Practical Synthesis Routes Towards Antitumor Antibiotic Duocarmycin SA

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Duocarmycin SA (1) is the most potent and most stable member among the antitumor antibiotics, including CC-1065 and Duocarmycin A,which bear cyclopropa [c] pyrrolo [3,2-e] indole pharmacophore.Our recent studies on the synthesis of this antibiotic clminated in achievement of three distinctive synthesis routes which are applicable to the preparation of synthetic analogs of 1.The initial rote realized the first enantio-selective synthesis of (+) -1. Pyrrolo [3,2-f] quinolinol derivative (2) , prepared from methyl 5-acetyl-4-bromopyrrole-2-carboxylate (3) in the steps, was readily optically resolved by use of Chiralcel OD HPLC column to (S)-2 and (R)-2. The former was led to (+) -1, and the latter unnatural isomer, was inverted to (S)-2 under the Mitsunobu reaction conditions. An enatio-convergent synthesis of (+) -1 was thus established.The second rote wa most featred by methyl 4- (methoxycarbonyloxy) pyrrolo [3,2-f] quinoline-2-carboxylate (4). The pyrrole derivative 3 was copled with 2-fluoro-3- (trimethylstannyl) pyridine under the Stille reaction conditions, and the resulting pyridylpyrrole derivative was cyclized to 4 in five steps involving a palladim-catalyzed arylation reaction of the acetyl group. It was then readily transformed to ( (]SY.+-。[) ) -2. The overall yield was much improved by this rote, and it was applied to the preparation of DSA furan and thiophene analogs.The third route is the first asymmetirc synthesis without an optical resolution among the syntheses of the duocarmycin class of antibiotics. A highly functionalized optica active indole derivative was prepared from L-malic acid adoptiong our indole formation reaction. The following C-ring formation gave the enatiomerically pure (S) -2, completing the third route. The absolute structure of (+) -1 was unequivocally established by this study.A further elaboration is now in progress.