Synthesis of spirocyclic scaffolds by aminoallylation RCM sequence and approach toward the total synthesis of the Macrolide Dictyostatin [Elektronische Ressource] = Synthese spiroverknüpfter Scaffolds durch eine Aminoallylierung-, Ringschluss-Metathese-Sequenz und ein Zugang zur Totalsynthese des Macrolids Dictyostatin / vorgelegt von Evgeny V. Prusov

Evgeny V. Prusov

Informations

• Publié par: eberhard_karls_universitat_tubingen
• Publié le: 01 janvier 2008
• Nombre de lectures: 11
• Langue: English
• Poids de l'ouvrage: 4 Mo

Extrait

Synthesis of Spirocyclic Scaffolds by Aminoallylation/RCM
Sequence
and
Approach Toward the Total Synthesis of the Macrolide
Dictyostatin



Synthese Spiroverknüpfter Scaffolds durch eine
Aminoallylierung/Ringschluss Metathese Sequenze
und
ein Zugang zur Totalsynthese des Macrolids Dictyostatin


DISSERTATION

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




2007


vorgelegt von
Evgeny V. Prusov
























Tag der mündlichen Prüfung:

Dekan: Prof. Dr. L. Wesemann
1. Berichterstatter: Prof. Dr. M. E. Maier
2. Prof. Dr. Th. Ziegler
This doctoral thesis was carried out from August 2003 to October 2007 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 thank him not only for providing me with the
lab facilities but also for his confidence and unlimited trust in me and for the multitude of little
advices he has given me during the course of this work.


I personally thank Mr. Graeme Nicholson and Mr. Paul Schuler for their skilful technical
assistance in numerous measurements, 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 Hartmut Röhm, Julia Jägel, and Claudia Braun for their
assistance in the synthesis of many important substances.

I thank all my friends, especially Georgy Varseev and Anton Khartulary, for their help during
my stay in Tübingen.

Special thanks to Dr. E. P. Zakurdaev for giving me my first experimental skills, Prof. Dr. V.
G. Nenajdenko for teaching me chemistry and Dr. A. Gavrushin for introducing me into the
fantastic world of total synthesis.

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 Schick, who stood with me all the times, for her
infinite love and support that gave me the courage and perseverance to achieve this milestone
in my life.






















my Grandmother


Publications:

E. V. Prusov, M. E. Maier, Synthesis of nitrogen containing spirocyclic scaffolds
via aminoallylation/RCM sequence. Tetrahedron 2007, 63, 10486–10196.

E. V. Prusov, H. Röhm, M. E. Maier, Chemoenzymatic Synthesis of the C10-
C23 Segment of Dictyostatin. Org. Lett. 2006, 8, 1025–1028.

V. G. Nenajdenko, E. P. Zakurdaev, E. V. Prusov, E. S. Balenkova, A novel
convenient approach to the synthesis of 2-substituted analogs of ornithine and
homolysine. Russian Chemical Bulletin 2005, 53, 2866–2870.

V. G. Nenajdenko, E. P. Zakurdaev, E. V. Prusov, E. S. Balenkova, Convenient
synthesis of melatonin analogues: 2- and 3-substituted -N-
acetylindolylalkylamines. Tetrahedron 2004, 60, 11719–11724.



Table of Contents

Chapter I Synthesis of Spirocyclic Scaffolds by Aminoallylation/RCM sequence
1 Introduction ..................................................................................................................1
2 Literature Review .........................................................................................................4
2.1 Privileged structures and scaffolds in modern drug discovery.........................4
2.2 Natural compounds and drugs containing a spiroheterocyclic skeleton...........6
2.3 Overview of Known Methods for the Preparation of Various Spirocyclic
structures.....................................................................................................................11
2.3.1 1-Azaspiro[5.5]undecane...............................................................................11
2.3.2 2-Azaspiro[21
2.3.3 3-Azaspiro[5.5]undecane, 3,9-Diazaspiro[5.5]undecane, and 2,9-
Azaspiro[5.5]undecane..................................................................................................28
2.3.4 1,8-Diazaspiro[5.5]undecane and 1,9-Diazaspiro[5.5]undecane...................31
2.3.5 2,8-Azaspiro[5.5]undecane............................................................................32
3 Goal of Research ........................................................................................................35
4 Results and Discussion ...............................................................................................37
4.1 Initial investigation of RCM strategy on N-alkyl protected spirocycles........37
4.2 Preparation of Spirocyclic Scaffolds and their Derivatization .......................39
4.2.1 Extension of the Veenstra methodology to the ketones ................................39
4.2.2 Allylation of carbamates................................................................................41
4.2.3 RCM of carbamate protected diallylamines ..................................................43
4.2.4 Conversion to spirocyclic ketones.................................................................45
4.2.5 Further reactions on carboxyl and carbonyl groups ......................................47
5 Conclusion I................................................................................................................49
Chapter II Approach towards the Total Synthesis of the Macrolide Dictyostatin
6 Introduction53
7 Literature review ........................................................................................................55
7.1 Cancer treatment with microtubule stabilizing agents ...................................55
7.2 Previous Dictyostatin syntheses .....................................................................60
7.2.1 Synthesis of Dictyostatin by Paterson and Curran ........................................60
7.2.2 Synthesis by Philipps.....................................................................................68
7.2.3 Synthesis by Ramachandran..........................................................................71
7.3 Overview of the key reactions used................................................................75
7.3.1 Evans aldol reaction ......................................................................................75
7.3.2 Addition of chiral allenylzinkates to aldehydes ............................................77
7.3.3 Syn-reduction of β-hydroxyketones...............................................................80
7.3.4 Enzyme catalyzed kinetic resolution and desymmetrization.........................84 Table of Contents
7.3.5 Yamaguchi macrolactonization..................................................................... 90
7.3.6 Intramolecular Nozaki-Hiyama-Kishi reaction............................................. 94
8 Results and Discussion............................................................................................... 97
8.1 Retrosynthetic analysis of dictyostatin........................................................... 97
8.2 Syntheses of the Key Precursors .................................................................. 101
8.2.1 Desymmetrysation of meso-2,4-dimetyl-1,5-pentanediol........................... 101
8.2.2 Abiko auxiliary............................................................................................ 104
8.2.3 Preparation of chiral propargyl mesylate .................................................... 105
8.2.4 Synthesis of right-hand fragment ................................................................ 106
8.3 Attempted extension via Abiko aldol and Stork-Zhao reactions ................. 108
8.4 Extension via Marshall allenylzincate methodology.................................... 109
8.5 Coupling of the right and left fragments via alkyllithium addition to Weinreb
amide 111
8.6 Z-vinyl iodide synthesis and syn-selective reduction................................... 113
8.7 Synthesis of C1-C9 fragment ....................................................................... 116
8.8 Attempted Nozaki-Hiyama-Kishi macrocyclization.................................... 116
8.9 Study of alternative coupling strategy.......................................................... 118
8.10 Completion of the synthesis ......................................................................... 120
9 Conclusion II ............................................................................................................ 124
10 Experimental Section ............................................................................................... 126
10.1 General Remarks ...........................................................................