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
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
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DOI：
10.1021/jo9707085
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发表时间：
1997-08-22
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CC-1065和倍癌霉素的烷基化亚基的七元C环类似物1，2，3，4，11，11 a-六氢环丙烯并[c]萘并[2，1-B]氮杂卓-6-酮（CNA）的合成。通过分子内Heck反应组装关键的三环四氢萘并[2，1-B]氮杂卓骨架，最后通过Winstein Ar-3'螺环化反应引入活性环丙烷，制备了CNA的核心结构。N-BOC-CNA的溶剂分解反应性的研究揭示，与相应的五元C环类似物相比，七元稠合C环系统的掺入使反应性增加4750倍。溶剂分解发生与S（N）2亲核攻击更多的取代碳的活性环丙烷，以提供专门的异常环膨胀产物的反应，这是显示：进行完全反转的构型在反应中心。对N-CO2 Me-CNA（29）和CNA（11）的单晶X射线结构分析及其与相应的五元和六元C环类似物的X射线结构的比较揭示了溶剂分解区域选择性和反应性的结构起源。区域选择性可归因于两个可用的环丙烷键与环己二烯酮π-系统的立体电子排列，对于29，环己二烯酮π-系统与延伸到更多取代的环丙基碳的键一起存在。增加的反应性可能部分是由于环丙烷的几何排列，但更重要的是与N-2酰胺中的扭曲有关。X射线分析提供了乙烯基乙酰胺稳定性破坏的证明，如通过伴随N-2酰胺的X（1）二面角扭曲的诊断性C-N键的延长所测量的。随着交叉共轭的乙烯基乙酰胺稳定性的降低，环丙烷共轭、键长和所得反应性增加。天然产物特有的带有烷基化亚基的五元C环的不寻常的稳定性与这种乙烯基乙酰胺缀合的程度密切相关，并且研究支持这样的提议，即DNA烷基化反应的催化可能是由于DNA结合诱导的试剂中的构象变化，该试剂用于扭曲连接的N-2酰胺，破坏乙烯基乙酰胺的稳定性，和活化试剂进行S（N）2亲核攻击。
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-b]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 4750x compared to the corresponding five-membered C-ring analog. Solvolysis occurs with S(N)2 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 pi-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 N-2 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 chi(1) dihedral angle of the N-2 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 N-2 amide, disrupting the vinylogous amide stabilization, and activating the agents for S(N)2 nucleophilic attack.