The title synthesis was achieved by featuring the optical resolution of two types of the tricyclic intermediates and the synthetic scheme established in the synthesis of racemic compounds. In vitro cytotoxicity assay against P388 murine leukemia obviously showed that the absolute configuration of cyclopropane moiety in (+)-I is closely related to its cytotoxicity. Duocarmycin A (1) isolated from Strepzornyces sp. is a novel antitumor antibiotic which is effective against various strains of murine tumors .4 The structural similarity of cyclopropadienone moiety in 1 to the cyclopropapyrroloindole (CPI) ring system in the potent antitumor antibiotic CC-1065 (2) as well as its prominent antitumor activity made 1 the exceptionally attractive target not only for total synthesis but also for exploration of novel anticancer agents designed based on 1. The cyclopropadienone systems present in 1 and 2 have been postulated to be the sites of nucleophilic attack by adenine N-3 in DNA, inducing their potent antitumor activity.5
Since 2 caused unusual delayed lethality in clinical trials,6 a less toxic analogue U-71,184 (3) involving modified middle and left hand segments has been developed. Sa.7 Of most interest was that in vifro cytotoxicity of the enantiomer of 3 (ent-3) to Ll210 cells was three orders of magnitude less than that of 3.5a As described in the preceding paper,l we have disclosed that our synthetic racemic 1 @l-l) exhibits in vitro cytotoxicity being almost half of that of natural 1 [(+)-l] against P388 murine leukemia. Thus, it was hypothesized that there