Biocatalytic Preparation of Chiral Sulfoxides through Asymmetric Reductive Resolution by Methionine Sulfoxide Reductase A

Abstract

Here we report an environmentally friendly method for the preparation of chiral sulfoxides under high substrate concentration using recombinant methionine sulfoxide reductase A from Pseudomonas monteilii (pmMsrA) as a biocatalyst. Our results show that this enzyme can effectively accomplish the preparation of (R)‐sulfoxides with approximately 50 % yield and 94–99 % enantiomeric excess through asymmetric reductive resolution of racemic sulfoxide. With the establishment of the enzyme regeneration system, the initial substrate concentration could be increased 40–100 times compared to our original report. The (R)‐sulfoxides were obtained with high enantioselectivity under the substrate concentration up to 200 mm (approximately 32 g L−1), representing a quite high substrate concentration in biocatalytic preparation of chiral sulfoxides. Moreover, this system showed fairly good activity and enantioselectivity towards a series of ortho‐ and para‐substituted phenyl methyl sulfoxides under high substrate concentration.

Progress on Biological Activity Study and Enantioselective Synthesis of Sulfoxides

“…之后, Gao 课题组采用此类锰络合物催化剂进行杂 芳基硫醚的不对称氧化, 可以直接得到结构多样的手性 亚砜产物 [124] . Míšek 课题组 [125] 和 Yang 课题组 [126] 采用蛋 体中心(Schemes 16b, iv). 平行动力学拆分策略是利用 两个对映体具有相同的反应速率却具有不同反应位点 的特点, 给出易分离的反应产物(Schemes 16, ii).…”

Unconventional Biocatalytic Approaches to the Synthesis of Chiral Sulfoxides

“…[24] Noteworthy, a highly stereoselective kinetic resolution of racemic alkyl-aryl-sulfoxides using purified MsrA regenerated by the cheap and widely available dithiothreitol (DTT) was achieved, demonstrating that isolated Msrs are equally efficient for the synthesis of chiral sulfoxides. Following this work, Chen and Yang developed a crude pmMsrA-DTT system that could tolerate substrate concentrations up to 200 mM (37 g L À 1 ), [25] and was found to reduce 50 and 200 mM rac-5 in 30 minutes and 4 hours, respectively, retaining > 99 % ee in both cases (Scheme 2). Theoretically, in this system, only 0.5 equivalents of DTT should be necessary, as (R)-5 is only half of the overall amount of rac-5.…”

Sulfoxide Reductases and Applications in Biocatalytic Preparation of Chiral Sulfoxides: A Mini-Review

“…In our previous pm MsrA whole-cell system, the catalytic efficiency also decreased greatly under the substrate concentration higher than 5 mM. Thus, we considered establishing a MsrA enzyme regeneration system to improve the initial substrate concentration ( Peng et al, 2018 ). Based on the catalytic mechanism of MsrA, the 0.6-fold of rac substrate amount of dithiothreitol (DTT) was used as a reductant to regenerate the enzyme after catalysis.…”

“…The ( R )-sulfoxides were obtained with high enantioselectivity ( ee > 99%, E > 200) under the substrate concentration up to 200 mM in 4 h. The substrate tolerance of this system was much better than most reported biocatalytic asymmetric oxidation strategies. Moreover, this system was also capable of preparing ( R )-sulfoxides with substituents at the aromatic ring efficiently ( Peng et al, 2018 ).…”