γ-aminoadamantane [Gamma-aminoadamantane] carboxylic acids [Elektronische Ressource] : orientating building blocks in peptide chemistry / vorgelegt von Lukas Wanka

Informations

• Publié par: justus-liebig-universitat_giessen
• Publié le: 01 janvier 2008
• Nombre de lectures: 44
• Langue: Deutsch
• Poids de l'ouvrage: 14 Mo

Extrait

γ-Aminoadamantane Carboxylic Acids:
Orientating Building Blocks in
Peptide Chemistry
Inaugural-Dissertation zur Erlangung des Doktorgrades
der Naturwissenschaftlichen Fachbereiche
(Fachbereich 08 – Biologie und Chemie)
der Justus-Liebig-Universität Giessen

Vorgelegt von
Lukas Wanka
aus Wöllstadt
Giessen 2007
Die vorliegende Arbeit wurde am Institut für Organische Chemie der Justus-Liebig
Universität Giessen von Juli 2002 bis Juni 2007 unter der Anleitung von Herrn Prof.
Dr. Peter. R. Schreiner, Ph.D. angefertigt. Ihm gebührt mein Respekt und Dank für
die außergewöhnliche Freiheit bei der Durchführung der hier beschriebenen Arbeiten
und das immanente „forward-thinking“ sowie seine Unterstützung, die über die
Promotion in seinem Arbeitskreis weit hinaus reicht.

























sometimes is seen a strange spot in the sky
a human being that was given to fly














Für Christina


















γ-Aminoadamantane carboxylic acids I

Contents

1. Abstract ...................................................................................................................1

2. Zusammenfassung .................................................................................................4

3. Introduction.............................................................................................................8

3.1. Natural products incorporating the adamantane motif........................................8
3.2. Medicinal chemistry of adamantane derivatives ...............................................10

4. Project....................................................................................................................44

5. Direct Functionalization of Adamantanes...........................................................47

A5.1. Xaas through bromine-free C–H to C–N bond amidations..............................47
A5.2. Xaas through PTC-halogenation and subsequent conversions. .....................55

6. Peptide chemistry.................................................................................................59

6.1. Protective groups and strategy.........................................................................59
6.2. Peptide synthesis in solution ............................................................................60
6.3. Solid phase peptide synthesis (SPPS) .............................................................64
6.4. Cyclizations ......................................................................................................67
6.5. Summary..........................................................................................................72

7. Biological Properties ............................................................................................73

7.1. Anti Influenza A activity ....................................................................................73
A7.2. Xaas as analogues of GABA ..........................................................................75
II Contents
8. Peptidic Organocatalysts.....................................................................................78
A8.1. Peptidic catalysts incorporating Gly ................................................................78
8.2. Peptidic thioureas and organocatalytic Morita-Baylis-Hillman reactions...........81

9. Structural Features ...............................................................................................90

9.1. Computational methods and strategy...............................................................90
9.2. Infrared spectroscopy.......................................................................................95
9.3. NMR spectroscopy ...........................................................................................95
A9.4. Minimum requirements for an Gly induced turn motif .....................................96
A9.5. Homooligomeric Gly .....................................................................................112
A A t9.6. Alternating peptides: Fmoc-Gly- Gly-Gly- Gly-O Bu ......................................118
A9.7. Conformational analysis of Xaa based organocatalysts incorporating His
residues.................................................................................................................118
A9.8. Conformational analysis of Xaa based thiourea organocatalysts..................125

10. Summary & Outlook .........................................................................................131

11. Acknowledgement ............................................................................................136

12. Experimental Part .............................................................................................139

12.1. General remarks...........................................................................................139
12.2. General procedures......................................................................................139
12.3. Direct C–H to C–N acetamidations...............................................................141
12.4. Synthesis of γ-aminoadamantane-1-carboxylic acids...................................148
12.5. Direct C–H to C–N- amidations using amides as the nucleophiles...............151
12.6. Oxyfunctionalizations ...................................................................................153
12.7. PTC halogenations and subsequent conversions ........................................155
12.8. Protective group chemistry...........................................................................161
12.9. Peptide chemistry.........................................................................................167
A12.10. Solid phase peptide synthesis of Gly homooligomers...............................179 γ-Aminoadamantane carboxylic acids III
12.11. Solid phase synthesis of cyclization precursors .........................................182
A12.12. Cyclization experiments: Synthesis of cyclo-(D-Ala- Gly-L-Ala) ................182 2
12.13. Biological tests ...........................................................................................183
A12.14. Gly-based peptidic organocatalysts incorporating His residues................184
A12.15. Synthesis of peptidic thiourea organocatalysts incorporating Gly .............192
12.16. Catalyst screening of peptidic thioureas in the Morita-Baylis-
Hillman reaction.....................................................................................................203
12.17. Solid phase peptide synthesis of model peptides.......................................204
12.18. Miscellaneous: Synthesis of compound 266...............................................206

13. Abbreviations296

14. References.........................................................................................................299

15. Bibliography......................................................................................................311