Mechanistic Studies of Enantioselective Alkene Bromolactonisation Reactions

326 Pages·2014·11.75 MB·English

by  A Jones

Mechanistic Studies of
Enantioselective Alkene
Bromolactonisation Reactions

A thesis submitted by

Alexander X. Jones

To Imperial College London in partial fulfilment of the
requirements for the degree of

Doctor of Philosophy

Department of Chemistry
Imperial College London
South Kensington
London SW7 2AZ
United Kingdom March 2014
Declaration of Originality

This thesis is submitted in partial fulfilment of the requirements for the degree
of Doctor of Philosophy. It describes work carried out in the Department of
Chemistry, Imperial College London between October 2010 and March 2014.
Unless otherwise stated, the research described is my own and not the
product of collaboration.

Alexander X. Jones
9th March 2014

Copyright Declaration
The copyright of this thesis rests with the author and is made available under
a Creative Commons Attribution Non-Commercial No Derivatives licence.
Researchers are free to copy, distribute or transmit the thesis on the condition
that they attribute it, that they do not use it for commercial purposes and that
they do not alter, transform or build upon it. For any reuse or redistribution,
researchers must make clear to others the licence terms of this work.
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Abstract

Asymmetric alkene halofunctionalisation is a vibrant and rapidly expanding field.
Several promising organocatalysts have emerged based on privileged binaphthyl
phosphoric acid and cinchona alkaloid scaffolds. However, there is still significant
potential for improvement. Many catalyst systems are limited in substrate scope and
mechanistic understanding.

In this thesis we describe the development of asymmetric bromolactonisation
reactions catalysed by bis-cinchona alkaloid, (DHQD) PHAL, as modified by added
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carboxylic acids. This combination delivers bromolactones with enantioselectivity at
a comparable level to bespoke organocatalysts previously optimised for particular
substrate classes. The utility of our system is based on the commercial availability of
all reagents and the ability to tune the performance of (DHQD) PHAL with reaction
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additives.

