Enantiocontrol with Chiral Sulfoxides and Diastereocontrol in the Cross-Couplings of Substituted Cycloalkyl and Piperidinyl Derivatives [Elektronische Ressource] / Tobias Thaler. Betreuer: Paul Knochel

Tobias Thaler

Informations

• Publié par: ludwig-maximilians-universitat_munchen
• Publié le: 01 janvier 2011
• Nombre de lectures: 21
• Langue: English
• Poids de l'ouvrage: 13 Mo

Extrait

Dissertation zur Erlangung des Doktorgrades
der Fakultät für Chemie und Pharmazie
der Ludwig-Maximilians-Universität München






Enantiocontrol with Chiral Sulfoxides and
Diastereocontrol in the Cross-Couplings of Substituted
Cycloalkyl and Piperidinyl Derivatives




von

Tobias Johannes Werner Thaler


aus


München



2011


Erklärung

Diese Dissertation wurde im Sinne von § 13 Abs. 3 bzw. 4 der Promotionsordnung vom 29.
Januar 1998 (in der Fassung der vierten Änderungssatzung vom 26. November 2004) von Herrn
Prof. Dr. Paul Knochel betreut.




Ehrenwörtliche Versicherung

Diese Dissertation wurde selbständig und ohne unerlaubte Hilfe bearbeitet.


München, am 02. Januar 2011




…..……………………………………
Tobias Thaler



Dissertation eingereicht am ………………. 2011

1. Gutachter: Prof. Dr. Paul Knochel
2. Gutachter: Prof. Dr. Herbert Mayr

Mündliche Prüfung am …21.02. 2011


This work was carried out from April 2007 to February 2011 under the guidance of Prof. Dr. Paul
Knochel at the Department Chemie und Pharmazie of the Ludwig-Maximilians-Universität,
Munich.



I would like to thank Prof. Dr. Paul Knochel for giving me the opportunity to accomplish my
Ph.D. in his group and for his guidance, helpful advice and support during the course of my
scientific research.

I am very grateful to Prof. Dr. Herbert Mayr for agreeing to be the second reviewer of this thesis
as well as Prof. Dr. Dirk Trauner, Prof. Dr. Konstantin Karaghiosoff, Prof. Dr. Manfred
Heuschmann and Prof. Dr. Rudolf Knorr for accepting to be coreviewers.

I really would like to thank Andreas Steib and Dr. Xavier Mollat du Jourdin for careful
proofreading of this manuscript.

I thank all past and present coworkers I have met in the Knochel group for making everyday
laboratory work so enjoyable. Special thanks to Stephanie Seel, Andreas Steib, Sebastian
Bernhardt, Dr. Shigeyuki Yamada, Dr. Hongjun Gao, Dr. Andrei Gavryushin and Dr. Zhibing
Dong.

I explicitly thank Stephanie Seel, Dr. Li-Na Guo and Andreas Steib who have considerably
contributed to the final success of this thesis. I also thank Keishi Takatsu, Dr. Mihai Raducan,
Dr. Ken-ichi Yamagata, Prof. Dr. Kimihiro Komeyama, Ludwig Schenk, Alexander Sachse,
Andreas Preimesser and Florian Geittner for their cooperation in the course of their short stays at
the Knochel group. I would also like to thank “my Nachbar” Benjamin Haag, Cong Zhang and
Prof. Dr. Hendrik Zipse for the performance of DFT calculations. Moreover, I am grateful to
Prof. Dr. Konstantin Karaghiosoff, Katrin Schober, Evelyn Hartmann and Prof. Dr. Ruth M.
Gschwind for the performance and design of NMR studies with Rh-, Zn- and Pd-intermediates.

I would also like to thank Renate Schröder, Simon Matthe, Yulia Tsvik and Dr. Vladimir
Malakhov for their help with organizational issues, as well as the analytical team of the LMU for
their invaluable help.

I would like to thank my family, my parents and my brothers, for their great support throughout
my studies.


