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 we want to present our research work (1) finalized to optimize known (2) biocatalysed kinetic resolutions, through the hydrolysis of some acyl derivatives of compounds I and II. Investigated variables of this process were : nature of solvents, type of commercially available free or immobilized biocatalysts, ratio (w/w) between substrate and catalyst amounts, length of acyl chain. Furthermore, preliminary attempts to invert configuration of the wrong enantiomer were also performed and will be here discussed.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.
|Titolo:||Optimization of Biocatalysed Kinetic Resolutions in the Synthesis of Some Enantiopure Hydroxy-N-Heterocycles|
|Anno del prodotto:||2013|
|Appare nelle tipologie:||4.1 Contributo in Atti di convegno|