174868-40-7Relevant academic research and scientific papers
Alternative synthesis of duocarmycin SA using a tricyclic heteroaromatic intermediate prepared by palladium-catalyzed coupling reactions
Muratake, Hideaki,Tonegawa, Miyuki,Natsume, Mitsutaka
, p. 1631 - 1633 (1996)
Alternative synthesis of duocarmycin SA (1) was achieved by developing a novel preparation method using palladium catalysts for a tricyclic heteroaromatic compound 4b, followed by transformation into the previously reported intermediates 13 and 14a by way of the alcohol 10b.
New synthetic method for indole-2-carboxylate and its application to the total synthesis of duocarmycin SA
Hiroya, Kou,Matsumoto, Shigemitsu,Sakamoto, Takao
, p. 2953 - 2956 (2007/10/03)
(Equation Presented) The sequential coupling and cyclization reactions between aryl halides and methyl propiolate were investigated. The electron-withdrawing groups on the aromatic ring are essential for producing the methyl indole-2-carboxylate derivativ
Synthesis of duocarmycin SA by way of methyl 4-(Methoxycarbonyl)oxy-3H- pyrrolo[3,2-f]quinoline-2-carboxylate as a tricyclic heteroaromatic intermediate
Muratake, Hideaki,Tonegawa, Miyuki,Natsume, Mitsutaka
, p. 400 - 412 (2007/10/03)
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.
Preparation of alkyl-substituted indoles in the benzene portion. Part 14. Synthesis of (±)-duocarmycin SA, natural (+)-duocarmycin SA and non-natural (-)-duocarmycin SA
Muratake,Abe,Natsume
, p. 67 - 79 (2007/10/03)
Total synthesis of duocarmycin SA (1), an extremely potent cytotoxic antibiotic, was achieved in the racemic form at first by effectively utilizing two reactions as key steps, (i) an intramolecular Heck reaction of the benzyl ether 21a, derived from a dihydropyridine 13a and a pyrrole derivative 11, to form tricyclic compounds 25a and 26a, and (ii) a modified Mitsunobu reaction on the diol derivative 40 for the construction of compound 41 having the pivotal pharmacophore of a cyclopropanoindolinone partial structure, which is critical for the high biological activities of 1. Next, optical resolution of an intermediary racemic secondary alcohol 50 was cleanly attained by derivatizing it to (R)-O-methylmandelates 52 and 53, and the resulting chiral alcohols (+)-50 and (-)-50 were respectively transformed into unnatural (-)-1 and natural (+)-1. Finally inversion of the secondary alcohol (+)-50 to the enantiomer (-)-50 was effected by using the Mitsunobu reaction. This constitutes an enantio-convergent total synthesis of natural duocarmycin SA (1) starting from a racemic compound.
