Synthesis of Benzomorphan scaffolds by intramolecular Buchwald-Hartwig arylation and approach towards the total synthesis of the macrolide queenslandon [Elektronische Ressource] = Synthese von Benzomorphan-Scaffolds durch intramolekulare Buchwald-Hartwig-Arylierung und ein Zugang zur Totalsynthese des Macrolids Queenslandon / vorgelegt von Anton S. Khartulyari

Synthesis of Benzomorphan Scaffolds by Intramolecular
Buchwald–Hartwig Arylation
and
Approach Towards the Total Synthesis of the Macrolide
Queenslandon



Synthese von Benzomorphan Scaffolds durch Intramolekulare
Buchwald–Hartwig Arylierung
und
ein Zugang zur Totalsynthese des Macrolids Queenslandon



DISSERTATION

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




2007


vorgelegt von
ANTON S. KHARTULYARI
























Tag der mündlichen Prüfung: 14.06.2007

Dekan: Prof. Dr. L. Wesemann
1. Berichterstatter: Prof. Dr. M. E. Maier
2. Prof. Dr. Th. Ziegler
3. Dr. S. Laschat
This doctoral thesis was carried out from August 2003 to October 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.



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 would like to thank Prof. Dr. Thomas Ziegler for his helpful reviewing the doctoral thesis
and for giving precious comments and suggestions.

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 Viktor Vintonyak, Vaidotos Navickas, Markus Ugele, and Dr.
Manmohan Kapur for their assistance in the synthesis of many important substances.

I thank all my friends and specially Georgy Varseev, Evgeny Prusov, Pavel and Anna Levkin
and Dr. Srinivasa Marimganti for their help during my stay in Tübingen.

Special thanks to V. V. Menshikov for introducing me into the fantastic world of chemistry.
Thank you for planting the virus of loving chemistry in me.

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 bride, Stefanie Reit, 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 Mother


Publications:

A. S. Khartulyari, M. E. Maier, Synthesis of Benzomorphan Analogues by Intramolecular
Buchwald-Hartwig Cyclization. Eur. J. Org. Chem. 2007, 317–324.

A. S. Khartulyari, M. Kapur, M. E. Maier, A Concise Strategy to the Core Structure of the
Macrolide Queenslandon. Org. Lett. 2006, 8, 5833–5836.

M. Kapur, A. Khartulyari, M. E. Maier, Stereoselective Synthesis of Protected 1,2-Diols and
1,2,3-Triols by a Tandem Hydroboration-Coupling Sequence. Org. Lett. 2006, 8, 1629–1632.

A. Y. Lebedev, A. S. Khartulyari, A. Z. Voskoboynikov, Synthesis of 1-Aryl-1H-indazoles via
Palladium-Catalyzed Intramolecular Amination of Aryl Halides. J. Org. Chem. 2005, 70, 596–
602.

A. L. Krasovsky, A. S. Hartulyari, V. G. Nenajdenko, E. S. Balenkova, Efficient Syntheses of
new CF -containing diazolopyrimidines. Synthesis, 2002, 1, 133–137. 3

A. Z. Voskoboynikov, V. V. Izmer, A. F. Asachenko, I. P. Beletskaya, P. I. Dem'yanov, D. N.
Kazyul'kin, A. Yu. Lebedev, M. V. Nikulin, V. S. Petrosyan, A. N. Ryabov, A. S. Khartulyari,
K. Yu. Chernichenko, Chemistry of Metallocene Catalysts for Olefin Polymerization:
Technological Aspects. Ross. Khim. Zhurnal 2001, 45, 118–125 (journal written in russian).

Poster presentations:

A. Khartulyari, M. E. Maier, Approach to the Macrolide Queenslandon. International
Symposium on Chemistry, Biology and Medicine (C.B.M. 06), Cyprus, Paphos 2006.

thA. Khartulyari, M. Kapur, M. E. Maier, Total Synthesis of the Macrolide Queenslandon. 9
SFB-Symposium (SFB 380 "Asymmetric Syntheses with Chemisty and Biology Methods"),
Germany, Aachen 2005.

M. Kapur, A. Khartulyari, M. E. Maier, Synthesis of anti-Diols by a Hydroboration-Suzuki
Sequence: A Stereoselective Approach to the Core Structure of the Macrolide Queenslandon.
th9 SFB-Symposium (SFB 380 "Asymmetric Syntheses with Chemisty and Biology
Methods"), Germany, Aachen 2005.

A. Khartulyari, M. E. Maier, Synthesis of Benzomorphan Analogs: Palladium-Catalyzed
Intramolecular Arylation of Piperidone Derivatives. International Symposium on Advances in
Synthetic, Combinatorial, and Medicinal Chemistry (A.S.C.M.C. 04), Russia, Moscow 2004.

V. Nenajdenko, A. Gavryushin, E. Zakurdaev, A. Karpov, N. Shevchenko, D. Gribkov, A.
Hartulyari, M. Lebedev, N. Khajrutdinov, E. Balenkova, A library of tryptamines as building
thblocks for synthesis of pharmacologically active compounds. XIX European colloquium on
heterocyclic chemistry, Aveiro, Portugal 2000.

Table of Contents
Table of Contents

Chapter I Synthesis of Benzomorphan Scaffolds by Intramolecular Buchwald-
Hartwig Arylation

1 Introduction .........................................................................................................................1
2 Literature Review................................................................................................................6
2.1 Benzomorphans – a Structural Feature of Analgesic Drugs ........................................6
2.2 Clinically Used Benzomorphan Derivatives ..............................................................10
2.3 Overview of Known Methods for the Preparation of Various Benzomorphans ........15
2.3.1 The Tetralone Route .......................................................................................15
2.3.2 Grewe-type Cyclization..................................................................................31
2.3.3 Other Routes to the Benzomophan Ring Skeleton .........................................34
3 Goal of Research................................................................................................................41
4 Results and Discussion ......................................................................................................45
4.1 Synthesis of Benzomorphans by Intramolecular Buchwald-Hartwig Arylation of
Substituted N-Benzyl-Piperidone Derivatives ...........................................................45
4.2 Synthesis of Benzomorphans by Intramolecular Buchwald-Hartwig Arylation of
Substituted N-Methyl-Piperidone Derivatives ...........................................................53
4.3 Preparation of Benzomorphan Scaffold and Its Derivatization..................................56
5 Conclusion I .......................................................................................................................60

Chapter II Approach towards the Total Synthesis of the Macrolide Queenslandon

6 Introduction .......................................................................................................................63
7 Literature review ...............................................................................................................66
7.1 The Family of 14-Membered Resorcylic Acid Lactones ...........................................66
7.2 Chemical Syntheses of 14-Membered RALs .............................................................73
8 Results and Discussion ......................................................................................................99
8.1 Retrosynthetic Analysis..............................................................................................99
8.2 Syntheses of the Key Precursors ..............................................................................103
8.2.1 Substitued β-iodostyrenes.............................................................................103
8.2.2 Protected (R)- δ-hydroxyhexanal (8-6)..........................................................105
8.2.3 Chiral glycolate auxiliary (8-7)....................................................................108 Table of Contents
8.3 Model Studies on the Tandem Hydroboration/Suzuki Coupling Sequence............. 111
8.3.1 Preparation of the Required Substrates ........................................................ 116
8.3.2 Studies on the Tandem Hydroboration/Suzuki Coupling Sequence ............ 120
8.4 Synthesis of the Core Structure of the Macrolide Queenslandon ............................ 128
9 Conclusion II................................................................................................................