Highly Enantioselective Borane Reduction of Prochiral Ketones Catalyzed by C ₃-Symmetric Tripodal β-Hydroxy Amides

Abstract

The asymmetric borane reduction of prochiral ketones with a series of easily constructed chiral C ₃-symmetric tripodal tris(β-hydroxyamide) ligands was investigated. The borane complex of chiral ligand 1,1′,1′′-(1,3,5-benzenetricarbonyl)-tris[(2S)-α,α-diphenyl-2-pyrrolidinemethanol] (1h) was found to be an efficient catalyst in asymmetric borane reduction of prochiral ketones and excellent enantioselectivities were obtained with both electron-deficient and electron-rich prochiral ketones (up to 97% ee).

asymmetric reduction - borane - ketone - β-hydroxy­amide - C ₃ symmetry

References and Notes

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11

N,N′,N′′ -Tris[(1S)-1-hydroxymethyl-2-methylpropyl]-1,3,5-benzenetricarboxamide (1a): 75% yield; colorless solid, mp 301-303 °C; [α]_D ²⁰ -47.1 (c 0.73, CH₂Cl₂-MeOH = 4:1). IR (KBr): ν = 3484, 3241, 2960, 1637, 1556, 1463, 1302, 1051, 729, 692 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.38 (s, 3 H), 8.28 (d, J = 8.7 Hz, 3 H), 4.63 (t, J = 4.8 Hz, 3 H), 3.85 (s, 3 H), 3.55 (s, 6 H), 1.98-1.91 (m, 3 H), 0.95-0.90 (m, 18 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 166.0, 135.3, 128.7, 61.3, 57.0, 28.6, 19.8, 18.9. HRMS-FAB: m/z calcd for C₂₄H₄₀N₃O₆: 466.2911; found: 466.2909 [M + H⁺].
N,N′,N′′ -Tris[(1S)-1-hydroxymethyl-3-methylbutyl]-1,3,5-benzenetricarboxamide (1b): 91% yield; colorless solid, mp 283-285 °C; [α]_D ²⁰ -59.1 (c 0.96, CH₂Cl₂-MeOH = 4:1). IR (KBr): ν = 3279, 2956, 2868, 1637, 1545, 1469, 1298, 1070, 1031, 706 cm^-1. ¹H NMR (400 MHz, DMSO-d ₆): δ = 8.40 (s, 3 H), 8.31 (d, J = 8.6 Hz, 3 H), 4.74 (t, J = 5.6 Hz, 3 H), 4.14-4.08 (m, 3 H), 3.50-3.36 (m, 6 H), 1.68-1.61 (m, 3 H),1.53-1.46 (m, 3 H), 1.42-1.36 (m, 3 H), 0.92-0.89 (m, 18 H). ¹³C NMR (50 MHz, DMSO-d ₆): δ = 165.5, 135.1, 128.6, 63.9, 49.7, 24.4, 23.5, 21.9. HRMS-FAB: m/z calcd for C₂₇H₄₆N₃O₆: 508.3381; found: 508.3383 [M + H⁺].
N,N′,N′′ -Tris[(1S)-1-benzyl-2-hydroxy-2-methylpropyl]-1,3,5-benzenetricarboxamide (1e): 71% yield; colorless solid, mp 214-216 °C; [α]_D ²⁰ -190.8 (c 1.12, CH₂Cl₂-MeOH = 5:1). IR (KBr): ν = 3307, 2973, 1642, 1533, 1278, 1131, 1083, 915, 747, 697 cm^-1. ¹H NMR (300 MHz, DMSO-d ₆): δ = 8.22 (d, J = 9.6 Hz, 3 H), 8.16 (s, 3 H), 7.26-7.08 (m, 15 H), 4.67 (s, 3 H), 4.20 (t, J = 9.9 Hz, 3 H), 3.15 (d, J = 12.6 Hz, 3 H), 2.77 (d, J = 12.0 Hz, 3 H), 1.24 (s, 9 H), 1.19 (s, 9 H). ¹³C NMR (75 MHz, DMSO-d ₆): δ = 165.5, 140.3, 134.8, 128.9, 128.5, 127.9, 125.6, 71.9, 59.4, 34.2, 28.0, 25.7. HRMS-FAB: m/z calcd for C₄₂H₅₂N₃O₆: 694.3850; found: 694.3800 [M + H⁺].
