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“Carbon Assimilation” Inspired Design and Divergent Synthesis of Drimane Meroterpenoid Mimics as Novel Fungicidal Leads

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journal contribution
posted on 26.09.2017, 00:00 by Shasha Zhang, Dangdang Li, Zehua Song, Chuanli Zang, Lu Zhang, Xiushi Song, Shengkun Li
With structural diversity and versatile biological properties, drimane meroterpenoids have drawn remarkable attention in drug development. The stagnant progress made in the structure optimization and SAR study of this kind of natural product for agrochemicals was mainly a result of inefficient construction. Compared with the reported challenging coupling reaction (“1 + 1” tactic), “carbon assimilation” was conceived and used for the rapid construction of drimanyl meroterpenoid mimics, in which the newly formed covalent bond was directly from the old one of the drimanyl subunit (“2 + 0” tactic), which features atom economy, step economy, and facile preparation. The accompanying introduction of versatile heterocycles and application of easily available feedstocks are beneficial for novel green agrochemical discovery, in view of economic efficiency and improvement of physicochemical properities. Heterocyclic mimics 3a and 3c are presented as potent fungicidal leads with novel skeletons against Botrytis cinerea, >25-fold and >40-fold more promising than the commercial fungicide carbendazim, respectively. Our design was also rationalized by the 6-step synthesis and antifungal assay of the original model of natural meroterpenoids. This tactic can also be fostered or transferred directly to the design of novel natural product mimics for medicinal chemistry or other related biological exploration.