A short approach to cytogenin and first total synthesis of aspergisocoumarin A and fusarimarin C

Abstract

A novel, efficient route to the first total synthesis of the bioactive isocoumarins aspergisocoumarin A, fusarimarin C and cytogenin is demonstrated. This approach features a groundbreaking single-step synthesis of isocoumarins utilizing a challenging cross-ester coupling of ethyl dimethoxy orsellinate and ethyl glycolate in the presence of a LiBr-LiTMP complex. The process leverages bromide ion-induced aggregation to facilitate a one-pot tandem reaction sequence: lateral lithiation, acylation, enolization, and lactonization. This innovative method directly produces the isocoumarin moiety with high efficiency. Subsequent transformations include selective BBr₃-mediated demethylation, oxidation, and Wittig reactions. The streamlined synthetic routes demonstrated: a two-step pathway to cytogenin and a four-step sequence to aspergisocoumarin A and fusarimarin C, achieving overall yields of 37 %, 27 %, and 27 % respectively.