Optimization of Biocatalysed Kinetic Resolutions in the Synthesis of Some Enantiopure Hydroxy-N-Heterocycles

N-benzyl-3-hydroxypyrrolidine (I) and N-benzyl-3-hydroxypiperidine (II) are valuable intermediates in the synthesis of numerous pharmaceutical active ingredients. Different preparative strategies have been accomplished using stereotechnologies such as for example asymmetric hydrogenation, enantioselective addition of water on suitable unsatured compounds, use of some chiral synthons, kinetic resolution and resolution by diastereoselective crystallization. All these techniques present some advantages, but also one or more drawbacks for a sustainable process; in this communication our research work finalized to optimize biocatalysed kinetic resolutions to obtain these target compounds and some acyl derivatives will be presented. Under the best reaction conditions, both target compounds were obtained with a near theoretically yield (50%) and enantiomeric excess up to 99.5%, determined by HPLC, on chiral stationary phases. Also the inversion of configuration of a wrong enantiomer (S, e.e. >99%) was realized in few steps with about 95% yield and the enantiomeric excess of recovered compound (R) was >95%. Finally preliminary experiments in a semi-continuous process with recycle of used immobilized biocatalyst, at least for five times, seem very encouraging for a sustainable scale up.