A new total synthetic pathway to cryptophycin-3 and an analogue as well as an efficient approach to the total synthesis of the proteasome inhibitor epoxomicin [Elektronische Ressource] = Ein neuer kompletter Syntheseweg für Cryptophycin-3 und ein Analogon sowie ein effizienter Zugang zur Totalsynthese des Proteasom-Inhibitors Epoxomicin / vorgelegt von Paulami Danner

Informations

• Publié par: eberhard_karls_universitat_tubingen
• Publié le: 01 janvier 2007
• Nombre de lectures: 17
• Langue: English
• Poids de l'ouvrage: 2 Mo

Extrait

A New Total Synthetic Pathway to Cryptophycin-3
and an Analogue as well as
an Efficient Approach to the Total Synthesis
of the Proteasome Inhibitor Epoxomicin



Ein neuer kompletter Syntheseweg für Cryptophycin-3
und ein Analogon sowie
ein effizienter Zugang zur Totalsynthese
des Proteasom Inhibitors Epoxomicin




DISSERTATION


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







2007


vorgelegt von

PAULAMI DANNER

























Tag der mündlichen Prüfung: 19.01.2007

Dekan: Prof. Dr. L. Wesemann
1. Berichterstatter: Prof. Dr. M. E. Maier
2. Beri Prof. Dr. Th. Ziegler


This doctoral thesis was carried out from February 2003 to September 2005 at the Institute
of Organic Chemistry, Faculty of Chemistry and Pharmacy, Eberhard-Karls-University
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 providing the opportunity to
study under his excellent guidance during my Ph.D period in Tübingen. I also appreciate
his detailed teaching of synthesis techniques in organic chemistry, his very kind assistance,
generous advice throughout the course of the research project as well as his flexibility due
to the arrival of my daughter Nisha.

I would like to thank Prof. Dr. Thomas Ziegler for his helpful reviewing the doctoral thesis
and giving valuable comments and suggestions.
Personally I thank Mr. Graeme Nicholson and Mr. Paul Schuler for their skillful technical
assistance in various measurements, Mrs. Munari for preparing the absolute solvents and
for her great and kind help in the laboratory.

I thank all my working group members for their valuable discussions, suggestions and their
friendly nature. Special thanks to Dr. R. Jogireddy, Dr. S. Marimganti, S. Yasmin for
constructive team work and a nice atmosphere in the lab as well as to Mrs Naiser for her
always helpful and competent organization.

Especially I would like to thank Dr. Anup Biswas for tireless transatlantic advice during
writing my thesis and Orun Biswas for support concerning English vocabulary and
grammar.

Further I would like to thank my family in India for their endless love and encouragement
which I have obtained during my studies and my doctoral thesis, although they are living
far away from me.

Finally I would like to thank my new family in Germany, especially my parents-in-law and
my brother-in-law for their constant and loving support as well as my husband Michael for
his permanent help, love and understanding and Nisha for her patience with a busy mother.
i PUBLICATION


P. Danner, M. Bauer, P. Phukan, M. E. Maier, Total Synthesis of Cryptophycin-3,
Eur. J. Org. Chem. 2005, 317-325






























ii












for Michael





















iii

































iv
TABLE OF CONTENTS


I. INTRODUCTION 1-4

II. THE FAMILY OF CRYPTOPHYCINS 5-65
1. Biological activity of Cryptophycins ..............................................................................5
2. Structure-activity relationships of Cryptophycins ......................................................7
3. Previous total and formal syntheses of Cryptophycins ................................................9
3.1 The first Tius synthesis ...............................................................................................9
3.2 The Leahy-Gardinier synthesis .................................................................................13
3.3 The Tius-Li synthesis................................................................................................15
3.4. The synthesis of unit A ............................................................................................18
3.4.1 The Sih chemoenzymatic synthesis...................................................................18
3.4.2 The Lilly chemoenzymatic synthesis ................................................................19
3.4.3 Synthesis via [2,3]-Wittig rearrangement .........................................................20
3.4.4 Asymmetric crotylboration................................................................................21
3.4.5 Noyori hydrogenation − Frater alkylation23
3.4.6 (S)-(−)-2-Acetoxysuccinic anhydride as starting material ...............................23
3.4.7 Vinyl epoxide reduction ...................................................................................25
3.4.8 Synthesis via Mitsunobu reaction......................................................................26
3.5. Syntheses of some important Cryptophycin analogues ...........................................27
3.5.1. Synthesis of stable Cryptophycin-52 (4) ......................................................... 27
3.5.2 1-Aza-Cryptophycin-1, an unstable Cryptophycin 28
3.5.3 Synthesis of Cryptophycin-24 (3) ..................................................................... 29
3.5.3.1 Synthesis via N-Acyl-β-lactam macrolactonization.................................. 29
3.5.3.2 Synthesis via RCM approach 30
4. Key reactions and mechanisms..................................................................................... 31
4.1. Aldol reaction........................................................................................................... 31
4.1.1 Syn selective Crimmins aldol ............................................................................ 32
4.2 Wittig reaction 33
4.3 Coupling reactions .................................................................................................... 35
4.3.1. Coupling by carbodiimides .............................................................................. 36
4.3.2 Coupling by uoninium and phophonium salts of Benzotriazoles...................... 38
4.4 Yamaguchi esterification .......................................................................................... 38
4.5 Macrolactonization 40
4.5.1 Corey and Nicolaou reactions ........................................................................... 40
4.5.2 The Mukaiyama methods .................................................................................. 41
4.5.3 Mitsunobu reaction............................................................................................ 42
5. Goal of research .............................................................................................................43
6. Results and discussion ...................................................................................................45
6.1 Retrosynthetic analysis of Cryptophycin-3 (5) .........................................................45
6.2 Synthesis of 5-hydroxy ester 12b (unit A) ................................................................45
6.2.1 Retrosynthetic analysis of 5-hydroxy ester 12b (unit A)...................................46
6.2.2. Aldol reaction with Evans methodology..........................................................46
6.2.3 Further synthetic pathway to 5-hydroxy ester 12b............................................47
v 6.2.4 Aldol reaction using the Seebach auxiliary....................................................... 51
6.3. Synthesis of amino acid 13c (unit B) by enantioselective alkylation ...................... 53
6.3.1 Synthesis of chiral catalyst 147......................................................................... 54
6.3.2 Preparation of N-(Diphenylmethelene)glycine tert-butyl ester 148.................. 55
6.3.3 Synthetic pathway to amino acid 13c (unit B).................................................. 56
6.4 Synthesis of β-amino acid 14c (unit C) .................................................................... 57
6.5 Syα-hydroxy ester 15b (unit D) ............................................................... 58
6.6 Assembly of tripeptide derivative acid 126 (D + C + B section) ............................. 59
6.7 Synthesis of protected seco-compound 127 and macrocyclization .......................... 60
6.8 Synthesis of cryptophycin analogue 11 63
6.8.1 Retrosynthetic analysis ..................................................................................... 63
6.8.2 Synthesis of tripeptide derivative 174 63
6.8.3 Synthesis of seco-compound 177 and final cyclization ..........