Lipase-catalyzed kinetic resolution of racemic 1-heteroarylethanols—experimental and QM/MM study

• Published in: Tetrahedron: asymmetry 2008-08, Vol.19 (15), p.1844-1852
• Main Authors: Toşa, Monica, Pilbák, Sarolta, Moldovan, Paula, Paizs, Csaba, Szatzker, Gábor, Szakács, György, Novák, Lajos, Irimie, Florin-Dan, Poppe, László
• Format: Article
• Language: English
• ISSN: 0957-4166; 1362-511X
• DOI: 10.1016/j.tetasy.2008.07.004

The kinetic resolution of racemic 1-(benzothiazol-2-yl)ethanol rac- 2a, 1-(benzo[ b]thiophen-2-yl)ethanol rac- 2b, 1-(benzo[ b]furan-3-yl)ethanol rac- 2c and 1-(benzo[ b]thiophen-3-yl)ethanol rac- 2d was studied by enantiomer selective acylation catalyzed by a selection of commercially available and in house produced lipases. Alcoholysis of the corresponding racemic acetates rac- 3a– d catalyzed by Candida antarctica lipase B (CaLB) was also investigated. Two racemic 1-heteroarylethanols rac- 2a, b were prepared by addition of the corresponding lithiated heteroarylic compounds 1a, b to acetaldehyde, whereas two others, rac- 2c, d were synthesized by the addition of MeMgI onto the corresponding heteroaryl-carbaldehydes 1c, d. The high enantiomer selectivities of CaLB in the acylation of racemic 1-heteroarylethanols rac- 2a– d allowed the determination of the enantiomeric preference of these enzymatic acetylation reactions by QM/MM [pm3/uff or hf(3-21+g∗∗)/uff] calculations. For acetylation of each of the racemic alcohols rac- 2a– d, four possible tetrahedral intermediate states were compared and analyzed.