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

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.

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

References and Notes

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19

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]⁺.

20

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]⁺.

21

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]⁺.

22

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]⁺.

23

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).

24

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.

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