Synthesis and evaluation of a series of C3-substituted CBI analogues of CC-1065 and the duocarmycins

The synthesis and evaluation of a series of C3-substituted 1,2,9,9a-tetrahy drocyclopropa[c]benz[e]indol-4-one (CBI) analogues of the CC-1065 and duoca rmycin alkylation subunits are detailed, including methyl and the full seri es of halogens. Introduction of the key substituent was accomplished throug h directed metalation of the seco-CBI core followed by reaction of the resu ltant aryllithium with an appropriate electrophile. C3-Bromo and iodo subst ituents were only effectively installed on the hindered aryllithium interme diate using a novel halogen source, 1-bromo- and 1-iodophenylacetylene, tha t should prove generally useful beyond the studies we describe. X-ray cryst al. structures of the series show substantial distortion in the vinylogous amide due to unfavorable steric interactions between the C3-substituent and the N-2-carbamate. In the halogen series, the N2-C2a bond length and the t orsional angle chi (1) smoothly increase with the increasing size of the C3 substituent indicative of decreasing vinylogous amide conjugation through the series (H > F > Cl > Br > I). Unlike N-Boc-CBI, this series of substitu ted CBI analogues proved remarkably reactive toward solvolysis even at pH 7 , where the reaction is uncatalyzed and the reactivity order (I > Br > Cl > F > H) follows a trend consistent with the extent of vinylogous amide conj ugation and stabilization. The implications of these observations on the so urce of catalysis for the DNA alkylation reaction of the natural products a re discussed.