Difference between Enzymatic and Chemical N-methylations of Protoberberine-Type Alkaloid, Dependent on the Stereoisomer of (-)-N-methyl-7,8,13,13a-tetrahydroberberinium Salt

A possible relation between the stereostructure of (-)-(13aS)-tetrahydroberberine (1) and its enzymatic/chemical N-methylation, an important biosynthetic reaction to isoquinoline alkaloids in plants, was examined by CD spectroscopic, X-ray crystallographic, and energy calculation methods. The CD measurements indicated that 1 has two conformers (cis and trans) concerning the ring junction of the quinolizidine skeleton, and exist with a cis/trans ratio of about 1/4 in a diethyl ether : 2methylbutane : ethanol (5 : 5 : 2) mixture. The dimensional/conformational difference between these cis and trans conformers was clarified by the X-ray crystalstructure analyses of two stereoisomers of N-methylated 1 (3 and 4). By using these structural parameters, the progress of N-methylation was simulated by energy profile calculations, suggesting that the cis and trans conformers are the major substrate for the enzymatic and chemical N-methylation reactions, respectively. Taking these results and the simulation of N-methylation of 1 by S-adenosyl-L-methionine at the binding pocket of N-methyltransferase into consideration, different pathways for chemical and enzymatic N-methylations of 1 have been proposed.