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Issue 19, 2013
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Total synthesis and structure–activity relationship study of the potent cAMP signaling agonist (−)-alotaketal A

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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.

Graphical abstract: Total synthesis and structure–activity relationship study of the potent cAMP signaling agonist (−)-alotaketal A

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Publication details

The article was received on 21 Jan 2013, accepted on 22 Mar 2013 and first published on 27 Mar 2013


Article type: Paper
DOI: 10.1039/C3OB40120K
Citation: Org. Biomol. Chem., 2013,11, 3212-3222
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    Total synthesis and structure–activity relationship study of the potent cAMP signaling agonist (−)-alotaketal A

    J. Huang, J. R. Yang, J. Zhang and J. Yang, Org. Biomol. Chem., 2013, 11, 3212
    DOI: 10.1039/C3OB40120K

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