Chiral derivatives of γ-aminobutyric acid are widely used as medicines and can be obtained by organocatalytic Michael additions. We show here the stereoselective synthesis of 4-methylpregabalin stereoisomers using a Michael addition of dimethyl malonate to a racemic nitroalkene. The key step of the synthesis operates as a kinetic resolution with a chiral squaramide catalyst. Furthermore, specific organocatalysts can provide respective stereoisomers of the key Michael adduct in up to 99:1 er.
Enantioselective organocatalytic Michael additions serve as the key step in syntheses of chiral drugs based on γ-aminobutyric acid. The applicability of various squaramide catalysts for these Michael-type reactions has been assessed. Very good results in terms both activity and enantioselectivity were obtained in the Michael addition of dimethyl malonate to β-nitrostyrenes. On the other hand, a complementary approach, the addition of nitromethane to cinnamaldehydes, worked well with a squaramide catalyst possessing an adjacent pyrrolidine moiety. The corresponding Michael adducts obtained in the best conditions are suitable chiral intermediates for the synthesis of therapeutically useful GABA derivatives. Polymer-immobilized squaramides afforded the Michael adduct in high enantiomeric purity, but yield deterioration was observed between runs. Two different formal total syntheses of baclofen have also been accomplished.
Abstract This work describes the enantioselective synthesis of chiral 2,3‐dihydrofurocoumarins by squaramide‐catalyzed Michael addition of 4‐hydroxycoumarins to β‐nitrostyrenes, followed by a cyclization reaction. A coumarin moiety is present in many chiral bioactive compounds, but the organocatalysis has still not reached its full potential in the synthesis of chiral coumarins. Here, we used squaramide catalysts comprising two chiral units, ( S )‐phenylethylamine and cyclohexane‐1,2‐diamine. These catalysts showed high reactivity and enantioselectivity in this transformation. Following this procedure, we prepared a series of 2,3‐dihydrofurocoumarin derivatives in 47‐93% yields and enantiomeric purities in the range of 78‐94% ee. Polystyrene‐immobilized squaramide catalyst performed well for the initial two reaction cycles but then slowly degraded. The absolute configuration of 2,3‐dihydrofurocoumarin products was determined by the comparison of the experimental and density functional theory‐calculated electronic circular dichroism spectra.
Asymmetric organocatalytic 1,4-additions provide access to a large number of biologically relevant compounds. Chiral squaramides efficiently catalyse enantioselective Michael addition of 1,3-dicarbonyl compounds to aliphatic nitroalkenes. The resulting γ-nitro carboxylic derivatives were obtained in high yields and in high enantiomeric purities. Quantum chemical calculations helped us to devise a transition state model, which explains the observed stereochemical course of the addition. The best results were obtained with Meldrum's acid as a donor, with which enantiomeric purity of the Michael adduct was 97 : 3 e.r. Using this methodology pregabalin was synthesized in three steps in overall 52% yield.
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