Catalyst-Controlled Stereoselective Combinatorial Synthesis

摘要

Combinatorial chemistry is an important method for the development of pharmaceuticals, agrochemicals, catalysts, and materials. It can be performed either on a solid phase or in solution and in some cases, the advantages of solid- and liquid-phase synthesis may be combined, if the products can be precipitated as salts. The aim of combinatorial chemistry is the preparation of a multitude of organic compounds with constitutional diversity. Stereochemical aspects have so far played only a minor role, although the configuration of a molecule can have a considerable effect on its biological activity; this applies to both the absolute as well as the relative configuration. Herein we present a method to access stereochemical diversity of nonpeptidic active compounds as a new combinatorial strategy. By using enantiomerically pure catalysts, several stereogenic centers are constructed in a catalyst-controlled manner. This general concept is introduced with the example of the synthesis of 12 stereoisomers of the biologically highly active ipecacuanha alkaloid emetine (1), which contains four stereogenic centers. The ruthenium complexes (R, R)-5 and (S, S)-5 developed by Noyori and co-workers were used as catalysts. The key step of the synthesis is the enantio- or diastereoselective hydrogenation of imines, which can be prepared either by oxidation of a secondary amine or by a Bischler-Napieralski reaction.