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Synlett 2009(14): 2356-2360  
DOI: 10.1055/s-0029-1217710
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Highly Enantioselective Direct Aldol Reactions Catalyzed by Proline Derivatives Based on a Calix[4]arene Scaffold in the Presence of Water

Zheng-Yi Lia, Jia-Wen Chena, Leyong Wang*a, Yi Pan*b
a Key Laboratory of Mesoscopic Chemistry of Ministry of Education, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing 210093, P. R. of China
Fax: +86(25)83317761; e-Mail: lywang@nju.edu.cn;
b State Key Laboratory of Coordination Chemistry, Nanjing University, Nanjing 210093, P. R. of China
e-Mail: yipan@nju.edu.cn;
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Publication History

Received 3 April 2009
Publication Date:
31 July 2009 (online)

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Abstract

A series of proline-derived organocatalysts based on a calix[4]arene scaffold have been developed to catalyze direct aldol reactions in the presence of water. Under the optimal conditions, high yields (up to >99%), good enantioselectivities (up to >99% ee) and diastereoselectivities (up to 90:10) were obtained.

Key words

proline - calix[4]arene - organocatalyst - aldol reaction - water

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Analytical data for compound 1: Yield: 47%. White solid, mp 233-235 ˚C. [α]D ²6 +21.6 (c = 1.0, CHCl3). ¹H NMR (300 MHz, DMSO-d 6): δ = 1.11 [s, 9H, C(CH3)3], 1.16 [s, 18H, 2 × C(CH3)3], 1.17 [s, 9H, C(CH3)3], 3.34 (d, J = 8.1 Hz, 2H, CH2), 3.40-3.47 (m, 4H, ArCH2Ar), 3.34 (d, J = 12.3 Hz, 2H, NCH2), 4.03-4.09 (m, 4H, ArCH2Ar), 4.37-4.43 (m, 2H, NCHCO + OCH), 4.59 (s, 1H, NH), 6.98-7.22 (m, 8H, ArH). ¹³C NMR (75 MHz, DMSO-d 6): δ = 31.4, 31.7, 32.6, 34.1, 34.3, 36.4, 51.0, 60.5, 84.1, 125.2, 126.1, 126.5, 128.2, 128.4, 130.2, 130.4, 133.6, 133.8, 143.0, 146.4, 148.3, 148.6, 148.9, 150.8, 171.8. IR (KBr): 3440, 2959, 2869, 1629, 1485, 1364, 1299, 1262, 1204, 1031, 909, 874, 802 cm-¹. Anal. Calcd for C49H63NO6: C, 77.23; H, 8.33; N, 1.84. Found: C, 77.52; H, 8.06; N, 1.65. ESI-MS: m/z (%) = 762 (8) [M + 1]+, 784 (100) [M + Na]+.

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Analytical data for compound 2: Yield: 78%. White solid, mp 261-263 ˚C. [α]D ²6 +43.0 (c = 1.0, CHCl3). ¹H NMR (300 MHz, CD3OD): δ = 1.07 [s, 18H, 2 × C(CH3)3], 1.24 [s, 18H, 2 × C(CH3)3], 2.72 (m, 2H, CH2), 2.84-2.90 (m, 2H, CH2), 3.35-3.48 (m, 4H, ArCH2Ar), 3.68-3.74 (m, 2H, NCH2), 4.17-4.38 (m, 8H, NCH2 + ArCH2Ar + OCH), 4.65-4.69 (m, 2H, NCHCO), 5.08 (s, 2H, NH), 7.05-7.16 (m, 8H, ArH). ¹³C NMR (75 MHz, CDCl3): δ = 30.8, 31.5, 33.7, 51.2, 60.0, 85.1, 124.8, 124.9, 125.5, 125.9, 127.9, 128.0, 128.5, 131.0, 131.1, 131.7, 141.9, 146.5, 149.9, 173.6, 173.7. IR (KBr): 3448, 2961, 2868, 1632, 1485, 1393, 1362, 1300, 1203, 1124, 1035, 979, 873 cm-¹. Anal. Calcd for C54H70N2O8: C, 74.11; H, 8.06; N, 3.20. Found: C, 74.32; H, 7.86; N, 3.45. ESI-MS: m/z (%) = 898 (100) [M + Na]+.

