Syntheses and biological evaluation of cruentaren A and neopeltolide as well as their analogues [Elektronische Ressource] = Synthesen und biologische Evaluierung der Makrolide Cruentaren A und Neopeltolid sowie deren Analoga / vorgelegt von Viktor V. Vintonyak

Vintonyak

Informations

• Publié par: eberhard_karls_universitat_tubingen
• Publié le: 01 janvier 2008
• Nombre de lectures: 25
• Langue: English
• Poids de l'ouvrage: 3 Mo

Extrait

Syntheses and Biological Evaluation of Cruentaren A and
Neopeltolide as well as their Analogues






Synthesen und Biologische Evaluierung der Makrolide
Cruentaren A und Neopeltolid sowie deren Analoga


DISSERTATION

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




2008


vorgelegt von
Viktor V. Vintonyak
























Tag der mündlichen Prüfung: 16.09.2008

Dekan: Prof. Dr. L. Wesemann
1. Berichterstatter: Prof. Dr. M. E. Maier
2. Prof. Dr. Th. Ziegler
3. Prof. Dr. A. Kirschning This doctoral thesis was carried out from August 2005 to March 2008 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.

Foremost, I am indebted to Prof. Dr. Martin E. Maier, my supervisor, for his support and
excellent guidance during this research work. I am grateful to Prof. Dr. Martin E. Maier, not
only for the endowed confidence and freedom in the choice of my research and the execution
of my own ideas, but also for his competent advice, constant encouragement and limitless
patience through the course of the highly interesting research projects of my doctoral thesis.

I would like to thank Prof. Dr. Thomas Ziegler for reviewing the doctoral thesis and for giving
valuable comments and suggestions for its improvement.

I would like to express my sincere gratitude to Dr. Florenz Sasse and Dr. Brigitte Kunze
(Helmholtz-Zentrum für Infektionsforschung, Braunschweig) for helpful collaboration and
support with biological assays. I personally thank Mr. Graeme Nicholson and Mr. Paul
Schuler for their skilful technical assistance in numerous measurements, and Mrs. Maria
Munari for well organized supply of chemicals and her great help in the laboratory.

I thank all my working group members for valuable discussions and their friendly nature. I
would like to specially thank Vaidotas Navickas, Marcellino Calà, and Claudia Braun for their
assistance in the synthesis of many important substances. Special appreciation goes to Dr.
Anton Khartulyari, Dr. Evgeny Prusov and Georgy Varseev for many valuable suggestions
and guidance in all chemistry questions.

Special thanks to Dr. O. V. Khilya for giving me my first experimental skills, Prof. Dr. Ju. V.
Volovenko for teaching me chemistry and V. V. Basanec for introducing me into the fantastic
world of chemistry.

Finally, I am thankful to the love of my parents, without whom I would not be what I am
today. And of course I thank my wife, Olga Virstyuk, who has standed me all times, for her
infinite love and support that gave me the courage and perseverance to achieve this milestone
in my life.






















my Parents


Publications:

V. V. Vintonyak, M. E. Maier, Formal Total Synthesis of Neopeltolide, Org.
Lett. 2008, 10, 1239–1242.

V. V. Vintonyak, M. Calà, F. Lay, B. Kunze, F. Sasse, M. E. Maier, Synthesis
and Biological Evaluation of Cruentaren A Analogues, Chem. Eur. J. 2008, 14,
3709–3720.

V. V. Vintonyak, M. E. Maier, Total Synthesis of Cruentaren A, Angew. Chem.
2007, 119, 5301–5303; Ang. Chem. Int. Ed. 2007, 46, 5209–5211.

V. V. Vintonyak, M. E. Maier, Synthesis of the Core Structure of Cruentaren A,
Org. Lett. 2007, 9, 655–658.


Poster presentations:

V. V. Vintonyak, M. E. Maier, Synthesis and Biological Evaluation of
thNeopeltolide and Analogues. 11 Belgian Organic Synthesis Symposium (BOSS
XI), Belgium, Ghent 2008.
Table of Contents
Table of Contents

Chapter I Total Synthesis of Cruentaren A and Analogues................................................1

1 Introduction.......................................................................................................................1
2 Literature Review..............................................................................................................3
2.1 Biological Activity of Cruentaren A ...........................................................................3
2.2 Synthesis of Cruentaren A by Fürstner........................................................................7
2.3 Key Reactions and its Mechanisms12
2.3.1 Ring closing alkyne metathesis .........................................................................12
2.3.2 Evans aldol reaction..........................................................................................18
2.3.3 Addition of chiral allenylzincates to aldehydes (Marshall–Tamaru reaction) ..23
2.3.4 Synthesis of enamides via copper-catalyzed coupling of amides with vinyl
halides ...........................................................................................................................28
3 Results and Discussion ....................................................................................................32
3.1 Retrosynthetic Analysis.............................................................................................32
3.2 Ring Closing Metathesis Model Study......................................................................35
3.2.1 Synthesis of diene 3-11 .....................................................................................35
3.2.2 Ring closing metathesis of diene 3-11...............................................................36
3.3 Epoxide Opening Strategy.........................................................................................38
3.3.1 Synthesis of alkyne 3-30 ...................................................................................38
3.3.2 epoxide 3-42 .................................................................................39
3.3.3 Coupling of alkyne 3-30 with epoxide 3-42......................................................41
3.4 Ring Closing Alkyne Metathesis Strategy ................................................................43
3.4.1 Synthesis of functionalized benzoic acid 3-50 ..................................................43
3.4.2 alcohol 3-60 ..................................................................................44
3.4.3 Esterification of acid 3-50 with alcohol 3-60 ....................................................46
3.4.4 Synthesis of diol 3-71........................................................................................48
3.4.5 Esterification of acid 3-50 with diol 3-71..........................................................49
3.4.6 Ring closing metathesis reaction and synthesis of the core structure of
cruentaren A ......................................................................................................................51
3.4.7 Connection of the propargyl amide side chain ..................................................52
3.4.8 Completion of the synthesis of cruentaren A ....................................................55
3.5 Synthesis and Biological Evaluation of Cruentaren A Analogues............................56
3.5.1 Synthesis of 3-OMe cruentaren (3-90) ..............................................................56
3.5.2 Modification of the carboxylic acid part of the amide ......................................58
3.5.3 the enamide analogue 3-100 .........................................................60
3.5.4 Synthesis of the oxazinan-4-one analogue 3-102..............................................62
3.5.5 the vinyl iodide 3-119 ...................................................................63
3.5.6 the homologated enamide 3-122...................................................65
3.5.7 Synthesis of the oxazinan-4-one analogue 3-12466
3.5.8 Biological testing...............................................................................................67
4 Conclusion I.....................................................................................................................69

Chapter II Synthesis and Biological Evaluation of Neopeltolide and Analogues............71

5 Introduction....73 Table of Contents
6 Literature Review............................................................................................................76
6.1 Isolation and Biological Activity of Neopeltolide.....................................................76
6.2 Previous Neopeltolide Syntheses ..............................................................................78
6.2.1 Synthesis of Neopeltolide by Panek and co-workers ........................................78
6.2.2 Neopeltolide by Scheidt and co-workers ......................................80
6.2.3 Neopeltolide by Lee and co-workers ............................................83
6.2.4 Synthesis of Neopeltolide by Sasaki and co-workers85
6.3 Key Reactions and its Mechanisms.....................