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
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
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DOI：
10.1021/jo9605298
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发表时间：
1996-07-26
影响因子：
3.6
通讯作者：
Kitos, PA
中科院分区：
文献类型：
--
作者：
Boger, DL;Han, NH;Kitos, PA
7-氰基-1,2,9,9 - a-四氢环丙烯[c]苯并[e]吲哚-4- 1 （CCBI）的合成，是一种含有C7氰基的取代CBI衍生物，本文描述了这些试剂的功能反应活性的潜在电子效应的大小。CCBI烷基化亚基通过Stobbe缩合/Friedel-Crafts酰化反应生成相应功能化的萘前体，然后通过5-外三芳基自由基烯烃环化反应合成1,2-二氢- 3h -苯并[e]吲哚骨架，最后通过Ar-3'烷基化反应引入活化的环丙烷。最简洁的方法提供了CCBI子单元及其直接的前体，在极好的总体转换（15-20%）中有14-15个步骤。详细介绍了直接CCBI前体的分离及其与34-39的对映体，CC-1065的类似物和duocarmycin的结合。一项关于N-BOC-CCBI的溶剂分解反应性和区域选择性的研究（25）表明，引入C7腈会减慢溶剂分解的速度，但幅度非常小。经典Hammett定量的效应提供了一个非常小的rho(-0.3)，表明C7取代基对功能反应性的电子效应非常小。酸催化的亲核加成反应的动力学研究证明，与C4羰基质子化反应作为慢速决定速率的步骤不一致，但与质子化反应是快速可逆的，随后是需要亲核试剂的存在和辅助的慢速决定速率的亲核加成反应（S(N)2机制）是一致的。毫无疑问，这有助于这类试剂的DNA烷基化选择性，并表明可接近的亲核试剂（腺嘌呤N3）的定位而不是C4羰基质子化是控制DNA烷基化反应序列选择性的速率决定步骤，这种对溶剂溶解速率的小电子效应对溶剂溶解区域选择性没有影响。在活性环丙烷的最小取代碳上观察到立体电子控制的亲核加成反应。与过去的研究一致，我们观察到溶解稳定性和细胞毒性之间的直接关系，其中ccbi衍生的药物提供了CBI系列中最有效的类似物，这些观察结果与可预测的Hammett取代基效应有关。对于天然对映体，这种异常小的电子对功能反应性的影响对其DNA烷基化选择性没有明显的影响。C7氰基取代基对天然对映体的影响也类似，它们比相应的基于CCBI的天然对映体的效力高4-10倍，比CCBI天然对映体的效力低4-70倍。
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.