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1490712 
Journal Article 
Synthesis, chemical properties, and preliminary evaluation of substituted CBI analogs of CC-1065 and the duocarmycins incorporating the 7-cyano-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one alkylation subunit: Hammett quantitation of the magnitude of electronic effects on functional reactivity 
Boger, DL; Han, NH; Tarby, CM; Boyce, CW; Cai, H; Jin, Q; Kitos, PA 
1996 
Yes 
Journal of Organic Chemistry
ISSN: 0022-3263
EISSN: 1520-6904 
61 
15 
4894-4912 
English 
WOS:A1996UZ74000012 
The synthesis of 7-cyano-1,2,9,9a-tetrahydrocyclopropa[c]
benz[e]indol-4-one (CCBI), a substituted CBI derivative bearing a C7 cyano group, is described in
efforts that establish the magnitude of potential electronic effects on the functional reactivity
of the agents. The CCBI alkylation subunit was prepared by a modified Stobbe
condensation/Friedel-Crafts acylation for generation of the appropriately functionalized
naphthalene precursors followed by 5-exo-trig aryl radical-alkene cyclization for synthesis of
the 1,2-dihydro-3H-benz[e]indole skeleton and final Ar-3' alkylation for introduction of the
activated cyclopropane. The most concise approach provided the CCBI subunit and its immediate
precursor in 14-15 steps in superb overall conversions (15-20%). Resolution of an immediate CCBI
precursor and its incorporation into both enantiomers of 34-39, analogs of CC-1065 and the
duocarmycins, are detailed. A study of the solvolysis reactivity and regioselectivity of N-BOC-
CCBI (25) revealed that introduction of the C7 nitrile slowed the rate of solvolysis but only to
a surprisingly small extent. Classical Hammett quantitation of the effect provided a remarkably
small rho (-0.3), indicating an exceptionally small C7 substituent electronic effect on
functional reactivity. Additional kinetic studies of acid-catalyzed nucleophilic addition proved
inconsistent with C4 carbonyl protonation as the slow and rate-determining step but consistent
with a mechanism in which protonation is rapid and reversible followed by slow and rate-
determining nucleophilic addition to the cyclopropane requiring both the presence and assistance
of a nucleophile (S(N)2 mechanism). No doubt this contributes to the DNA alkylation selectivity
of this class of agents and suggests that the positioning of an accessible nucleophile (adenine
N3) and not C4 carbonyl protonation is the rate-determining step controlling the sequence
selectivity of the DNA alkylation reaction, This small electronic effect on the solvolysis rate
had no impact on the solvolysis regioselectivity, and stereoelectronically-controlled
nucleophilic addition to the least substituted carbon of the activated cyclopropane was observed
exclusively. Consistent with past studies, a direct relationship between solvolysis stability and
cytotoxic potency was observed with the CCBI-derived agents providing the most potent analogs in
the CBI series, and these observations were related to the predictable Hammett substituent
effects. For the natural enantiomers, this unusually small electronic effect on functional
reactivity had no perceptible effect on their DNA alkylation selectivity. Similar effects of the
C7 cyano substituent on the unnatural enantiomers were observed, and they proved to be 4-10x more
effective than the corresponding CBI-based unnatural enantiomers and 4-70x less potent than the
CCBI natural enantiomers.