An efficient synthesis of diltiazem has been developed using dynamic kinetic resolution (DKR) as a key step. The methyl (2S,3S)-2-chloro-3-hydroxy-3-(4-methoxyphenyl)propionate was synthesized from a racemic mixture of a-chloro-b-keto ester, with high anti diastereoselectivity (92%) and enantioselectivity (95%), based on an asymmetric hydrogenation reaction with a chiral ruthenium(II) catalyst, simply prepared by mixing Ru(cod)(2-methylallyl) 2 with the atropisomeric ligand (S)-MeO-BIPHEP. By treatment of this a-chloro-b-hydroxy ester with a base, the corresponding trans methyl glycidate, a key intermediate of diltiazem, was easily obtained.Diltiazem (1), a typical calcium channel blocker, is commonly used for the treatment of angina pectoris and hypertension. 3 Only the (+)-(2S,3S)-isomer among the four possible stereoisomers presents this potent coronary vasodilating activity, therefore diltiazem has been developed and marketed as a single stereoisomer. For its synthesis, many pathways had been investigated and the trans methyl (2R,3S)-3-(4-methoxyphenyl)glycidate (-)-2 was recognized as a practical and efficient intermediate ( Figure 1). A large number of formal synthesis of (-)-2 have been reported using various strategies including asymmetric epoxidations, 4 aldol 5 or Darzens 6 reactions, asymmetric reductions, 7 preferential crystallizations 8 or enzymatic approaches. 9 At the industrial scale, (-)-2 has been prepared by enzymatic resolution of the racemic glycidate (±)-2 based on a lipase-catalyzed enantioselective hydrolysis; 9c however the maximum yield cannot exceed 50%. In spite of all these studies, there is still a need for developing an efficient process for the synthesis of enantiopure (-)-2 in terms of yield, stereoselectivity and amount of chiral material at stake in the key step.In our continuous work on ruthenium-catalyzed asymmetric hydrogenation, 10 and its applications to the synthesis of biologically and industrially relevant molecules, 11 we report in this paper an asymmetric synthesis of diltiazem (1) based on the dynamic kinetic resolution of a racemic a-chloro-b-keto ester. The asymmetric hydrogenation of a-substituted b-keto ester bearing a configurationally labile stereogenic center with chiral Ru(II) catalysts is known to give preferentially one of the four possible diastereoisomers via dynamic kinetic resolution (DKR), 12 under optimized conditions. The selectivity of this DKR has already been studied by Noyori and our group and depends on the nature of the group borne at the a-position and on the reaction conditions. Whereas the hydrogenation of a-acetamido-b-keto esters 13 gave the syn adducts, cyclic a-alkyl-b-keto esters 14,12a,b or g-amino-a-methyl-bketo esters derived from (S)-proline 15 were reduced to the corresponding anti a-substituted b-hydroxy esters. Some preliminary studies on the asymmetric hydrogenation of a-chloro-b-keto esters 16a indicated that the anti diastereoisomer could also be obtained. 16b Therefore, the retrosynthetic plan (Scheme 1) we chose for diltiaz...

An efficient and rapid synthesis of a new class of chiral oxime ethers has been achieved via two-step reaction in which the first step is the reaction of oximes 1a-f with ethyl bromoacetate in the presence of sodium hydride to give oxime ethers 2a-f which are subsequently, in the second step, reacted with different commercially available chiral amines under microwave irradiation conditions to give compounds 3a-l in good to excellent yields. Through this method, we have observed a decrease in reaction time and excellent yields than the previously described conventional method.

1,3-dipolar cycloaddition of arylnitrile oxides with allyl ester prepared from eugenol afforded new chiral isoxazolines in good yields. The chemical structure of this compounds was characterized by 1H NMR,13C NMR, 2D NMR and TOF-MS analysis. All the cycloadducts were obtained through a regiospecific and stereospecific pathway and all cases, only one isomer was isolated, as established by unambiguous NMR analysis