Greenhalgh Mark D, Qu Shen, Slawin Alexandra M Z, Smith Andrew D
EaStCHEM , School of Chemistry , University of St Andrews , North Haugh , St Andrews KY16 9ST , UK . Email:
Chem Sci. 2018 May 4;9(21):4909-4918. doi: 10.1039/c8sc01324a. eCollection 2018 Jun 7.
An isothiourea-catalysed Michael addition-annulation process using β-fluoroalkyl-substituted α,β-unsaturated aryl esters and a range of 2-acylbenzazoles is reported for the enantioselective synthesis of dihydropyranone and dihydropyridinone products bearing polyfluorinated stereocenters (29 examples, up to 98% yield, >99 : 1 er). The choice of aryl group of the aryl ester proved essential in determining reaction enantioselectivity and dihydropyranone : dihydropyridinone product selectivity. The aryloxide leaving group is shown to play a number of essential additional roles, operating (i) as a Brønsted base, circumventing the need for an auxiliary base; and (ii) as a Lewis base to catalyse the isomerisation of dihydropyranone products into thermodynamically-favoured dihydropyridinones. After optimisation, this isomerisation process was exploited for the selective synthesis of dihydropyridinone products using acylbenzothiazoles, and either dihydropyranone or dihydropyridinone products using acylbenzoxazoles. Finally, the phenol derivative, produced following protonation of the aryloxide, is proposed to act as a Brønsted acid, which promotes an isothiourea-catalysed kinetic resolution of benzoxazole-derived dihydropyranones.
报道了一种异硫脲催化的迈克尔加成-环化反应，该反应使用β-氟烷基取代的α,β-不饱和芳基酯和一系列2-酰基苯并唑，用于对映选择性合成带有多氟立体中心的二氢吡喃酮和二氢吡啶酮产物（29个实例，产率高达98%，对映体比例>99:1）。芳基酯的芳基选择对于确定反应对映选择性和二氢吡喃酮:二氢吡啶酮产物选择性至关重要。芳氧基离去基团显示出许多重要的额外作用，其作用如下：(i)作为布朗斯特碱，无需辅助碱；(ii)作为路易斯碱催化二氢吡喃酮产物异构化为热力学上更有利的二氢吡啶酮。优化后，利用这种异构化过程，使用酰基苯并噻唑选择性合成二氢吡啶酮产物，使用酰基苯并恶唑选择性合成二氢吡喃酮或二氢吡啶酮产物。最后，芳氧基质子化后生成的酚衍生物被认为可作为布朗斯特酸，促进异硫脲催化的苯并恶唑衍生二氢吡喃酮的动力学拆分。
