Functional analogs of CC-1065 and the duocarmycins incorporating the 9a-(chloromethyl)-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (C2BI) alkylation subunit: Synthesis and preliminary DNA alkylation studies

Article abstract of DOI:10.1021/ja00050a012

A concise and effective nine to ten step synthesis of 9a-(chloromethyl)-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (C₂BI) is detailed based on the implementation of a key 5-exo-trig aryl radical-alkene cyclization for direct introduction of a selectively protected 3,3-bis(hydroxymethyl)indoline. The incorporation of C₂BI into functional analogs of CC-1065 and the duocarmycins (C₂BI-COPI₁, C₂BI-CDPI₂, C₂BI-TMI, and C₂BI-indole₂) is described. The fundamental solvolytic behavior of N-BOC-C₂BI is detailed (t_1/2 = 433 h, pH = 3) in studies which reveal that the agent is approximately 12 times more stable than the authentic alkylation subunit of CC-1065 and that it participates in the stereoelectronically-controlled reaction with nucleophilic addition to the least substituted cyclopropane carbon. Preliminary studies demonstrating the DNA alkylation and cross-linking properties of C₂BI-CDPI₂ are presented.