Abstract
Numerous cinchona organocatalysts with different substituents at their quinuclidine unit have been described and tested, but the effect of those saturation has not been examined before. This work presents the synthesis of four widely used cinchona-based organocatalyst classes (hydroxy, amino, squaramide, and thiourea) with different saturation on the quinuclidine unit (ethyl, vinyl, ethynyl) started from quinine, the most easily available cinchona derivative. Big differences were found in basicity of the quinuclidine unit by measuring the pKa values of twelve catalysts in six solvents. The effect of differences was examined by testing the catalysts in Michael addition reaction of pentane-2,4-dione to trans-β-nitrostyrene. The 1.6–1.7 pKa deviation in basicity of the quinuclidine unit did not result in significant differences in yields and enantiomeric excesses. Quantum chemical calculations confirmed that the ethyl, ethynyl, and vinyl substituents affect the acid-base properties of the cinchona-thiourea catalysts only slightly, and the most active neutral thione forms are the most stable tautomers in all cases. Due to the fact that cinchonas with differently saturated quinuclidine substituents have similar catalytic activity in asymmetric Michael addition application of quinine-based catalysts is recommended. Its vinyl group allows further modifications, for instance, recycling the catalyst by immobilization.
Highlights
Asymmetric syntheses went through explosive growth in the last decades [1,2,3,4,5]
Since the strength of hydrogen bonding interactions plays an important role in H-bond organocatalysis [16,25,26,27], determination of pKa values could help understanding the mechanisms and catalytic activity, it can contribute the design of more efficient catalytic systems
To get further insight into the H-bond organocatalytic behavior of the aforementioned twelve catalysts, the pKa values of all four compound classes were measured in six different solvents by UV-spectrophotometric titrations (Pion Inc., Forest Row, UK) (Table 1 and Tables S1–S4)
Summary
After transition metal- and enzyme-based catalysis, the application of organocatalysis has gained ground in the field of asymmetric syntheses. The aim of enantioselective organocatalytic synthesis is to produce enantiopure compounds from achiral substrates facilitated by asymmetric organocatalysts. This bifunctionality means the capability to activate two components of a reaction simultaneously [6]. Cinchona moiety is one of the privileged chiral skeletons in asymmetric organocatalysis [7]. The tertiary amino group in the quinuclidine ring gives basic character for the molecule, this can activate/fix nucleophile or electrophile, and possessing a chiral skeleton, cinchona unit is responsible for chiral induction
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