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Total synthesis reveals atypical atropisomerism in a small-molecule natural product, tryptorubin A

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Science  24 Jan 2020:
Vol. 367, Issue 6476, pp. 458-463
DOI: 10.1126/science.aay9981

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A twisted small-molecule synthesis

Some molecules are easy to draw on paper, whereas others contain rings and contortions that require one to think in three dimensions. Reisberg et al. set out to synthesize the bicyclic small molecule tryptorubin A but found that their initial attempt produced a molecule with the right bonds but the wrong molecular shape, a form of noncanonical atropisomerism. The authors then devised a synthesis where they locked in the correct isomer before forming the second ring, which produced a product indistinguishable from the authentic natural product. Such structural isomers may be lurking when working with complex small molecules with constrained rotation.

Science, this issue p. 458

Abstract

Molecular shape defines function in both biological and material settings, and chemists have developed an ever-increasing vernacular to describe these shapes. Noncanonical atropisomers—shape-defined molecules that are formally topologically trivial but are interconvertible only by complex, nonphysical multibond torsions—form a unique subset of atropisomers that differ from both canonical atropisomers (e.g., binaphthyls) and topoisomers (i.e., molecules that have identical connectivity but nonidentical molecular graphs). Small molecules, in contrast to biomacromolecules, are not expected to exhibit such ambiguous shapes. Using total synthesis, we found that the peptidic alkaloid tryptorubin A can be one of two noncanonical atropisomers. We then devised a synthetic strategy that drives the atropospecific synthesis of a noncanonical atrop-defined small molecule.

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