An efficient synthesis of furano analogs of duocarmycin CI and C2: seco-iso-cyclopropylfurano[e]indoline-trimethoxyindoIe and seco-cyclopropylfurano[f]quinoline-trimethoxyindole

摘要

seco-Iso-cyclopropylfurano[e]indoline-trimethoxyindole 1 and seco-cyclopropylfurano[f]quinoline-trim-ethoxyindole 2 are potent cytotoxic agents. Previous synthesis of these compounds was inefficient and the approach required separation of a mixture containing the isomeric indoline and quinoline intermediates 11 and 12, formed from radical cyclization of allylic bromide 10. Reported herein is an efficient and selective synthesis of either intermediate 11 or 12, thus product 1 or 2, as needed. The conditions of the Stobbe condensation, bromination, 5-exo-trig radical cyclization, amine-carboxylic acid coupling, and debenzylation were optimized for multi gram scale. As a result, the reaction times were shortened, the products were readily isolated, and the yields and purity improved.