Nimmo Alastair J, Goodfellow Alister S, Guntley Jacob T, McKay Aidan P, Cordes David B, Bühl Michael, Smith Andrew D
EaStCHEM, School of Chemistry, University of St Andrews Fife KY16 9ST UK
Chem Sci. 2025 Apr 30. doi: 10.1039/d5sc02435h.
Symmetrical and unsymmetrical thioureas, as well as unsymmetrical selenoureas, are used in an isothiourea-catalysed Michael addition-lactamisation protocol using α,β-unsaturated pentafluorophenyl esters to generate iminothia- and iminoselenazinanone heterocycles with high enantioselectivity (up to 99 : 1 er). The scope and limitations of this process have been widely investigated (40 examples in total) with unsymmetrical thio- and selenoureas containing -substituted -aryl substituents giving atropisomeric products, leading to an effective process for iminothia- and iminoselenazinanones heterocyclic products containing both point and axially chiral stereogenic elements with excellent stereocontrol (up to >95 : 5 dr and 98 : 2 er). Mechanistic investigation showed that (i) the catalytically liberated aryloxide could deprotonate an electron-deficient thiourea; (ii) in the absence of an isothiourea catalyst, this leads to formation of racemic product; (iii) a crossover experiment indicates the reversibility of the thia-Michael addition. Computational analysis has identified the factors leading to enantioselectivity within this process, with stereocontrol arising from the lactamisation step within the catalytic cycle.
对称和不对称硫脲以及不对称硒脲用于异硫脲催化的迈克尔加成-内酰胺化反应中，该反应使用α,β-不饱和五氟苯基酯来生成具有高对映选择性（高达99:1的对映体过量）的亚氨基硫杂和亚氨基硒杂氮杂环丁烷酮杂环。该过程的适用范围和局限性已得到广泛研究（总共40个实例），含对位取代芳基取代基的不对称硫脲和硒脲会生成阻转异构产物，从而形成一种有效方法，用于制备同时含有点手性和轴手性立体中心元素且具有出色立体控制（高达>95:5的非对映体过量和98:2的对映体过量）的亚氨基硫杂和亚氨基硒杂氮杂环丁烷酮杂环产物。机理研究表明：（i）催化释放的芳氧基可以使缺电子硫脲去质子化；（ii）在没有异硫脲催化剂的情况下，这会导致外消旋产物的形成；（iii）交叉实验表明硫杂迈克尔加成反应具有可逆性。计算分析已确定了该过程中导致对映选择性的因素，立体控制源自催化循环中的内酰胺化步骤。
