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Synlett 2008(8): 1255-1259  
DOI: 10.1055/s-2008-1072586
LETTER
© Georg Thieme Verlag Stuttgart · New York

Molecular-Sieves Controlled Diastereo- and Enantioselectivity: Unexpected Effect in the Organocatalyzed Direct Aldol Reaction

Xiao-Juan Li, Guang-Wu Zhang, Lian Wang, Ming-Qing Hua, Jun-An Ma*
Department of Chemistry, School of Science, Tianjin University, Tianjin 300072, P. R. of China
Fax: +86(22)27403475; e-Mail: majun_an68@tju.edu.cn;
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Publication History

Received 28 December 2007
Publication Date:
16 April 2008 (online)

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Abstract

An efficient asymmetric organocatalyst was developed for the direct aldol reaction between ketones and aldehydes to afford β-hydroxy ketones in high stereoselectivity (anti/syn up to 92:8, ee up to >99%). The key of the success was the use of activated molecular sieves (4 Å MS), which acted as a water scavenger. The influence of additives such as water or different types of molecular sieves on the reactivity and stereoselectivity of the reaction was also studied.

Key words

asymmetric catalysis - aldol reaction - stereoselectivity - molecular sieves - aldehyde

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Screening of the other solvents for the model aldol reaction: toluene (yield >99%, anti/syn = 82:18, anti = 82% ee), DMSO (yield 98%, anti/syn = 74:26, anti = 77% ee), CHCl3 (yield 96%, anti/syn = 75:25, anti = 67% ee), neat (yield >99%, anti/syn = 70:30, anti = 74% ee).

