Modular asymmetric synthesis of functionalized azaspirocycles based on the sulfoximine auxiliary [Elektronische Ressource] / vorgelegt von Adeline Adrien

Cerise

Informations

• Publié par: rheinisch-westfalischen_technischen_hochschule_-rwth-_aachen
• Publié le: 01 janvier 2008
• Nombre de lectures: 20
• Langue: English
• Poids de l'ouvrage: 1 Mo

Extrait

Modular Asymmetric Synthesis of Functionalized
Azaspirocycles Based on the Sulfoximine Auxiliary
Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der Rheinisch-
Westfälischen Technischen Hochschule Aachen zur Erlangung des akademischen Grades
einer Doktorin der Naturwissenschaften genehmigte Dissertation
vorgelegt von
Master of Science
Adeline Adrien
aus Lille (Frankreich)
Berichter: Universitätsprofessor Dr. Ing. Hans-Joachim Gais
Universitätsprofessor Dr. rer. nat. Dieter Enders
Tag der mündlichen Prüfung: 14. März 2008
Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verfügbar. The work presented in this thesis was carried out at the Institute of Organic Chemistry of the
RWTH Aachen University between January 2005 and December 2007 under the supervision
of PROF. DR. HANS-JOACHIM GAIS.
First I would like to thank PROF. DR. HANS-JOACHIM GAIS for giving me the opportunity to
work on this exciting research topic and for the useful discussions. Then I would like to thank
PROF. DR. DIETER ENDERS for his kind assumption of the co-reference.
Furthermore I would like to thank the personnel of the Organic Chemistry Institute of the
RWTH Aachen for their appreciated help during my work, and all the members of the GAIS
group. I would like to thank my labmates FABIEN LEMASSON, DR. VASILY TSAREV and DR.
PRABAL BANERJEE for the very nice atmosphere during these three years. Special thanks are
going to CORNELIA VERMEEREN and MAGDALENA GERENCER for carrying out analytical as
well as preparative HPLC. I sincerely thank VERENA SCHIRRA and BJÖRN SOMMER for the
preparation of starting materials.
I would like to thank all people who made my time in Aachen so nice, I will not forget you!
Last but not least, I would like to thank my family and friends for being always by my side
and supporting me.
Parts of this work have already been published in
A. Adrien, H.-J. Gais, F. Köhler, J. Runsink, G. Raabe
„Modular Asymmetric Synthesis of Functionlized Azaspirocycles Based on the
Sulfoximine Auxiliary“
Org. Lett. 2007, 9, 2155-2158. A Franz,
A mes parents, Table of contents
A. THEORETICAL PART ..................................................................................................... 1
1. Introduction to azaspirocycles and aims of the project ................................................................................. 2
1.1 Naturally occurring azaspirocycles .............................................................................................................. 2
1.2 Retrosynthetic analysis of azaspirocyclic core structures............................................................................. 5
1.3 Total syntheses of halichlorine and pinnaic acid.......................................................................................... 6
1.4 Our approach to azaspirocycles.................................................................................................................... 8
2. Construction of the carbocycle having an amino-substituted tertiary C atom.......................................... 10
2.1 The chiral auxiliary .................................................................................................................................... 10
2.1.1 Properties of the chiral auxiliary......................................................................................................... 10
2.1.2 Preparation of chiral auxiliary 15 ....................................................................................................... 11
2.2 Synthesis of oxazinones 29a and 29b ........................................................................................................ 12
2.3 Synthesis of cyclic allylic sulfoximines ..................................................................................................... 12
2.4 Hydroxyalkylation of allylic sulfoximines................................................................................................. 13
2.4.1 Introduction to hydroxyalkylation of cyclic allylic sulfoximines....................................................... 13
2.4.2 Application of the hydroxyalkylation reaction to the synthesis of azaspirocycles ............................. 15
2.4.3 Rationalization of the stereoselectivity outcome ................................................................................ 16
2.5 Formation of carbamates from homoallylic alcohols 28a and 28b ............................................................ 19
2.5.1 Results ................................................................................................................................................ 19
2.5.2 Mechanism for the Z/E isomerization................................................................................................. 20
2.6 Aza-MICHAEL addition............................................................................................................................... 22
2.6.1 Results ................................................................................................................................................ 22
2.6.2 Discussion........................................................................................................................................... 22
2.7 Possible structural variations of the carbocycle and the side chain............................................................ 25
2.7.1 Variations of the carbocycle ............................................................................................................... 26
2.7.2 Hydroxyalkylation with other aldehydes............................................................................................ 27
3. The Ring-closing metathesis route................................................................................................................. 28
3.1 The plan...................................................................................................................................................... 28
3.2 Synthesis of amino alcohol 49 from sulfoximine 29a ................................................................................ 28
3.3 Iodide substitution ...................................................................................................................................... 29
3.4 Cuprate substitution.................................................................................................................................... 31
3.5 Ring-Closing Metathesis ............................................................................................................................ 33
3.6 Structural variations of the target molecule................................................................................................ 34
4. Cycloalkylation and removal of the sulfoximine group ............................................................................... 36
4.1 The plan...................................................................................................................................................... 36
4.1.1 Target molecule .................................................................................................................................. 36
4.1.2 Dilithiated sulfoximines in the literature ............................................................................................ 36
4.1.3 From dilithiated sulfoximines to the synthesis of the heterocycle...................................................... 37Table of contents
4.2 Cycloalkylation: Similar examples in the literature ................................................................................... 37
4.2.1 With sulfone and carbamate ............................................................................................................... 37
4.2.2 With sulfone and amide...................................................................................................................... 38
4.2.3 With sulfoxide/sulfone and sulfonamide ............................................................................................ 39
4.3 Cycloalkylation: Results............................................................................................................................. 40
4.4 Cycloalkylation: Discussion....................................................................................................................... 41
4.4.1 Determination of the configuration at the newly formed stereogenic center...................................... 41
4.4.2 Rationalization of the observed conversions ...................................................................................... 43
4.4.3 Rationalization of the stereoselectivity outcome ................................................................................ 44
4.5 Chloride substitution of the sulfoximine group of the tricycle................................................................... 47
4.5.1 Results ................................................................................................................................................ 47
4.5.2 Determination of the absolute configuration ...................................................................................... 47
4.5.3 Mechanism of the substitution of secondary sulfoximines................................................................. 48
4.6 Reduction of the sulfoximine moiety ............