Design, Synthesis and Use of Novel 3,3′-Disubstituted 2,2′-Bipyridine-Based Chiral Ligands: Asymmetric Catalysis in Direct Aldol Reactions

Abstract

A wide range of chiral ligands based on the 2,2′-bipyridine scaffold were designed and synthesized. In complexation with metal Lewis acids, the reactivity and stereoselectivity of the prepared chiral ligands were examined in asymmetric catalytic direct aldol reactions, thus providing the desired products with high stereo­selectivities.

Key words

2,2′-bipyridine - bifunctional catalysis - direct aldol reaction - Lewis acid - Lewis base

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• 8 General Procedure of the Asymmetric Aldol Reaction Ketone (1 mL) and distilled H₂O (25 μL) were added to a test tube with ligand 1 (1.9 mg, 0.005 mmol, 5 mol%) and stirred for 15 min, then Yb(OTf)₃ (3.1 mg, 0.005 mmol, 5 mol%) was added to the mixture and stirred for 30 min. After the mixture was cooled to 0 °C, the corresponding aldehyde (0.1 mmol) was added, and the whole mixture was stirred at 0 °C for 96—168 h. After dried with anhyd Na₂SO₄ (200 mg), the reaction mixture was purified by flash chromatography on silica gel (eluent: EtOAc–PE) to give a mixture of syn- and anti-aldol products. The dr and ee values were determined by chiral HPLC analysis. 2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone (Table 2, Entry 1) Reaction time 96 h; yield 89% (a mixture of syn and anti products). anti-Diastereomer: ¹H NMR (400 MHz, CDCl₃): δ = 8.21 (d, J = 8.4 Hz, 2 H), 7.51 (d, J = 8.8 Hz, 2 H), 4.90 (dd, J = 2.8, 8.4 Hz, 1 H), 4.07 (d, J = 3.2 Hz, 1 H), 2.36–2.61 (m, 3 H), 2.09–2.14 (m, 1 H), 1.36–1.85 (m, 6 H). syn-Diastereomer: ¹H NMR (400 MHz, CDCl₃): δ = 8.21 (d, J = 8.4 Hz, 2 H), 7.49 (d, J = 8.8 Hz, 2 H), 5.49 (s, 1 H), 3.17 (d, J = 2.8 Hz, 1 H), 2.36–2.65 (m, 3 H), 2.10–2.13 (m, 1 H), 1.51–1.88 (m, 6 H). HPLC separation conditions: Chiralcel AD, solvent: hexane–i-PrOH (90:10), flow rate: 1.0 mL/min, λ = 254 nm; retention time: t _R (syn) = 17.655 min; t _R (syn) = 20.648 min; t _R (anti) = 23.230 min; t _R (anti) = 31.517 min; dr (anti/syn) = 95:5; ee (anti) = 85%.