Design, synthesis and structural evaluation of peptidomimetics with a defined secondary structure [Elektronische Ressource] / Régis Delatouche

Redge

Informations

• Publié par: universitat_regensburg
• Publié le: 01 janvier 2008
• Nombre de lectures: 8
• Langue: English
• Poids de l'ouvrage: 4 Mo

Extrait

Design, synthesis and structural evaluation of peptidomimetics
with a defined secondary structure


Dissertation

Zur Erlangung des Doktorgrades der Naturwissenschaften (Dr. rer. nat.) der Fakultät für Chemie und
Pharmazie der Universität Regensburg und der Universität von Insubria (Italien)

Co-tutored Ph.D obtained at the University of Regensburg (Germany) and the
University of Insubria (Italy)




Régis Delatouche

From

Rennes (France)



Regensburg 2008









This work was supervised by Prof. Dr. Oliver Reiser and Prof. Dr. Umberto Piarulli

Thesis submission on November 13th, 2008

rd
Thesis defence on December 3 , 2008

Examination committee: Prof.Dr. Sigurd Elz
Prof. Dr. Oliver Reiser
Prof. Dr. Umberto Piarulli
Prof. Dr. Burkhard König

The following research was perfomed from October 2005 to September 2007 in the Institute of Organic
Chemistry at the University of Regensburg under the supervision of Prof. Dr. Oliver Reiser and from October
2007 to September 2008 at the Institute of Organic Chemistry of the University of Insubria in Como under the
supervision of Prof. Dr. Umberto Piarulli.

































I would like to thank Prof. O. Reiser and Prof. U. Piarulli for having given me the opportunity to work in their
research groups on such interesting subjects.
I also thank the Marie Curie commission for financial support during this Ph.D programme.




















To my spouse Virginie, for her support and encouragements, my son Erwan and my family.
Index

Chapter 1 2

I. Introduction 2

1. Generalities about peptides 2

2. Conformational studies for peptide secondary structure characterisation 6

3. Peptide coupling: overview 9

4. Synthesis of unnatural amino acids 13

II. Syntheses of δδδδ-amino acids 15

1. Synthesis of linear δ-amino acids 15

2. Synthesis of cyclic δ-amino acids 30

III. δ-amino acids in foldamers 37

IV. Aim of this work 41

V. Synthesis of γ-butyrolactonaldehyde 43

1. Asymmetric cyclopropanation of furan methyl ester 43

2. Ozonolysis 43

3. Sakurai allylation 44

4. Retroaldol lactonisation 44

VI. Synthesis of the δ-amino acid 46

1. Introduction of the nitrogen moiety by reductive amination 46

2. Boc protection of the secondary amine 47

3. PMB removal by cerium ammonium nitrate 47

4. Oxidation of the allylic double bond 48

VII. Investigations on the α-substitution of the lactone ring 48

1. Monomethylation of the lactone ring 48

2. Fluorination of the lactone ring 49

3. Dimethylation of the lactone ring 50

4. Synthesis of the dimethylated δ-amino acid 50


VIII. Introduction of the δ-amino acid into peptides 51

1. Synthesis of homopeptides of the δ-amino acid 51
2. Synthesis of alternated α-δ-peptides 52

3. Synthesis of a hairpin-like peptide 53

IX. Conformational studies of the peptides synthesised 55

1. Conformational studies of the α-δ-peptide 55

2. Conformational studies of the hairpin-like peptide 60

X. Conclusion 63

Chapter 2

I. Introduction 64

1. Diketopiperazines in natural products and biologically active compounds 64

2. Syntheses of diketopiperazines 66

3. Diketopiperazines in peptidomimetics 68

4. Diketopiperazines as organocatalysts 70

II. Synthesis of the diketopiperazine scaffold 71

1. Allylation of aspartic acid 71

2. Boc protection of β-allyl aspartic acid 72

3. Methyl esterification of serine 72

4. Reductive amination 73

5. Coupling of N-Boc-β-allyl-aspartic acid with N-benzyl serine methyl ester 73

6. Cyclisation of the dipeptide 73

7. Introduction of the nitrogen moiety by Mitsunobu reaction 74

8. Reduction of the azide to the protected amine by a Staudinger-like reaction 75

9. Deallylation catalysed by Pd(PPh ) 82 3 4

III. Introduction of the diketopiperazine building block into peptides and conformational analyses 77

1. β-bend ribbon 77

2. Synthesis of homopolymers of cis-diketopiperazine 79

3. Conformational analyses of the homopolymers of cis-diketopiperazine 80

4. Synthesis of cyclic peptides based on the trans-diketopiperazine building block 88

5. Conformational studies of the cyclic peptide 90 IV. Syntheses of potential organocatalysts based on a diketopiperazine scaffold 94

1. Amide-bonded organocatalyst synthesis 95

2. Ester-bonded organocatalyst synthesis 96

Experimental part 98

I. Instruments and general techniques 98

II. Synthesis of compounds 100

1. Synthesis of δ-amino acids 100

2. Synthesis of peptides containing δ-amino acids 116

3. Synthesis of the diketopiperazine scaffold 127

4. Synthesis of peptides containing the diketopiperazine scaffold 137

5. Synthesis of organocatalysts containing the diketopiperazine scaffold 144

Summary 148

References 152

Appendix of NMR 156


Abbreviations




9-BBN 9-borabicyclo[3.3.1]nonane HMPA hexamethylphosphoramide
Ala alanine HOAt hydroxyazabenzotriazole
Bn benzyl HOBt hydroxybenzotriazole
Boc tert-butyloxycarbonyl LDA lithium diisopropylamide
CAN cerium(IV) diammonium nitrate mCPBA 3-chloroperoxybenzoic acid
Cbz carboxybenzyloxy Me methyl
CH CN acetonitrile MEM methoxyethoxymethyl 3
d.e. diastereoisomeric excess Phe phenylalanine
d.r. diastereoisomeric ratio ppb part per billion
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene ppm part per million
DCC N,N'-dicyclohexyl carbodiimide Pro proline
DCM dichloromethane Ser serine
DIBAL-H diisobutyl aluminium hydride tBu tert-butyl
DIC N,N'-diisopropyl carbodiimide TEMPO 2,2,6,6-tetramethylpyridine-1-oxyl
DKP diketopiperazine TFA trifluoroacetic acid
DMAP dimethylaminopyridine THF tetrahydrofurane
DMSO dimethylsulfoxide TMU tetramethylurea
e.e. enantiomeric excess Tyr tyrosine
N-ethyl-N'-dimethylaminopropyl Val valine
EDC
carbodiimide
Et N triethylamine 3
Fmoc 9-fluorenylmethylchloroformate
Gln glutami