Structure-Guided Tuning of a Hydroxynitrile Lyase to Accept Rigid Pharmaco Aldehydes,ACS Catalysis

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Structure-Guided Tuning of a Hydroxynitrile Lyase to Accept Rigid Pharmaco Aldehydes
ACS Catalysis ( IF 11.3 ) Pub Date : 2020-04-28 , DOI: 10.1021/acscatal.0c01103
Yu-Cong Zheng ₁ , Fu-Long Li ₁ , Zuming Lin ₂ , Guo-Qiang Lin _{2,

3} , Ran Hong _{2,

3} , Hui-Lei Yu _{1,

4} , Jian-He Xu _{1,

4}

Affiliation

The chiral vicinal C–O/C–N bifunctional groups generated from enzymatic hydrocyanation represents a useful methodology. However, construction of the pharmacophore of β₂-adrenoreceptor agonists with this method remains a great challenge because of complete racemization of the benzylic alcohol during deprotection of the acetal groups. In this study, structure-guided redesign of a hydroxynitrile lyase originating from Prunus communis (PcHNL5) enables a highly enantioselective hydrocyanation of rigid benzo-ketal aldehyde which was proved to be resistant against racemization during the deprotection step, with dramatically improved productivity (>95% conversion vs <1%). X-ray structure analysis and kinetic study revealed the side chain of L331 tunes the substrate adaptability of bulky and rigid benzo-ketal aldehyde, thereby facilitating the formation of a series of valuable unnatural cyanohydrins in high enantiopurities and good yields. Furthermore, the HNL variant L331A was successfully applied for a gram-scale chemo-enzymatic synthesis of (R)-salmeterol, a long-term β₂-adrenoreceptor agonist, in an optically pure form (>99% ee) with an overall yield of 54%, which is the highest value reported.

中文翻译：

羟基腈裂解酶的结构导向调整，以接受刚性药典醛

由酶促氢氰化作用产生的手性邻位C–O / C–N双官能团代表了一种有用的方法。然而，β的药效建设₂用这种方法肾上腺素受体激动剂残留的缩醛基脱保护过程中，因为苯甲醇的完全外消旋化的一个巨大的挑战。在这项研究中，对来自李属李（Pc）的羟腈裂解酶进行结构指导的重新设计HNL5）可使硬质苯并缩酮醛发生高度对映选择性的氢氰化反应，事实证明该脱苯酮反应过程中的苯并酮缩醛具有抗外消旋作用，生产率大大提高（转化率> 95％，<1％）。X射线结构分析和动力学研究表明，L331的侧链可调节大体积和刚性苯并缩酮醛的底物适应性，从而有助于以高对映体纯度和高收率形成一系列有价值的非天然氰醇。此外，变体HNL L331A被成功地应用于（的克级化学-酶促合成- [R）-salmeterol，长期β ₂肾上腺素受体激动剂，其光学纯形式（> 99％ee）的与总产率54％，是报告的最高值。

更新日期：2020-04-28

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