Preparation of novel meta and para substituted N-benzyl protected quinuclidine esters and their resolution with butyrylcholinesterase

Since the optically active quinuclidin-3-ol is an important intermediate in the preparation of physiologically or pharmacologically active compounds, new biocatalytic method for the efficient production of chiral quinuclidin-3-ols was examined. Butyrylcholinesterase (BChE; EC 3.1.1.8) was chosen as a biocatalyst in a preparative kinetic resolution of enantiomers. [1-3] In this study a series of racemic, (R)- and (S)- esters of quinuclidin-3-ol and acetic, benzoic, phthalic and succinic acids were synthesized as well as their racemic and chiral, quaternary N-benzyl, meta and para N-bromobenzyl and meta and para N-methylbenzyl derivatives. After the resolution, all N-benzyl protected groups were successfully removed by catalytic transfer hydrogenation with ammonium formate (10% Pd-C). The stereoselectivity of hydrolysis with horse serum BChE was investigated. The rates of hydrolyses were monitored at 37 ^oC in 0.1 M phosphate buffer pH 7.4 (2 mM concentrations of racemic esters). Hydrolyses studies confirmed [3] that all (R)-enantiomers of prepared esters are much better substrates than (S)-enantiomers. In the case of N-benzyl protected esters, the difference for all prepared esters was even more pronounced. Introduction of bromine atom or methyl group in the meta or para position on the phenyl ring of benzyl moiety resulted in a remarkable improvement of the stereoselectivity: (R)-acetates and (S)-alcohols were isolated in a high optical purity (> 95 %). Thus, optically pure quinuclidin-3-ols can be prepared in the high yields and enantiopurity by the esterification, quarternization with benzyl bromide, BChE-catalysed hydrolysis and finally catalytic transfer hydrogenation. [1] Ines Primozic, Tomica Hrenar, Srdjanka Tomic and Zlatko Meic, Journal of Physical Organic Chemistry 15 (2002) 608-614. [2] Ines Primozic, Tomica Hrenar, Srdjanka Tomic and Zlatko Meic, European Journal of Organic Chemistry (2003) 295-301. [3] Ines Primozic, and Srdjanka Tomic, Croatica Chemica Acta 84 (2011) 245-249.