State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin, 300071, China.
Nat Commun. 2023 Jun 7;14(1):3326. doi: 10.1038/s41467-023-38741-w.
Control of the regioselectivity of α-alkylation of carbonyl compounds is a longstanding topic of research in organic chemistry. By using stoichiometric bulky strong bases and carefully adjusting the reaction conditions, selective alkylation of unsymmetrical ketones at less-hindered α-sites has been achieved. In contrast, selective alkylation of such ketones at more-hindered α-sites remains a persistent challenge. Here we report a nickel-catalysed alkylation of unsymmetrical ketones at the more-hindered α-sites with allylic alcohols. Our results indicate that the space-constrained nickel catalyst bearing a bulky biphenyl diphosphine ligand enables the preferential alkylation of the more-substituted enolate over the less-substituted enolate and reverses the conventional regioselectivity of ketone α-alkylation. The reactions proceed under neutral conditions in the absence of additives, and water is the only byproduct. The method has a broad substrate scope and permits late-stage modification of ketone-containing natural products and bioactive compounds.
羰基化合物的α-烷基化反应的区域选择性控制是有机化学中一个长期存在的研究课题。通过使用等摩尔的大位阻强碱，并仔细调节反应条件，可以实现不对称酮在非位阻较大的α-位的选择性烷基化。相比之下，这种酮在位阻较大的α-位的选择性烷基化仍然是一个持续存在的挑战。在这里，我们报道了镍催化的不对称酮与烯丙醇在更位阻较大的α-位的烷基化反应。我们的结果表明，带有大位阻联苯双膦配体的空间受限镍催化剂能够使取代程度较大的烯醇盐优先于取代程度较小的烯醇盐进行烷基化，从而反转了酮α-烷基化的传统区域选择性。反应在中性条件下进行，无需添加助剂，水是唯一的副产物。该方法具有广泛的底物范围，并允许对含酮的天然产物和生物活性化合物进行后期修饰。
