Asymmetric syntheses of sceptrin and massadine and evidence for biosynthetic enantiodivergence

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Science  10 Oct 2014:
Vol. 346, Issue 6206, pp. 219-224
DOI: 10.1126/science.1255677

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Cycloaddition is an essential tool in chemical synthesis. Instead of using light or heat as a driving force, marine sponges promote cycloaddition with a more versatile but poorly understood mechanism in producing pyrrole–imidazole alkaloids sceptrin, massadine, and ageliferin. Through de novo synthesis of sceptrin and massadine, we show that sponges may use single-electron oxidation as a central mechanism to promote three different types of cycloaddition. Additionally, we provide surprising evidence that, in contrast to previous reports, sceptrin, massadine, and ageliferin have mismatched chirality. Therefore, massadine cannot be an oxidative rearrangement product of sceptrin or ageliferin, as is commonly believed. Taken together, our results demonstrate unconventional chemical approaches to achieving cycloaddition reactions in synthesis and uncover enantiodivergence as a new biosynthetic paradigm for natural products.

Sceptrin goes through the looking glass

Marine sponges produce a trio of compounds—sceptrin, massadine, and ageliferin—that have intrigued chemists because they seemed to result from ring-forming reactions outside the standard repertoire of enzyme catalysis. Ma et al. now report laboratory syntheses of the first two compounds that uncover a surprising twist: It turns out the real structure of sceptrin is the mirror image of the originally reported structure. The work partially bolsters the prevailing biosynthetic hypothesis, though its revelation of enantiodivergence (the emergence of distinct mirror-image motifs in one compound class) is a rare event in natural product chemistry.

Science, this issue p. 219

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