Convergent Total Synthesis of (+)-Cotylenin A

Herein, the convergent total synthesis of (+)-cotylenin A is described. A retrosynthetic analysis of cotylenin A generated three fragments—A- and C-ring fragments, and a sugar moiety fragment. The A-ring fragment was prepared via a catalytic asymmetric intramolecular cyclopropanation developed in our laboratory, while the C-ring fragment was prepared via the modified acyl radical cyclization of a known chiral compound. The two fragments were successfully assembled by the Utimoto coupling reaction, while the B-ring, a carbocyclic eight-membered ring, was efficiently constructed by palladium-mediated cyclization, which was discovered during our synthesis of taxol. All hydroxy groups in the 5-8-5 tricyclic scaffold were stereoselectively introduced. Moreover, a new modified reducing reagent, Me4NBH(O2CiPr)3, was developed during the course of this study. The sugar moiety fragment was successfully prepared for the first time via the consecutive carbon–oxygen bond-forming reactions and was terminated by an epoxide opening reaction. Finally, the first enantioselective total synthesis of cotylenin A was successfully accomplished in a highly convergent manner via glycosylation using Wan’s protocol. Moreover, this is the first report to investigate the specific rotation of cotylenin A through the total synthesis.