The Fruit of Gold: Biomimicry in the Syntheses of Lankacidins.

Natural products are constructed by organisms in impressive ways through various highly selective enzyme-catalyzed chemical reactions. Over the past century, there has been considerable interest in understanding and emulating the underlying biosynthetic logic for the target molecule. The successful implementation of a biomimetic strategy usually has some uniquely valuable benefits over other abiotic routes in total synthesis by (1) corroborating the chemical feasibility of a given biogenetic hypothesis and further unraveling some insightful implications for future biosynthetic studies and (2) providing remarkably more concise access to not only the original synthetic target but also diversified biogenetically related congeners, which may result in either the structural reassignment of previously disclosed natural products or the anticipation of undiscovered natural products. However, for the devised essential biomimetic transformation, fine-tuning the optimization of the substrates and the reaction conditions can sometimes be painstakingly challenging. Turning to nature for inspiration can provide additional impetus for methodological innovations.Previously used as oral veterinary drugs, lankacidins have potential as next-generation antibiotics to tackle the problems caused by multidrug-resistant bacteria with novel modes of action (MoAs). The hypersensitive and densely functionalized lactonic core within this family of macrocyclic polyketides poses a formidable challenge for chemical total synthesis and derivatization. In this account, we summarized the evolution of a unified biomimetic approach toward 10 lankacidin antibiotics and their linear biosynthetic intermediates in the longest linear 7-12 steps from readily available starting materials. Our endeavor commenced with an intermolecular bioinspired amido sulfone-based Mannich reaction approach to assemble 2 advanced fragments under mild biphasic organocatalytic conditions. It successfully gave rise to stereodivergent access to 4 C2/C18-isomeric lankacyclinols but failed to efficiently deliver lactone-containing congeners through Stille macrocyclization. Facilitated by the thermolysis chemistry of ,-acetal to generate the requisite -acyl-1-azahexatriene species, we realized the projected Mannich macrocyclization and eight macrocyclic lankacidins can be produced by orchestrated desilylative manipulations. In this process, we were able to perform structural reassignments of isolankacidinol ( to ) and isolankacyclinol ( to ) and, for the first time, elucidate the natural occurrence of 2,18-bis--lankacyclinol (). Moreover, the inability of the current biomimetic route to cofurnish the reported structure of 2,18--lankacidinol A () triggered a proposed structural revision that is rooted in reconsidered biogenesis and was confirmed by a divergent synthesis that enabled us to identify the correct isomer (). Finally, the modular, diversity-oriented design also provided streamlined entries to acyclic 2,18--lankacidinol B () and the biosynthetic intermediate LC-KA05 () together with its C7--deacetylated congeners in all C4/C5-stereochemical variations (, -), culminating in a need for structural revision to the six-membered lactonic segment in LC-KA05-2. The selection and execution of biomimetic strategies in lankacidin total synthesis give rise to all the previously mentioned advantages at the current stage. The modular-based, late-stage diversified complex construction offers an exceptionally high level of synthetic flexibility for future synthetic forays toward newly isolated or chemically modified congeners within the lankacidin family.