Synthetic Access to the Mandelalide Family of Macrolides: Development of an Anion Relay Chemistry Strategy

The Journal of Organic Chemistry
Minh H NguyenAmos B Smith

Abstract

The mandelalides comprise a family of structurally complex marine macrolides that display significant cytotoxicity against several human cancer cell lines. Presented here is a full account on the development of an Anion Relay Chemistry (ARC) strategy for the total synthesis of (-)-mandelalides A and L, the two most potent members of the mandelalide family. The design and implementation of a three-component type II ARC/cross-coupling protocol and a four-component type I ARC union permits rapid access respectively to the key tetrahydrofuran and tetrahydropyran structural motifs of these natural products. Other highlights of the synthesis include an osmium-catalyzed oxidative cyclization of an allylic 1,3-diol, a mild Yamaguchi esterification to unite the northern and southern hemispheres, and a late-stage Heck macrocyclization. Synthetic mandelalides A and L displayed potent cytotoxicity against human HeLa cervical cancer cells (EC50, 1.3 and 3.1 nM, respectively). This synthetic approach also provides access to several highly potent non-natural mandelalide analogs, including a biotin-tagged mandelalide probe for future biological investigation.

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Citations

Nov 6, 2018·Angewandte Chemie·Jaehoo Lee, David Y-K Chen
Feb 7, 2020·Natural Product Reports·Anthony R CarrollMichèle R Prinsep
Oct 28, 2019·Organic & Biomolecular Chemistry·Sandip Guchhait, Rajib Kumar Goswami
Mar 5, 2021·Natural Product Reports·Weicheng Zhang
Jun 3, 2021·Marine Drugs·Chatragadda RameshLaurent Dufossé

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