Synthesis of Duocarmycin SA by Way of Methyl 4-(Methoxycarbonyl)oxy-3H-pyrrolo[3, 2-f]quinoline-2-carboxylate as a Tricyclic Heteroaromatic Intermediate

Formal syntheses of (±)-duocarmycin SA, natural (+)-duocarmycin SA and unnatural (-)-duocarmycin SA were accomplished by way of a tricyclic heteroaromatic compound 10b. For the preparation of 10, an N-oxide route aiming at a process 20 in Chart 3 was first investigated by synthesizing 19, derived from Stille coupling products 13 between bromopyrrole 7a and 3-(tributylstannyl)pyridines 12, but without success. As the second approach, Stille coupling products 9a-c were prepared by condensation 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-arylation reaction in the presence of tributyltin fluoride and lithium chloride, affording 10a and 10b in excellent yields, especially from 35. Application to 10b of three successive operations, i.e., i) partial reduction of 10b to dihydropyridine derivatives 11a and 11b, ii) dihydroxylation of the double bonds formed to give 58 and 59, and iii) reductive elimination of the hydroxy groups adjacent to the nitrogen function and the aromatic ring, afforded 6 in fairly good yield. Compound 6 was readily converted to relay compounds 64 and 67, completing total syntheses of (±)-, (+)-, and (-)-duocarmycin SA. Both Sharpless asymmetric dihydroxylation (AD) and Jacobsen's asymmetric epoxidation were applied to 11a and 11b. At the best, 81% ee was observed in the AD reaction of 11a using 2, 5-diphenyl-4, 6-bis(9-O-dihydroquinyl)pyrimidine [(DHQ)2PYR], but the resulting 58 possessed an unnatural absolute configuration.