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Typical Procedure for the Preparation of Organocatalyst To a stirred solution of the corresponding N-(benzyl-oxycarbonyl)proline (2.5 mmol) and Et3N (0.9 mL, 6.8 mmol) in anhyd CH2Cl2 (10 mL) and under an argon atmosphere, were added bis(2-oxo-3-oxazolidinyl)phosphinic chloride (BOPCl, 0.63 g, 2.6 mmol) at 0 °C. After 30 min of stirring, the corresponding chiral amine (2.5 mmol) was added, and the mixture was further stirred for 24 h. It was diluted with 10 mL of CH2Cl2 and washed once with HCl (1 N), H2O, and brine. Then, it was dried over MgSO4, and the solvent was removed under reduced pressure to afford a residue. The resulting residue was dissolved in EtOAc (10 mL) and Pd/C (10 wt%) was added. The mixture was stirred at r.t. under hydrogen atmosphere (1 atm) overnight. Then, the mixture was filtered through Celite and the solvent evaporated under reduced pressure to afford the title compounds, which were purified over silica gel flash column chromatography [Et3N-EtOAc-PE, 1:20:100 (vol.)].
Compound 3a:11 yield 97%, mp 146-147 °C; [α]D 20 -162.5 (c 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ = 1.82-1.89 (m, 1 H, pyrrolidine-H), 1.95-2.02 (m, 2 H, pyrrolidine-H), 2.50-2.57 (m, 1 H, pyrrolidine-H), 3.03-3.07 (m, 1 H, pyrrolidine-H), 3.16 (br, 1 H, NH), 3.27-3.32 (m, 1 H, pyrrolidine-H), 3.56 (d, J = 13.5 Hz, 1 H, NCH), 3.97 (d, J = 12.5 Hz, 1 H, NCH), 4.19-4.22 (m, 1 H, pyrrolidine-H), 4.65 (d, J = 13.0 Hz, 1 H, NCH), 5.46 (d, J = 13.0 Hz, 1 H, NCH), 7.28-7.33 (m, 2 H, binaphthyl-H), 7.43 (d, J = 9.0 Hz, 1 H, binaphthyl-H), 7.49-7.54 (m, 4 H, binaphthyl-H), 7.62 (d, J = 8.5 Hz, 1 H, binaphthyl-H), 7.93-8.00 (m, 4 H, binaphthyl-H). 13C NMR (125 MHz, DMSO): δ = 171.6, 135.2, 135.0, 133.6, 133.0, 132.9, 131.4, 131.3, 130.6, 129.9, 129.1, 128.9, 128.5, 128.3, 127.8, 127.5, 127.3, 127.2, 126.6, 126.3, 126.2, 59.1, 48.9, 47.9, 47.5, 30.9, 26.6. IR (KBr): ν = 2927, 1641, 1508, 1453, 1398, 1249, 1211, 821, 752 cm-1. ESI-MS: m/z = 393.5 [M+ + 1]. ESI-HRMS: m/z calcd for [C27H24N2O + H]: 393.1961; found: 393.1960.
Compound 3b:11 yield 94%, mp 127-129 °C; [a]D 20 +20.3 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 1.84-1.88 (m, 1 H, pyrrolidine-H), 1.96-2.02 (m, 2 H, pyrrolidine-H), 2.51-2.55 (m, 1 H, pyrrolidine-H), 3.00-3.07 (m, 1 H, pyrrolidine-H), 3.10 (br, 1 H, NH), 3.27-3.32 (m, 1 H, pyrrolidine-H), 3.56 (d, J = 13.5 Hz, 1 H, NCH), 3.96 (d, J = 12.5 Hz, 1 H, NCH), 4.19-4.22 (m, 1 H, pyrrolidine-H), 4.65 (d, J = 13.0 Hz, 1 H, NCH), 5.46 (d, J = 13.0 Hz, 1 H, NCH), 7.27-7.33 (m, 2 H, binaphthyl-H), 7.42 (d, J = 9.0 Hz, 1 H, binaphthyl-H), 7.47-7.54 (m, 4 H, binaphthyl-H), 7.61 (d, J = 8.5 Hz, 1 H, binaphthyl-H), 7.95-8.00 (m, 4 H, binaphthyl-H). 13C NMR (125 MHz, CDCl3): δ = 170.8, 135.9, 135.1, 133.7, 133.6, 132.4, 131.7, 131.5, 131.4, 129.8, 129.6, 128.6, 128.5, 127.9, 127.7, 127.4, 126.7, 126.6, 126.5, 126.4, 126.2, 58.5, 48.8, 47.6, 47.0, 31.6, 26.3. IR (KBr): n = 3049, 2924, 1639, 1456, 1406, 1211, 1024, 819, 752 cm-1. ESI-MS: m/z = 393.5 [M+ + 1]. ESI-HRMS: m/z calcd for [C27H24N2O + H]: 393.1961; found: 393.1965.
Compound 3c: yield 81%, mp 123-125 °C; [α]D 20 +52.0 (c 1.0, CH2Cl2). 1H NMR (500 MHz, CDCl3): δ = 1.92 (br, 1 H, NH), 1.95-2.00 (m, 1 H, pyrrolidine-H), 2.82-2.87 (m, 1 H, pyrrolidine-H), 3.28-3.36 (m, 2 H, pyrrolidine-H), 3.48 (d, J = 13.5 Hz, 1 H, NCH), 3.92 (d, J = 13.0 Hz, 1 H, NCH), 4.54-4.71 (m, 3 H, NCH, 2 × pyrrolidine-H), 5.35 (d, J = 13.0 Hz, 1 H, NCH), 6.89 (br, 1 H, OH), 7.20-7.28 (m, 2 H, binaphthyl-H), 7.34 (d, J = 8.5 Hz, 1 H, binaphthyl-H), 7.40-7.48 (m, 3 H, binaphthyl-H), 7.53-7.59 (m, 2 H, binaphthyl-H), 7.86-7.94 (m, 4 H, binaphthyl-H). 13C NMR (125 MHz, CDCl3): δ = 169.3, 135.6, 135.3, 133.7, 133.6, 131.9, 131.6, 131.5, 131.4, 129.8, 129.7, 128.6, 127.8, 127.6, 127.4, 126.7, 126.5, 126.4, 126.2, 57.6, 54.9, 48.8, 47.1, 46.0, 40.4. IR (KBr): n = 3227, 2944, 1640, 1445, 1335, 1250, 1076, 820, 753 cm-1. ESI-MS: m/z 409.2 [M+ + 1]. ESI-HRMS: m/z calcd for [C27H24N2O2 + H]: 409.1911; found: 409.1907.
Compound 3d: yield 82%, mp 212-215 °C; [α]D 20 -119.4 (c 1.0, DMSO). 1H NMR (500 MHz, DMSO): δ = 1.86-1.92 (m, 1 H, pyrrolidine-H), 2.47-2.51 (m, 1 H, pyrrolidine-H), 3.32-3.35 (m, 1 H, pyrrolidine-H), 3.37-3.41 (m, 1 H, pyrrolidine-H), 3.62 (d, J = 14.0 Hz, 1 H, NCH), 3.93 (d, J = 13.0 Hz, 1 H, NCH), 4.57 (t, 1 H, J = 4.0 Hz, pyrrolidine-CHNH), 4.81 (d, J = 13.0 Hz, 1 H, NCH), 5.11-5.15 (m, 1 H, pyrrolidine-CHOH), 5.36 (d, J = 13.5 Hz, 1 H, NCH), 7.27-7.30 (m, 2 H, binaphthyl-H), 7.37-7.40 (m, 2 H, binaphthyl-H), 7.49-7.52 (m, 2 H, binaphthyl-H), 7.58 (d, J = 8.5 Hz, 1 H, binaphthyl-H), 7.76 (d, J = 8.0 Hz, 1 H, binaphthyl-H), 7.97-8.07 (m, 4 H, binaphthyl-H). 13C NMR (125 MHz, DMSO): δ = 168.5, 134.5, 134.4, 133.0, 132.9, 132.0, 131.9, 130.7, 130.6, 129.4, 129.3, 128.5, 127.7, 127.0, 126.6, 126.5, 126.4, 126.2, 126.1, 70.3, 57.0, 54.2, 47.9, 46.1, 45.2. IR (KBr): n = 3300, 2845, 1652, 1459, 1372, 1212, 1085, 814, 753 cm-1. ESI-MS: m/z = 409.2 [M+ + 1]. ESI-HRMS: m/z calcd for [C27H24N2O2 + H]: 409.1911; found: 409.1909.
Compound 3e: yield 51%, mp 84-86 °C. 1H NMR (500 MHz, CDCl3): d = 0.03 (s, 3 H, SiCH3), 0.05 (s, 3 H, SiCH3), 0.88 [s, 9 H, SiC(CH3)3], 2.04 (br, 1 H, NH), 2.95-3.00 (m, 1 H, pyrrolidine-H), 3.35-3.38 (m, 1 H, pyrrolidine-H), 3.57 (d, J = 13.5 Hz, 1 H, NCH), 3.90 (d, J = 13.0 Hz, 1 H, NCH), 4.41-4.44 (m, 1 H, pyrrolidine-H), 4.69 (t, J = 8.0 Hz, 1 H, pyrrolidine-H), 4.80 (d, J = 13.0 Hz, 1 H, NCH), 5.39-5.45 (m, 3 H, NCH, 2 × pyrrolidine-H), 7.27-7.31 (m, 2 H, binaphthyl-H), 7.43-7.51 (m, 4 H, binaphthyl-H), 7.59 (d, J = 8.0 Hz, 1 H, binaphthyl-H), 7.69 (d, J = 8.5 Hz, 1 H, binaphthyl-H), 7.95-8.01 (m, 4 H, binaphthyl-H). 13C NMR (125 MHz, CDCl3): d = 170.6, 135.4, 133.7, 133.6, 132.7, 131.9, 131.6, 131.5, 129.7, 129.6, 128.6, 128.5, 127.8, 127.7, 127.6, 127.4, 126.5, 126.4, 126.3, 126.2, 73.0, 57.5, 54.9, 48.9, 47.2, 40.1, 26.0, 18.2, -4.6, -4.5. IR (KBr): n = 2927, 1639, 1460, 1393, 1252, 1097, 827, 775 cm-1. ESI-MS: m/z = 523.6 [M+ - 1]. ESI-HRMS: m/z calcd for [C33H38N2O2Si + H]: 523.2775; found: 523.2771.

