Structurally modified antitumour agents. Part 2. Total synthesis of a cyclopropamitosene

Abstract

The total synthesis of the cyclopropapyrroloindolequinone (2), the cyclopropane analogue of the biologically active aziridinomitosene derived from N-methylmitomycin A, is described. The synthesis starts from commercially available 4-methylsalicylic acid, which is converted into 2-benzyloxy-3methoxy-4-methylbenzaldehyde (17), the key step being the selective ortho-formylation of the hydroxy ester(12) to introduce, after Baeyer-Villiger oxidation, the second oxygen substituent. The benzaldehyde (17) was converted into the 4,5,6-trisubstituted indole-2-ester (19) using the high yielding nitrene cyclisation method, subsequent functional group transformations giving the tosylhydrazone (23). Decomposition of the sodium salt of the tosylhydrazone resulted in intramolecular cycloaddition to give the tetracyclic cyclopropapyrroloindole (24) in excellent yield. The synthesis was completed by formylation, oxidation to the quinone, and elaboration of the side chain.