Toluene Dioxygenase-Mediated cis-Dihydroxylation of Aromatics in Enantioselective Synthesis. Asymmetric Total Syntheses of Pancratistatin and 7-Deoxypancratistatin, Promising Antitumor Agents1

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Abstract

Whole-cell biooxidation of bromobenzene with Pseudomonas putida 39D or the recombinant Escherichia coli JM109 (pDTG601) yields (1S,2S)-3-bromocyclohexa-3,5-diene-1,2-diol (9a), which is protected as the acetonide 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 N,N-dimethyl-2-[(tert-butyldimethylsilyl)oxy]-3,4-(methylenedioxy)benzamide) with aziridine 7 to generate 28, which contains the carbon framework of the title alkaloid. Functional group manipulations resulted in the preparation of epoxydiol 50, which was transformed in a unique fashion and under mild conditions (H2O/PhCO2Na) to (+)-pancratistatin, thus completing a concise synthesis of (+)-pancratistatin in 14 steps from bromobenzene (2% overall yield). To improve this first generation attempt, a new route was devised utilizing carbomethoxyaziridine 64 and its coupling to the cuprate of 3,4-(methylenedioxy)bromobenzene. The adduct was converted to (+)-7-deoxypancratistatin in a total of 11 steps from bromobenzene (3% overall yield), and the basis for further improvement toward a practical synthesis of pancratistatin-type alkaloids was formulated.

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