RESUMO
A biocatalytic approach for the synthesis of metaxalone and its analogues was developed based on the reaction of epoxides and cyanate catalyzed by halohydrin dehalogenase. Gram-scale synthesis of chiral and racemic metaxalone was achieved with 44% (98% ee) and 81% yields, respectively, by protein engineering of the halohydrin dehalogenase HHDHamb from Acidimicrobiia bacterium. Additionally, various metaxalone analogues were synthesized at 28-40% yields (90-99% ee) for chiral forms and 77-92% yields for racemic forms.
Assuntos
Oxazolidinonas , Engenharia de Proteínas , Biocatálise , BactériasRESUMO
Enantiopure ß-nitroalcohols, as an important class of nitro-containing compounds, are essential building blocks in pharmaceutical and organic chemistry, particularly for the synthesis of ß-adrenergic blockers. In this study, we present the successful protein engineering of halohydrin dehalogenase HHDHamb for the enantioselective bio-nitration of various phenyl glycidyl ethers to the corresponding chiral ß-nitroalcohols, using the inexpensive, commercially available, and safer nitrite as a nitrating agent. The chiral (R)- and (S)-1-nitro-3-phenoxypropan-2-ols were synthesized by the several enantiocomplementary HHDHamb variants through the whole-cell biotransformation, which showed good catalytic efficiency (up to 43% isolated yields) and high optical purity (up to >99% ee). In addition, we also demonstrated that the bio-nitration method was able to tolerate the substrate at a high concentration of 1000 mM (150 g/L). Furthermore, representative synthesis of two optically active enantiomers of the ß-adrenergic blocker metoprolol was successfully achieved by utilizing the corresponding chiral ß-nitroalcohols as precursors.
Assuntos
Antagonistas Adrenérgicos beta , Éteres Fenílicos , Antagonistas Adrenérgicos beta/química , Biocatálise , Catálise , EstereoisomerismoRESUMO
Expanding the enzymatic toolbox for the green synthesis of valuable molecules is still of high interest in synthetic chemistry and the pharmaceutical industry. Chiral thiiranes are valuable sulfur-containing heterocyclic compounds, but relevant methods for their enantioselective synthesis are limited. Herein, we report a biocatalytic thionation strategy for the enantioselective synthesis of thiiranes, which was developed based on the halohydrin dehalogenase (HHDH)-catalyzed enantioselective ring-opening reaction of epoxides with thiocyanate and a subsequent nonenzymatic rearrangement process. A novel HHDH was identified and engineered for enantioselective biocatalytic thionation of various aryl- and alkyl-substituted epoxides on a preparative scale, affording the corresponding thiiranes in up to 43 % isolated yield and 98 % ee. Large-scale synthesis and useful transformations of chiral thiiranes were also performed to demonstrate the utility and scalability of the biocatalytic thionation strategy.
Assuntos
Compostos de Epóxi , Compostos de Epóxi/química , Estereoisomerismo , BiocatáliseRESUMO
Systems containing 1-alkyl-3-methylimidazolium chloride ionic liquid and chlorine gas were investigated. Using relativistic density functional theory, we calculated the formation mechanism of trichloride and hydrogen dichloride anions in an Emim(+)Cl(-) + Cl(2) system. Emim(+)Cl(3)(-) forms without energy barriers. The more stable species ClEmim(+)HCl(2)(-) forms through chlorine substitution. Substitution of a H on the imidazolium ring is much easier than substitution on the alkyl side chains. Infrared, Raman, ESI-MS, and (1)H NMR spectra were measured for EmimCl, BmimCl, and DmimCl with and without Cl(2) gas. The coexistence of Cl(3)(-) and HCl(2)(-), as well as chlorine-substituted cations, was confirmed by detection of their spectroscopic signals in the Cl(2) added ionic liquids. Cl substitution appears less serious for cations with longer side chains.