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Synlett 2007(14): 2298-2300  
DOI: 10.1055/s-2007-985569
LETTER
© Georg Thieme Verlag Stuttgart · New York

Aldol Reactions in Water Using a β-Cyclodextrin-Binding Proline Derivative

Kegang Liu, Daniel Häussinger, Wolf-D. Woggon*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax: +41(61)2671102; e-Mail: wolf-d.woggon@unibas.ch;
Further Information

Publication History

Received 16 June 2007
Publication Date:
13 August 2007 (online)

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Abstract

The aldol reaction of various aromatic aldehydes with cyclohexanone is catalyzed by the inclusion complex of a proline derivative and β-cyclodextrin in water, yielding hydroxyketones with anti/syn ratio of up to 99:1 and ee values well above 90%.

Key words

adamantane - aldol reaction - β-cyclodextrin - proline - ­organocatalysis

9

Synthesis of 6 To a solution of 5 (70.8 mg, 0.2 mmol) in CH2Cl2 (1 mL) was added solid 1-adamantane carboxylic acid chloride 4 (44 mg, 0.22 mmol) at 0 °C, followed by addition of DIPEA (52 mg, 0.4 mmol). The reaction mixture was stirred for 4 h at r.t. and finally diluted with CH2Cl2 (5 mL). The organic phase was washed consecutively with 1 N HCl, H2O, brine and dried over Na2SO4.The solvent was removed under reduced pressure. Purification of the residue by flash chromatog-raphy using hexane-EtOAc (2:1) affords 6 as an oil (96 mg, 93%); [α]D 25 -32.1 (c 0.88, CHCl3). 1H NMR (400 MHz, CDCl3): δ = 7.23-7.37 (m, 10 H), 6.65 (d, 1 H, J = 9.2 Hz), 4.95-5.34 (m, 4 H), 4.69 (m, 1 H), 4.41-4.50 (m, 1 H), 3.51-3.71 (m, 2 H), 2.41-2.50 (m, 1 H), 2.00 (m, 3 H), 1.91 (m, 1 H), 1.63-1.73 (m, 12 H). 13C NMR (100 MHz, CDCl3): δ = 177.86, 177.78, 174.45, 155.16, 154.52, 136.65, 136.57, 135.68, 135.44, 129.06, 128.98, 128.94, 128.89, 128.57, 128.52, 128.44, 128.38, 128.23, 67.82, 67.73, 58.66, 58.20, 54.41, 54.12, 48.70, 47.72, 40.87, 40.86, 39.27, 39.26, 37.39, 36.87, 36.32, 28.47. ESI-MS: m/z = 539.2 [M + Na]+, 555.1 [M + K]+. Anal. Calcd (%) for C31H36N2O5: C, 72.07; H, 7.02; N, 5.42. Found: C, 71.27; H, 7.09; N, 5.20.

10

Synthesis of 1 To a solution of compound 6 (96 mg, 0.186 mmol) in MeOH (2 mL) was added 10% Pd/C (30 mg). The reaction mixture was stirred for 5 h under hydrogen, subsequently filtered through Celite and the catalyst was washed with MeOH three times. The combined organic solutions were concentrated under reduced pressure to afford the proline derivative 1 as a colorless solid (54 mg, 100%); mp 230-232 °C; [α]D 25 -32.9 (c 0.5, MeOH). 1H NMR (400 MHz, DMSO-d 6): δ = 7.60 (d, 1 H, J = 6.8 Hz), 4.34 (m, 1 H), 4.15 (t, 1 H, J = 8.4 Hz), 3.28 (dd, 1 H, J = 11.2, 7.2 Hz), 3.10 (dd, 1 H, J = 11.2, 6.0 Hz), 2.46 (m, 1 H), 1.91 (m, 4 H), 1.58-1.72 (m, 12 H). 13C NMR (100 MHz, DMSO-d 6): δ = 177.93, 170.99, 58.99, 49.98, 48.50, 39.30, 36.94, 34.67, 28.43. ESI-MS: m/z = 293.4 [M + 1]+. Anal. Calcd (%) for C16H24N2O3: C, 65.73; H, 8.27; N, 9.58. Found: C, 65.66; H, 8.18; N, 9.44.

