Application of a robustness screen for the evaluation of synthetic organic methodology
Application of a robustness screen for the evaluation of synthetic organic methodology
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DOI：
10.1038/nprot.2014.076
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发表时间：
2014-06-01
期刊：
影响因子：
14.8
通讯作者：
Glorius, Frank
中科院分区：
文献类型：
--
作者：
Collins, Karl D.;Ruehling, Andreas;Glorius, Frank
该方案提供了一种快速方法，用于评估给定的一组反应条件对宽范围的官能团的耐受性，以及官能团对反应条件的稳定性。当考虑在复杂化合物（包括天然产物或生物活性分子）的制备中应用给定的方案时，该信息是非常需要的。通过使用当代Rh（III）催化的C-H活化协议的吲哚衍生物的制备作为一个示范性的例子，在这里，我们描述了一个简单的过程，使用批量反应制备，小规模的平行反应技术，简化的气相色谱（GC）校准技术和GC分析，以快速和具有成本效益的方式进行这种评估。该分析提供了大量官能团和杂环的定量数据，并且它很容易适用于研究选择的结构基序，例如给定医药或农业化学项目或天然产物家族内的常见部分或官能团。根据反应时间，可以在类似于3d的时间内评估20种选定的添加剂加对照，根据反应，实际反应设置和分析需要12-24小时。
T his protocol provides a rapid method for evaluating the tolerance of a given set of reaction conditions to a wide range of functional groups, as well as the stability of functional groups to the reaction conditions. This information is highly desirable when considering the application of a given protocol in the preparation of complex compounds, including natural products or biologically active molecules. By using a contemporary Rh(III)-catalyzed C-H activation protocol for the preparation of indole derivatives as a demonstrative example, here we describe a simple process that uses batch reaction preparation, small-scale parallel reaction techniques, simplified gas chromatography (GC) calibration techniques and GC analysis to undertake this evaluation in a rapid and cost-effective manner. This analysis provides quantitative data for a large number of functional groups and heterocycles, and it is readily adaptable to investigate structural motifs of choice, such as common moieties or functional groups within a given medicinal or agrochemical project or within a family of natural products. Twenty chosen additives plus controls can be evaluated in similar to 3 d depending on the reaction time, with actual reaction setup and analysis taking 12-24 h depending on the reaction.