Parts of this Ph.D. thesis have been published

1) Tobias Thaler, Florian Geittner, Paul Knochel, “A Novel Synthetic Approach
towards Chiral QUINAP”, Synlett 2007, 2655.
2) Tobias Thaler, Benjamin Haag, Andrei Gavryushin, Katrin Schober, Evelyn
Hartmann, Ruth M. Gschwind, Hendrik Zipse, Peter Mayer, Paul Knochel, “Highly
3 2Diastereoselective Csp -Csp Negishi Cross-Coupling with 1,2-, 1,3- and 1,4-Substituted
Cycloalkylzinc Compounds”, Nature Chem. 2010, 2, 125.
3) Tobias Thaler, Li-Na Guo, Peter Mayer, Paul Knochel, “Highly Diastereoselective
3Csp -Csp Cross-Couplings between 1,3- and 1,4-Substituted Cyclohexylzinc Reagents
and Bromoalkynes via Remote Stereocontrol”, Angew. Chem. Int. Ed. 2011, 50, 2174.
4) Tobias Thaler, Andreas K. Steib, Kimihiro Komeyama, Peter Mayer, Paul Knochel,
2 3“Highly Diastereoselective Fe-Mediated Csp -Csp Cross-Couplings between Aryl
Grignard Reagents and Cyclic Iodohydrine Derivatives”, Angew. Chem. Int. Ed. 2011, 50,
in press.
5) Stephanie Seel, Tobias Thaler, Keishi Takatsu, Cong Zhang, Hendrik Zipse, Bernd
F. Straub, Paul Knochel, “Highly Diastereoselective Arylations of Substituted Piperidines
3 2via Pd-Catalyzed Csp -Csp Cross-Couplings”, manuscript submitted.
6) Tobias Thaler, Li-Na Guo, M. Raducan, Andreas K. Steib, Konstantin Karaghiosoff,
Paul Knochel, “Sulfoxide-Alkene Hybrids: A New Class of Chiral Ligands for the
Hayashi-Miyaura Reaction”, manuscript submitted.

Dotted lines indicate equal contribution with the respective author to the manuscript.








“To understand reality is not the same as to know about outward events. It is to perceive the
essential nature of things. The best-informed man is not necessarily the wisest. Indeed there is a
danger that precisely in the multiplicity of his knowledge he will lose sight of what is essential.
But on the other hand, knowledge of an apparently trivial detail quite often makes it possible to
see into the depth of things. And so the wise man will seek to acquire the best possible knowledge
about events, but always without becoming dependent upon this knowledge. To recognize the
significant in the factual is wisdom.“

Dietrich Bonhoeffer


Table of Contents
A. Introductio.n................................ ................................................................................................1
1. General Introduction ............................ ................................................................................2
2. Enantiocontrol with Chiral Sulfoxides ................... .......................................................7
2.1 Chiral sulfoxides as steering molecules in asymmetric synthesis ..................................................... 7
2.2 Sulfoxides as a relatively new class of chiral ligands for transition-metal catalyzed reactions ....... 11
3. Stereoselective Cross-Coupling Reactions ................. .............................................. 13
3.1 Transition-metal catalyzed cross-coupling as one of the most important C-C bond forming reactions
in modern organic synthesis ................................................................................................................... 13
3.2 Stereoselective cross-couplings using secondary alkyl halides ...................................................... 14
3.3 Stereoselective cross-couplings using secondary alkylmagnesium and –zinc reagents ................... 17
4. Objectives ................................. .............................................................................................. 21
B. Results and Discussio .n .......................... ............................................................................. 22
1. Enantiocontrol with Chiral Sulfoxides ................... .................................................... 25
1.1 A Novel Synthetic Approach towards Chiral QUINAP via Diastereomeric Sulfoxide Intermediates
25
1.1.1 Introduction ........................................................................................................................................................ 25
1.1.2 Novel synthesis and chiral resolution of QUINAP via chiral diastereomeric sulfoxide intermediates .............. 26
1.2 Sulfoxide-alkene hybrids: A new class of chiral ligands for the Hayashi-Miyaura reaction ........... 29
1.2.1 Introduction ........................................................................................................................................................ 29
1.2.2 Synthesis and resolution of the new sulfoxide-alkene hybrids ............................................................................ 30
1.2.3 Use as chiral ligands in the Hayashi-Miyaura reaction ..................................................................................... 31
1.2.4 Rationale for the observed stereochemical outcome .......................................................................................... 35
1.2.5 Influence of steric and electronic modulations at the ligand .............................................................................. 35

2. Diastereocontrol in the Cross-Couplings of Substituted Cycloalkyl and
Piperidinyl Derivatives ............................. ................................................................................ 38
3 22.1 Highly diastereoselective Csp -Csp Negishi cross-coupling with 1,2-, 1,3- and 1,4-substituted
cycloalkylzinc compounds ..................................................................................................................... 38
2.1.1 Introduction ........................................................................................................................................................ 38
2.1