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

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

J Org Chem. 2018 04 20;83(8):4287-4306

Authors: Nguyen MH, Imanishi M, Kurogi T, Wan X, Ishmael JE, McPhail KL, Smith AB

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.

PMID: 29480727 [PubMed - indexed for MEDLINE]

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