Asymmetric Formal Synthesis of (-)-Formoterol and (-)-Tamsulosin

Biologically important (2R)-2-amino-3-phenylpropanes consisted in commercial drugs including (R,R)-formoterol, and (R)-tamsulosin were prepared from chiral (2R)-aziridine-2-carboxylate without any chromatographic separation.Key reactions include regio-and stereoselective ring opening reaction of aziridin-2-yl-phenylmethanol and subsequent cyclization toward enantiopure 4,5-disubastitued oxazolidin-2-ones as synthetic intermediates.Synthesis of amine-containing chiral drugs is always an important subject not only for the industrial interest but for the biological evaluation of each enantiomers. 1Recently asymmetric synthesis of formoterol, β2-adrenoreceptor agonist to treat asthma and other bronchospastic conditions, attracts attention to find out the most active stereoisomer that was identified to be R of both stereocenters. 2 Its synthesis can achieve at ease from (2R)-2-amino-3-(4-methoxyphenyl)propane (1) and chiral epoxide. 3Similar compound (2R)-2-amino-3-(4-methoxy-3-amidosulfonylphenyl)propane (2) consists in tamsulosin, commercial drug for the treatment of benign prostatic hyperplasia by acting on prostatic A1 adrenoceptors. 4 Syntheses of (R,R)-formoterol and (R)-tamsulosin were known to be achieved from chiral amines 1 and 2 respectively by the known methods. 3,5Few methods were reported in the literature obtaining either 1 or 2 in optically pure form.These include separation of enantiomers or diastereomer with semipreparative HPLC and enzymatic resolution with limitation to get large scale of products in both cases. 6Reductive amination of aldehyde with chiral amine is one good way to proceed, but diasteromeric ratio was very poor with less than 50%.