The mode of substrate activation and the role of the carboxylic acid additive are
investigated. Asymmetric induction is strongly influenced by the concentration and
the stereoelectronic properties of the additive, and enantioselectivity deteriorates with
reaction conversion in its absence. Interactions between carboxylic acids and
(DHQD) PHAL are characterised by crystallographic and equilibrium 1H NMR
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analysis. 2D-NOESY experiments indicate that acids significantly restrict the
rotational flexibility of (DHQD) PHAL in solution. We propose that catalyst rigidity
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is essential for maximisation of enantioselectivity. This hypothesis leads to the
development of conformationally constrained catalyst derivatives which catalyse
bromolactonisation with greater enantioselectivity than (DHQD) PHAL.
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The relative stereoselectivities of successive alkene bromination and cyclisation steps,
and the configurational stability of intermediate bromonium ions are elucidated. An
unusual scenario is encountered whereby product e.r. is also determined by the
regioselectivity of lactonisation. Finally, a unifying model for asymmetric induction
is proposed which accounts for the absolute product configurations observed.
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Contents
DECLARATION OF ORIGINALITY 2
ABSTRACT 3
CONTENTS 4
ACKNOWLEDGEMENTS 8
ABBREVIATIONS 9
1 INTRODUCTION 11
1.1 The Applications of Alkene Halofunctionalisation 11
1.2 Historical Progress towards the Development of Asymmetric
Halofunctionalisation 14
1.3 Catalytic Enantioselective Halofunctionalisation 26
1.4 Type III Catalysis 42
1.5 (DHQD) PHAL Catalysed Halocyclisations 58
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1.6 Conclusion 70
1.7 Project Aims 72
1.8 Thesis Outline 73
2 RESULTS AND DISCUSSION 74
2.1 Investigation of Borhan’s Asymmetric Halolactonisation Reaction 74
2.2 The Additive Effect of Benzoic Acid on Asymmetric Halolactonisation 76
2.3 Optimisation if Asymmetric Bromolactonisation Reaction Conditions 77
2.4 Does Bromonium Ion Racemise Due to Alkene-Alkene Exchange? 93
2.5 Kinetic Experiments To Determine Effect Of Benzoic Acid on Rate of
Bromolactonisation 97
3 SUBSTRATE SYNTHESIS 100
3.1 Reasons for Substrate Selection 100
3.2 Synthesis of 1,1-Disubstituted Alkenoic Acid Substrates 103
4
3.3 Synthesis of Kinetic Resolution Substrate 150 113
3.4 Synthesis of Dihydrobenzoic acid (148) 114
3.5 Synthesis of Tri-substituted Alkene 157 115
3.6 Synthesis of Tetra-substituted Alkene 159 116
3.7 Synthesis of 1,2-disubstituted Alkenes (E)-73 and (Z)-76 119
3.8 Synthesis of o-vinyl Benzoic Acid (146) 122
3.9 Synthesis of o-allyl Benzoic Acid (147) 122
3.10 Synthesis of Stilbene-2-carboxylic Acid (78) 124
4 RESULTS OF BROMOLACTONISATION REACTIONS 125
4.1 Bromolactonisation of 1,1-Disubstituted Alkenoic Acids 125
4.2 The Influence of Alkene Substitution Pattern on Enantioselectivity of
Bromolactonisations 128
4.3 Bromolactonisation of (E) and (Z)-1,2 Disubstituted Alkenes 130
4.4 Bromolactonisation of o-vinyl and o-allyl Benzoic Acids 137
4.5 Kinetic Resolution by Bromolactonisation 137
4.6 Desymmetrisation by Bromolactonisation 140
4.7 Summary and Discussion 141
4.8 Mechanistic Insights from Substrate Screening Experiments 145
4.9 Interpretation of Results for Bromolactonisation of 1,2-Disubstituted Alkenes
149
4.10 Discussion of Change in e.r. with Conversion for Bromolactonisation of (E)-73
and 78 152
4.11 Conclusion 155
5 CONFORMATIONAL STUDIES OF (DHQD) PHAL:CARBOXYLIC ACID
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H-BONDED COMPLEXES 158
5.1 Conformations of Cinchona Alkaloids 159
5.2 Experimental Determination of Cinchona Alkaloid Conformations 166
5.3 Conformations Of Bis-Cinchona Alkaloid Catalysts 168
5.4 1H NMR Spectra of (DHQD) PHAL:Carboxylic Acid Mixtures 175
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5.5 X-ray Crystal Structure of (DHQD) PHAL:Anthranoic Acid Complex 179
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5.6 The Influence of Other Carboxylic Acids on (DHQD) PHAL Conformations 183
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5.7 Influence of Solvent on Conformations of (DHQD) PHAL 188
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5.8 Influence of Acid Concentration on Conformation of (DHQD) PHAL 190
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5.9 Catalyst Interactions with NBS 198
5.10 Calculation of Binding Constants 206
5.11 Discussion of Mechanistic Insights into Bromolactonisation Reaction without
Benzoic Acid 215
5.12 Discussion of Mechanistic Insights into Bromolactonisation Reaction with
Excess Acid 217
5.13 Design and Synthesis of Constrained Catalysts 221
5.14 Model for Asymmetric Induction 235
6 CONCLUSION 239
7 EXPERIMENTAL SECTION 242
7.1 General Experimental 242
7.2 Synthesis of 4-Phenyl-4-pentenoic acid (114) 244
7.3 Synthesis of 5-Phenylhexen-5-oic acid (101) 245
7.4 Synthesis of 6-Phenylhepten-6-oic acid (153) 247
7.5 Synthesis of 3-Phenylbut-3-enoic acid (151) 250
7.6 3-Methylidenebicyclo[2.2.1]hept-5-ene-2-carboxylic acid (150) 255
7.7 Dihydrobenzoic Acid (148) 256
7.8 Synthesis of (4Z)-4-phenylocta-4,7-dienoic Acid (157) 257
7.9 Synthetic Routes Towards 5-Methyl-4-phenylhex-4-enoic Acid (159) 259
7.10 Synthesis of (Z)-5-Phenylpent-4-enoic Acid (76) 265
7.11 Synthesis of (4E)-5-Phenylpent-4-enoic acid (73) 267
7.12 2-Vinyllbenzoic acid (146) 270
7.13 Synthesis of 2-(Prop-2-en-1-yl)benzoic acid (147) 272
7.14 Synthesis of 2-[(E)-2-phenylethenyl] Benzoic acid (78) 274
7.15 General Procedure for Bromolactonisation 275
7.16 Determination of Absolute Configuration of Product Bromolactones by
Comparison to Literature 287
7.17 Determination of Absolute Configuration by Radical Debromination 288
7.18 Determination of Absolute Configuration of Remaining Bromolactones 290
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7.19 Characterising Data for Constrained Catalysts 215 and 216 291
7.20 2D-NOESY Spectra 297
8 REFERENCES 302
APPENDIX 318

