Direct Asymmetric Aldol Reaction Catalyzed by an Imidazolium-Tagged trans-4-Hydroxy-l-proline under Aqueous Biphasic Conditions

Abstract

Imidazolium-tagged trans-4-hydroxy-l-proline, recently reported by us as an efficient catalyst for the asymmetric cross-aldol reaction in [bmim][Tf₂N], gives much better results in terms of catalytic activity and stereochemical performance under aqueous biphasic conditions, providing aldols with anti/syn ratios up to 98:2 and ee (anti) up to 99%. The peculiar solubility properties of imidazolium-tagged trans-4-hydroxy-l-proline ensure an efficient separation of the product from the catalyst and the recycling of trans-4-hydroxy-l-proline for five times without appreciable loss of catalytic activity and stereochemical performance.

Key words

asymmetric organocatalysis - aldol reactions - biphasic aqueous catalysis - ionic-tagged proline - catalyst recycling

References and Notes

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16

General Procedure for Cross-Aldol Condensation of Aromatic Aldehydes (Table 1, entry 1) Catalyst 1b (13.4 mg, 0.025 mmol) was stirred in H₂O
(0.8 mL) until a clear solution was obtained. Cyclohexanone (0.259 mL, 2.5 mmol) was added and the mixture was stirred for 20 min whereupon the reaction mixture became an emulsion. 4-Nitrobenzaldehyde (75.5 mg, 0.5 mmol) was then added, and the reaction mixture was allowed to stir for a further 24 h at 25 ˚C. Cyclohexanone and water were removed under reduced pressure and the residue was extracted with Et₂O (4 × 3 mL). The combined organic extracts were dried over Na₂SO₄, concentrated in vacuo, and purified by silica gel column chromatography (cyclohexane-EtOAc, 7:3) to obtain the pure anti-aldol adduct in 93% yield and the syn-adduct in 4%.

17

General Procedure for Cross-Aldol Condensation of Aliphatic Aldehydes (Table 3, entry 5) Catalyst 1b (26.8 mg, 0.05 mmol) was dissolved in cyclohexanone (0.259 mL, 2.5 mmol), H₂O was added (0.012 mL), and the solution was stirred for 10 min before the addition of isobutyraldehyde (0.046 mL, 0.5 mmol). The reaction mixture was allowed to stir for a further 72 h at 25 ˚C. Cyclohexanone and water were removed under reduced pressure and the residue was purified by silica gel column chromatography (cyclohexane-EtOAc, 9:1) to afford the pure anti-aldol adduct in 60% yield.

18

General Procedure for the Recycling Experiment (Table 4)
The recycling studies were performed using the same procedure reported above on a 1 mmol scale of 4-nitro-benzaldehyde. After completion of the workup, the reaction flask was dried under vacuum for 1 h and recharged with H₂O and the starting substrates.