SYNTHESIS OF DUOCARMYCIN SA BY WAY OF METHYL BONYL)OWY-3H-PYRROLO[3,2-F]QUINOLINE-2-CARBOXYLATE AS A TRICYCLIC HETEROAROMATIC INTERMEDIATE

Formal syntheses of (+/-)-duocarmycin SA, natural(+)-duocarmycin SA an d unnatural (-)-duocarmycin SA were accomplished by way of a tricyclic heteroaromatic compound 10b, For the preparation of 10, an N-oxide ro ute aiming at a process 20 in Chart 3 was first investigated by synthe sizing 19, derived from Stille coupling products 13 between bromopyrro le 7a and 3-(tributylstannyl)pyridines 12, but without success, As the second approach, Stille coupling products 9a-c were prepared by conde nsation between 7a and 2-substituted 3-(trialkylstannyl)pyridines 8a-f , Both 9b and 35, derived from 9c, were converted to their silyl enol ethers and then subjected to a palladium-catalyzed methyl ketone-aryla tion reaction in the presence of tributyltin fluoride and lithium chlo ride, affording 10a and 10b in excellent yields, especially from 35. A pplication to 10b of three successive operations, i.e., i) partial red uction of 10b to dihydropyridine derivatives 11a and 11b, ii) dihydrox ylation of the double bonds formed to give 58 and 59, and iii) reducti ve elimination of the hydroxy groups adjacent to the nitrogen function and the aromatic ring, afforded 6 in fairly good yield, Compound 6 wa s readily converted to relay compounds 64 and 67, completing total syn theses of (+/-)-, (+)-, and (-)-duocarmycin SA. Both Sharpless asymmet ric dihydroxylation (AD) and Jacobsen's asymmetric epoxidation were ap plied to 11a and 11b. At the best, 81% ee was observed in the AD react ion of 11a using 2,5-diphenyl-4,6-bis(9-O-dihydroquinyl)pyrimidine [(D HQ)(2)PYR], but the resulting 58 possessed an unnatural absolute confi guration.