Department of Chemistry and Biochemistry, University of Notre Dame, Notre Dame, IN, 46556, USA.
Departament de Química Física i Inorgànica, Universitat Rovira I Virgili, C/Marcel·li Domingo, 43007, Tarragona, Spain.
Nat Commun. 2021 Nov 18;12(1):6719. doi: 10.1038/s41467-021-27065-2.
The palladium-catalyzed enantioselective allylic substitution by carbon or nitrogen nucleophiles is a key transformation that is particularly useful for the synthesis of bioactive compounds. Unfortunately, the selection of a suitable ligand/substrate combination often requires significant screening effort. Here, we show that a transition state force field (TSFF) derived by the quantum-guided molecular mechanics (Q2MM) method can be used to rapidly screen ligand/substrate combinations. Testing of this method on 77 literature reactions revealed several cases where the computationally predicted major enantiomer differed from the one reported. Interestingly, experimental follow-up led to a reassignment of the experimentally observed configuration. This result demonstrates the power of mechanistically based methods to predict and, where necessary, correct the stereochemical outcome.
钯催化的对映选择性烯丙基取代反应由碳或氮亲核试剂进行，这是一种关键的转化，对于生物活性化合物的合成特别有用。不幸的是，合适的配体/底物组合的选择通常需要大量的筛选工作。在这里，我们表明，通过量子引导分子力学（Q2MM）方法得到的过渡态力场（TSFF）可用于快速筛选配体/底物组合。该方法在 77 个文献反应中的测试表明，在几种情况下，计算预测的主要对映异构体与报告的对映异构体不同。有趣的是，实验后续工作导致对实验观察到的构型进行重新分配。这一结果证明了基于机理的方法在预测和必要时纠正立体化学结果方面的强大功能。
