New Methodology for the synthesis of Chiral, non-racemic a-Tertiary Amine centres

203 Pages·2016·6.08 MB·English

New Methodology for the Synthesis of Chiral,
Non-Racemic α-Tertiary Amine Centres:
Application to the Synthesis of the Marine
Alkaloid Lepadiformine

A thesis submitted to the
University of Cape Town n
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In fulfilment of the requirements of tohe
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Degree of Doctor of Philoso phy
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By
Ana Andrijevic
Supervisor: Professor Roger Hunter
Department of Chemistry
University of Cape Town
Rondebosch, 7701
Cape Town July 2016
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The copyright of this thesis vests in the author. No
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quotation from it or information derived from it is to be

published without full acknowledgeement of the source.
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The thesis is to be used for private study or non-
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commercial research purposes only.

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Published by the Universit y of Cape Town (UCT) in terms
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of the non-exclusive license granted to UCT by the author.
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Declaration
I declare that “New Methodology for the Synthesis of Chiral, Non-Racemic α-Tertiary Amine
Centres: Application to the Synthesis of the Marine Alkaloid Lepadiformine” is my own work
and that all sources that I have used or quoted have been indicted and acknowledged by
means of complete references. I authorise the University to reproduce for the purpose of
research either the whole or any portion of the contents in any manner whatsoever.
Ana Andrijevic
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Abstract

The development of new methodology for the synthesis of a chiral, non-racemic quaternary carbon
bearing an α-nitrogen (an α-tertiary amine or ATA) continues to be an active area of modern
research in current synthetic organic chemistry. As a privileged biological scaffold, ATAs are
widespread amongst bioactive natural products, providing an inspiration in their complex
architecture to synthetic chemists in drug discovery programmes.
Three experimental endeavours comprise this project, which are presented as separate sections of
Chapter 2. The first part focuses on new methodology for all-carbon quaternization based on an
auxiliary-based diastereoselective alkylation of an auxiliary-malonate, in which an imidazolidinone
auxiliary provided excellent facial selectivities in the alkylation in conjunction with KHMDS as the
base. Five derivatives were generated in high yields (>85 %) and selectivities (dr >95:5). Extension of
the methodology to generate ATAs using the auxiliary-malonate system forms the basis of the
second section. This was achieved via a modified Curtius rearrangement protocol performed on
quaternary carboxylic acids, in turn obtained from a chemoselective cleavage of a PMB ester
malonate-auxiliary system. The ATA products were obtained in high yields and with retention of
stereoselectivity, and following the non-destructive removal of the auxiliary by methanolysis,
produced enantioenriched α,α-disubstituted alanine and phenylalanine methyl esters. Additional
steps on other suitable derivatives furnished quaternary proline and lysine derivatives, all in high
ees (96 – 98 %). The methodology offers a general approach to the production of enantioenriched
ATAs, and in particular, access to both natural and unnatural α,α-disubstituted amino acids.
Application to an attempted synthesis of lepadiformine is described in the final section, whereby the
ATA of the alkaloid is constructed in an acyclic form employing the newly developed methodology.
Reductive (non-destructive) removal of the auxiliary provided an amino alcohol derivative that was
further elaborated via a sequence involving ring-closing metathesis, hydrogenation, hydroxyl group
oxidation and Grignard addition to afford a functionalised A-ring of lepadiformine A, with key
functionality in place for elaboration to the target. However, dehydration of the tertiary alcohol
from the Grignard step, although successful in a related model study, led to problems, bringing the
total synthesis endeavour to a close. In spite of this setback, the divergent nature of the approach
allows for new designs in the synthetic plan, particularly regarding the order of which the
functionalised A ring from this work is elaborated into the A/B/C target.

