Rapid Enantiomeric Excess Measurements of Enantioisotopomers by Molecular Rotational Resonance Spectroscopy.
Rapid Enantiomeric Excess Measurements of Enantioisotopomers by Molecular Rotational Resonance Spectroscopy.
复制标题
通过分子旋转共振光谱法快速测量对映异构体过量。
DOI：
10.1021/acs.oprd.3c00028
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发表时间：
2023
影响因子：
3.4
通讯作者：
Clark,JosephR
中科院分区：
文献类型：
--
作者：
Sonstrom,ReillyE;Vang,ZouaPa;Scolati,HaleyN;Neill,JustinL;Pate,BrooksH;Clark,JosephR
最近的药物发现工作表明，选择性氘代小分子可以提高活性药物成分的安全性和有效性。这些优点来自于当氘取代在发生速率限制C-H键断裂的结构位置处的氢原子时由动力学同位素效应引起的代谢变化。这一应用推动了合成化学中精确氘代策略的发展，该策略可以以高区域选择性和立体控制安装氘原子。铜催化的烯烃转移氢化氘代化学最近已被证明对在代谢上重要的苄基C-H位置的氘代具有高立体选择性。在这种情况下，立体控制导致产生对映体同位素异构体-仅凭借氘取代而具有手性的分子-并且需要手性分析技术来评估反应选择性。近年来研究表明，手性标记分子旋转共振（MRR）光谱提供了一种测定对映体过量和确定对映异构体绝对构型的常规方法。需要手性标签MRR光谱的高通量实现来支持化学合成的优化。高通量手性分析的测量方法在这项工作中证明。高通量ee测量使用腔增强的MRR光谱，减少测量时间和样品消耗超过一个数量级相比，以前的对映体同位素分析使用宽带MRR光谱仪。它还表明，过渡监测对映异构体可以选择从宽带旋转光谱，而不需要光谱分析。手性标签MRR光谱的一般适用性说明了通过使用一个单一的分子作为标签的手性歧视对6个对映异构体反应产物进行手性分析。
Recent work in drug discovery has shown that selectively deuterated small molecules can improve the safety and efficacy for active pharmaceutical ingredients. The advantages derive from changes in metabolism resulting from the kinetic isotope effect when deuterium is substituted for a hydrogen atom at a structural position where rate limiting C–H bond breaking occurs. This application has pushed the development of precision deuteration strategies in synthetic chemistry that can install deuterium atoms with high regioselectivity and with stereocontrol. Copper-catalyzed alkene transfer hydrodeuteration chemistry has recently been shown to have high stereoselectivity for deuteration at the metabolically important benzyl C–H position. In this case, stereocontrol results in the creation of enantioisotopomers─molecules that are chiral solely by virtue of the deuterium substitution─and chiral analysis techniques are needed to assess the reaction selectivity. It was recently shown that chiral tag molecular rotational resonance (MRR) spectroscopy provides a routine way to measure the enantiomeric excess and establish the absolute configuration of enantioisotopomers. High-throughput implementations of chiral tag MRR spectroscopy are needed to support optimization of the chemical synthesis. A measurement methodology for high-throughput chiral analysis is demonstrated in this work. The high-throughput ee measurements are performed using cavity-enhanced MRR spectroscopy, which reduces measurement times and sample consumption by more than an order-of-magnitude compared to the previous enantioisotopomer analysis using a broadband MRR spectrometer. It is also shown that transitions for monitoring the enantiomers can be selected from a broadband rotational spectrum without the need for spectroscopic analysis. The general applicability of chiral tag MRR spectroscopy is illustrated by performing chiral analysis on six enantioisotopomer reaction products using a single molecule as the tag for chiral discrimination.