Synthesis of Nonracemic Pyrrolo‐allocolchicinoids Exhibiting Potent Cytotoxic Activity

An efficient eight‐step semisynthetic approach towards nonracemic pyrrolo‐allocolchicinoids starting from natural colchicine was developed by exploiting Pd‐catalyzed domino Sonogashira coupling/5‐ endo ‐ dig cyclization of a 2‐iodo‐trifluoroacetanilide intermediate to build up the heterocyclic ring system. The N ‐Me substitution of the pyrrole ring enhanced the antitumor activity of the prepared molecules by 2–3 orders of magnitude. Among the active compounds, the N ‐methylated colchicinoid exhibited powerful cytotoxic and antiproliferative properties at concentrations < 1 n m .