New Approaches for the Synthesis of Unusual Amino Acids

163 Pages·2008·1.29 MB·English

by  Kristoffer Graham

Fanning, Katherine Nora (2008) New approaches for the synthesis of
unusual amino acids. PhD thesis.

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New Approaches for the Synthesis of Unusual Amino
Acids

A thesis presented in part fulfilment of the requirements for the degree of Doctor of
Philosophy

Katherine Nora Fanning

Department of Chemistry
April 2008
2
Abstract
The thermal and metal-catalysed aza-Claisen rearrangement of allylic
trichlororacetimidates has found widespread application in the synthesis of nitrogen-
containing molecules including alkaloids, antibiotics and unnatural amino acids.1 We have
recently investigated the use of this reaction for the rearrangement of chiral molecules.2
This has led to the development of a highly diastereoselective, ether-directed
palladium(II)-catalysed process which has been used for the synthesis of β-hydroxy-α-
amino acids. To expand the scope and understanding of the rearrangement, a number of
analogues of 1 have been synthesised and subjected to a palladium(II)-catalysed
rearrangement (Figure 1).
Gizzerosine 2 ((S)-2-amino-9-(4-imidazolyl)-7-azanonanoic acid) is a potent agonist for
the H -receptor (Figure 1). It brings about gizzard erosion and ulceration in broiler
2
chickens. This disease is colloquially known as ‘Black Vomit’ due to bleeding of lesions
and subsequent regurgitation.3 Its biological profile suggests it could be a promising drug
candidate for gastric achlorhydria and osteoporosis, although only small amounts can be
isolated from fish meal for biological studies. A short and highly efficient synthesis has
been developed in ten steps and 31% overall yield.
Protein-protein inteactions are the key to organising cellular processes in space and time.
Protein-protein interactions are involved in viral fusion and so are promising targets for
anti-viral drugs. Photoactivatable amino acids have been used to identify these
interactions.4 Activation by ultraviolet light induces covalent cross-linking (known as
photo cross-linking) of the interacting proteins which can be detected with high specificity
by simple western blotting. Significant progress has been made towards the development
of a stereoselective synthesis of photoactivatable amino acids incorporating a diazirine
ring, such as photo-leucine 3, which generate a reactive carbene after the light induced loss
of nitrogen (Figure 1).
H
N
R
NH
N CO H
2
HN O CO2H N N NH
2
CCl NH
3 2
1 2 3
Figure 1
3
Table of Contents

Preface 6

Acknowledgements 7

Abbreviations 8

1. Introduction
1.1 The Synthesis of α-Amino Acids 10
1.2 The Asymmetric Strecker Reaction 11
1.2.1 The Strecker Reaction using Organocatalysts 12
1.2.2 The Strecker Reaction using Metal Catalysts 18
1.3 The Use of Glycine Equivalents 22
1.3.1 Phase-Transfer Catalysts 28
1.4 Asymmetric Carbon-Nitrogen Bond Forming Reactions 35
1.4.1 Nucleophilic Amination 35
1.4.2 Electrophilic Amination 41
1.5 Catalytic Asymmetric Hydrogenation 46
1.5.1 Rhodium 47
1.5.2 Ruthenium 50
1.6 Conclusions 54
4
2. Use of the 3,3-aza-Claisen Rearrangement
2.1 Introduction 55
2.2 Use of the Directed Rearrangement for the Synthesis of
β-Hydroxy-α-Amino Acids 61
2.3 Investigation of New Substrates for the Directed Rearrangement 67
2.4 Use of Nitrogen for the Directed Rearrangement 77

3. The Synthesis of (S)-Gizzerosine
3.1 Introduction 81
3.2 Previous Syntheses 82
3.3 Aims 87
3.4 The Synthesis of (S)-Gizzerosine 88

4. The Synthesis of Photo-Acids
4.1 Detecting Protein-Protein Interactions 100
4.2 Photo Cross-Linking with Diazirines 101
4.3 Photo Cross-Linking with Photo-Acids 102
4.4 Progress Towards the Synthesis of Photo-Acids 105

