Synthesis and Biological Evaluation of Siladenoserinol A Analogs Possessing a Diastereomeric 6,8-Dioxabicyclo[3.2.1]octane Skeleton

Abstract

The efficient synthesis of siladenoserinol analogs possessing a diastereomeric 6,8-dioxabicyclo[3.2.1]octane (6,8-DOBCO) skeleton has been achieved from commercially available carbohydrates as a chiral source. In this synthesis, we successfully determined the reaction conditions for the one-pot transformation using (PPh3)AuCl/AgSbF6/2,6-di-tert-butylpyridine (2,6-DTBP), leading to the desired bicycloketal without losing the TBS group. Elongation of two side chains by the Julia–Kocienski olefination and Horner–Wadsworth–Emmons reaction and subsequent chemoselective sulfamation furnished the two desired diastereomers from the corresponding carbohydrates, respectively. The inhibitory activities of the synthetic diastereomeric analogs against the p53–Hdm2 interaction were slightly weaker than that of natural siladenoserinol A, resulting in the fact that the stereochemistry on the 6,8-DOBCO skeleton would be one of the fundamental factors to control the potency of inhibition of the p53–Hdm2 interaction but not an essential one. We successfully achieved the synthesis of siladenoserinol A analogs through one-pot bicycloketal formation using a catalytic amount of (PPh3)AuCl/AgSbF6 and AlCl3. Biological evaluation of the natural product and synthetic analogs revealed that the stereochemistry on the 6,8-DOBCO skeleton would be one of the fundamental factors to control the potency of inhibition of the p53–Hdm2 interaction but not an essential one.