Modular asymmetric synthesis of functionalized azaspirocycles based on the sulfoximine auxiliary

Azaspirocycles are found as structural motif in a number of highly interesting natural products. In particular the marine alkaloid halichlorine has been target of many synthetic approaches because of its interesting biological activities and intricate structure. Even so there is still an interest in the development of a more general method for the asymmetric synthesis of azaspirocycles. The synthesis of azaspirocycles involves two synthetic challenges. The first one is the stereoselective construction of the tertiary spiro C-atom bearing a N-atom. The second challenge is the formation of the spirocyclic ring system, namely the carbocycle and the heterocycle. Our synthetic approach to azaspirocycles is characterized by a two-step strategy in which the carbocycle with the future spiro C-atom is constructed at first, followed by formation of the heterocycle to complete the spiro-ring system. The synthesis of carbocycles having an amino-substituted tertiary C-atom and three contiguous stereogenic centers was achieved in three steps from cyclic allylic sulfoximines. The first key step was a titanium-mediated gamma-hydroxyalkylation of named sulfoximines. In the course of this reaction two new stereogenic centers and a double bond were created diastereoselectively. The key step for installation of the tertiary carbon atom bearing the amino group was a highly diastereoselective intramolecular aza-MICHAEL addition on chiral vinyl sulfoximines. Having achieved an efficient synthesis of the carbocycle, a modular approach to the heterocycle was developed which permitted flexible control of the ring size and substitution pattern. Three different routes were followed, including (1) a stereoselective addition to a N acyliminium ion, (2) a ring-closing metathesis reaction, and (3) the cycloalkylation of a carbamate-sulfoximine dianion. Using the N-acyliminium ion strategy, azaspirocycles having functionalities at the alpha and/or beta position to the nitrogen were prepared. Synthesis of azaspirocycles having functionalization at the beta,gamma-position was achieved by ring-closing metathesis. Cycloalkylation reactions permitted the synthesis of azaspirocycles having a variety of substituents at the delta-position. In conclusion, we have developed a new and modular stereoselective approach to highly substituted azaspirocycles, being of interest for the synthesis of natural products with intriguing biological activities and derivatives thereof.

Grantor dc:publisher

Publikationsserver der RWTH Aachen University

Year dc:date

2008

Author dc:creator

• Adrien, Adeline

Contributors dc:contributor

• Gais, Hans-Joachim

• info:eu-repo/classification/ddc/540
• Asymmetrische Synthese
• Sulfoximin
• Chemie
• Azaspirocyclen
• Chirales Auxiliar
• Halichlorin
• Azaspirocycles
• Asymmetric Synthesis
• Sulfoximine
• Chiral Auxiliary
• Halichlorine

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

https://publications.rwth-aachen.de/search?p=id:%22RWTH-CONV-112627%22

OAI record oai:identifier

https://publications.rwth-aachen.de/oai2d?verb=GetRecord&metadataPrefix=oai_dc&identifier=oai%3Apublications.rwth-aachen.de%3A50064