Synthesis and conformational analysis of jasplakinolide analogues and approach towards the synthesis of the stereotetrad of cruentaren A [Elektronische Ressource] = Synthese und Konformations-Analyse von Jasplakinolidanaloga sowie ein Vorschlag zur Synthese der Stereotetrade von Cruentaren A / vorgelegt von Srinivasa Marimganti

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Informations

• Publié par: eberhard_karls_universitat_tubingen
• Publié le: 01 janvier 2006
• Nombre de lectures: 19
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

Synthesis and Conformational Analysis of Jasplakinolide
Analogues and Approach towards the Synthesis of the
Stereotetrad of Cruentaren A

Synthese und Konformations Analyse von
Jasplakinolidanaloga sowie ein Vorschlag zur Synthese der
Stereotetrade von Cruentaren A



DISSERTATION

der Fakultät für Chemie und Pharmazie
der Eberhard-Karls-Universität Tübingen
zur Erlangung des Grades eines Doktors
der Naturwissenschaften






2006


vorgelegt von
Srinivasa Marimganti

























Tag der mündlichen Prüfung: 23.11.2006

Dekan: Prof. Dr. L. Wesemann
1. Berichterstatter: Prof. Dr. M. E. Maier
2. Dr. Th. Ziegler
This doctoral thesis was carried out from August 2003 to May 2006 at the Institut für
Organische Chemie, Fakultät für Chemie und Pharmazie, Eberhard-Karls-Universität
Tübingen, Germany, under the guidance of Professor Dr. Martin E. Maier.

First of all, I would like to thank Prof.Dr. Martin E. Maier for his excellent guidance during
my Ph.D period in Tüebingen. Whenever I want to discuss with him, with his limitless
patience he never denied me how much ever busy with his schedule. In such a wonderful
atmosphere I had enough time to achieve my goal without any problem. His teaching
assistance in every little aspect about synthetic organic chemistry, generous advice and
constant encouragement and limitless patience helped me to improve my knowledge in
various aspects.

I would like to thank Prof. Dr. Thomos Ziegler for his helpful reviewing the doctoral thesis
and for giving valuable comments and suggestions and Prof. Mariappan Periasamy for his
valuable suggestions during my Master’s Degree.

I personally thank Dr. Florenz Sasse for testing the biological activity, Mr. Graeme Nicholson
for his skillful technical assistance in various measurements, Mrs. Munari for preparing the
absolute solvents and for her kind help in the laboratory.

I thank all my working group members for their valuable discussions, suggestions and their
friendly nature. I specially thank Dr. Rajamalleswaramma Jogireddy, Dr. Andreas Petri,
Evgeny Prusov, Anton Khartulyari, Jan Ritschel, Markus Ugele, Dr. Manmohan Kapur and
Mrs. Naiser for their valuable suggestions in various aspects.

I would like to thank Murthy, Mahesh, Bhavani, Vikram, Surya, and Vamshi for their
tremendous support during my research period.

I would like to pay tribute to the constant support of my parents and brother for their love,
understanding and encouragement throughout my life. I don’t have words to explain about my
wife Prativa, I could say without her I might have not finished my Ph. D. in time.


























for prativamayee

Publications:

S. Marimganti, S. Yasmeen, D. Fischer, M. E. Maier, Synthesis of Jasplakinolide Analogues
containing a Novel ω-Amino Acid. Chem. Eur. J. 2005, 11, 6687-6700.

S. Marimganti, M. E. Maier, Synthesis and Conformational analysis of Geodiamolide
Analogues Eur. J. Org. Chem. submitted.

Poster presentations:

S. Marimganti, M. E. Maier, Synthesis and Conformational analysis of Geodiamolide
thAnalogues containing Novel ω-amino and hydroxy acids. 9 International SFB-Symposium
SFB-380, Aachen, Germany, October 10-11, 2005.
Table of Contents
Table of Contents
Chapter I
1 Introduction ............................................................................................................................1
2 Literature Review...................................................................................................................5
2.1 Summary of biological activity of Jasplakinolide and other related compounds......5
2.2 Modeling the jasplakinolide binding site on actin filaments .......................................7
2.3 The family of Jasplakinolide...........................................................................................8
2.4 Conformational (peptidomimetical) studies of small peptides..................................11
2.4.1 Secondary Structure Motifs: β turns.........................................................................13
2.4.2 Sugar Amino acids (SAA)........................................................................................14
2.4.3 β-Amino acids ..........................................................................................................17
2.4.4 N-Methyl amino acids (NMA) .................................................................................18
2.4.5 Non bonded interactions19
2.5 Key reactions and mechanisms ....................................................................................23
2.5.1 Stereo selective alkylation’s using chiral auxiliaries................................................23
2.5.2 Enzymatic hydrolysis using Pig liver esterase (PLE, EC 3.1.1.1)............................27
2.5.3 Formation of protected amines (carbamates) via Curtius Rearrangement ...............31
2.5.4 Ireland-Claisen Rearrangement ................................................................................35
2.5.5 Syn selective Evans Aldol reaction...........................................................................39
2.5.6 Esterification using the Yamaguchi method and DCC/DMAP conditions ..............43
2.5.7 Coupling reagents in solution phase peptide synthesis ............................................47
3 Goal of research....................................................................................................................53
4 Results and Discussion .........................................................................................................55
4.1 Design of the novel ω-amino and hydroxy acids.........................................................55
4.2 Retrosynthetic analysis and synthetic pathways for amino and hydroxy acids ......58
4.2.1 Retrosynthetic analysis of amino acid 95.................................................................58
4.2.2 Synthesis of amino acid 95.......................................................................................60
4.2.3 Synthesis of jasplakinolide analogues by incorporating the amino acid 95.............65
4.2.4 Retrosynthetic analysis of hydoxy and amino acids 96 and 97................................68
4.2.5 Synthetic pathway for hydroxy acid 96....................................................................69
4.2.6 Retrosynthetic analysis of amino acid 9773
4.2.7 Synthetic pathway for am .......................................................................74
4.2.8 Synthesis of jasplakinolide (geodiamolide) analogues using 96 and 97 ..................77
4.2.9 Synthesis of Nor-methyl Chondramide C 185 .........................................................88
4.2.10 Design and the synthesis of analogues of hydroxy acid 96....................................93
4.2.11 Retrosynthetic analysis and synthesis of amino acid 194.......................................94
4.2.12 Synthesis of hydroxy acid 195 ...............................................................................98
4.3 Conformational studies ...............................................................................................100
4.3.1 Conformational studies of jasplakinolide analogues 129, 134, 135 and 136 .........100
4.3.2 Conformational studies of geodiamolide analogues 159 and 160..........................105

Table of Contents
Chapter II
5 Introduction ........................................................................................................................110
6 Synthesis of stereo tetrad 212............................................................................................ 112
6.1.1 Retrosynthetic analysis of stereo tetrad 212...........................................................112
6.1.2 Synthesis of aldehyde 215...................................................................................... 113
6.1.3 Second retrosynthetic pathway for epoxide 212 .................................................... 115
6.1.4 Synthetic pathway .................................................................................................. 116
7 Summary and Conclusion.................................................................................................. 122
8 Experimental Section ......................................................................................................... 128
8.1 General Remarks 128
8.1.1 Chemicals and Working Techniques......................................................................128
8.1.2 NMR-spectroscopy.................................................................................................128
8.1.3 Mass Spectrometry129
8.1.4 Infrared Spectroscopy.............................................................................................129
8.1.5 Polarimetry ...............