Synthesis of conformationally restricted amino acids - Highly versatile scaffolds

179 Pages·2009·5.72 MB·English

by  Florian Sahr

Synthesis of conformationally
restricted amino acids – Highly
versatile scaffolds

Dissertation
zur Erlangung des Doktorgrades
Dr. rer. nat.
an der Fakultät für Chemie und Pharmazie

der Universität Regensburg

vorgelegt von

Florian A. Sahr

aus

Regensburg

Regensburg 2009
Diese Arbeit wurde angeleitet von: Prof. Dr. Oliver Reiser

Promotionsgesuch eingereicht am: 14. Juli 2009

Promotionskolloquium am: 6. August 2009

Prüfungsauschuß: Vorsitz: Prof. Dr. Sigurd Elz
1. Gutachter: Prof. Dr. Oliver Reiser
2. Gutachter: Prof. Dr. Umberto Piarulli
3. Prüfer: Prof. Dr. Jörg Heilmann
Die vorliegende Arbeit wurde unter Leitung von Herrn Prof. Oliver Reiser in der Zeit von
November 2005 bis März 2009 am Institut für Organische Chemie der Universität
Regensburg, sowie von April 2009 bis Juni 2009 am Dipartimento di Scienze Chimiche e
Ambientali der Università dell’ Insubria unter Leitung von Prof. Umberto Piarulli angefertigt.

Herrn Prof. Oliver Reiser möchte ich für die Überlassung des interessanten Themas und seine
Unterstützung während der Durchführung dieser Arbeit danken. Herrn Prof. Umberto Piarulli
möchte für die freundliche Aufnahme in seinen Arbeitskreis und seine Unterstützung während
der Zeit an der Università dell’ Insubria danken.

Meinen Eltern

Experience is the name everyone
gives to their mistakes.

Oscar Wilde,
Lady Windermere’s Fan, 1892, Act III
Index

A. Introduction 1

A. 0. Preface 1
A. 1. Synthetic strategies towards α-amino acids 2
A. 1. 1. Racemic syntheses of α-amino acids 2
A. 1. 2. Asymmetric syntheses of α-amino acids 4
A. 2. Synthetic strategies towards β- and γ-amino acids 7
A. 2. 1. Applications of β- and γ-amino acids 11

B. Main part 19

B. 1. Development of conformationally constrained β-amino acids 19
- New cispentacin derivatives
B. 1. 1. Cispentacin and other cyclic β-amino acids 19
- Highly versatile scaffolds
B. 1. 1. 2. Structure inducing amino acids in 20
Neuropeptide Y (NPY) analogues
B. 1. 2. Synthesis of new cispentacin derivatives 23
B. 1. 2. 1. Synthesis of the γ-butyrolactone framework 23
B. 1. 2. 2. Synthesis of lactone fused cyclopentanes 26
B. 1. 3 Modification of the lactone moiety – Synthetic access 35
to different α-amino acid side chains
B. 1. 4. Application of new cispentacin analogues in peptides 39
B. 1. 4. 1. Solid phase peptide synthesis (SPPS) 39
B. 1. 4. 2. Structural investigations of α-β-peptides and biological 45
activity of NPY analogues
B. 2. Preparation of a bicyclic β-proline derivative as potential new 49
organocatalyst
B. 2. 1. Introduction 49
B. 2. 2. Synthesis of bicyclic homoproline 50
B. 3. Conformationally restricted γ-amino acids 54
B. 3. 1. Introduction 54
B. 3. 2. Synthesis of trans C5 amino acids 57
β,γ
B. 4. Preparation of diketopiperazine (DKP) amino acids and their 60
application in organocatalysis
B. 4. 1. Introduction 60
B. 4. 2. Synthesis of trans-DKP scaffold 61

C. Experimental part 75

D. Summary 108

E. Appendix 111

E. 1. NMR spectroscopic data 111
E. 2. X-ray crystallographic data 145
Abbreviations

Ala alanine GABA γ-amino butyric acid
β-ACC β-amino Gln glutamine
cyclopropanecarboxylic acid Gly glycine
Asp asparagine HATU 2-(7-aza-benzotriazole-1-l)-
Bn benzyl 1,1,3,3-tetramethyluronium)
Boc tert-butyloxycarbonyl hexafluorophosphate
Cbz carboxybenzyloxy HBTU O-benzotriazole-N,N,N',N'-
CD circular dichroism tetramethyluronium
CH CN acetonitrile hexafluoro phosphate
3
DABCO 1,4-diazabicycl[2.2.2]octane HOAt hydroxyazabenzotriazole
d.e. diastereoisomeric excess HOBt hydroxybenzotriazole
d.r. diastereoisomeric ratio LAH lithium aluminiumhydride
DBU 1,8-diazabicyclo LDA lithium diisopropylamide
[5.4.0]undec-7-ene Me methyl
DCC N,N'-dicyclohexyl NPY neuropeptide Y
carbodiimide Ph phenyl
DCM dichloromethane ppb part per billion
DIBAL-H diisobutyl aluminium ppm part per million
hydride Pro proline
DIC N,N'-diisopropyl RNA ribonucleic acid
carbodiimide Ser serine
DIPEA diisopropylethylamine SPPS Solid phase peptide
DKP diketopiperazine synthesis
DMAP dimethylaminopyridine TBDMS tert-butyldimethylsilyl
DMSO dimethylsulfoxide TEMPO 2,2,6,6-tetramethylpyridine-
e.e. enantiomeric excess 1-oxyl
EDC N-ethyl-N'- TFA trifluoroacetic acid
dimethylaminopropyl THF tetrahydrofurane
carbodiimide TMEDA tetramethylethylendiamine
Fmoc 9-fluorenylmethyl Tyr tyrosine
chloroformate Val valine

A. Introduction 1
A. Introduction

A. 0. Preface

Small molecules played the crucial role in the beginning of life.
Hence, of course also amino acids are basic building blocks of all vital existence. This appears
to be the appropriate expression since only 20 different amino acids display the smallest unit
of peptides and proteins which are responsible for innumerable various activities. They are the
monomers of entities that build up and maintain life’s structure and are involved in
coordination of almost all physiological processes. Consequently, they give the cell structure
and stability through proteins like collagen or elastin. Furthermore, amino acids build up
macro biopolymers like enzymes as well as many other peptides which play important roles in
coordination and maintenance of living organisms. Peptides, but also amino acids themselves,
as well as biogenic amines (generally derived from amino acids) are the major substrates for
targets like enzymes and receptors.
Amino acids are naturally synthesised from intermediates of the major metabolic pathways
like glycolysis or the citric acid cycle. Here α-keto acids like α-ketoglutarate are converted to
the corresponding α-amino acids by transfer of ammonia catalysed by enzymes, e.g.
glutaminase to produce glutamate. Other amino acids can be synthesised by transaminases in
the presence of glutamate or aspartate as amine source.
The first laboratory preparation of an amino acid was accomplished by Adolph Strecker
(Figure 1) in 1850. In his pioneering work he was able to synthesise α-amino acids from
simple readily available building blocks which will be described in the next chapter.

Figure 1. Oil painting of Adolph Strecker.1