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Acknowledgements

I would like to express my gratitude to the following people for their assistance towards this thesis:
An enormous amount of gratitude is due to my supervisor, Professor Roger Hunter whose
passion and intense love for organic chemistry was a true inspiration to me, and ultimately the
driving force behind all my scientific achievements. Thank you for playing psychologist at times,
accepting and understanding me, however difficult that may have been at times. A sincere thank you
for your unfailing belief in me since the very beginning and for motivating me to always learn more,
dig deeper, create artfully.
A special thank you goes to Sophie Rees-Jones. A more selfless person I have not met, always
willing to help and do for others, you really are the glue that holds the group together. Apart from
that, you have been a wonderful, supportive friend and I thank you sincerely for that.
Professor David Gammon, for planting the chemistry fascination seed early on, and for the
useful discussions.
Mahesh Gokada for picking up the reins so skilfully and for being a fantastic person to work
with.
Yassir Younis, Rudy Cozett, Gregory Bowden, Wade Petersen, Myles Smith for the late lab
nights, loud music and philosophical (and nonsensical) discussions over Pick n’ pay chicken dinners
and boerie platters. Nashia Zibeyaz, Ebrahim Mohammed, Seanette Wilson, Henok Kinfe and Philip
Richards for all their assistance in the early days. Athi Msutu for the singing; Shankari Nair for the
snacks and Daniel Kuzsa for the interesting world-view chats.
Colleauges past and present in the Hunter group, Thobela Bixa, Mandla Mabunda, Cathryn
Driver, Fabrizio L’Abatte, Jasmin Ferreira, Rukaya Mansoor, Stefan Benjamin and John Woodland.
Noel Hendricks, Pete Roberts, Piero Benincasa, Hong Su and the Stellenbosch mass
spectrometry unit for their analytical services.
The National Research Foundation for financial support.
My super-woman mom, who has been a pillar of strength and support throughout my life.
Thank you for your constant encouragement and for always standing by me no matter what. My late
father, who always made me believe that I could be and do whatever I wanted to. You both worked
tirelessly and sacrificed much so that we have can have these opportunities and I am very thankful
for that and love you both dearly. My brother, who was always more than willing to lend a helping
hand in hard times, love you too Nexy!
My dear friend Erik Regenbrecht for always being there for me.
Finally, my love Pedja Nikolic, for enduring difficult and challenging times with me, comforting
me and standing by me always- thank you and I love you.
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This thesis is dedicated to Elena and Mateja Nikolic, my precious star-children. You have moulded
me, centred me enriched my life in unimaginable ways and I learn from you every day. I may have
birthed you, but you have given me life and my love for you knows no bounds.

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Abbreviations

Ac Acetyl
ACN Acetonitrile
AcOH Acetic Acid
aq. Aqueous
Ar Aromatic
Ar Aromatic quaternary
q
ATA α-Tertiary amine

Bn benzyl
BnBr Benzyl Bromide
Boc tert-butoxy carbonyl
Boc O Di-tert-butyl dicarbonate
2
bs Broad singlet
BtCl 1-Chlorobenzotriazole
BtH 1-H-benzotriazole
BtOH 1-Hydroxybenzotriazole
Bu Butyl
Bz Benzoyl
BzCl Benzoyl chloride

CAN Ceric ammonium nitrate
cat. Catalytic
Cbz Benzyloxycarbamate
CF COOH Trifluoreoacetic acid
3
CH Cl Dichloromethane / Methylene chloride
2 2
CH CN Acetonitrile
3
c-Hex Cyclohexyl
COSY Correlation spectroscopy
C Quaternary carbon
q
CSA Camphorsulfonic acid

d Doublet
DCC 1,3-Dicyclohexylcarbodiimide
DCM Dichloromethane / Methylene chloride
dd Doublet of doublets
DIAD Diisopropylazodicarboxylate
DIBAL Diisobutyl aluminium hydride
DIPEA Diisopropylethylamine
DMAP 4-Dimethyamino pyridine / N,N-Dimethyamino pyridine
DME Dimethyl ether
DMF Dimethylformamide
DMSO Dimethylsulfoxide
DPPA Diphenyl phosphoryl azide
dr diastereomeric ratio
dt Doublet of triplets

E+ Electrophile
E1 Unimolecular elimination
E2 Bimolecular elimination
ee Enantiomeric excess
eq. Equivalent
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Et Ethyl
Et O Diethyl ether
2
Et N Triethylamine
3
EtOAc Ethyl acetate
EtOH Ethanol

g Grams

H+ Acidic conditions
HCl Hydrochloric acid
Hex Hexyl
HMPA Hexamethylphosphoric triamide
HOBt 1-Hydroxybenzotriazole
HOMO Highest occupied molecular orbital
HPLC High-performance liquid chromatography
h Hour
HRMS High-resolution mass spectrometry
HSQC Heteronuclear single quantum coherence
Hz Hertz

i-Pr Isopropyl
IR Infrared spectrometry

J Coupling constant

KHMDS Potassium hexamethyldisilazide

LDA Lithium diisopropylamide
LiAlH Lithium aluminium hydride
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lit. Literature
LUMO Lowest unoccupied molecular orbital

m Meta
m multiplet
M.p. Melting point
m/z Mass to charge ratio
M+ Molecular ion
Me Methyl
MeOH Methanol
mg Milligram(s)
MHz Megahertz
ml Millilitre(s)
mmol Millimole(s)
Ms Methanesulfonyl

