Antineoplastic agents 442. Synthesis and biological activities of dioxostatin

A high-yield regioselective synthesis of (E)-combretastatin A-1 2b was completed using methoxymethyl (MOM) protection and a Wadsworth-Emmons reaction as key steps. In turn, (E)-stilbene 11 was converted by convenient syntheses to both (S,S)- and (R,R)-1, 3-dioxolanes 5a and 6a. A Sharpless asymmetric dihydroxylation reaction was employed for preparation of intermediates (S,S)-12 and (R,R)-13. The (4S,5S)-4-(2′,3′-dihydroxy-4′-methoxyphenyl)-5- (3″,4″,5″-trimethoxyphenyl)-1, 3-dioxolane 5a was found to be a highly potent inhibitor of microtubule assembly (IC₅₀ = 0.59 μM) and was designated dioxostatin. Conversion to sodium phosphate 17 (P388 lymphocytic leukemia cell line: ED₅₀ = 0.2 μg/ml) provided a very useful water-soluble prodrug.