The evolution of strategies toward the syntheses of melicolones A and B are disclosed. The melicolones are rearranged polyprenylated acylphloroglucinol (PPAP) natural products isolated in 2015 from the deciduous shrub Melicope ptelefolia as an epimeric racemic mixture. This non-selective biosynthesis has inspired several synthetic strategies for preparing the natural products with absolute stereocontrol. We recognized an element of hidden symmetry within the melicolone skeleton wherein a central 5-membered ring is cyclized about two prenyl groups through C–C and C–O bond forming events. Reduction of this complexity results in a symmetric bisprenylated 1,3-cyclopentanedione derivative which served as a launching point for investigating enantioselective strategies for assembling the melicolone core. The skeleton was successfully constructed through a reductive cyclization of bisepoxide substrates, but the process was not stereoselective. We then turned our attention to MHAT mediated reductive cyclizations, which succeeded in diastereoselective synthesis of the core, but necessitated further oxidation and was not enantioselective. Attempts to install the desired oxidation through C–H functionalization reactions were unsuccessful but gave insight into the reactivity of this complex system. Finally, the enantioselective [2+2] cycloaddition was employed to form the requisite C–C bond of the core while forming a highly strained caged intermediate. The strained C–C bond of this intermediate could be leveraged to deliver the desired oxidation of the melicolone core in stereoselective fashion. This work highlights the power of symmetry-based strategies for the synthesis of natural products in a stereoselective fashion. Furthermore, we were able to investigate C–H functionalization strategies in complex settings and leverage strained C–C bonds to give formal C–H oxidation. These insights will be useful not only in the synthesis of PPAP natural products, but more broadly in the context of stereoselective synthesis.

Hidden symmetry guided strategies toward the enantioselective syntheses of melicolones A and B

ACS Spring 2022

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