Wang Gang, Chen Tian, Jia Kuiyong, Ma Wencheng, Tung Chen-Ho, Liu Lei
School of Chemistry and Chemical Engineering, Shandong University, Jinan 250100, China.
School of Pharmaceutical Sciences & Institute of Materia Medica, Shandong First Medical University, Jinan 250117, China.
J Am Chem Soc. 2023 Oct 11;145(40):22276-22283. doi: 10.1021/jacs.3c09172. Epub 2023 Sep 29.
Chiral hydroxylamines are increasingly common structural elements in pharmaceuticals and agrochemicals, but their asymmetric synthesis remains challenging. Although enantioselective oxidation is the most straightforward method to prepare chiral oxides with a higher oxidation state, asymmetric and even nonasymmetric amine oxidation to hydroxylamines has been poorly addressed. We report a titanium-catalyzed asymmetric oxidation of racemic amines providing a broad range of structurally diverse chiral hydroxylamines with excellent chemo- and enantioselectivity. Notably, hydroxylamines bearing diverse substituent patterns on the stereocenters, including α,α-ester-alkyl, α,α-amide-alkyl, α,α-aryl-alkyl, α,α-alkynyl-alkyl, and α,α-dialkyl, are well tolerated with good functional group compatibility. Catalyst turnover numbers up to 5000 and selectivity factors up to 278 are observed. This finding offers a democratized platform to chiral hydroxylamines as design elements for drug discovery and provides insights into metal-catalyzed asymmetric oxidation of challenging substrates.
手性羟胺在药物和农用化学品中是越来越常见的结构单元，但其不对称合成仍然具有挑战性。尽管对映选择性氧化是制备具有较高氧化态的手性氧化物最直接的方法，但不对称甚至非不对称的胺氧化为羟胺的研究却很少。我们报道了一种钛催化的外消旋胺的不对称氧化反应，该反应能提供一系列结构多样的手性羟胺，具有优异的化学选择性和对映选择性。值得注意的是，在手性中心带有不同取代基模式的羟胺，包括α,α-酯基-烷基、α,α-酰胺基-烷基、α,α-芳基-烷基、α,α-炔基-烷基和α,α-二烷基，都具有良好的官能团兼容性。观察到催化剂的周转数高达5000，选择性因子高达278。这一发现为手性羟胺作为药物发现的设计元素提供了一个通用平台，并为具有挑战性的底物的金属催化不对称氧化提供了见解。
