Zhu Haoxiang, Manchado Alejandro, Omar Farah Abdikani, McKay Aidan P, Cordes David B, Cheong Paul Ha-Yeon, Kasten Kevin, Smith Andrew D
EaStCHEM, School of Chemistry, University of St Andrews, St Andrews, Fife, KY16 9ST, UK.
Departamento de Química Orgánica, Facultad de Ciencias Químicas, Universidad de Salamanca, Plaza de los Caídos 1-5, 37008, Salamanca, Spain.
Angew Chem Int Ed Engl. 2024 Sep 9;63(37):e202402908. doi: 10.1002/anie.202402908. Epub 2024 Aug 6.
The development of methods to allow the selective acylative dynamic kinetic resolution (DKR) of tetra-substituted lactols is a recognised synthetic challenge. In this manuscript, a highly enantioselective isothiourea-catalysed acylative DKR of tetra-substituted morpholinone and benzoxazinone-derived lactols is reported. The scope and limitations of this methodology have been developed, with high enantioselectivity and good to excellent yields (up to 89 %, 99 : 1 er) observed across a broad range of substrate derivatives incorporating substitution at N(4) and C(2), di- and spirocyclic substitution at C(5) and C(6), as well as benzannulation (>35 examples in total). The DKR process is amenable to scale-up on a 1 g laboratory scale. The factors leading to high selectivity in this DKR process have been probed through computation, with an N-C=O⋅⋅⋅isothiouronium interaction identified as key to producing ester products in highly enantioenriched form.
开发能够实现四取代乳糖醇选择性酰化动态动力学拆分（DKR）的方法是一项公认的合成挑战。本文报道了一种高度对映选择性的异硫脲催化的四取代吗啉酮和苯并恶嗪酮衍生乳糖醇的酰化DKR。已拓展了该方法的适用范围和局限性，在一系列包含N(4)和C(2)位取代、C(5)和C(6)位的二环和螺环取代以及苯并环化的底物衍生物中均观察到了高对映选择性和良好至优异的产率（高达89%，对映体比例为99:1）（总共超过35个实例）。该DKR过程适合在1 g实验室规模上进行放大。通过计算探究了该DKR过程中导致高选择性的因素，确定N-C=O···异硫脲鎓相互作用是生成高对映体富集形式酯产物的关键。
