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Total synthesis and structure-activity relationship study of the potent cAMP signaling agonist (-)-alotaketal A.

ABSTRACT: A detailed account of the first total synthesis of alotaketal A, a tricyclic spiroketal sesterterpenoid that potently activates the cAMP signaling pathway, is provided. The synthesis employs both intra- and intermolecular reductive allylation of esters for assembling one of the fragments and their coupling. A Hg(OAc)2-mediated allylic mercuration is used to introduce the C22-hydroxyl group. The subtle influence of substituents over the course of the spiroketalization process is revealed. The synthesis confirms the relative and absolute stereochemistry of (-)-alotaketal A and allows verification of alotaketal A's effect over cAMP signaling using reporter-based FRET imaging assays with HEK 293T cells. Our studies also revealed alotaketal A's unique activity in selectively targeting nuclear PKA signaling in living cells.

SUBMITTER: Huang J

PROVIDER: S-EPMC3677522 | biostudies-literature | 2013 May

REPOSITORIES: biostudies-literature

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Total synthesis and structure-activity relationship study of the potent cAMP signaling agonist (-)-alotaketal A.

Huang Jinhua J Yang Jessica R JR Zhang Jin J Yang Jiong J

Organic & biomolecular chemistry 20130412 19

A detailed account of the first total synthesis of alotaketal A, a tricyclic spiroketal sesterterpenoid that potently activates the cAMP signaling pathway, is provided. The synthesis employs both intra- and intermolecular reductive allylation of esters for assembling one of the fragments and their coupling. A Hg(OAc)2-mediated allylic mercuration is used to introduce the C22-hydroxyl group. The subtle influence of substituents over the course of the spiroketalization process is revealed. The syn ...[more]

PMID: 23584129

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