Enantioselective bifunctional iminophosphorane catalyzed sulfa-Michael addition of alkyl thiols to unactivated β-substituted-α,β-unsaturated esters

Abstract

The highly enantioselective sulfa-Michael addition of alkyl thiols to unactivated β-substituted-α,β-unsaturated esters catalyzed by a bifunctional iminophosphorane (BIMP) organocatalyst is described. The low acidity of the alkyl thiol pro-nucleophiles is overcome by the high Brønsted basicity of the catalyst and the chiral scaffold/thiourea hydrogen-bond donor moiety provides the required enantiofacial discrimination in the addition step. The reaction is broad in scope with respect to the alkyl thiol and β-substituent of the α,β-unsaturated ester, affords sulfa-Michael adducts in excellent yields (up to >99%) and enantioselectivity (up to 97 : 3 er) and can operate down to 1 mol% catalyst loading.

Fig. 1. Bifunctional Brønsted base/H-bond donor organocatalytic SMA to α,β-unsaturated ester derivatives.

Fig. 2. Bifunctional iminophosphorane (BIMP) organocatalysts used in the optimization of the SMA reaction. PMP = p-methoxyphenyl.

Fig. 3. Scope of the SMA of alkyl thiols to β-substituted-α,β-unsaturated esters. Reactions were carried out with 0.20 mmol 2 and 0.60 mmol 3. Yields are isolated yields and enantiomeric ratios were determined by HPLC analysis or GC analysis on a chiral stationary phase. ^aThe reaction was performed at –15 °C. ^bThe reaction was quenched after 96 h. ^cAbsolute configuration of 4n determined by chemical correlation (see ESI†).

Scheme 1. Preparative scale synthesis of 4e.

Scheme 2. Derivatization. (a) TFA, Et₂O, 0 °C to rt, then SOCl₂, MeOH, 0 °C to rt, 78% yield over two steps, 94 : 6 er. (b) m-CPBA, CH₂Cl₂, 0 °C, 2 h, 96% yield, 94 : 6 er. (c) DIBAL-H, THF, –60 °C, 2 h, 93% yield, 93 : 7 er.