A practical chemoenzymatic process to access (R)-quinuclidin-3-ol on scale

Abstract (±)-3-Butyryloxyquinuclidinium butyrate 6 (2 M, 571 g/L), prepared from (±)-quinuclidin-3-ol 1 and butyric anhydride, undergoes enantioselective hydrolysis by an Aspergillus melleus protease {1.0% (w/v)} in water in the presence of Ca(OH) 2 to keep the reaction at pH 7 and trap butyric acid that is introduced as part of (±)- 6 and generated by the enzymatic hydrolysis. After a 24 h period, extraction with n -heptane provides ( R )-quinuclidin-3-yl butyrate 5a , which, on methanolysis with Na 2 CO 3 , is converted into ( R )- 1 , a common pharmacophore of neuromodulators acting on muscarinic receptors, in 96% ee and 42% overall yield from (±)- 1 . The unwanted antipode ( S )- 1 , which is extracted into n -butanol and purified via its hydrochloride salt in 89% ee and 40% overall yield from (±)- 1 , can be racemized by the catalysis of Raney Co at 140°C under an atmosphere of H 2 (5 kg/cm 2 ) to regenerate (±)- 1 in 97% yield.