Asymmetric Syntheses of Polycyclic Amines

202 Pages·2017·5.83 MB·English

by  Ian Houlsby

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Asymmetric Syntheses of
Polycyclic Amines

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

by

Ian T. T. Houlsby

St Catherine’s College Trinity Term
Oxford 2017

Declaration

The work described in this thesis was carried out in the Chemistry Research Laboratory,
University of Oxford from September 2013 until June 2017, under the supervision of Professor
Stephen G. Davies. All of the work is my own unless otherwise stated and has not been
submitted previously for any other degree at this or any other university.

Ian Houlsby
June 2017

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"The structure known, but not yet accessible by synthesis, is to the chemist what the
unclimbed mountain, the uncharted sea, the untilled field, the unreached planet, are to other
men… The unique challenge which chemical synthesis provides for the creative imagination
and the skilled hand ensures that it will endure a long as men write books, paint pictures,
and fashion things which are beautiful, or practical, or both."

Robert Woodward, 1963
Abstract
Ian Houlsby D. Phil. Thesis
St Catherine's College Trinity Term 2017

This thesis centres on the asymmetric synthesis of polycyclic amines, focussing on three distinct classes
of polycyclic alkaloid natural products. The work aims to use common methodology of lithium amide
conjugate additions as the source of asymmetry in all cases, and for each product class a single strategy
is used to synthesise a variety compounds.
Chapter 1 describes the importance of the synthesis of polycyclic alkaloids, highlighting three classes
of compounds and documenting prior synthetic strategies. The classes discussed are: the Hancock
alkaloids, hydroxymethyl-substituted azabicycles, and the tetraponerine alkaloids.
Chapter 2 describes two separate synthetic strategies towards the Hancock alkaloid (–)-cuspareine, one
using a benzyne mediated cyclisation and one a Buchwald-Hartwig cyclisation. The Buchwald-Hartwig
methodology was also applied in the synthesis of two more Hancock alkaloids (–)-galipinine and
(–)-galipeine; the synthesis of (–)-galipeine led to a reassignment of the structure of the natural product.
Chapter 3 describes work in the synthesis of four [x.y.0]-azabicycles with differing in ring sizes
(x, y = 3, 4). The strategy employs sequential S 2-like ring-closing reactions to form the bicyclic
N
structures where pyrrolizidine, indolizidine and quinolizidine scaffolds can be accessed. Amongst the
products are two natural alkaloids, (–)-lupinine and (+)-isoretronecanol.
Chapter 4 describes the synthesis of all eight tetraponerine alkaloids T1–8. Two sequential lithium
amide conjugate addition reactions allow for the synthesis of the differing ring-sizes and
diastereoisomers displayed by the eight alkaloids. Ring-closing metathesis and diamine condensation
with 4-bromobutanal provide the ring-closing steps in the syntheses.
Chapter 5 contains full experimental procedures and characterisation data for all compounds synthesised
in Chapters 2–4.
Acknowledgements
We're rarely given the opportunity to thank the people who have had an impact on our lives. I have
no doubt that without the opportunity provided to me by Prof S. Davies, chemistry and I would still be
strangers. The input and funding he has supplied over the years has given me the opportunity
to undertake my D.Phil and progress as a synthetic chemist. His support did not come unaided and I'd
love to thank the postdocs Jim, Paul and Ai for all their day to day help with lab work and writing up.
You really made the whole process of working towards, and writing my D.Phil much easier. I
know there are numerous people within the SGD group who I should thank, and here I can mention
the specific people who have helped me out throughout the years. Currently in G10, the
rules are upheld wonderfully by David and Matt who not only force me to close my fumehood
and fill up acetone bottles, but have been good friends from the very start of my D.Phil,
so I'd like to thank the pair of them for four excellent years and I hope that they
do their best to finish up their work a little more promptly than I have.
I would be remiss to remember only the current members of the group and I should thank
a few people who helped and supported me, and have now moved on to greater things. A
full list would be impractical so I'd like to thank Aileen, Marta and Alex for their
commitment's to the SGD social life. Aileen was effectively group social sec, and really nailed unifying
what was a bunch of very disorganised people into a great social group. From dinners to catalyst football,
I'm remembering these times with fond memories. As I moved through the years of my D.Phil, I was
thinking about travelling outside the UK to see more of the world under the thinly veiled guise
of going to an international conference. This is where Marta stepped up, and for some inexplicable reason
you decided it would be a good idea to come with me to Pacifichem in Hawaii, and somehow thought it
wouldn't be a bad idea to spend Xmas and New Year with me (and Britney) and I'm glad we managed to
get through a month without killing each other. Despite taking numerous holidays from the lab,
this D.Phil proved to be tiring work, and that is where Alex White came in perfectly.
From a cheeky Tuesday beer to a New College bar night on Wednesday, to a Uni Club Friday (or
any other day of the week), you were always there to keep my spirits high (both emotionally and with
Acknowledgements

