Asymmetric synthesis of bioactive alkaloids from Amaryllidaceae

182 Pages·2013·6.85 MB·English

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UNIVERSITY OF SOUTHAMPTON

FACULTY OF NATURAL AND ENVIRONMENTAL SCIENCES

Department of Chemistry

Asymmetric synthesis of bioactive alkaloids from Amaryllidaceae

Valerio Isoni

Thesis for the degree of Doctor of Philosophy

May 2013

UNIVERSITY OF SOUTHAMPTON

ABSTRACT

FACULTY OF NATURAL AND ENVIRONMENTAL SCIENCES

SCHOOL OF CHEMISTRY

Doctor of Philosophy

ASYMMETRIC SYNTHESIS OF BIOACTIVE ALKALOIDS FROM
AMARYLLIDACEAE

By Valerio Isoni

A new route towards the diasteroselective synthesis of (+)-maritidine, a bioactive alkaloid
from Amaryllidaceae, has been proposed. In our approach, an intramolecular Heck
reaction was used to form the quaternary stereocentre C driven by the stereochemical
10b
information at C of the precursor. Allylic oxidation of intermediate 3.25 followed by
4a
diasteroselective reduction, introduced the alcohol at C with the correct stereochemistry.
3
An advanced intermediate (3.29) in the synthesis of (+)-maritidine was produced, and
routes to complete the total synthesis were proposed.

A series of polymer-supported sulfonate ester linkers were developed for use in the resin-
linker-vector (RLV) approach for the synthesis of [18F]-radiopharmaceuticals used as
imaging probes in positron-emission-tomography (PET). Upon exposure of the RLV
construct to [18F]-fluoride, a small quantity of [18F]-radiotracer is released in solution
which is separated from the unreacted material and cleaved resin, by simple filtration.
The RLV strategy was successfully applied for the synthesis of the known
radiopharmaceutical O-(2-[18F]-fluoroethyl)-L-tyrosine, [18F]-FET.

A C-H activation-cyclisation sequence was used to achieve the synthesis of the
Amaryllidaceae alkaloid oxoassoanine as well as a phenanthridinoid analogue, part of
potential non-charged dual reactivators of acetylcholinesterase (AChE) poisoned by
organophosphorous (OP) nerve agents.

Contents

Contents ............................................................................................................................ i
Declaration ......................................................................................................................iii
Acknowledgements ......................................................................................................... iv
Abbreviations................................................................................................................... v
Chapter 1 – Introduction ................................................................................................ 1
1.1 The Amaryllidaceae family ............................................................................... 1
1.2 Biosynthesis of Amaryllidaceae alkaloids ........................................................ 2
1.3 Pancratium maritimum: a source of crinine alkaloids ...................................... 3
1.4 Previous syntheses: an overview ....................................................................... 4
1.5 The Brown group approach to Amaryllidaceae alkaloids:
synthesis of (−)-galanthamine ......................................................................... 12
1.6 Second generation synthesis of (−)-galanthamine .......................................... 15
1.7 The Brown group approach towards (+)-maritidine ....................................... 16
Chapter 2 – First approach to (+)-maritidine ............................................................ 19
2.1 Synthesis of propargylic alcohol (±)-1.59 ....................................................... 19
2.2 Synthesis of benzyl bromide 2.06 ................................................................... 20
2.3 Synthesis of cyclohexadiene (±)-2.08 ............................................................. 21
2.4 Synthesis of dimethoxybenzoates ................................................................... 25
2.5 Conclusions ..................................................................................................... 32
Chapter 3 – Towards the synthesis of (+)-maritidine ................................................ 33
3.1 A convergent, new approach to cyclohexadiene 2.07 ..................................... 33
3.2 Benzylic etherification: an extended study ..................................................... 36
3.3 The Heck reaction: a closer look ..................................................................... 43
3.4 Benzylic and Allylic oxidations ...................................................................... 49
3.5 Stereoselective reduction of enone 3.28.......................................................... 53
3.6 Introduction of nitrogen at C ........................................................................ 56
4a
3.7 Conclusions ..................................................................................................... 60
3.8 Future work ..................................................................................................... 61

