Flow-Assisted Synthesis of Alkyl Citrate Natural Products

    • Nikolai Piers Rossouwa
    • Mark A. Rizzacasa*a
    • Anastasios Polyzos*a,b
    • aSchool of Chemistry, The University of Melbourne, Parkville 3010, Victoria, Australia
    • bCSIRO Manufacturing, Research Way, Clayton 3168, Victoria, Australia

    The development of a flow-assisted synthesis of alkyl citrate natural products is described. The flow route harnesses a number of steps including the generation of ketene silyl acetal, a formal [2 + 2] cycloaddition, and a methanolysis cascade to efficiently generate a highly substituted, and stereodefined tetrahydrofuran intermediate. A heterogeneous pseudo-Finkelstein reaction and zinc-mediated elimination furnish a key alkene alkyl citrate fragment in high yield over a multistep sequence that provides direct entry to compounds such as (−)-CJ-13982 (1), (−)-CJ-13,981 (2), L-731,120 (3), and related natural products. The flow methodology developed in this study enables a new machine-assisted approach toward the efficient and scalable synthesis of the alkyl citrate family of natural products.

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