TOLUENE DIOXYGENASE-MEDIATED CIS-DIHYDROXYLATION OF AROMATICS IN ENANTIOSELECTIVE SYNTHESIS - ASYMMETRIC TOTAL SYNTHESES OF PANCRATISTATIN AND 7-DEOXYPANCRATISTATIN, PROMISING ANTITUMOR AGENTS

Whole-cell biooxidation of bromobenzene with Pseudomonas putida 39D or the recombinant Escherichia coli JM109 (pDTG601) yields (1S,2S)-3-bro mocyclohexa-3,5-diene-1,2-diol (9a), which is protected as the acetoni de and converted to vinylaziridines 7, 15a, 63, and 64. Our route to ( +)-pancratistatin features the coupling of a higher order cyanocuprate (derived by ortho-metalation from ldimethylsily)oxy]-3,4-(methyl-ened ioxy)benzamide) with aziridine 7 to generate 28, which contains the ca rbon framework of the title alkaloid. Functional group manipulations r esulted in the preparation of epoxydiol 50, which was transformed in a unique fashion and under mild conditions (H2O/PhCO(2)Na) to (+)-pancr atistatin, thus completing a concise synthesis of (+)-pancratistatin i n 14 steps from bromobenzene (2% overall yield). To improve this first generation attempt, a new route was devised utilizing carbomethoxyazi ridine 64 and its coupling to the cuprate of 3,4-(methylenedioxy)bromo benzene. The adduct was converted to (+)-7-deoxypancratistatin in a to tal of 11 steps from bromobenzene (3% overall yield), and the basis fo r further improvement toward a practical synthesis of pancratistatin-t ype alkaloids was formulated.