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Acknowledgements

First, and foremost, I would like to thank my supervisors; Dr. Chris Braddock and
Prof. Alan Armstrong, for the opportunity to work on this project. Due to their
enthusiasm, support and direction I have found this project extremely enjoyable and
rewarding. I would also like to thank my industrial supervisor Dr. Stacy Clark for her
support and insights during my placement in Stevenage, and for her advice on
presentation skills. I am very grateful to GSK for funding the project. The assistance
and advice of the analytical services at Imperial, and particularly of Pete Haycock
have also been essential.
I would of course like to thank the members of the Braddock, Armstrong and Bull
groups for making the past three years so enjoyable. James Bull, Karl Bonney, Matt
Hughes and Jordi Bures have been excellent role models and I have learnt a lot from
them. Further thanks go to Karl for helping me initially to settle into the lab and for
the great trip to Zurich. I would also like to thank Gökhan Yahioglu for encouraging
me to maintain broader interests in and out of chemistry. Jared Marklew and James
Clarke have helped a lot with the proofreading, and along with Ioanna Stamati and
Harry Milner have been really good friends.
I would also especially like to thank Tyler, Alex, Stella, Oleg and Miriam for getting
me out the lab every now and again for unforgettable long weekends away.
Finally, I would like to dedicate this thesis to my parents and brothers who deserve
the greatest thanks, and to whom I am extremely grateful for their support and
encouragement.

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Abbreviations

Å Angstrom
[A] concentration of A
Ac acetyl
Ad adamantyl
Ar aromatic
Boc t-butoxycarbonyl
br broad (NMR)
Bu butyl
BzOH benzoic acid
Cat. catalyst
CI chemical ionisation (MS)
cm-1 wavenumbers
COSY correlation spectroscopy (NMR)
Cy cyclohexyl
 chemical shift (NMR)
 change in chemical shift (NMR)
DCM dichloromethane
(DHQD) PHAL bis-(dihydroquinidinyl)phthalazine
2
DMF dimethylformamide
DMAP dimethylaminopyridine
DMSO dimethylsulfoxide
d.r. diastereomer ratio
e.e. enantiomeric excess
EI electron ionisation (MS)
eq. equivalent
e.r. enantiomer ratio
ES electrospray ionisation
Et ethyl
FT-IR Fourier transform infrared spectroscopy
g gram(s)
h hour(s)
HPLC high performance liquid chromatography
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HRMS high resolution mass spectrometry
Hz Hertz
IR infrared spectroscopy
Me methyl
min. minutes
mM millimolar
mg milligrams
mmol millimoles
n- normal-
MS mass spectrometry
nm nanometre
NBS N-bromosuccinimide
NCS N-chlorosuccinimide
NIS N-iodosuccinimide
NMR nuclear magnetic resonance
NOESY nuclear Overhauser effect spectroscopy
Ns p-nitrophenyl sulfonyl
o- ortho-
i-Pr isopropyl
p- para-
ppm parts per million (NMR)
Ph phenyl
R undefined alkyl or aryl substituent
rt room temperature
t- tertiary-
TBDMS tert-butyldimethylsilyl
TFA trifluoroacetic acid
THF tetrahydrofuran
TIPS triisopropylsilyl
TLC thin-layer chromatography
Tr trityl
 frequency (IR)
X Any halide
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