SYNTHESIS AND EVALUATION OF CC-1065 AND DUOCARMYCIN ANALOGS INCORPORATING THE A-HEXAHYDROCYCLOPROPA[C]NAPHTHO[2,1-B]AZEPIN-6-ONE (CNA) ALKYLATION SUBUNIT - STRUCTURAL FEATURES THAT GOVERN REACTIVITY AND REACTION REGIOSELECTIVITY

The synthesis of a-hexahydrocyclopropa[c]naphtho[2,1-b]azepin-6-one (C NA), a seven-membered C-ring analog of the alkylation subunits of CC-1 065 and the duocarmycins, is detailed. The core structure of CNA was p repared through the implementation of an intramolecular Heck reaction for assemblage of the key tricyclic tetrahydronaphtho[2,1-b]azepine sk eleton and a final Winstein Ar-3' spirocyclization for introduction of the reactive cyclopropane. A study of the solvolysis reactivity of N- BOC-CNA revealed that incorporation of the seven-membered fused C-ring system increased the reactivity 4750x compared to the corresponding f ive-membered C-ring analog. Solvolysis occurs with S(N)2 nucleophilic attack at the more substituted carbon of the activated cyclopropane to afford exclusively the abnormal ring expansion product in a reaction that was shown : to proceed with complete inversion of configuration a t the reaction center. Single crystal X-ray structure analyses of N-CO 2Me-CNA (29) and CNA (11) and their comparisons with X-ray structures of the corresponding five-and six-membered C-ring analogs revealed the structural origins of the solvolysis regioselectivity and reactivity. The regioselectivity may be attributed to the stereoelectronic alignm ent of the two available cyclopropane bonds with the cyclohexadienone pi-system which for 29 resides with the bond that extends to the more substituted cyclopropyl carbon. The increased reactivity may be due in part to the geometric alignment of the cyclopropane but more signific antly is linked to a twist in the N-2 amide. X-ray analysis provides d ocumentation of the disruption in the vinylogous amide stabilization a s measured by a lengthening of the diagnostic C-N bond that accompanie s the twist in the chi(1) dihedral angle of the N-2 amide. As the cros s-conjugated vinylogous amide stabilization is diminished, the cyclopr opane conjugation, bond lengths, and resulting reactivity increase. Th e unusual stability of the five-membered C-ring bearing alkylation sub units characteristic of the natural products is intimately linked to t he extent of this vinylogous amide conjugation, and the studies suppor t the proposal that catalysis for the DNA alkylation reaction may be d ue to a DNA binding-induced conformational change in the agents which serves to twist the linking N-2 amide, disrupting the vinylogous amide stabilization, and activating the agents for S(N)2 nucleophilic attac k.