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Total Synthesis and Biological Evaluation of Siladenoserinol A and its Analogues
Author(s) -
Yoshida Masahito,
Saito Koya,
Kato Hikaru,
Tsukamoto Sachiko,
Doi Takayuki
Publication year - 2018
Publication title -
angewandte chemie
Language(s) - English
Resource type - Journals
eISSN - 1521-3757
pISSN - 0044-8249
DOI - 10.1002/ange.201801659
Subject(s) - moiety , chemistry , regioselectivity , derivative (finance) , total synthesis , yield (engineering) , protecting group , stereochemistry , combinatorial chemistry , catalysis , organic chemistry , materials science , alkyl , financial economics , economics , metallurgy
The total synthesis of siladenoserinol A, an inhibitor of the p53–Hdm2 interaction, has been achieved. AuCl 3 ‐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.