RESUMO
Herein we describe the total synthesis of five guaianolide natural products: thapsigargin, thapsivillosin C, thapsivillosin F, trilobolide and nortrilobolide. Prodrug derivatives of thapsigargin have shown selective in vivo cytotoxicity against prostate tumours and the need for further investigation of this phenomenon highlights the importance of these total syntheses. The first absolute stereochemical assignment of thapsivillosin C is also delineated.
Assuntos
Inibidores Enzimáticos/síntese química , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Sesquiterpenos de Guaiano/síntese química , Tapsigargina/síntese química , Alcenos/química , Fatores Biológicos/síntese química , Fatores Biológicos/química , Fatores Biológicos/farmacologia , Ciclização , Relação Dose-Resposta a Droga , Retículo Endoplasmático/enzimologia , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacologia , Estrutura Molecular , Nanotecnologia , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/química , Sesquiterpenos de Guaiano/química , Sesquiterpenos de Guaiano/farmacologia , Estereoisomerismo , Tapsigargina/análogos & derivados , Tapsigargina/farmacologiaRESUMO
The enantioselective total synthesis of thapsigargin, a potent, selective inhibitor of the Ca2+ pump SERCA, is described. Starting from ketoalcohol 8, key steps involve regioselective introduction of the internal olefin at C4-C5, judicious protecting group choice to allow chelation-controlled reduction at C3, and chemoselective introduction of the angelate ester function at C3-O. A selective esterification approach completes the total synthesis in a total of 42 steps and 0.61% overall yield (88.6% average yield per step). [reaction: see text].
Assuntos
Inibidores Enzimáticos/síntese química , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/antagonistas & inibidores , Tapsigargina/síntese química , Álcoois/química , Alcenos/química , Quelantes/química , Indicadores e Reagentes , Oxirredução , EstereoisomerismoRESUMO
1,3-dipolar cycloaddition reactions of nitrones with alkenes and alkynes are well-studied reactions in solution-phase organic chemistry. However, the number of studies concerned with their application in solid-phase organic synthesis is rather low compared to other 1,3-dipoles, e.g. azides or nitrile oxides. This tutorial review aims to summarise the main approaches towards the application of nitrones in 1,3-dipolar cycloaddition reactions on solid supports in addition to subsequent transformations with polymer-bound isoxazolidines and reactions using polymer-bound catalysts.
