Synthesis and Biological Evaluation of 6,6-Spiroketal Natural Products: Reveromycin A, B and Spirofungin A,B

The first asymmetric total synthesis of reveromycin A (1), a potent inhibitor of isoleucyl tRNA synthetase, has been accomplished based on the stereocontrolled construction of the 6,6-spiroketal system, efficient succinylation of the tert-alcohol under high pressure as a key step. The stereocontrolled total synthesis of (-)-spirofungin A (5) and (+)-spirofungin B (6a), polyketide-type antibiotics having various antifungal activities, has been achieved employing the Weinreb amide, the alkyne and the vinyl boronate readily available from the common intermediate employing Horner-Emmons reaction and Suzuki coupling reaction for the construction of the both side chains. The succinates of the tertiary hydroxyl group having the formyl group in the structures were conveniently synthesized by oxidative cleavage of the dihydropyrans prepared from the lactone via coupling of the ketene acetal triflates and zinc homoenolate. Various derivatives of 1, 5 and 6a were synthesized and their inhibitory effects on both the isoleucyl-tRNA synthetase activity and the survival of osteoclasts, and activities on the morphological reversion of src(ts)-NRK cells were examined.