Application to the Asymmetric Aldol Reaction

146 Pages·2012·4.05 MB·English

Durham E-Theses
Organocatalysis using Bifunctional Aminoboronic Acids
(cid:21) Application to the Asymmetric Aldol Reaction
GEORGIOU, IRENE
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Organocatalysis using Bifunctional Aminoboronic Acids –
Application to the Asymmetric Aldol Reaction

Irene Georgiou

A thesis submitted in partial fulfilment of the requirements for the degree of Doctor
of Philosophy

Department of Chemistry
Durham University
March 2012
Declaration
The work described in this thesis was carried out in the Department of Chemistry at
Durham University between October 2008 and October 2011, under the supervision
of Prof. Andy Whiting. The material contained has not been previously submitted for
a degree at this or any other university. The research reported within this thesis has
been conducted by the author unless indicated otherwise.

Statement of Copyright
The copyright of this thesis rests with the author. No quotations from it should be
published without prior consent and information derived from it should be
acknowledged.

i
Abstract
The organocatalytic iminium activation strategy acting cooperatively with a Lewis
acidic group has been applied to the development of a novel generation of proline-
based aminoboronic acid catalysts.
Key steps for their synthesis included (-)-sparteine mediated asymmetric
deprotonation of N-Boc-pyrrolidine, copper(I) catalysed borylation of alkylhalides
and catalysed hydroboration of alkenes. The evaluation of the first proline-based
aminoboronic acids is described in the context of organocatalysed aldol reactions
between p-nitrobenzaldehyde and acetone. Enhanced reactivity and
enantioselectivity observed in the presence of a boronate ester analogue of the
catalyst resulted in further examination regarding the role of the esterification diol in
these organocatalytic reactions. Notably, 11B NMR studies have been assessed,
allowing the evaluation of different diols in terms of stability and Lewis acid tuning,
and plausible identification of the catalytic species present.
The feasibility of the catalyst under optimised reaction conditions was
demonstrated in the aldol reaction of different substrates. Extended mechanistic
studies lead to the proposal of a catalytic cycle in which a highly organised transition
state plays a key role for both the reactivity and enantioselectivity observed. Finally,
strategies employed to further examine both reactivity and asymmetric induction of
the free boronic acid catalyst are discussed, examing the carbon length chain
between the secondary amine moiety and the boronic acid group of the catalyst.

ii
"Σαν βγεις στο πηγαιμό για την Ιθάκη,
να εύχεσαι νάναι μακρύς ο δρόμος,
γεμάτος περιπέτειες γεμάτος γνώσεις.
Τους Λαιστρυγόνας και τους Κύκλωπας,
τον θυμωμένο Ποσειδώνα μη φοβάσαι ...
Πολλά τα καλοκαιρινά πρωιά να είναι
που με τι ευχαρίστησι, με τι χαρά
θα μπαίνεις σε λιμένας πρωτοειδωμένους ..."

Κ .Π.Καβάφης, Ιθάκη, 1911

"As you set out on the way to Ithaca
hope that the road is long one,
filled with adventures, filled with understanding.
The Laestrygonians and the Cyclopes,
Poseidon in his anger: do not fear them ...
Many may the summer mornings be
when-with what pleasure, with what joy-
you first put in to harbors new to your eyes ..."

K. P. Cavafy, Ithaca, 1911

iii
To my parents and Aggelos

iv
Acknowledgments
First of all, I would like to express my profound gratitude to my supervisor Prof.
Andy Whiting for his invaluable guidance, support, suggestions and repeated
explanations throughout my research work. His passion for research and active
encouragement the last three years will always be an inspiration to me.
I am grateful for the cooperation of the analytical services at Durham
University. In particular, Dr. Alan Kenwright, Mr. Ian McKeag and Mrs. Catherine
Hefferman of the NMR service; Dr. Jackie Mosely of the mass spectroscopy service;
Dr. Andrei Batsanov of the single X-ray crystallography service; and Dr. Ritu
Kataky and Mrs. Judith Magee from elemental analysis. My special thanks are given
to Dr. Aileen Congreve and Dr. Ellie Hurst for their invaluable and much
appreciated help with the HPLC instruments. In addition, I would like to thank the
National Mass Spectrometry Centre in Swansea for carrying out some high
resolution mass spectroscopy analysis.
Moreover, I would like to acknowledge One North East and the Department
of Chemistry at Durham University for funding my project.
I would also like to take this opportunity to thank all the people who made up
our research group, past and present. I have been benefited working in a unique
environment of not only highly dedicated scientists but also friends. In particular, I
would like to thank Dr. Jonathan Knowles and Dr. Alexander Gehre for providing
useful comments and sharing their experience and knowledge with me during my
studies. A big thank you goes to Ricardo Girling whose contribution in both the
experimental section and writing up procedure of my thesis proved to be invaluable.
My special thanks are due also to Dr. Genaddiy Ilyashenko, Dr. Craig McNair, Andy
Henderson, Fathia Mosa, Garr-Layy Zhou, Adam Calow, Farhana Ferdousi and Nim
Chaiyaveij. I wish them all the best for the future.
But above all, within the group, I was fortunate to make amazing friends such
as Hayley Charville, Benjamin Smith and Vicki O’Connor. Their support has been
unwavering; they have been my strength when times were hard, the greatest fan
when days were bright and the family away from home. A special thank you also
v
goes to Dimitris, who convinced me in the first place to apply for a Ph.D and
supported me all the way through.
Finally, and most importantly, I would like to thank my parents, Nicos and
Leda Georgiou. They have done their best so that Aggelos and I could understand
and appreciate the value of family. Their high expectations for us were always
accompanied with their support, encouragement and love.

vi
Abbreviations
aq. Aqueous
ASAP Atmospheric Solids Analysis Probe
Boc N-tert-Butoxycarbonyl
bp Boiling point
brd Broad doublet
brs Broad singlet
n-BuLi n-Butyllithium
s-BuLi sec-Butyllthium
t-BuLi tert-Butyllithium
n-BuOH n-Butanol
t-Bu tert-Butyl
c Concentration
cod Cyclooctadiene
d Doublet
dd Doublet of doublets
DCM Dichloromethane
de Diastereomeric excess
DMA Dimethylacetamide
DMAP 4-Dimethylaminopyridine
DMS Dimethyl sulphide
DMSO Dimethylsulfoxide
DMF Dimethylformamide
DoE Design of Experiment
dppe Diphos; 1,2-Bis(diphenylphosphino)ethane
dr Diastereoselectivity
ee Enantiomeric excess
EI Electron impact ionization
Et Ethyl
ES Electrospray ionization
FTMS Fourier Transform Mass Spectroscopy
GC Gas Chromatography
HPLC High-Performance Liquid Chromatography
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