Divergent Total Synthesis of Indoxamycins A, C, and F

Divergent Total Synthesis of Indoxamycins A, C, and F

He, C.; Zhu, C.; Dai, Z.; Tseng, C.-C.; Ding, H. Angew. Chem. Int. Ed. 2013, 52, 13256–13260.

DOI: 10.1002/anie.201307426

The concise and divergent total synthesis of (−)-indoxamycins A, C, and F has been completed for the first time by using a tricyclic enone as the common late-stage intermediate. The key steps of the strategy are based on an Ireland–Claisen rearrangement, a stereodivergent reductive 1,6-enyne cyclization, and a tandem 1,2-addition/oxa-Michael/methylenation reaction.

 

As a novel class of polyketides, indoxamycins A–F were isolated in 2009 by Sato et al. from saline cultures of marine- derived actinomycetes.  The indoxamycin skeleton consists of an unprecedented [5,5,6] tricyclic cage-like carbon framework and two side chains having a trisubstituted olefin and an unsaturated carboxylic acid, respectively.  In 2012, Carreira and co-workers reported an elegant total synthesis of rac-indoxamycin B ((1’’E)-2-epi-2), which led to a structural reassignment of the relative configuration at the C2 position and the geometry of the trisubstituted alkene in the side chain.[1]

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In this paper, Ding and coworkers report a divergent approach for the total synthesis of indoxamycins A, C, and F, which culminated in the elucidation of the stereochemistry of these natural products.

The key steps of the strategy entail an Ireland–Claisen rearrangement, a stereo- divergent reductive 1,6-enyne cyclization, and a tandem 1,2- addition/oxa-Michael/methylenation reaction.

 

  • References

[1] “Total Synthesis and Stereochemical Reassignment of (±)-Indoxamycin B”

Jeker, O. F.; Carreira, E. M. Angew. Chem. Int. Ed. 2012, 51, 3474–3477. DOI: 10.1002/anie.201109175

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Revised version: The first total synthesis of indoxamycin B leads to a stereochemical reassignment of the natural product (see picture). The synthetic route features an efficient carboannulation sequence to rapidly access the dihydroindenone system. Moreover, a series of AuI-catalyzed transformations served in the construction of the sterically congested core framework.

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