Structure-reactivity study of O-tosyl Cinchona alkaloids in their new synthesis and in hydrolysis to 9-epibases. Unexpected formation of cinchonicine enol tosylate accelerated by microwave activation

Abstract

New methods for O-tosylation of the natural Cinchona alkaloids have been discovered as a biphasic processes with Bu3N as a catalyst. The optimized excess of tosyl chloride, necessary for transformation of each of the four alkaloids into O-tosyl derivative, decreases in the following order: quinine, quinidine, cinchonidine and cinchonine. The same decreasing order has been noticed for the hydrolysis rate of the appropriate tosylates to 9-epibases. Difficult conversion of O-tosylcinchonine in the hydrolytic medium of aqueous tartaric acid gives 9-epicinchonine together with parallel formation of cinchonicine enol tosylate. The latter product is obtained as the main when both cinchonine and cinchonidine tosylates react in the presence of salicylic acid under controlled microwave heating. On the basis of X-ray structure of the new alkene product, the stereoselective syn-E2 quinuclidine ring opening process, competing to the SN2 hydrolysis is postulated for this transformation. © ARKAT-USA, Inc.