i
Chapter 4 – Radiochemistry and C-H activation: development of neuroscientific
tools within a European collaboration ................................................... 63
4.1 A Resin-Linker-Vector (RLV) approach to radiopharmaceuticals
containing 18F ............................................................................................................. 63
4.1.1 Introduction .................................................................................................................... 63
4.1.2 The RLV strategy for the synthesis of radiotracers containing 18F ................................... 65
4.1.3 Synthesis of 4-alkylphenylsulfonate linkers .................................................................... 66
4.1.4 The RLV approach to O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]-FET) .............................. 71
4.1.5 Conclusions .................................................................................................................... 76
4.2 Development of dual AChE reactivators within a European collaboration .... 76
4.2.1 Background .................................................................................................................... 76
4.2.2 Synthesis of phenanthridinoid alkaloids and analogues via C-H activation-cyclisation .... 82
4.2.3 Conclusions .................................................................................................................... 87
4.2.4 The RLV approach to O-(2-[18F]-fluoroethyl)-L-tyrosine ([18F]-FET) .............................. 71
4.2.5 Conclusions .................................................................................................................... 87
Chapter 5 – Experimental Details ................................................................................ 89
References .................................................................................................................... 162

ii
Declaration
I declare that the work presented in this thesis is of my own composition and has
been generated by me as a result of my own original research while in candidature at
this university for the degree of Doctor of Philosophy, with the exception of the
experiments carried out by scientists at GE Healthcare, Dr. Amy C. Topley and Dr.
Lynda J. Brown, which are acknowledged. Where I have consulted the published
work of others, this is clearly attributed. Where I have quoted from the work of
others, the source is always given and with exception of such quotations this thesis is
entirely my own work. No part of this work has previously been published, submitted
for a degree or other qualification, with the exception of the radiochemistry section
4.1.1,2

This copy is supplied on the understanding that it is copyright material and that no
quotation from this thesis may be published without proper acknowledgement.

Valerio Isoni, May 2013
iii
Acknowledgements
I wish to thank the following people for their help, support and good moments spent
together during the course of my PhD.

A big thank you to the members of the Brown group, past and present, for the fun,
productive and unique lab environment, where chemistry and different cultures
blended, especially at tea breaks. Thanks to Alex H, Alex P, Ali, Amanda, Amy,
Azzam, Dr Lynda Brown, Dr Joe Hill-Cousins, Maxime, Mohammad, Patrick, Paul,
Rob G, Rob H, Sam and Sherif.

From other departments within the school, I would like to thank Neil Wells for the
NMR service, as well as John Langley and Julie Herniman for the mass spectrometry
service.

I gratefully acknowledge the European Regional Development Fund (ERDF,
INTERREG IVa program 4061) for funding my studentship as part of the ISCE-
Chem project. Special thanks to Dr. Cecile Perrio for her assistance with the
radiochemistry experiments carried out in Cyceron, Caen.

A big thank you to Richard for his careful supervision of all projects, showing great
enthusiasm and proposing creative ideas, especially during the challenging moments.

Special thanks to my parents and my brother for their continuous love and support
throughout all the years of my never-ending education.

Finally, thank you Melody, for being understanding, loving and supporting in
difficult moments, especially in the last few months.
iv
Abbreviations
Ac Acetyl
apt Apparent
aq aqueous
Ar Aryl
BBN Borabicyclo[3.3.1]nonane
BTEAC Benzyltriethylammonium chloride
Boc tert-Butyl carbonate
BP Boiling point
Bu Butyl
Bz Benzoyl
CAN Ceric ammonium nitrate
CI Chemical Ionisation (mass spectroscopy)
CSA Camphorsulfonic acid
Cy Cyclohexyl
DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene
DCC Dicyclohexylcarbodiimide
DCM Dichloromethane
DDQ 2,3-Dichloro-5,6-dicyanobenzoquinone
DEAD Diethyl azodicarboxylate
DIAD Diisopropyl azodicarboxylate
DIBAL-H Diisobutyl aluminium hydride
DIC 1,3-Diisopropylcarbodiimide
DIPEA N,N-Diisopropylethylamine
DMAC N,N-Dimethylacetamide
DMAP 4-Dimethylaminopyridine
DMB Dimethoxybenzyl
DMF N,N-Dimethylformamide
DMSO Dimethylsulfoxide
dppf 1,1’-Bis(diphenylphosphanyl)ferrocene
dppp 1,3-Bis(diphenylphosphino)propane
ee Enantiomeric excess
EI Electron Impact (mass spectroscopy)
v