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Representative Procedure for Organoatalyzed Direct Aldol Reaction The mixture of l-prolinamide derivative 3d (0.1 mmol), cyclohexanone (5.0 mmol), 4-nitrobenzaldehyde (1.0 mmol), and MS in THF (1 mL) was stirred at -20 °C under an argon atmosphere for 72 h. The reaction mixture was directly purified through flash column chromatography on silica gel [gradient increasing from 20 → 25 → 30% EtOAc in PE (60-90 °C)] to give the adduct product; yield >99%; anti/syn = 92:8.
anti-Diastereomer: 1H NMR (400 MHz, CDCl3): d = 1.35-1.87 (m, 6 H), 2.09-2.13 (m, 2 H), 2.47-2.51 (m, 1 H), 4.08 (s, 1 H), 4.89 (d, J = 8.4 Hz, 1 H), 7.49 (d, J = 8.0 Hz, 2 H), 8.19 (d, J = 8.4 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d = 24.6, 27.4, 31.5, 42.0, 57.2, 73.9, 123.5, 127.6, 147.8, 148.5, 213.5. HPLC analysis Daicel Chiralpak AD-H, i-PrOH-hexane (20:80), 254 nm, 0.5 mL/min, t R = 25.7 min (minor), 32.8 min (major); ee: >99%.
syn-Diastereomer: 1H NMR (400 MHz, CDCl3): d = 1.50-1.89 (m, 6 H), 2.35-2.43 (m, 2 H), 2.57-2.62 (m, 1 H), 3.18 (s, 1 H), 5.48 (d, J = 8.0 Hz, 1 H), 7.50 (t, J = 8.4 Hz, 1 H), 8.21 (d, J = 8.4 Hz, 2 H). 13C NMR (100 MHz, CDCl3): d = 24.8, 26.0, 28.4, 42.6, 57.0, 70.2, 123.4, 126.8, 147.0, 149.1, 213.8. HPLC analysis Daicel Chiralpak AD-H, i-PrOH-hexane (20:80), 254 nm, 0.5 mL/min, t R = 21.7 min and 23.7 min.