Diversity Oriented Synthesis of a Vinblastine-Templated Library of 7‑Aryl-Octahydroazonino[5,4‑<i>b</i>]indoles via a Three-Component Reaction

A vinblastine-templated library of 7-aryl-octahydroazonino­[5,4-<i>b</i>]­indoles was prepared by a three-component reaction from indolizino­[8,7-<i>b</i>]­indoles, chloroformates, and activated arenes via a chloroformate mediated fragmentation of the indolizinoindole nucleus followed by insertion of an activated arene. In addition to N3-carbamoyl-7-aryl-octahydroazonino­[5,4-<i>b</i>]­indoles prepared in one step, a wide range of N3-substituted substrates were synthesized in one pot via the derivatization of a versatile N3–H-azonino­[5,4-<i>b</i>]­indole intermediate generated in situ by application of the same strategy. A subset of 308 compounds out of a virtual library of 3216, representing 13 different chemotypes, was prepared by high throughput solution-phase synthesis and subsequently purified by mass-triggered high performance liquid chromatography (HPLC). A total of 188 compounds with a minimum purity of 80% by UV<sub>214 nm</sub> and 85% by evaporative light scattering detection (ELSD) was isolated for primary screening.