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Organocatalytic diastereo and enantioselective strategies for the synthesis and functionalization of N-heterocycles

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Author(s):
José Tiago Menezes Correia
Total Authors: 1
Document type: Doctoral Thesis
Press: Campinas, SP.
Institution: Universidade Estadual de Campinas (UNICAMP). Instituto de Química
Defense date:
Examining board members:
Fernando Antonio Santos Coelho; Ronaldo Aloise Pilli; Paulo Cesar Muniz de Lacerda Miranda; Silvio do Desterro Cunha; Paulo Roberto Ribeiro Costa
Advisor: Fernando Antonio Santos Coelho
Abstract

The development of new synthetic methodologies for the synthesis and/or functionalization of heterocycles is an issue of constant investigation by the synthetic community. This is justified by the great diversity of alkaloids and drugs containing this kind of systems in their structures. In this PhD thesis, four studies are described, which are organized in two chapters. In the first chapter, studies towards the development of two organocatalytic strategies for the preparation of the indolizidinic and quinolizidinic cores of Pumiliotoxin, Allopumilitoxin and Homopumiliotoxins are described. In the first strategy, a cyclization step via an intramolecular N-heterocyclic carbene (NHC) catalyzed SN2 reaction was investigated as the key step. Although it has not been extensively explored, this strategy showed to be challenging due the instability of the Breslow intermediate and did not afford the desired product. In the second one, an intramolecular diastereoselective benzoin condensation was the key step. After a screening of conditions, an optimized condition was obtained, which afforded the indolizidinic esqueleton in 69% yield and diastereoisomeric ratio of 75:25, in favor of the diastereoisomer that presents the same relative stereochemistry of the natural products. With this strategy in hand, the advanced intermediate to the synthesis of Allopumiliotoxin 225E and Pumiliotoxin 209F was prepared in 7 steps, 10% overall yield and diastereoisomeric ratio of 85:15. In the second chapter, studies on the development of two synthetic methodologies for the enantioselective functionalization of indolizines are described. In the first one, an enantioselective Friedel-Crafts reaction between indolizines and ?,?-unsaturated ketones was developed. Good yields and enantiomeric ratios up to 98:2 could be obtained. In parallel, the [8+2] cycloaddition between indolizines and maleimides was investigated. The enantiomeric ratio reached in this second strategy was 80:20. These results are the first reports on the enantioselective functionalization of this class of molecules, and formidable precedents to the development of new methodologies (AU)

FAPESP's process: 12/21809-0 - Organocatalysed synthesis of indolizidinic and quinolizidinic N-heterocycles from Morita-Baylis-Hillman adducts
Grantee:José Tiago Menezes Correia
Support Opportunities: Scholarships in Brazil - Doctorate