Organocatalytic Enantioselective Direct Aldol Reaction in Aqueous Media Catalyzed by a Bifunctional Diamine Catalyst

Abstract

Organocatalytic direct asymmetric anti-aldol reaction was developed in aqueous medium using a BINOL-derived diamine/protic acid bifunctional catalyst. The catalytic protocol could offer the opportunity to access anti-aldol products with high level of enantioselectivities with moderate diastereoselectivities.

Key words

aldol reaction - aqueous medium - organocatalyst - diamine - protic acid - enantioselectivity

References and Notes

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17

General Procedure for the Direct Aldol Reaction with the Catalyst 3 in Brine: An aldehyde (0.5 mmol) was added to a mixture of ketone (2 mmol) and an organocatalyst 3 (10 mol%) with DNBSA (10 mol%) in brine (0.5 mL) at r.t. The reaction mixture was stirred and the progress of the reaction was monitored by TLC. After reaction was over (as indicated by TLC), the reaction mixture was diluted with EtOAc (2 mL). The organic layer was separated and dried over anhyd Na₂SO_4. It was purified over silica gel by column chromatography. The enantiomeric excess(ee) of the aldol product was determined by chiral HPLC analysis. The relative and absolute configurations of the products were determined by comparison with the known ^¹H NMR, chiral HPLC analysis, and optical rotation values.

20

Compound characterization data for selected compounds:
(2S,1′ R )-2-[Furan-2-yl(hydroxy)methyl]cyclohexan-1-one (4f): It was obtained in a maximum of 80% yield and 96% ee. The optical purity was determined by HPLC on chiralpak AD-H column (hexane-2-propanol, 90:10); flow rate 0.5 mL/min, 220 nm; t _{R ( major)} = 26.8 min, t _{R ( minor)} = 31.2 min; [α]^²5 _D +21 (c = 1.0, CHCl₃). ^¹H NMR (500 MHz, CDCl₃): δ = 1.23-1.35 (m, 1 H), 1.61-1.71 (m, 3 H), 1.83-1.85 (m, 1 H), 2.10-2.37 (m, 1 H), 2.38-2.49 (m, 2 H), 2.89-2.95 (m, 1 H), 3.89 (br s, 1 H), 4.83 (d, J = 8.6 Hz, 1 H), 6.27-6.34 (m, 2 H), 7.36-7.38 (m, 1 H). Anal. Calcd for C₁₁H₁₄O₃: C, 68.02; H, 7.27. Found: C, 68.09; H, 7.25.
(2S,1′ R )-2-[Hydroxy(naphthalene-2-yl)methyl]-cyclohexan-1-one (4g): It was obtained in a maximum of 88% yield and 96% ee. The optical purity was determined by HPLC on chiralpak AS-H column (hexane-2-propanol, 90:10); flow rate 0.5 mL/min; t _{R ( major)} = 26.6 min, t _{R ( minor)} = 30.8 min; [α]^²5 _D +5.8 (c = 1.3, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 1.25-1.35 (m, 2 H), 1.48-1.76 (m, 3 H), 2.04-2.09 (m, 1 H), 2.36-2.51 (m, 2 H), 2.69-2.75 (m, 1 H), 4.08 (br s, 1 H), 4.96 (d, J = 8.8 Hz, 1 H), 7.45-7.49 (m, 2 H), 7.71-7.89 (m, 5 H). Anal. Calcd for C₁₇H₁₈O₂: C, 80.28; H, 7.13. Found: C, 80.18; H, 7.11.
(2S,1′ R ) 3-[Hydroxy(phenyl)methyl]tetrahydrothio-pyran-4-one (5b): It was obtained in a maximum of 77% yield and 98% ee. The optical purity was determined by HPLC on chiralpak OD-H column (hexane-2-propanol, 98:2); flow rate 0.5 mL/min, t _{R ( major)} = 60.6 min, t _{R ( minor)} = 87.1 min; [α]^²5 _D +17.1 (c = 1.4, CHCl₃). ^¹H NMR (400 MHz, CDCl₃): δ = 2.48-2.60 (m, 2 H), 2.75-2.81 (m, 1 H), 2.83-2.88 (m, 1 H), 2.92-3.04 (m, 3 H), 3.42 (br s, 1 H), 4.97
(d, J = 8.8 Hz, 1 H), 7.26-7.39 (m, 5 H). Anal. Calcd for C₁₂H₁₄O₂S: C, 64.83; H, 6.35. Found: C, 64.89; H, 6.33.