Sojdak Christopher A, Polefrone David A, Shah Hriday M, Vu Cassandra D, Orzolek Brandon J, Jimenez Antenucci Pedro M, Bush Micah Valadez, Kozlowski Marisa C
Department of Chemistry, Roy and Diana Vagelos Laboratories, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, United States.
ACS Cent Sci. 2025 Feb 14;11(2):272-278. doi: 10.1021/acscentsci.4c01765. eCollection 2025 Feb 26.
C-H functionalization of complex substrates is highly enabling in total synthesis and in the development of late-stage drug candidates. Much work has been dedicated to developing new methods as well as predictive modeling to accelerate route scouting. However, workflows to identify regioisomeric products are arduous, typically requiring chromatographic separation and/or nuclear magnetic resonance spectroscopy analysis. In addition, most reports focus on major products or do not assign regioisomeric products, which biases predictive models constructed from such data. Herein, we present a novel approach to complex reaction analysis utilizing partial deuterium labels, which enables direct product identification via liquid chromatography-mass spectrometry. When combined with spectral deconvolution, the method generates product ratios while circumventing chromatography altogether. Competitive kinetic isotope effects can also be determined. The resultant data are expected to be useful in the construction of predictive models across several dimensions including reaction selectivity, the impact of structure on mechanism, and mass spectral ionization patterns and expedite the identification of drug metabolites.
复杂底物的碳-氢官能化在全合成以及后期药物候选物的开发中具有很强的推动作用。许多工作致力于开发新方法以及预测模型以加速路线筛选。然而，鉴定区域异构体产物的工作流程很艰巨，通常需要色谱分离和/或核磁共振光谱分析。此外，大多数报告关注主要产物或未对区域异构体产物进行归属，这会使基于此类数据构建的预测模型产生偏差。在此，我们提出一种利用部分氘标记进行复杂反应分析的新方法，该方法能够通过液相色谱-质谱直接鉴定产物。与光谱去卷积相结合时，该方法可生成产物比例，同时完全避免了色谱分析。还可以确定竞争动力学同位素效应。预期所得数据将有助于在多个维度构建预测模型，包括反应选择性、结构对机理的影响以及质谱电离模式，并加快药物代谢物的鉴定。
