Multiple roles of aryloxide leaving groups in enantioselective annulations employing α,β-unsaturated acyl ammonium catalysis

Abstract

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.

Scheme 1. Previous uses of aryl ester substrates in NHC and tertiary amine catalysis.

Scheme 2. Isothiourea-catalysed Michael addition–annulation of homoanhydrides with 2-acylbenzazole derivatives.

Fig. 1. Isomerisation of dihydropyranone 11 to dihydropyridinone: (a) general reaction scheme; (b) temporal change in the concentration of 11 under different reaction conditions; (c) proposed mechanism for isomerisation.

Scheme 3. Optimised Michael addition–annulation–isomerisation reaction.

Scheme 4. Proposed mechanism for the kinetic resolution of (±)-50.

Scheme 5. Proposed mechanism and stereochemical rationale.