Novel Axially Unfixed Biaryl-Based Water-Compatible Organocatalysts: Design, Synthesis and Their Asymmetric Catalysis in Direct Aldol Reactions in Water

Abstract

A family of novel axially unfixed biaryl-based, water-compatible bifunctional organocatalysts were designed and synthesized for asymmetric catalytic direct aldol reactions in water. These organocatalysts are comprised of prolinamide, aromatic sulfonamide and biaryl motifs. Under the optimal reaction conditions, one organocatalyst in particular delivered excellent stereocontrol (up to 99% ee and 99:1 dr) in direct aldol reactions of cyclohexanone with a variety of aromatic aldehydes in water.

Key words

axially unfixed biaryl - water - organocatalysts - aldol reaction - stereoselectivity

• References and Notes


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• 11 Asymmetric Aldol Reaction in Water; General Procedure: A mixture of catalyst 5a1 (4.3 mg, 0.01 mmol) and ketone (0.1 mmol) in H₂O (0.5 mL) was stirred at r.t. for 30 min. The corresponding aldehyde (0.1 mmol) was added and the mixture was stirred for 12–54 h. The mixture was extracted with CH₂Cl₂ (2 × 5 mL) and the organic layers were dried over anhydrous Na₂SO₄ and concentrated in vacuo. The aldol product was obtained through flash chromatography on silica gel (petroleum ether–EtOAc, 4:1). The dr and ee values were determined by chiral HPLC analysis. (S)-2-[Hydroxy(4-nitrophenyl)methyl]cyclohexanone (Table 2, entry 1): Reaction time: 12 h. Yield: 99%; dr = 97:3 (anti/syn); ee = 97% (anti). ¹H NMR (400 MHz, CDCl₃): δ (anti) = 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). ¹H NMR (400 MHz, CDCl₃): δ (syn) = 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 (Chiralcel AD; hexane–i-PrOH, 90:10; 1.0 mL/min; λ = 254 nm): t­ _R = 16.68 (syn), 20.79 (syn), 23.11 (anti, minor), 30.89 (anti, major) min.