Synthesis and evaluation of a carbocyclic analogue of the CC-1065 and duocarmycin alkylation subunits: Role of the vinylogous amide and implications on DNA alkylation catalysis
Synthesis and evaluation of a carbocyclic analogue of the CC-1065 and duocarmycin alkylation subunits: Role of the vinylogous amide and implications on DNA alkylation catalysis
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DOI：
10.1021/jo981698q
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发表时间：
1998-10-30
影响因子：
3.6
通讯作者：
Turnbull, P
中科院分区：
文献类型：
--
作者：
Boger, DL;Turnbull, P
详细介绍了 1,2,9,9a-四氢-1H-环丙[c]苯并[e]茚-4-酮 (CBIn, 10)（CC-1065 和 duocarmycin 烷基化亚基的碳环 C 环类似物）的合成和化学性质。 CBIn 的核心结构是通过分子内 Heck 反应来组装关键三环骨架和最终的 Winstein Ar-3' 螺环化以安装反应性环丙烷来制备的。对 CBIn 溶剂分解反应性、区域选择性和机理的研究表明，脱氮和产生的插烯酰胺稳定化使反应活性提高了 3200x (pH 3)，并逆转了固有的区域选择性，但没有改变 S(N)2 反应机理。因此，天然存在的烷基化亚基中发现的插烯酰胺是其异常稳定性的原因，并且在不改变亲核加成的固有 S(N)2 机制的情况下显着影响区域选择性。更重要的是，这种溶剂分解反应性被证明与 4-12 范围内的 pH 值无关，包括生理相关的 5.0-8.0 范围，其中 CBI 完全稳定。酸催化和非催化反应的速率常数分别为 0.093 +/- 0.001 M(-1) s(-1) 和 4.2 +/- 0.4 x 10(-5) s(-1)，并且在 pH 大于或等于 4 时非催化反应占主导地位。这些观察结果对催化来源具有重要意义。 CC-1065/duocarmycin DNA 烷基化反应支持最近的提议，即它不是源自酸催化和 C4 羰基质子化，而是源自 DNA 结合诱导的构象变化，破坏了交叉共轭插烯酰胺的稳定性。
The synthesis and chemical properties of 1,2,9,9a-tetrahydro-1H-cyclopropa[c]benz[e]inden-4-one (CBIn, 10), a carbocyclic C-ring analogue of the alkylation subunits of CC-1065 and the duocarmycins, are detailed. The core structure of CBIn was prepared with an intramolecular Heck reaction for assembly of the key tricyclic skeleton and a final Winstein Ar-3' spirocyclization to install the reactive cyclopropane. A study of the CBIn solvolysis reactivity, regioselectivity, and mechanism revealed that removal of the nitrogen and resulting vinylogous amide stabilization increased the reactivity 3200x (pH 3) and reversed the inherent regioselectivity, but did not alter the S(N)2 reaction mechanism. Thus, the vinylogous amide found in the naturally occurring alkylation subunits is responsible for their unusual stability and significantly impacts the regioselectivity without altering the inherent S(N)2 mechanism of nucleophilic addition. More importantly, this solvolysis reactivity proved independent of pH throughout the range of 4-12 including the physiologically relevant range of 5.0-8.0 where CBI is completely stable. Rate constants of 0.093 +/- 0.001 M(-1) s(-1) and 4.2 +/- 0.4 x 10(-5) s(-1) for the respective acid-catalyzed and uncatalyzed reactions were established, and the uncatalyzed reaction dominates at pH greater than or equal to 4. These observations have important implications on the source of catalysis for the CC-1065/duocarmycin DNA alkylation reaction supporting the recent proposal that it is not derived from acid catalysis and C4 carbonyl protonation but rather a DNA binding-induced conformational change that disrupts the cross-conjugated vinylogous amide stabilization.