Journal
ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
Volume 57, Issue 18, Pages 5147-5150Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/anie.201801659
Keywords
bicycloketals; natural products; inhibitors; siladenoserinolA; total synthesis
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Funding
- JSPS KAKENHI [JP15H05837]
- Platform Project for Supporting Drug Discovery and Life Science Research - Japan Agency for Medical Research and Development (AMED)
- Grants-in-Aid for Scientific Research [17H04646, 17H03994] Funding Source: KAKEN
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The total synthesis of siladenoserinolA, 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 siladenoserinolA, 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.
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