A GENERAL SYNTHETIC APPROACH TO THE (20S)-CAMPTOTHECIN FAMILY OF ANTITUMOR AGENTS BY A REGIOCONTROLLED CASCADE RADICAL CYCLIZATION OF ARYL ISONITRILES

A general and efficient synthesis of (20S)-camptothecin (1a) is report ed. A key common intermediate containing the pyridone and lactone (DE) rings of camptothecin and most derivatives was constructed from 2-tri methylsilyl-6-methoxypyridine by a series of metalation reactions and a Heck cyclization to provide an achiral bicyclic enol ether. Sharples s asymmetric dihydroxylation followed by lactol oxidation and iododesi lylation produced the key intermediate in 94% enantiomeric excess. Alk ylation with propargyl bromide and a cascade radical reaction with phe nyl isonitrile then produced 1a. About 20 other penta- and hexacyclic analogues of camptothecin with differing single or multiple substituen ts at C7, C9, C10, C11, and/or C12 were made by changing the propargyl ating agent and the isonitrile. Included among these are several drug candidates and the approved drugs topotecan and irinotecan. The synthe sis of the prodrug irinotecan is direct one that does not pass through the active metabolite. The use of ortho-trimethylsilyl-substituted is onitriles allows the regioselective synthesis of camptothecin analogue s in cases where isomeric mixtures are formed from the parent isonitri les. The synthesis of the derivatives relies on the broad scope and fu nctional group tolerance of the key cascade radical reaction.