13692-14-3Relevant articles and documents
Lipase mediated enzymatic kinetic resolution of phenylethyl halohydrins acetates: A case of study and rationalization
Fonseca, Thiago de Sousa,Vega, Kimberly Benedetti,da Silva, Marcos Reinaldo,de Oliveira, Maria da Concei??o Ferreira,de Lemos, Telma Leda Gomes,Contente, Martina Letizia,Molinari, Francesco,Cespugli, Marco,Fortuna, Sara,Gardossi, Lucia,de Mattos, Marcos Carlos
, (2020/02/18)
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 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.
Synthesis of Conformationally Locked and C-Linked Analogues of Imidazole-Based Ketene Dithioacetal Fungicides
Gagnepain, Julien,Jeanmart, Stephane,Bonvalot, Damien,Jacob, Olivier,Lamberth, Clemens
supporting information, p. 59 - 62 (2019/01/04)
First examples with the unknown tricyclic 4,8 b -dihydro-3 aH -indeno[1,2- d ][1,3]dithiole ring system have been prepared. Also, imidazoles linked in ring position 5 to a ketene dithioacetal and 1,3-dithiane derivatives with an exocyclic cyano- and imidazole-substituted C-C double bond are completely new. All these compounds are either conformationally locked, C-linked or six-ring analogues of the antifungal agent luliconazole. Synthesis and fungicidal activity of these sterol biosynthesis inhibitors are reported.
Chemoenzymatic Synthesis of Luliconazole Mediated by Lipases
Fonseca, Thiago de S.,Lima, Lara D.,de Oliveira, Maria da C. F.,de Lemos, Telma L. G.,Zampieri, Davila,Molinari, Francesco,de Mattos, Marcos C.
, p. 2110 - 2116 (2018/05/31)
A straightforward chemoenzymatic synthesis of luliconazole has been developed. The key step involved the preparation of the enantiomerically pure β-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. The latter enzyme proved to be a robust biocatalyst for the kinetic resolution, and the (S)-β-halohydrin was obtained with high selectivity (ee > 99 %, E > 200) after just 15 min, at 45 °C. It could be reused five times with maintenance of high values of both conversion and enantioselectivity. Subsequently, the (S)-β-halohydrin was subjected to a mesylation reaction; the mesylated derivative reacted with 1-cyanomethylimidazole in the presence of CS2 to give luliconazole in 43 % yield with >99 % ee.
