Towards the Synthesis of the ABC Tricycle of Taxol

166 Pages·2014·5.07 MB·English

Wilkes, Antonia (2015) Towards the synthesis of the ABC tricycle of
Taxol. PhD thesis.

http://theses.gla.ac.uk/5885/

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Towards the Synthesis of the ABC Tricycle of Taxol

Antonia Wilkes (MChem)

Thesis submitted in part fulfillment of the requirements for the
Degree of Doctor of Philosophy

School of Chemistry
College of Science & Engineering
July 2013
Abstract

Taxol is one of the world’s most successful drugs used in the treatment of cancers.
Isolated from the bark of the Pacific yew tree (Taxus brevifolia), it is a molecule of great
interest within organic chemistry; with six total syntheses and a number of synthetic works
having been published since its discovery.

A semi-convergent synthesis of an intermediate in Holton’s synthesis was planned. The
overall synthetic plan is shown below. The A ring would be installed by an intramolecular
pinacol condensation. The BC bicycle would be closed by ring-closing metathesis at C10-
C11. The ketone at C12 would be protected as an alkyne and the BC bicycle precursor
would be obtained by coupling fragment A and the C ring.

This thesis describes the preparation of a model C ring, without the oxygenated
functionality at C7, was successfully synthesised along with fragment A. Metathesis
precursors were synthesised and gold hydration reactions were attempted.
ii
Contents

Abstract ii
Acknowledgements v
Author’s Declaration vi
Abbreviations vii

Chapter I: Introduction 1
1.1 Generalities of Taxol 2
1.2 Discovery of Taxol 2
1.3 Structure and nomenclature 5
1.4 Biosynthesis 7
1.5 Mode of Action 9
1.6 Structure and Reactivity 12
1.7 Previous syntheses of taxol 13
1.7.1 Semi-synthesis of taxol 13
1.7.2 Total syntheses of taxol 15
A. Fragmentation methods of synthesising taxol or taxane derivatives 15
B. Syntheses of taxol or its derivatives using the Diels-Alder reaction 20
C. Convergent syntheses of taxol 22
D. Other examples towards taxol 27
1.8 Cyclooctene formation using metathesis reactions 29
1.8.1 Introduction to metathesis 29
1.8.2 Formation of cyclooctenes by ring-closing metathesis 31

Chapter II: Towards Taxol- Synthesis of fragment A and ring C 35
2.1 Previous work in the lab 36
2.1.1 First approach to taxol 36
2.1.2 Work by Benoît Muller 37
A. Synthesis of the A ring 37
B. First coupling of the A and C rings 38
C. Test metathesis reactions: closing the B ring 39
2.1.3 Work by Damien Bourgeois 40
A. Convergent approach 40
B. Semi-convergent approach 43
iii
2.1.4 Work by Stéphanie Schiltz 48
2.1.5 Work by Cong Ma 52
A. Optimisation of the metathesis 52
B. Synthesis of fragment A 55
C. New fragment A route 58
D. Towards 7-deoxytaxol 58
2.2 Aim of the project 61
2.3 Modified retrosynthesis 62
2.4 Towards the Shapiro coupling 64
2.4.1 Synthesis of the model C ring 64
2.4.2 Synthesis of fragment A 68

Chapter III: Towards 7-deoxy taxol and ring-closing metathesis 78
3.1 Shapiro coupling 79
3.2 Synthesis of Metathesis Precursors 86
3.3 Synthesis of enantiopure fragment A 101
4.1 Conclusions and future work 106
4.1.1 Conclusions 106
4.1.2 Future work 108

Chapter IV: Experimental details 109

References 144

iv
Acknowledgements

Firstly, I would like to thank Dr Joëlle Prunet for all her help and support during this
project. Her patience and understanding during the first two years of the project, when
nothing seemed to be working, are greatly appreciated. The fact that she still manages to
remain calm constantly amazes me.

I would also like to thank everyone I have worked with over the past three and a half years.
Everyone in the Loudon and Raphael labs, both past and present including Michael, Anna,
Lewis, Jo, Pooja and all the “frenchies” who I am constantly surrounded by. The ‘Frunet’
group are a great bunch of people and I hope we keep in touch in the future.

To everyone else in the department who has helped and encouraged me, Ted and Shaun
from stores, Elizabeth, Alexis and all three Jims for their help and guidance on issues
regarding the department, again many thanks.

Thanks also go to the volcano that erupted in 2010 and made me realise that you have to
keep pushing and motivate yourself rather than just give up. Even to the woman who
kicked a football at me, thus breaking my wrist, and keeping me out of the lab for two
months.

Finally, I would like to thank my family and friends who have kept me sane during this
period.

v
Author’s Declaration

This thesis represents the original work of Antonia Wilkes unless stated otherwise within
the text. The research was carried out at the University of Glasgow in the Raphael
Laboratory under the supervision of Dr. Joëlle Prunet during the period of October 2009 to
November 2012.

vi
Abbreviations

Ac Acetate
Aq. Aqueous
Ar Aromatic
Bn/Bz Benzyl
BOM Benzyloxymethyl
Br Broad
Bu Butyl
Cat. Catalytic
CDI Carbonyl diimidazole
Conc. Concentrated
d Doublet
DABCO 1, 4-Diazabicyclo[2.2.2]octane
DAMP Dimethyl diazomethylphosphonate
DCE Dichloroethane
DDQ 2,3-Dichloro-5,6-dicyanobenzoquinone
(DHQD) AQN Hydroquinidine (anthraquinone-1, 4-diyl) diether
2
DIBAL Diisobutylaluminium hydride
DMAP 4-Dimethylaminopyridine
DMP Dess-Martin Periodinane
DMSO Dimethyl sulfoxide
DPC Di-2-pyridyl carbonate
e.e. Enantiomeric excess
EE Ethoxyethyl
EI Electron impact
Equiv. Equivalent
Et Ethyl
Et O Diethyl ether
2
EtOAc Ethyl acetate
g Grams
h Hours
1H Proton
HCl Hydrochloric acid
Hex Hexyl
Hz Hertz
vii
IBX Iodoxybenzoic acid
Im Imidazole
iPr Isopropyl
IR Infrared
J NMR spectra coupling constant
KHMDS Potassium hexamethyldisilazide
M Molar
m Multiplet
m-CPBA Chloroperbenzoic acid
Me Methyl
MeOH Methanol
Mg Milligram(s)
Min Minutes
mL Millilitre(s)
MOM Methoxymethyl
Mp Melting point
N Normal
NMR Nuclear Magnetic Resonance
Nu Nucleophile
PAM Peptidylglycine monooxygenase
Ph Phenyl
PMB p-Methoxybenzyl
PPM Parts per million
PTSA p-Toluenesulfonic acid
Py Pyridine
q Quartet
quin Quintet
s Singlet
rt Room temperature
t Triplet
TBAF Tetrabutylammonium fluoride
TESCl Triethylsilyl chloride
Tris Triisopropylbenzenesulfonyl
Troc Trichloroethyl carbonate
Ts Tosyl
viii
Chapter I

Introduction