Antineoplastic agents 442. Synthesis and biological activities of dioxostatin

A high-yield regioselective synthesis of (E)-combretastatin A-1 2b was comp leted using methoxymethyl (MOM) protection and a Wadsworth-Emmons reaction as key steps. In turn, (E)-stilbene 11 was converted by convenient synthese s 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 high ly potent inhibitor of microtubule assembly (IC50 = 0.59 muM) and was desig nated dioxostatin. Conversion to sodium phosphate 17 (P388 lymphocytic leuk emia cell line: ED50 = 0.2 mug/ml) provided a very useful water-soluble pro drug.