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Analytical data for compound 3: Yield: 96%. White solid, mp 137-139 ˚C. [α]D ²7 -6.7 (c = 8.5, CHCl3). ¹H NMR (300 MHz, CDCl3): δ = 0.82 [s, 9H, C(CH3)3], 0.94 [s, 9H, C(CH3)3], 1.06 (t, J = 7.2 Hz, 3H, CH3), 1.25 [s, 9H, C(CH3)3], 1.31 [s, 9H, C(CH3)3], 1.58-1.72 (m, 2H, CH2), 1.81-1.98 (m, 2H, CH2), 2.43-2.52 (m, 1H, CH2), 2.65-2.82 (m, 1H, CH2), 3.21-3.34 (m, 4H, ArCH2Ar), 3.58 (br s, 2H, ArOCH2), 3.91-3.96 (m, 2H, NCH2), 4.01-4.28 (m, 4H, ArCH2Ar), 4.39-4.51 (m, 2H, OCH + NCHCOO), 6.53-6.81 (m, 4H, ArH), 6.98-7.06 (m, 4H, ArH). ¹³C NMR (75 MHz, CDCl3): δ = 14.0, 19.3, 33.7, 33.8, 34.9, 59.7, 84.0, 124.8, 125.1, 125.3, 125.7, 125.8, 127.0, 127.3, 128.2, 128.4, 131.5, 132.1, 132.2, 141.4, 146.3, 146.8, 149.3, 149.4, 150.2, 173.1. IR (KBr): 3441, 2960, 2870, 1717, 1635, 1485, 1392, 1362, 1300, 1201, 1123, 1026, 872 cm-¹. Anal. Calcd for C53H71NO6: C, 77.81; H, 8.75; N, 1.71. Found: C, 77.42; H, 8.96; N, 1.45. ESI-MS: m/z (%) = 818 (23) [M + 1]+, 840 (100) [M + Na]+.

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Analytical data for compound 4: Yield: 75%. White solid, mp 157-159 ˚C. [α]D ²7 -31.3 (c = 1.0, CHCl3). ¹H NMR (300 MHz, CDCl3): δ = 0.84 [s, 9H, C(CH3)3], 0.87 [s, 9H, C(CH3)3], 0.91 (t, J = 7.2 Hz, 3H, CH3), 1.27 [s, 9H, C(CH3)3], 1.29-1.31 (m, 5H, CH2), 1.32 [s, 9H, C(CH3)3], 1.46-1.51 (m, 2H, CH2), 1.60-1.65 (m, 1H, CH2), 1.80-1.94 (m, 2H, CH2), 2.33 (t, J = 7.5 Hz, 2H, OOCCH2), 2.71-2.93 (m, 2H, CH2), 3.23-3.39 (m, 4H, ArCH2Ar), 3.76 (d, J = 13.5 Hz, 2H, NCH2), 3.99-4.16 (m, 4H, ArCH2Ar), 4.01-4.48 (m, 2H, OCH + NCHCOO), 5.50 (s, 1H, OH), 5.63 (s, 1H, OH), 6.57-7.08 (m, 8H, ArH). ¹³C NMR (75 MHz, CDCl3): δ = 14.1, 22.5, 24.9, 29.0, 29.1, 30.7, 30.8, 31.3, 31.4, 31.6, 33.8, 35.5, 49.0, 59.9, 84.3, 124.8, 125.0, 125.3, 126.0, 126.9, 127.3, 127.6, 127.7, 129.0, 130.7, 131.0, 131.4, 132.0, 141.8, 142.0, 142.2, 147.0, 148.0, 148.3, 149.7, 149.9, 172.0, 173.3, 178.0. IR (KBr): 3520, 2957, 2868, 1761, 1634, 1485, 1363, 1301, 1204, 1139, 1122, 1037, 873 cm-¹. Anal. Calcd for C57H77NO7: C, 77.08; H, 8.74; N, 1.58. Found: C, 77.34; H, 8.46; N, 1.35. ESI-MS: m/z (%) = 888 (26) [M + 1]+, 910 (100) [M + Na]+.

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General procedure for asymmetric aldol reactions: Catalyst 1 (2 mol%) was added to a suspension of aldehyde (1.0 mmol) and ketone (3.0 mmol) in water (324 µL, 18 mmol) at room temperature. The mixture was allowed to stir for the given time, then ethyl acetate (10 mL) and anhydrous MgSO4 (0.6 g) were added. After filtration, the solvent was evaporated under vacuum and the crude products were purified by flash chromatography (hexane-EtOAc). The anti/syn ratio (diastereoselectivity) and enantiomeric excess (enantioselectivity) were determined by chiral HPLC analysis (see ref 24).

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Compound 7a: Yield: 73%; Ratio anti/syn = 90:10. HPLC conditions: Daicel Chiralpak AD-H column; i-PrOH-Hexane, 5:95; flow rate 1.0 mL/min; λ = 254 nm; 20 ˚C. anti-Diastereomer: t R(major) = 60.2 min and t R(minor) = 43.5 min; 98% ee. For further data on 7 and HPLC spectra, see Supporting Information.