other kinds of spirits). For his similar support in distractions from work with trips to the pub, another
guy I should thank is Stefan Verhoog who has been a good friend to me over the last few years.
I must also thank Carole Bataille for her support and for numerous reasons other than
just being an unwavering presence for a Friday drink. In my 4th year, I moved for a brief time to G8 and
want to thank Carole for being so accommodating and helpful in the transition period moving
to another lab. There are many other stories from my early years in the group I would like to
tell and I thank the numerous part time students for your involvement and wish you well wherever
you may now be. One student of mine who I should thank is Solange; I'm still not sure
how you were ever tempted back after my supervision but thank you for your work on benzyne that
I'm so inexplicably keen on. Working in the SGD group for the last four years has given me a great
feeling of comradery and I thank all those involved.
Gotta be honest on this one, the CRL has had its ups and downs with performance but trying to
make this place function efficiently is a mammoth task, so I must thank all the service staff in the CRL,
you provided excellent facilities for the research undertaken. I sometimes find it difficult to
understand where inspiration or motivation comes from, but one factor for me starting my D.Phil, I will
never forget. Kristina Csatayová, who is sadly no longer with us, was my first supervisor and was always
gonna be someone I'd want to thank. She inspired me to undertake a D.Phil and she worked hard to
give me the best grounding in synthetic chemistry and a fantastic introduction to the SGD group.
You really can never predict how your decisions will pan out over the years, but if it was
up to me to restart my postgrad research I would choose to work here in the SGD group again. I will
never forget my time here in Oxford and all the people and experiences that have shaped my work. I'm
gonna leave you with my memories of fantastic music in the SGD labs G9 and G10, and I will
let you in on my final thoughts as I finish my time here. I know these acknowledgements that
you just read are a little rambling and incoherent, but that is for your benefit, so you can read
down the first word of each line. Thank you all again for your support and taking time to read this.
Abbreviations
[α] Specific rotation
D
δ NMR chemical shift
Δ Reflux
ν Infrared absorption maximum
max
Å Angstrom
Ac Acetyl
app Apparent
Ar Aryl
atm Atmospheres
ATR Attenuated total reflectance
aq Aqueous
BINAP 2,2'-Bis(diphenylphosphino)-1,1'-binaphthalene
1D NOE 1 Dimensional nuclear Overhauser effect
DIPEA Diisopropylethylamine
DMSO Dimethylsulfoxide
BMI Butylmethylimidazolinium
Bn Benzyl
Boc tert-Butoxycarbonyl
br Broad
Bu Butyl
tBu tert-Butyl
c Concentration
°C Degrees Celsius
Cbz Carboxybenzyl
cm Centimeters
cm-1 Wavenumbers
CSO Camphorsulfonyloxaziridine
Abbreviations

Cy Cyclohexyl
d Doublet
DCC N,N′-Dicyclohexylcarbodiimide
DEAD Diethyl azodicarboxylate
deg Degrees
DET Diethyl tartrate
DIBAL-H Diisobutylalumnium hydride
DMAP 4-Dimethylaminopyridine
DMF N,N-Dimethylformamide
DMSO Dimethylsulfoxide
dr Diastereomeric ratio
E Electrophile
E Entgegen
E Elimination, unimolecular
1
ee Enantiomeric excess
epi Epimeric
er Enantiomeric ratio
ESI+ Positive electrospray ionisation
Et Ethyl
equiv Equivalents
FT Fourier transform
g Grams
GC Gas chromatography
Grubbs I Benzylidene-bis(tricyclohexylphosphine)dichlororuthenium
Grubbs II (1,3-Bis(2,4,6-trimethylphenyl)-2-imidazolidinylidene)dichloro
(phenylmethylene)(tricyclohexylphosphine)ruthenium
h Hours
HIV Human immunodeficiency virus
HMBC Heteronuclear Multiple Bond Correlation
Abbreviations

HMDS Bis(trimethylsilyl)amide
HMPA Hexamethylphosphoramide
HMPT Hexamethylphosphorous triamide
HRMS High resolution mass spectrometry
HSQC Heteronuclear single quantum coherence
Hz Hertz
i Ipso
IBX 2-Iodoxybenzoic acid
IR Infrared
J Coupling constant
L Litres
μL Microlitres
LC/MS Liquid chromatography mass spectrometry
LDA Lithium diisopropylamine
lit. Literature
m Multiplet
m Meta
M Molar/Molecular ion
m/z Mass to charge ratio
m-CPBA meta-Chloroperoxybenzoic acid
Me Methyl
mg Milligrams
MHz Megahertz
min Minutes
mL Millilitres
mmol Millimoles
Moc Methyl carbonyl
mol Moles
mp Melting point