Since its isolation two decades ago, five asymmetric syntheses of the marine natural product frondosin B (1) have been reported. Surprisingly, in view of this attention from the synthetic community, uncertainty still surrounds the configuration of the molecule’s lone stereogenic center, which has been the subject of some debate in the literature. To date, the discordant assignments made by different groups have been attributed to unexpected stereochemical outcomes (i.e. the occurrence of an untoward inversion) in various chemical steps, and these arguments have been predicated on the measurement of the optical rotation of the natural product at the end of the synthesis. During a re-examination of key intermediates from Trauner’s and Danishefsky’s syntheses using vibrational (VCD) and electronic (ECD) circular dichroism, a number of interesting findings were made, namely (1) that the absolute configuration of natural (+)-1 be can confidently be assigned as (R); (2) that contrary to proposals made by Wright and MacMillan, in our hands no unexpected inversion occurs during the Trauner synthesis of 1; and (3) the formation of a hard-to-detect impurity with a large optical rotation formed during a late key step shared by Trauner’s and Wright’s syntheses of 1 may have contributed to the confusion surrounding the target’s absolute stereochemistry. This work showcases the benefits of going beyond optical rotation in total synthesis to incorporate modern analytical techniques that—in conjunction with computational methods—allow for the direct and rapid assignment of the stereochemistry of non-crystalline intermediates.

Beyond optical rotation in total synthesis: New insights into the stereochemical confusion surrounding frondosin B

256th National Meeting (2018)

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