Enantioselective Synthesis of Cyanohydrins by a Novel Aluminum Catalyst

Abstract

The development of a new chiral aluminum catalyst is reported. This catalyst has been applied efficiently to the asym­metric cyanosilylation of aldehydes.

Key words

aldehyde - cyanohydrin - trimethylsilylcyanide - asymmetric addition - aluminum

References

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6

Temperature of a cold room.

7

Typical Procedure
Catalysis Generation: A 2 M solution of trimethylalu-minum in toluene (25 µL, 0.05 mmol) was added dropwise to a solution of ligand 1 (36 mg, 0.056 mmol) in 1.0 mL of chlorobenzene at r.t. After stirring for 30 min at the same temperature, the resulting solution was cooled to 4 °C to be used as catalyst. TMSCN Addition: Aldehyde 2 (0.5 mmol) was added in one portion to the catalyst solution at 4 °C and after 10 min TMSCN (73 µL, 0.55 mmol) was added over 2 min. The reaction mixture was stirred at the same temperature for 24 h. Then the reaction was quenched with 2.0 mL of pH 7 buffer phosphate solution (Na₂HPO₄/NaH₂PO₄) and extracted with EtOAc (3 × 5 mL). The combined organic layers were washed with brine (5 mL), dried over MgSO₄ and concentrated to give a colorless oil. The crude was purified by flash chromatography on silica gel (petroleum ether-EtOAc, 5:1) to yield the corresponding silylated cyanohydrins.

9

Characterization of the New Compounds:
Compound 3c: ¹H NMR (300 MHz, CDCl₃): δ = 7.32 (s, 2 H), 7.26 (s, 1 H), 5.66 (s, 1 H), 2.59 (s, 3 H), 0.48 (s, 9 H) ppm. ¹³C NMR (300 MHz, CDCl₃): δ = 138.8, 136.2, 131.0, 124.2, 119.5, 63.8, 21.3, -0.1 ppm. IR (neat): 2960, 2921, 1612, 1464, 1255, 1159, 1101, 846, 754, 692 cm^-1. Anal. Calcd for C₁₃H₁₉NOSi: C, 66.90; H, 8.21; N, 6.00. Found: C, 66.67; H, 7.95; N, 5.95. Enantiomer separation by HPLC (Daicel Chiralpak AD, λ = 250 nm, heptane-i-PrOH = 99.95:0.05; 1.0 mL/min; 57% ee): t _R = 6.83 (major) and 7.98 min. [α]_D -16.28 (c 2.12, CHCl₃).
Compound 3f: ¹H NMR (300 MHz, CDCl₃): δ = 7.36 (m, 3 H), 5.43 (s, 1 H), 0.27 (s, 9 H) ppm. ¹³C NMR (300 MHz, CDCl₃): δ = 139.5, 135.7, 129.6, 124.8, 118.3, 62.4, -0.2 ppm. IR (neat): 3083, 2961, 2901, 1592, 1574, 1435, 1259, 1202, 1119, 872, 805, 754 cm^-1. Anal. Calcd for C₁₁H₁₃Cl₂NOSi: C, 48.18; H, 4.78; N, 5.11. Found: C, 48.61; H, 5.17; N, 5.03. Enantiomer separation by HPLC (Daicel Chiralpak AD, λ = 235 nm, heptane-i-PrOH = 99.5:0.5; 0.6 mL/min; 80% ee): t _R = 9.80 and 10.48 (major) min.
[α]_D -12.52 (c 2.91, CHCl₃).
Compound 3g: ¹H NMR (300 MHz, CDCl₃): δ = 7.69 (m, 1 H), 7.55 (m, 2 H), 5.43 (s, 1 H), 0.27 (s, 9 H) ppm. ¹³C NMR (300 MHz, CDCl₃): δ = 139.9, 135.1, 128.1, 123.5, 118.2, 62.2, -0.2 ppm. IR (neat): 3076, 2959, 1589, 1562, 1427, 1256, 1193, 1118, 1095, 848, 742 cm^-1. Anal. Calcd for C₁₁H₁₃Br₂NOSi: C, 36.38; H, 3.61; N, 3.86. Found: C, 36.01; H, 2.99; N, 3.94. Enantiomer separation by HPLC (Daicel Chiralcel OD, λ = 235 nm, heptane-i-PrOH = 99.8:0.2, 1.0 mL/min; 85% ee): t _R = 11.69 (major) and 16.01 min.
[α]_D -9.39 (c 2.53, CHCl₃).
Compound 3h: ¹H NMR (300 MHz, CDCl₃): δ = 7.49 (s, 1 H), 7.39-7.32 (m, 3 H), 5.45 (s, 1 H), 2.44 (t, J = 6.9 Hz, 2 H), 1.60-1.47 (m, 4 H), 0.98 (t, J = 6.9 Hz, 3 H) ppm. ¹³C NMR (300 MHz, CDCl₃): δ = 136.4, 132.5, 129.5, 128.9, 125.4, 125.0, 119.0, 91.6, 79.9, 63.4, 30.8, 22.1, 19.1, 13.7, -0.2 ppm. IR (neat): 2959, 2934, 2873, 2230, 1603, 1482, 1431, 1330, 1256, 1108, 1082, 860, 848 cm^-1. Anal. Calcd for C₁₇H₂₃NOSi: C, 71.53; H, 8.12; N, 4.91. Found: C, 70.98; H, 8.51; N, 5.05. Enantiomer separation by HPLC (Daicel Chiralcel OD, λ = 250 nm, heptane-i-PrOH = 99.7:0.3; 1.0 mL/min; 82% ee): t _R = 18.16 (major) and 30.05 min. [α]_D -9.11 (c 0.26, CHCl₃).