Efficient Synthesis of Achiral seco-Cyclopropylbenz[2,3-e]indoline Analogues:  [4-Amino-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl Chloride and [4-Hydroxy-2-(5,6,7-trimethoxyindole-2-carboxamido)naphthalen-1-yl]ethyl Chloride

Abstract

Achiral seco-aminocyclopropylbenz[2,3-e]indoline and seco-hydroxycyclopropylbenz[2,3-e]indoline (seco-CBI) analogues of the duocarmycins and CC-1065, e.g., 7 and 8, are potent anticancer agents. This paper describes significantly improved synthetic strategies for preparing these compounds. Starting from Martius acid (9), the new strategy gave a 13-fold increase in the overall yield of 7, and the use of di-tert-butyl malonate was economically beneficial. For compound 8, the new strategy employed an Emmons-Horner reaction, followed by a Stobbe condensation, and the overall yield was improved 15-fold.