Comparative study of conformational effects on stereoselective lipase catalysed acetylation of sec hydroxy groups in diastereomeric 14-membered lactones and their acyclic analogs

Stereoselective acetylation of sec hydroxy groups in a diastereomeric (1:1) mixture of macrocyclic lactones 14, 15, catalysed by seven microbial lipases in n-heptane afforded the C(7)-O-acetyl derivative 17 with up to 99% diastereomeric excess (d.e.), whereas acetylation of their acyclic analogs 10, 11 afforded C(5)-O-acetyl derivative 13 with up to 93% d.e. Six lipases, from Pseudomonas cepacia (PCL), Pseudomonas fluorescens (PFL), Geotrichum candidum (GCL), Candida cylindracea (CCL) and Pseudomonas cepacia immobilised on ceramics (PS-C) predominantly acetylate cyclic diastereomer (3S,7S)-15 to (3S,7S)-17; only Candida antarctica-B (CAL-B) lipase predominantly acetylates (3S,7R)-14 to (3S,7R)-16. With acyclic analogs 10, 11 the same set of lipases exhibited different diastereoselective bias; CAL-B, GCL and CCL predominantly acylate (1S,5S)-11 to (1S,5S)-13, whereas PCL, PS-C, PFL and PSL acylate predominantly (1S,5R)-10 to (1S,5R)-12. Only GCL exhibited higher stereoselectivity for an acyclic pair of stereoisomers with higher conformational flexibility, over cyclic diastereomeric substrates with a conformationally restricted macrocyclic ring. The preference of PCL for macrocyclic substrates is particularly interesting, in view of the recently suggested binding mode of a series of acyclic sec alcohols in the extended conformation.