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Spectroscopic Data of Inclusion Complex 3
1H NMR (600 MHz, D2O): δ = 5.04 (d, 7 H, H-1′), 4.55 (m, 1 H, H-γ), 4.22 (dd, 1 H, H-α), 3.89 (m, 7 H, H-6′′), 3.87 (m, 7 H, H-3′), 3.84 (m, 7 H, H-6′), 3.75 (m, 7 H, H-5′), 3.64 (dd, 7 H, H-2′), 3.60 (dd, 1 H, H-δ cis), 3.56 (dd, 7 H, H-4′), 3.46 (dd, 1 H, H-δ trans), 2.66 (m, 1 H, H-β cis), 2.20 (m, 1 H, H-β trans to Hα), 2.18 (s, 3 H, H-3), 1.91 (s, 6 H, H-2), 1.78 (s, 6 H, H-4). 1H NMR (600 MHz, H2O): δ = 7.37 (d, 1 H, NHC=O). 13C NMR (151 MHz, D2O): δ = 180.7 (NHC=O), 174.3 (COOH), 102.7 (C-1′), 81.9 (C-4′), 73.5 (C-3′), 72.4 (C-2′), 72.3 (C-5′), 60.6 (C-α), 60.5 (C-6′), 50.4 (C-δ), 49.2 (C-γ), 40.9 (C-1), 38.9 (C-2), 36.8 (C-4), 34.8 (C-β), 27.8 (C-3).

13

The NOESY spectrum was acquired on an equimolar mixture of 1 and 2 in D2O using a mixing time of 500 ms and 512 (142 ms) and 2048 (285 ms) points (acquisition times) in the F1 and the F2 dimension. Assignment of the resonances of this complex was accomplished using standard COSY, HMQC, and HMBC pulse sequences. NMR data were processed using Bruker XWINNMR software.

14

General Procedure for the Aldol Reaction Catalyzed by the Inclusion Complex of 1 and β-Cyclodextrin 2 To a suspension of the proline derivative 1 (5.84 mg, 0.02 mmol) in H2O (0.2 mL) was added β-cyclodextrin 2 (22.7 mg, 0.02 mmol) and stirred for 10 min at r.t. until a clear solution was obtained; then cyclohexanone (80 µL, 0.8 mmol) was added. The reaction mixture was stirred at r.t. for further 10 min and subsequently aldehyde 7 (0.2 mol) was added. The reaction mixture was stirred for 3-96 h (TLC monitoring the consumption of aldehyde). The reaction was quenched with aq NH4Cl and extracted with EtOAc. The combined organic layers were washed with H2O and brine, dried over Na2SO4. Purification by flash chromatography (silica gel, hexane-EtOAc, 2:1) gave the pure aldol products for further analysis.
For Recycle Case
After the completion of reaction, the reaction mixture was directly extracted with CH2Cl2 for three times. The aqueous-phase-containing catalyst was reused again for next time after removing a little amount of CH2Cl2 under reduced pressure.

15

Absolute configuration of the aldol products anti-9 were determined by optical rotation in comparison to reported values6 except compound 9h.
The following are the analytical data of 2-hydroxy-methylene-(2′,6′-dichlorophenyl) cyclohexanone (9h): anti-9h: 1H NMR (400 MHz, CDCl3): δ = 7.29 (m, 2 H), 7.13 (m, 1 H), 5.82 (dd, 1 H, J = 9.6, 4.4 Hz), 3.67 (d, 1 H, J = 4.4 Hz), 3.46-3.49 (m, 1 H), 2.35-2.52 (m, 2 H), 2.05-2.09 (m, 1 H), 1.78-1.82 (m, 1 H), 1.62-1.69 (m, 2 H), 1.49-1.53 (m, 1 H), 1.34-1.41 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 214.85, 136.08, 135.10, 129.92, 70.97, 54.04, 42.85, 30.26, 28.04, 25.10. ESI-MS: m/z (%) = 295.3 (100) [M + Na]+. The ee of anti-9h (97%) was determined by HPLC with a Chiralpak AD-H column (heptane-2-PrOH, 90:10), 20 °C, 210 nm, 0.5 mL/min; major enantiomer t R = 24.2 min, minor enantiomer t R = 30.9 min.
syn-9h: 1H NMR(400 MHz, CDCl3): δ = 7.08-7.31 (m, 3 H), 5.73 (t, 1 H, J = 7.6 Hz), 3.27-3.33 (m, 1 H), 2.84 (d, 1 H, J = 7.6 Hz), 1.17-2.40 (m, 8 H). The ee was determined by HPLC with a Chiralpak AD-H column (heptane-2-PrOH, 90:10), 20 °C, 210 nm, 0.5 mL/min, one enantiomer t R = 20.2 min, another enantiomer t R = 22.1 min.