Chun-Xi Huang (Irganic Chemistry) Supervised By Prof.Wei--Sheng Tian And Associated Prof. Jing-Rong Lin

Based on our groups research on rational utlization of resource compounds, we initiated a project to synthesize betamethasone, a glucocorticoid steroid with great pharmaceutical value, using pregnane-3,16,20-triol (produced through a green degradation of Tigogenin) as starting material. Described herein are the research of C16–C17α-epoxide opening by methylmetallic reagents, and a tandem semipinacol rearrangement/chelation-controlled ketone addition process we discovered.An acetylation-bromination of pregan-3,16,20-triol, followed by an elimination and a stereoselective epoxidation provided C16–C17α-epoxide. After screening the methylmetallic reagents and the protecting groups of C3/C20-OH, we founded that refluxing of a methyl/methoxymethyl ether-protecting epoxide and MeMgCl in the presence Cu (I) salt afforded the desired epoxide-opeing product in high yield, hence enabling the introduction of C16-Me-C17α-OH unit of betamethasone.With or without protecting the C20-OH as acetate, the C16–C17α-epoxide was treated with alkylmetallic reagents (Li, Mg, Cu, etc.) to yield an unprecedented C16α-OH-C17α-substituted structure unit. After careful experimental study, we found that the reaction proceeded through a tandem semipinacol rearrangement/chelation- controlled ketone addition process, and the configuration of C20(S)-OH and the cleavage of the protecting group of C20-OH were crucial to this process. These results offer unique opportunities to generating proucts with novel steroidal skeleton which are not accessible by other synthetic methods.