Enantioselective Copper final version

158 Pages·2010·7.24 MB·English

by  Claire Oswald

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

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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

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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

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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!!

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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
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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.
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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
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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
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