Large-Scale Synthesis of Enantio- and Diastereomerically Pure (R,R)-Formoterol

( R, R )-Formoterol ( 1 ) is a long-acting, very potent β 2 -agonist, which is used as a bronchodilator in the therapy of asthma and chronic bronchitis. Highly convergent synthesis of enantio- and diastereomerically pure ( R, R )-formoterol fumarate is achieved by a chromatography-free process with an overall yield of 44%. Asymmetric catalytic reduction of bromoketone 4 using as catalyst oxazaborolidine derived from (1 R, 2 S )-1-amino-2-indanol and resolution of chiral amine 3 are the origins of chirality in this process. Further enrichment of enantio- and diastereomeric purity is accomplished by crystallizations of the isolated intermediates throughout the process to give ( R, R )-formoterol ( 1) as the pure stereoisomer (ee, de >99.5%).