Reactions and Related Modifications.............................41
 i 1.5.1
 Introduction............................................................................................41
 1.5.2
 Stoichiometric Reductive Aldol Reactions............................................44
 1.5.3
 Catalytic Reductive Aldol Reactions.....................................................46
 1.5.4
 Reductive Henry Reactions....................................................................58
 1.5.5
 Reductive Mannich Reactions................................................................59
 1.5.6
 Conclusion..............................................................................................61
 1.6
 Conclusion..................................................................................................62
 2
 Enantioselective Copper-Catalysed Reductive Michael Cyclisations...............63
 2.1
 Introduction................................................................................................63
 2.1.1
 Metal-Mediated Reductive Michael Reactions......................................64
 2.1.2
 Organocatalysed Reductive Michael Reactions.....................................68
 2.2
 Results and Discussion...............................................................................72
 2.2.1
 Nitrogen-Tethered Substrates.................................................................72
 2.2.1.1
 Preparation of Cyclisation Precursors............................................72
 2.2.1.2
 Ligand Optimisation.......................................................................74
 2.2.1.3
 Substrate Scope..............................................................................76
 2.2.1.4
 Conclusions....................................................................................79
 2.2.2
 Carbon- and Oxygen-Tethered α,β-Unsaturated Ester Substrates.........80
 2.2.2.1
 Preparation of Cyclisation Precursors............................................80
 2.2.2.2
 Ligand Optimisation.......................................................................80
 2.2.2.3
 Substrate Scope..............................................................................82
 2.2.2.4
 Mixed α,β-Unsaturated Ketone and Ester substrates.....................85
 2.2.3
 Carbon- and Oxygen-Tethered α,β-Unsaturated Ketone Substrates.....88
 ii 2.2.3.1
 Preparation of Cyclisation Precursors............................................88
 2.2.3.2
 Optimisation and Scope.................................................................89
 2.3
 Conclusions and Future Work....................................................................98
 2.4
 Experimental............................................................................................100
 2.4.1
 General Information.............................................................................100
 2.4.2
 Perparation of Cyclisation Precursors..................................................101
 General Procedure A: Synthesis of Nitrogen-Tethered Cyclisation Precursors ......................................................................................................................101
 General Procedure B: Synthesis of Nitrogen-Tethered Cyclisation Precursors ......................................................................................................................101
 General Procedure C: Preparation of Phosphonium Ylides.........................107
 General Procedure D: Wittig Reactions.......................................................108
 General Procedure E: Heck Reactions.........................................................108
 2.4.3
 Racemic Reductive Michael Cyclisations............................................118
 General Procedure F: Racemic Reductive Michael Cyclisations with Cu(OAc) ·H O, rac-Binap and TMDS........................................................118
 2 2 General Procedure G: Racemic Reductive Michael Cyclisations with Cu(OAc) ·H O, dppf and TMDS.................................................................119
 2 2 2.4.4
 Enantioselective Reductive Michael Cyclisations...............................133
 General Procedure H: Enantioselective Reductive Michael Cyclisations with Cu(OAc) ·H O and TMDS...........................................................................133
 2 2 3
 References........................................................................................................140 4 Appendix.......................................................................................................... 144 iii Acknowledgements Firstly, I would like to thank Hon for giving me the opportunity to work within his research group. I am extremely grateful for the advice and guidance you have given me over the past few years. I would also like to thank Justine Peterson and Dr Reddy’s for funding and support over the past few years. Thank you for your time and patience during my 2 month stay in Cambridge. Thanks to all of the people who have made the Lam group such an amazing place to work during my time in Edinburgh, including Old Gordon, Isabel, Pekka, Oscar, Ralph, Myriam, Leszek, Yi, Benoit, New Gordon, Sam, Charlene, Aakarsh and Serghei. Thanks also to all of the project students and the newbies – Darryl, Donna, and Graham. I have enjoyed working with all of you, and wish you all the best for the future. Of all the people I have worked with, in particular, I would like to thank Mairi, a.k.a Magsi, for being such a great friend over the past few years. I’m sure the experience would not have been the same without you! I would also like to thank all those who have made Edinburgh such an amazing place to live over the past few years, including Audrey, Lauren and fellow ChemSoc committee members Philip, Nat and JC. Thanks to all those who played 5-a-side football with me – long live the Miss-fits, Moobs and Boobs and the Laminators. We were amazing and everybody knows it!! iv Thanks to my family – Mam, Dad and Stuart for all your support (financial and otherwise!) over the past few years. I hope you enjoy my “book”, even if this is the only page you read. Last, but not least, I would like to thank my lovely Euey. Thanks for your never- ending words of encouragement and general nagging during the writing of this thesis. Your love and support over the past two years has made everything so much easier. You ease my troubles, that’s what you do. x v Abstract Hydrometalation of α,β-unsaturated carbonyl compounds provides access to reactive metal enolates, which can then be trapped by a suitable electrophile. The copper- catalysed reductive aldol reaction involves hydrometalation of an α,β-unsaturated carbonyl compound, followed by an inter- or intramolecular aldol reaction. While there have been numerous examples of copper-catalysed reductive aldol reactions reported in the literature, the corresponding reductive Michael reaction has been relatively understudied. Herein, the copper-catalysed reductive Michael cyclisation of substrates containing two α,β-unsaturated carbonyl moieties is described. A range of structurally and electronically diverse substrates were prepared by various different methods. Both α,β-unsaturated ketones and esters underwent cyclisation, in the presence of a copper catalyst, a bisphosphine ligand, and a stoichiometric reductant, to afford 5- and 6- membered carbocyclic and heterocyclic products, with good-to-excellent levels of diastereo- and enantiocontrol. Furthermore, the diastereochemical outcome of these reactions is dependent on the specific reaction conditions used. vi Abbreviations Ac acetyl aq aqueous Ar aryl Bn benzyl br broad COSY Correlation Spectroscopy d doublet DCE dichloroethane DIBAL diisobutylaluminium hydride DMA dimethylacetamide DMAP 4-(dimethylamino)pyridine DME dimethoxyethane DMF N,N-dimethylformamide DMI 1,3-dimethylimidazolidinone dpm bis(2,2,6,6-tetramethyl-3,5-heptadionate) dppf (1,1’)-bis(diphenylphosphino)ferrocene dr diastereomeric ratio ee enantiomeric excess EI electron impact vii equiv. equivalent ES electrospray FT Fourier transform HMBC Heteronuclear Multiple Bond Correlation HMPA hexamethylphosphoramide HPLC high performance liquid chromatography HRMS high resolution mass spectrometry HSQC Heteronuclear Single Quantum Coherence IR infrared spectroscopy LDA lithium diisopropylamide MOM methoxymethyl ether m.p. melting point NHC N-heterocyclic carbene NMO N-methylmorpholine NMR nuclear magnetic resonance nOe nuclear Overhauser effect piv pivaloyl PMHS poly(methylhydrosiloxane) PMP 4-methoxyphenyl PMB 4-methoxybenzyl viii

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1.4.6 Copper-Catalysed Asymmetric Reduction of Other Electron Deficient. Alkenes. Serghei. Thanks also to all of the project students and the newbies – Darryl, Donna, and Graham. I have enjoyed there have been numerous examples of copper-catalysed reductive aldol reactions reported in the
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