An efficient enantioselective synthesis of (R,R)-formoterol, a potent bronchodilator, using lipases

0The potent beta(2)-adrenergic receptor agonist formoterol (R,R)-1 has been obtained in enantiomerically pure form by a convenient chemoenzymatic appr oach by coupling of epoxide (R)-6 with the unprotected primary amine (R)-9. Both chiral precursors have been prepared by enantiodifferentiation proces ses involving Pseudomonas cepacia (lipase PS) and Candida antarctica lipase (CALB), respectively. For the resolution of amine 9, we have found that ut ilization of triethylamine as non-reactive base enhances the reaction rate and the enantioselectivity of the process. The key coupling reaction of (R) -6 and (R)-9 has been conducted through derivatization of the amine with th e labile trimethylsilyl group, which liberates the amino group of the resul ting amino alcohol (R,R)-11 upon column chromatography purification. In thi s way, the overall approach is shorter than others previously described. (C ) 2000 Elsevier Science Ltd. All rights reserved.