Applications of Lewis acids for the efficient syntheses of diltiazem, cephems, and taxoids

An efficient method is described for preparation of diltiazem hydrochloride (Herbesser(R)), a marketed calcium antagonist widely used for the treatmen t of ischemic heart disease. In the reaction of 2-nitrothiophenol (1) with trans-3-phenylglycidic esters (2) carrying various substituents on the benz ene ring, both reactivity and stereoselectivity of the oxirane ring opening of the glycidates were markedly influenced by the electronic nature of the substituents. As a result of our investigation on the catalytic effect of various Lewis acids in the reaction of 2a with 1, tin compounds were found to be effective catalysts for the cis-opening and readily produced the thre o-nitro ester (3a-t), a key intermediate for the synthesis of diltiazem. Is olation of the crystalline complex from the reaction of 1 and SnCl4; and it s efficient catalytic activity similar to that of SnCl4 suggests that the t ransition state involves co-coordination of tin derivatives both with 1 and the epoxy oxygen of 2a to result in highly specific cis-opening. We have a lso amplified this chemistry into other fields, leading to applications in the syntheses of cephem and taxoid templates. (C) 2000 John Wiley & Sons, I nc.