Dalton Derek M, Walroth Richard C, Rouget-Virbel Caroline, Mack Kyle A, Toste F Dean
Department of Synthetic Molecule Process Chemistry, Genentech, Inc., South San Francisco, California 94080, United States.
Department of Chemistry, University of California, Berkeley, California 94720, United States.
J Am Chem Soc. 2024 Jun 12;146(23):15779-15786. doi: 10.1021/jacs.4c01616. Epub 2024 May 28.
Utopia Point Bayesian Optimization (UPBO) was used to identify reaction conditions that are highly selective for the formation of N1 and N2-methyl-3-aryl pyrazole constitutional isomers. UPBO was used to explore a wide chemical space and identify basic reaction conditions for a typically acid-catalyzed Knorr pyrazole condensation. These studies revealed that selectivity in the reaction stems from a condition-dependent equilibrium of intermediates prior to dehydration. For the N2-methyl isomer reaction pathway, a hemiaminal intermediate was found to form reversibly under the reaction conditions, enabling a highly selective synthesis of the N2 isomer upon dehydrative workup. UPBO was able to successfully optimize conversion and selectivity simultaneously with search spaces of >1 million potential variable combinations without the need for high-performance computational resources.
乌托邦点贝叶斯优化（UPBO）被用于确定对N1和N2-甲基-3-芳基吡唑结构异构体形成具有高度选择性的反应条件。UPBO被用于探索广阔的化学空间，并确定典型酸催化的诺尔吡唑缩合反应的基本反应条件。这些研究表明，反应中的选择性源于脱水前中间体的条件依赖性平衡。对于N2-甲基异构体反应途径，发现半缩醛胺中间体在反应条件下可逆形成，从而在脱水后处理时能够高度选择性地合成N2异构体。UPBO能够在超过100万个潜在变量组合的搜索空间中同时成功优化转化率和选择性，而无需高性能计算资源。
