Chemoenzymatic Synthesis of Luliconazole Mediated by Lipases

A straightforward chemoenzymatic synthesis of luli- conazole has been developed. The key step involved the preparation of the enantiomerically pure beta-halohydrin (1S)-2-chloro- 1-(2,4-dichlorophenyl)-1-ethanol through kinetic resolution of the corresponding racemic acetate. This was achieved by a hydrolytic approach, mediated by the lipase from Thermomyces lanuginosus or Novozym 435\uae. The latter enzyme proved to be a robust biocatalyst for the kinetic resolution, and the halohydrin was obtained with high selectivity (ee > 99%, E > 200) after just 15 min, at 45 \ub0C. It could be reused five times with maintenance of high values of both conversion and enantioselectivity. Subsequently, the (S)-beta-halohydrin was sub- jected to a mesylation reaction; the mesylated derivative re- acted with 1-cyanomethylimidazole in the presence of CS2 to give luliconazole in 43 % yield with >99 % ee

Lipase mediated enzymatic kinetic resolution of phenylethyl halohydrins acetates: A case of study and rationalization

Racemic phenylethyl halohydrins acetates containing several groups attached to the aromatic ring were resolved via hydrolysis reaction in the presence of lipase B from Candida antarctica (Novozym\uae 435). In all cases, the kinetic resolution was highly selective (E > 200) leading to the corresponding (S)-\u3b2-halohydrin with ee > 99 %. However, the time required for an ideal 50 % conversion ranged from 15 min for 2,4-dichlorophenyl chlorohydrin acetate to 216 h for 2-chlorophenyl bromohydrin acetate. Six chlorohydrins and five bromohydrins were evaluated, the latter being less reactive. For the \u3b2-brominated substrates, steric hindrance on the aromatic ring played a crucial role, which was not observed for the \u3b2-chlorinated derivatives. To shed light on the different reaction rates, docking studies were carried out with all the substrates using MD simulations. The computational data obtained for the \u3b2-brominated substrates, based on the parameters analysed such as NAC (near attack conformation), distance between Ser-O and carbonyl-C and oxyanion site stabilization were in agreement with the experimental results. On the other hand, the data obtained for \u3b2-chlorinated substrates suggested that physical aspects such as high hydrophobicity or induced change in the conformation of the enzymatic active site are more relevant aspects when compared to steric hindrance effects

Lipase mediated enzymatic kinetic resolution of phenylethyl halohydrins acetates: A case of study and rationalization

11siRacemic phenylethyl halohydrins acetates containing several groups attached to the aromatic ring were resolved via hydrolysis reaction in the presence of lipase B from Candida antarctica (Novozym® 435). In all cases, the kinetic resolution was highly selective (E>200) leading to the corresponding (S)-β-halohydrin with ee>99 %. However, the time required for an ideal 50 % conversion ranged from 15 min for 2,4-dichlorophenyl chlorohydrin acetate to 216 h for 2-chlorophenyl bromohydrin acetate. Six chlorohydrins and five bromohydrins were evaluated, the latter being less reactive. For the β-brominated substrates, steric hindrance on the aromatic ring played a crucial role, which was not observed for the β-chlorinated derivatives. To shed light on the different reaction rates, docking studies were carried out with all the substrates using MD simulations. The computational data obtained for the β-brominated substrates, based on the parameters analysed such as NAC (near attack conformation), distance between Ser-O and carbonyl-C and oxyanion site stabilization were in agreement with the experimental results. On the other hand, the data obtained for β-chlorinated substrates suggested that physical aspects such as high hydrophobicity or induced change in the conformation of the enzymatic active site are more relevant aspects when compared to steric hindrance effects.partially_openopenThiago de Sousa Fonseca, Kimberly Benedetti Vega, Marcos Reinaldo da Silva, Maria da Conceição Ferreira de Oliveira, Telma Leda Gomes de Lemosa, Martina Letizia Contenteb, Francesco Molinari, Marco Cespugli, Sara Fortuna, Lucia Gardossi, Marcos Carlos de Mattos,de Sousa Fonseca, Thiago; Benedetti Vega, Kimberly; Reinaldo da Silva, Marcos; da Conceição Ferreira de Oliveira, Maria; Leda Gomes de Lemosa, Telma; Letizia Contenteb, Martina; Molinari, Francesco; Cespugli, Marco; Fortuna, Sara; Gardossi, Lucia; Carlos de Mattos, Marco