Absolute Configuration Determination of Chiral API Molecules by MicroED Analysis of Cocrystal Powders Formed Based on Cocrystal Propensity Prediction Calculations.
Absolute Configuration Determination of Chiral API Molecules by MicroED Analysis of Cocrystal Powders Formed Based on Cocrystal Propensity Prediction Calculations.
复制标题
通过基于共晶倾向预测计算形成的共晶粉末的 MicroED 分析来确定手性 API 分子的绝对构型。
DOI：
10.1002/chem.202203970
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Bruhn,JessicaF
中科院分区：
文献类型：
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作者：
Shah,HarshS;Yuan,Jiuchuang;Xie,Tian;Yang,Zhuocen;Chang,Chao;Greenwell,Chandler;Zeng,Qun;Sun,GuangXu;Read,BrandonN;Wilson,TimothyS;Valle,HenryU;Kuang,Shanming;Wang,Jian;Sekharan,Sivakumar;Bruhn,JessicaF
建立手性活性药物成分（API）的绝对构型非常重要。单晶 X 射线衍射 (scXRD) 传统上是此类分析的首选方法，但 scXRD 需要生长大晶体，这可能具有挑战性。在这里，我们提出了一种不依赖于大晶体生长的确定绝对构型的方法。通过检查用手性探针（小手性化合物，例如氨基酸）形成的微晶体，可以通过微晶电子衍射（MicroED）明确确定绝对构型。我们的简化方法采用三个步骤：（1）虚拟筛选以识别有前途的手性探针，（2）实验共晶筛选和（3）通过 MicroED 和绝对构型分配确定结构。我们成功应用该方法分析了目前市场上的两种手性 API 分子，其中未使用 scXRD 来确定绝对构型。
Establishing the absolute configuration of chiral active pharmaceutical ingredients (APIs) is of great importance. Single crystal X‐ray diffraction (scXRD) has traditionally been the method of choice for such analysis, but scXRD requires the growth of large crystals, which can be challenging. Here, we present a method for determining absolute configuration that does not rely on the growth of large crystals. By examining microcrystals formed with chiral probes (small chiral compounds such as amino acids), absolute configuration can be unambiguously determined by microcrystal electron diffraction (MicroED). Our streamlined method employs three steps: (1) virtual screening to identify promising chiral probes, (2) experimental cocrystal screening and (3) structure determination by MicroED and absolute configuration assignment. We successfully applied this method to analyze two chiral API molecules currently on the market for which scXRD was not used to determine absolute configuration.