RESUMO
The decalin structure is found in bioactive molecules. We have developed catalytic enantioselective formal (4+2) cycloaddition reactions via aldol-aldol cascade reactions between pyruvate-derived diketoester derivatives and cyclohexane-1,3-dione derivatives that afford highly functionalized decalin derivatives. The reactions were performed using a quinidine-derived catalyst under mild conditions. Decalin derivatives bearing up to six chiral carbon centers including tetrasubstituted carbon centers were synthesized with high diastereo- and enantioselectivities. Five to six stereogenic centers were generated from achiral molecules with the formation of two C-C bonds in a single transformation resulting in the formation of the decalin system.
RESUMO
Synthesis of new functionalized molecules and identification of biofunctional molecules can lead to the development of therapeutic leads and molecular tools for biomedical research. We have recently reported oxa-hetero-Diels-Alder reactions of enones with isatins to provide functionalized spirooxindole tetrahydropyran derivatives. Twenty-one compounds from the spirooxindole tetrahydropyran derivatives and related molecules were screened for inhibition of sterol O-acyltransferase (SOAT) isozymes SOAT1 and SOAT2. Three racemic derivatives inhibited the SOAT2 isozyme with three-fold or better selectivity for SOAT2 than for SOAT1. The enantiomerically enriched forms of the most efficient racemic inhibitor of SOAT2 were further evaluated; one enantiomer inhibited SOAT2 with an IC50 of 1.5µM and was 10-fold more selective for SOAT2 than SOAT1.
Assuntos
Descoberta de Drogas , Inibidores Enzimáticos/farmacologia , Piranos/farmacologia , Bibliotecas de Moléculas Pequenas/farmacologia , Esterol O-Aciltransferase/antagonistas & inibidores , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Humanos , Estrutura Molecular , Piranos/síntese química , Piranos/química , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química , Esterol O-Aciltransferase/metabolismo , Relação Estrutura-Atividade , Esterol O-Aciltransferase 2RESUMO
The development of concise methods for the synthesis of functionalized small molecules is important in the search for new bioactive molecules. To contribute to this, we have developed oxa-hetero-Diels-Alder reactions of enones with isatins catalyzed by amine-based catalyst systems. Various spirooxindole tetrahydropyranones were synthesized either in enantiomerically enriched forms or as racemic forms depending on the catalyst system. The reaction products were further transformed at the ketone carbonyl group and the indole nitrogen. Using these reactions, functionalized spirooxindole tetrahydropyran derivatives with functional groups in four directions in a three-dimensional space were concisely obtained. From these synthesized compounds, an inhibitor of human ion channel Nav1.7 with µM-level activity was identified, indicating that the developed reaction methods are useful for providing molecules for the discovery of new biofunctional molecules.
Assuntos
Aminas/química , Isatina/química , Cetonas/química , Canal de Sódio Disparado por Voltagem NAV1.7/metabolismo , Piranos/farmacologia , Compostos de Espiro/farmacologia , Catálise , Reação de Cicloadição , Relação Dose-Resposta a Droga , Descoberta de Drogas , Humanos , Estrutura Molecular , Piranos/síntese química , Piranos/química , Compostos de Espiro/síntese química , Compostos de Espiro/química , Relação Estrutura-AtividadeRESUMO
Concise cascade reactions of pyruvates with aldehydes that generate functionalized dihydropyran derivatives in one pot have been developed. The products, dihydropyrans, were further concisely transformed to various molecules.
Assuntos
Aldeídos/química , Piranos/química , Piranos/síntese química , Piruvatos/química , Catálise , Técnicas de Química SintéticaRESUMO
The HKR of racemic syn- or anti- alkoxy- and azido epoxides catalyzed by Co(salen) complex affords a practical access to a series of enantioenriched syn- or anti- alkoxy- and azido epoxides and the corresponding 1,2-diols. This strategy has been successfully employed in the concise, enantioselective synthesis of bioactive molecules such as (S,S)-reboxetine and (+)-epi-cytoxazone.