5. Experimental Section
5.1 General Experimental 122
5.2 Chapter 2 122
5
5.3 Chapter 3 139
5.4 Chapter 4 147
6. References
156
6
Preface

This thesis represents the original work of Katherine Nora Fanning unless stated otherwise
in the text. The research described herein was carried out in the Loudon and Henderson
Laboratories of the University of Glasgow, between October 2004 and September 2007,
under the supervision of Dr. Andrew Sutherland. Part of this thesis has been published
previously.
K. N. Fanning, A. G. Jamieson and A. Sutherland, Org. Biomol. Chem., 2005, 3, 3749.
K. N. Fanning, A. G. Jamieson and A. Sutherland, Curr. Org. Chem., 2006, 10, 1007.
K. N. Fanning and A. Sutherland, Tetrahedron Lett., 2007, 48, 8479.
7
Acknowledgements
First and foremost, I would like to thank my supervisor, Dr. Andrew Sutherland, for giving
me the opportunity to work with him. He has been a constant source of information,
support and encouragement throughout my Ph.D.
I would also like to thank my second supervisior, Dr. Andrei Malkov, for his valuable
input into my research.
I would like to extend my gratitude to all the staff in the Joseph Black Building including
Jim Tweedie (Mass Spectrometry), David Adam (NMR Spectroscopy), Alec James and
Ted Eason (Stores), Stuart MacKay (IT Support) and the administration staff who are
always willing to help.
Special thanks to my collegues and friends, past and present, who were always willing to
give advice or have a laugh. Those in the Sutherland Group include Jonathan, Andy,
Caroline, Jenny, Nicola, Mike and Louise. Those in Dr. Hartley’s group include Stuart,
Carolyn, Calver, Louis, Linsey, Ching Ching, Caroline and Guilaine.
I would like to thank all my ‘chemistry girls’, with whom I’ve had many glasses of wine
and in-depth life discussions! Gemma, Jenny, Nicola and Katrina, you’ve made my years
in Glasgow very memorable and special.
To Stoff, champion tea-maker and provider of bear hugs! Thank you for all your patience,
strength and love.
This thesis is dedicated to my loving family.

Níl aon tintéan mar do thintéan féin.
8
Abbreviations
Å ångstrom
Ac acetyl
Ar aryl
Bn benzyl
Boc tert-butoxy carbonyl
Bu butyl
Cbz benzyloxycarbonyl
CI chemical ionisation
cod cyclooctadiene
COSY correlated spectroscopy
d doublet (NMR)
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM dichloromethane
d.e. diastereomeric excess
DEAD diethyl azodicarboxylate
DIBAL-H diisobutylaluminium hydride
DIPEA diisopropylethylamine (Hünig’s Base)
DMAP 4-dimethylaminopyridine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
DTT dithiothreitol
EDCI 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide
e.e. enantiomeric excess
EI electron impact
Et ethyl
FAB fast atom bombardment
h hour(s)
HMPA hexamethylphosphoramide
i iso
IR infrared
LDA lithium diisopropylamine
M molar (mol L-1)
m multiplet (NMR)
m meta
9
MCPBA m-chloroperbenzoic acid
Me methyl
MEM 2-methoxyethoxymethyl
min minutes(s)
mol mole
MOM methoxymethyl
Ms methanesulfonyl (mesyl)
n normal
MS molecular sieves
NBS N-bromosuccinimide
NMI N-methylimidazole
NMR nuclear magnetic resonance
o ortho
p para
PCC pyridinium chlorochromate
Ph phenyl
PPM parts per million
q quartet (NMR)
r.t. room temperature
s singlet (NMR)
t tertiary
t triplet (NMR)
TBAF tetra-n-butylammonium fluoride
TEA triethylamine
TBDPS tert-butyldiphenylsilyl
TBDMS tert-butyldimethylsilyl
TMG tetramethylguanidine
TMS trimethylsilyl
Troc trichloroethoxy carbonyl
Ts p-toluenesulfonyl (tosyl)