The synthesis of 2,3,10,10a-tetrahydro-1H-cyclopropa[d]benzo[f]quinol-5-one (10, CBQ), containing a deep-seated structural variation in the CC-1065 and duocarmycin alkylation subunits with incorporation of a ring expanded fused six-versus five-membered ring, and its incorporation into analogs of the natural products are detailed. The approach was based on a key 6-exo-trig aryl radical-alkene cyclization of 22 to provide 23 in which an enol ether acceptor alkene served to reinforce the preferred 6-exo-trig versus 7-endo-trig cyclization and directly provided a suitably functionalized 1,2,3,4-tetrahydrobenzo[f]quinoline precursor. Conversion of 23 to 26 followed by Winstein Ar-3' alkylation cleanly permitted the introduction of the activated cyclopropane and completed the synthesis of the CBQ nucleus. The evaluation of the CBQ-based agents revealed an exceptional solvolysis reactivity and mixed solvolysis regioselectivity. N-BOC-CBQ (9, t(1/2) = 2.1 h, k = 9.07 x 10(-5) s(-1), pH 3) proved to be 63 x more reactive than N-BOC-CBI (t(1/2) = 133 h, k = 1.45 x 10(-6) s(-1), pH 3) and its solvolysis was found to proceed with cleavage of both the external C9b-C10 and internal C9b-C10a cyclopropane bonds. The latter was shown to occur with exclusive inversion of stereochemistry illustrating for the first time that the solvolysis and alkylation reactions proceed by S(N)2 versus S(N)1 cyclopropane ring opening upon activation by C5 carbonyl protonation. A comparison of the X-ray crystal structures of the CPI alkylation subunit taken from (+)-CC-1065, the CBI alkylation subunit, and N-BOC-CBQ (9) provided the structural basis for this altered solvolysis reactivity and regioselectivity. The increased inherent reactivity and the loss of stereoelectronic control for cyclopropane ring opening may be attributed to the idealized alignment and conjugation of the activated cyclopropane with the cyclohexadienone pi-system. The fundamental insight derived from the comparisons was not the rapid solvolysis or mixed solvolysis regioselectivity of the CBQ agents, but rather the surprising stability and solvolysis selectivity of the CBI and DSA alkylation subunits. In spite of the apparent structural features that intuitively suggest a high reactivity, the latter agents have proven to be uncharacteristically stable. This unusual stability and the solvolysis regioselectivity are imposed by fusion of the activated cyclopropane to the five-membered ring which constrains it to a nonideal alignment and overlap with the cyclohexadienone pi-system. In addition, the in vitro cytotoxic potencies of the CBQ-based agents were found to qualitatively and quantitatively follow the well-established trend where the chemically more stable agents provide the more potent activity.
