Total Synthesis and Biological Evaluation of Siladenoserinol A and its Analogues. Issue 18 (22nd March 2018)

• Record Type: Journal Article
• Authors: Yoshida, Masahito; Saito, Koya; Kato, Hikaru; Tsukamoto, Sachiko; Doi, Takayuki
• Is Part Of: Angewandte Chemie international edition. Volume 57:Issue 18(2018)
• Page Start: 5147
• Page End: 5150
• Publication Date: 2018-03-22
• Subjects: bicycloketals -- natural products -- inhibitors -- siladenoserinol A -- total synthesis; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201801659
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: The total synthesis of siladenoserinol A, an inhibitor of the p53–Hdm2 interaction, has been achieved. AuCl3 ‐catalyzed hydroalkoxylation of an alkynoate derivative smoothly and regioselectively proceeded to afford a bicycloketal in excellent yield. A glycerophosphocholine moiety was successfully introduced through the Horner–Wadsworth–Emmons reaction using an originally developed phosphonoacetate derivative. Finally, removal of the acid‐labile protecting groups, followed by regioselective sulfamate formation of the serinol moiety afforded the desired siladenoserinol A, and benzoyl and desulfamated analogues were also successfully synthesized. Biological evaluation showed that the sulfamate is essential for biological activity, and modification of the acyl group on the bicycloketal can improve the inhibitory activity against the p53–Hdm2 interaction. Abstract : Total synthesis of siladenoserinol A, an inhibitor of the p53–Hdm2 interaction, has been achieved. A catalytic amount of AuCl3 efficiently promoted double hydroalkoxylation to give the bicycloketal. Unique side chains were introduced through Julia–Kocienski and Horner–Wadsworth–Emmons reactions. Finally, regioselective sulfamate formation at the serinol moiety furnished siladenoserinol A and its analogues.