194221-89-1Relevant articles and documents
Synthesis and Evaluation of CC-1065 and Duocarmycin Analogs Incorporating the 1,2,3,4,11,11a-Hexahydrocyclopropa[c]naphtho[2,1-b]azepin-6-one (CNA) Alkylation Subunit: Structural Features that Govern Reactivity and Reaction Regioselectivity
Boger, Dale L.,Turnbull, Philip
, p. 5849 - 5863 (2007/10/03)
The synthesis of 1,2,3,4,11,11a-hexahydrocyclopropa[c]naphtho[2,1-b]azepin-6-one (CNA), a seven-membered C-ring analog of the alkylation subunits of CC-1065 and the duocarmycins, is detailed. The core structure of CNA was prepared through the implementation of an intramolecular Heck reaction for assemblage of the key tricyclic tetrahydronaphtho[2,1-6]azepine skeleton 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 4750 × compared to the corresponding five-membered C-ring analog. Solvolysis occurs with SN2 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 at the reaction center. Single crystal X-ray structure analyses of N-CO2Me-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 alignment of the two available cyclopropane bonds with the cyclohexadienone π-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 significantly is linked to a twist in the N2 amide. X-ray analysis provides documentation of the disruption in the vinylogous amide stabilization as measured by a lengthening of the diagnostic C-N bond that accompanies the twist in the χ1 dihedral angle of the N2 amide. As the cross-conjugated vinylogous amide stabilization is diminished, the cyclopropane conjugation, bond lengths, and resulting reactivity increase. The unusual stability of the five-membered C-ring bearing alkylation subunits characteristic of the natural products is intimately linked to the extent of this vinylogous amide conjugation, and the studies support the proposal that catalysis for the DNA alkylation reaction may be due to a DNA binding-induced conformational change in the agents which serves to twist the linking N2 amide, disrupting the vinylogous amide stabilization, and activating the agents for SN2 nucleophilic attack.
