Synthesis of Epoxytrichothecenes: Verrucarin J and Verrucarin J Isomers

Article abstract of DOI:10.1021/jo00184a021

A five-step synthesis of verrucarin J (1) from verrucarol (2) is described.Esterification of (E)-21 and 2 with DDC in the presence of catalytic DMAP was highly regioselective but afforded a 3-4:1 mixture of (E)-23 and the corresponding Z olefin isomer.Two routes from (E)-23 to seco acid 13 are described, the most efficient of which involves the coupling of (E)-24 ("verrol") with muconate ester 28.Macrolactonization of seco acid 13 via mixed anhydride 31 afforded 55-60percent of 1 together with 25-30percent of E,E,E isomer 32.Although attempts to suppress the formation of 32were unsuccessful, treatment of 32 with I2 in C6H6 effected clean isomerization to a 2:1 mixture of 1 and E,Z,E isomer 33.The overall yield of verrucarin J from verrucarol, after a recycle of 32, was 27-30percent .Also described are syntheses of (Z,E,Z)-verrucarin (40) and Z,E,E isomer 41.Verrucarins 1 and 40 are nearly equipotent in the in vitro L1210 mouse leukemia assay, but the (E,E)-muconate isomers 32 and 41 are less active by an order of magnitude.These data may reflect the solvolytic reactivity of 32 and 41, since these compounds rapidly transesterify in EtOH.Seco acid 13 was essentially inactive in the L1210 assay.