Synthesis and cytotoxicity of natural (+)-duocarmycin A and its three possible stereoisomers
The title synthesis was accomplished by featuring 1) novel methoxy- carbonylation of the C-4 position of the 5-aminoindoline (dl-13) by way of the isatin (dl-15), 2) the Dieckmann cyclization of diester (dl-19) to the methyl 2- methylindoxyl-2-carboxylates (dl-20 and dl-21), 3) the Wierenga-Kelly-Winstein Ar-3' cyclization as key steps and by employing optical resolutions of various key synthetic intermediates (dl-26, dl-28, dl-34, and dl-36). In vitro cytotoxicity assay of the produced title compounds obviously disclosed that their cytotoxicity is closely related to absolute stereochemistries of cyclopropane moieties. Duocarmycins A (l), C1 (2), C2 (3), B1 (4) and B2 (5) isolated from Streptomyces sp. by a research group at Kyowa Hakko are novel antitumor antibiotics which are effective against various strains of murine cancers (ref. 1 and 2). Almost the same time, workers at Meiji Seika also reported pyrindamycins A and B being identical with 3 and 2, respectively (ref. 1 and 2). Following to 1 - 5, the isolation of duocarmycin SA (6) which is more stable than 1 was recently reported (ref. 1 and 2). The structures of 1 - 6 have been established by X-ray diffraction analysis of 3, chemical derivation of 1 to 2 and 3 or 4 and 5, and consideration of analogy of the structure and biosynthetic process of 6 to those of 1