NaHMDS Sodium hexamethyl disilazide
NaOMe Sodium methoxide
NMM N-Methylmorpholine
Nu Nucleophile

o Ortho
p Para
P.T. Proton transfer
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Pd/C Palladium-on-carbon
PG Protecting group
Ph Phenyl
PMB p-Methoxy benzyl
PPh Triphenylphosphine
3
PTC Phase transfer catalysis
Pyr. Pyridine

q Quartet

rt room temperature

s Singlet
SM Starting material
S 1 Unimolecular nucleophilic substitution
N
S 2 Biomolecular nucleophilic substitution
N

t Triplet
TBAI Tetrabutylammonium iodide
TBDPS tert-Butyldiphenylsilyl
TBS tert-Butyldimethylsilyl
t-Bu t-Butyl
td Triplet of doublets
TFA Trifluoroacetic acid
THF Tetrahydrofuran
tlc Thin layer chromatography
TPAP tetrapropylammonium perruthenate
Ts p-Toluenesulfonyl

UV Ultraviolet

δ Chemical shift in ppm

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Table of Contents
Declaration _____________________________________________________________________ i
Abstract ______________________________________________________________________ ii
Acknowledgements _____________________________________________________________ iii
Abbreviations __________________________________________________________________ iv
Table of Contents ______________________________________________________________ viii
Chapter 1: Introduction ______________________________________________________ 1
1.1 Chiral α-Tertiary Amines ______________________________________________________ 1
1.2 The Synthesis of Enantiopure Compounds ________________________________________ 2
1.2.1 Catalytic Enantioselective Synthesis____________________________________________________ 2
1.2.2 Auxiliary-controlled diastereoselective synthesis _________________________________________ 7
1.3 Categories of Asymmetric ATA Syntheses _________________________________________ 8
1.4 C-C Bond Formation via an Electrophilic N-α-Carbon ________________________________ 9
1.4.1 Ketimine alkylation _______________________________________________________________ 9
1.4.2 Strecker reaction _______________________________________________________________ 11
1.4.3 Mannich reactions ______________________________________________________________ 13
1.4.4 Addition to Hydrazones __________________________________________________________ 15
1.4.5 Addition to Nitrones _____________________________________________________________ 16
1.4.6 Aza-Prins ______________________________________________________________________ 18
1.5 C-C Bond Formation via an N-α-Carbanion _______________________________________ 22
1.5.1 -Carbanions with Memory of Chirality ________________________________________________ 22
1.5.2 Chiral Amino Acid Enolate Equivalents ________________________________________________ 23
1.5.3 α-Amidomalonate Carbanions _______________________________________________________ 31
1.5.4 α-Aziridinyl Carbanions _____________________________________________________________ 31
1.5.5 α-Amino Nitrile Carbanions _________________________________________________________ 33
1.5.6 Addition of N carbanion to Allenoates ______________________________________________ 35
1.5.7 Rearrangements involving an N-α carbanion ____________________________________________ 36
1.6 C-N Bond Formation via an Electrophilic Nitrogen _________________________________ 39
1.6.1 Electrophilic amination with an azodicarboxylate ________________________________________ 39
1.6.1.1 Aldehyde Enamines ____________________________________________________________ 40
1.6.1.2 Ketone activation ______________________________________________________________ 42
1.6.1.3 Ketenes and Lewis Base Catalysis _________________________________________________ 42
1.6.1.4 Stabilised enolates _____________________________________________________________ 43
1.6.2 Electrophilic Azidations _____________________________________________________________ 44
1.7 C-N Bond Formation via a Nucleophilic Nitrogen __________________________________ 46
1.7.1 Aza-Michael Addition ______________________________________________________________ 46
1.7.2 S 2 with NaN ____________________________________________________________________ 47
N 3
1.7.3 S 2 via Mitsunobu _________________________________________________________________ 48
N
1.8 Radical Azidation ___________________________________________________________ 49
1.9 Molecular Rearrangements ___________________________________________________ 50
1.9.1 Curtius rearrangement _____________________________________________________________ 51
1.9.2 Schmidt rearrangement ____________________________________________________________ 52
1.9.3 [3,3] sigmatropic rearrangements ____________________________________________________ 54
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