The two dimeric trans-epoxyamides, Chrysamides A and B have been isolated from a deep-sea-derived Penicillium chrysogenum found in the Indian Ocean. Though nitro compounds are rarely isolated from natural sources, those molecules are of great interest by their wide range of biological activities. A noteworthy feature of our approach is the efficient solid-phase preparation of chiral 2,5-diketopiperazines alanine subunit from N-Boc protected D-Alanine amino acid. Taking advantage of the availability of unnatural chiral amino acids as chiral synthons, the alanine 1,4-piperazine ring was synthesized via chiral diamides reduction from 2,5-diketopiperazine precursors. The synthesis of Chrysamide A is a completely different synthetic challenge with the presence of a substituted oxabicyclo[2.2.1]heptane and requires a more complex approach than its piperazine derivative. The oxigen bridge of Chrysamide B can be obtained through an elegant dimerisation of an amino-aldehyde moiety. The high convergency of the synthetic methodology opens the way to a rapid access of Chrysamide's natural products analogs by a simple double amidation coupling reaction as the final step. A library englobing stereochemical and structural diversity would then be assessed. A diversity of substituted cis and trans 1,4-piperazine and oxygenated rings and could be prepared in parallel, taking advantage of solid-state synthesis and the easily availalble natural and non-natural amino acids. Our synthetic strategy gave access to a rapid and efficient preparation of Chrysamide A and B by a convergent approach establishing the basis of our methodology and giving the possiblity to fashion a library of analogs of those two natural products.

Total synthesis of chrysamides A and B

256th National Meeting (2018)

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