两种酯酶依次拆分 (S) 和 (R)-6-fluoro-chroman-2-carboxy 酸,Green Chemistry

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两种酯酶依次拆分 (S) 和 (R)-6-fluoro-chroman-2-carboxy 酸
Green Chemistry ( IF 9.3 ) Pub Date : 2022-03-14 , DOI: 10.1039/d1gc04512a
Min Jiang ₁ , Yong-Jun Liu ₁ , Guo-Song Liu ₁ , Wei Zhou ₁ , Ya-Ling Shen ₁ , Bei Gao ₁ , Feng-Qing Wang ₁ , Dong-Zhi Wei ₁

Affiliation

具有 ( S ) 和 ( R )-构型的光学纯 6-氟-色满-2-羧酸 (FCCA)是制药行业的关键手性构件。迄今为止，( S )和( R )-FCCA的生产主要依靠化学拆分，这是一个复杂、低收率和高污染的过程。在这里，我们提出了一种实用的 FCCA 酶拆分方法，该方法基于从 Geobacillus thermocatenulatus 中分离出来的两种酯酶 EstS 和EstR。使用外消旋的 6-氟-色满-2-羧酸甲酯 (MFCC) 作为水-甲苯双相体系中的底物，( S ) 和 ( R)-FCCAs 由 EstS 和 EstR 催化产生，对映体过量 (ee) 值分别 > 99% 和 95-96%，并且通过分子模拟揭示了高度对映选择性机制。为了简化拆分过程并提高生产力，我们进一步设计了一种创新的方法，用于固定化细胞的 MFCC 的“连续双相批量拆分”。每批只需要更换水相，依次更换EstS或EstR的固定化细胞，依次回收光学纯的FCCA，而有机相保留，每两批后继续补充MFCC。在这项研究中，进行了 10 批顺序分离，229.3 mM ( S )-FCCA 具有 96.9% ee，和 224.1 mM ( R)-FCCA 在 40 小时内获得 99.1% ee，总摩尔产率为 93.5%。这是首次报道的 FCCA 酶拆分技术，与那些化学拆分方法相比具有显着优势。

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Sequential resolution of (S) and (R)-6-fluoro-chroman-2-carboxylic acid by two esterases in turn

Optically pure 6-fluoro-chroman-2-carboxylic acids (FCCAs), with (S) and (R)-configurations, are pivotal chiral building blocks in the pharmaceutical industry. To date, the production of (S) and (R)-FCCAs mainly depends on chemical resolution, which is a complex, low yield, and highly polluting process. Here, we present a practical enzymatic resolution method of FCCAs based on two esterases, EstS and EstR, isolated from Geobacillus thermocatenulatus. Using the racemic methyl 6-fluoro-chroman-2-carboxylate (MFCC) as the substrate in an aqueous–toluene biphasic system, (S) and (R)-FCCAs were produced by EstS and EstR catalysis with an enantiomeric excess (ee) value >99% and 95–96%, respectively, and the highly enantioselective mechanisms were revealed by molecular simulations. To simplify the resolution process and enhance the productivity, we further designed an innovative methodology for the “sequential biphasic batch resolution” of MFCC with immobilized cells. In each batch, only the aqueous phase needs to be replaced to sequentially change the immobilized cells of EstS or EstR and recover optically pure FCCAs in turn, while the organic phase was retained and MFCC was continually supplemented after every two batches. In this study, ten batches of sequential resolution were performed, and 229.3 mM (S)-FCCAs with 96.9% ee, and 224.1 mM (R)-FCCAs with 99.1% ee were obtained in 40 h, affording a 93.5% total mole yield. This is the first reported enzymatic resolution technique of FCCAs, and represents significant advantages over those chemical resolution methods.

更新日期：2022-03-14

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