N,N′,N′′ -Tris[(1S)-1-benzyl-2-hydroxy-2,2-diphenyl-ethyl]-1,3,5-benzenetricarboxamide (1f): 70% yield; colorless solid, mp 152-154 °C; [α]_D ²⁰ -207.1 (c 0.94, EtOAc). IR (KBr): ν = 3410, 3060, 3027, 1654, 1509, 1496, 1449, 1061, 906, 748, 699 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.62 (d, J = 7.6 Hz, 6 H), 7.49 (d, J = 7.3 Hz, 6 H), 7.39-7.03 (m, 36 H), 6.33 (d, J = 7.9 Hz, 3 H), 5.18 (d, J = 6.7 Hz, 3 H), 4.33 (br s, 3 H), 2.93 (d, J = 6.2 Hz, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.1, 145.2, 144.6, 138.5, 135.0, 129.2, 128.6, 128.4, 128.2, 127.6, 127.2, 126.9, 126.5, 125.6, 125.5, 80.9, 59.3, 35.5. HRMS-FAB: m/z calcd for C₇₂H₆₃N₃O₆Na: 1088.4609; found: 1088.4616 [M + Na⁺].
N,N′,N′′ -Tris[(1S)-2-methyl-1-diphenylhydroxymethyl-propyl]-1,3,5-benzenetricarboxamide (1g): 87% yield; colorless solid, mp 177-179 °C; [α]_D ²⁰ -148.3 (c 1.59, EtOAc). IR (KBr): ν = 3421, 2961, 2873, 1650, 1510, 1448, 1309, 1063, 746, 701 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.82 (s, 3 H), 7.52 (dd, J = 5.6, 7.2 Hz, 12 H), 7.32 (t, J = 7.6 Hz, 6 H), 7.24-7.14 (m, 9 H), 7.04 (t, J = 7.2 Hz, 3 H), 6.80 (d, J = 9.6 Hz, 3 H), 5.09 (dd, J = 2.0, 9.8 Hz, 3 H), 3.49 (s, 3 H), 1.99-1.93 (m, 3 H), 0.86 (d, J = 6.7 Hz, 9 H), 0.94 (d, J = 6.7 Hz, 9 H). ¹³C NMR (75 MHz, CDCl₃): δ = 166.2, 146.0, 145.2, 135.5, 128.4, 128.3, 127.7, 126.9, 125.33, 125.27, 82.2, 59.0, 29.1, 22.9, 18.1. HRMS-FAB: m/z calcd for C₆₀H₆₃N₃O₆Na: 944.4609; found: 944.4626 [M + Na⁺].
1,1′,1′′-(1,3,5-Benzenetricarbonyl)-tris[(2S)-α,α-diphenyl-2-pyrrolidinemethanol] (1h): 80% yield; colorless solid, mp 170-172 °C; [α]_D ²⁰ -14.8 (c 0.95, EtOAc). IR (KBr): ν = 3298, 3058, 2965, 2886, 1613, 1447, 1401, 1197, 1033, 759, 700 cm^-1. ¹H NMR (300 MHz, CDCl₃): δ = 7.59 (d, J = 6.9 Hz, 6 H), 7.47-7.25 (m, 24 H), 6.20 (s, 3 H), 5.35 (t, J = 7.8 Hz, 3 H), 3.15-3.00 (m, 6 H), 2.19-1.98 (m, 6 H), 1.61-1.56 (m, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 170.3, 145.1, 143.2, 136.5, 127.9, 127.7, 127.6, 127.5, 127.4, 82.0, 67.6, 51.8, 29.6, 24.5. HRMS-FAB: m/z calcd for C₆₀H₅₇N₃O₆Na: 938.4139; found: 938.4155 [M + Na⁺].

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13

Typical Procedure for 1,1′,1′′-(1,3,5-Benzene-trimethylene)tris[(2S)-α,α-diphenyl-2-pyrrolidine-methanol] (2).
A 50-mL round-bottom flask was charged with tris(β-hydroxyamide) 1h (0.61 g, 0.67 mmol) and THF (10 mL), BH₃·SMe₂ (2 M solution in THF, 7.0 mL) was added via syringe and the mixture was stirred at reflux for 22 h. After slow addition of 2 mL of H₂O to destroy excess BH₃, the organic solvent was removed by rotary evaporation. Then, 20% KOH solution (15 mL) was added and refluxed for 6 h. After cooling to r.t., the mixture was extracted with CH₂Cl₂ (3 × 10 mL), dried over anhyd Na₂SO₄. Purification by column chromatography on silica gel (PE-EtOAc = 5:1) to afford a colorless solid (0.17 g, 29% yield); mp 114-116 °C; [α]_D ²⁰ +110.9 (c 1.2, CH₂Cl₂). IR (KBr): ν = 2969, 2803, 1491, 1449, 1371, 1107, 909, 732, 705 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 7.77 (d, J = 7.6 Hz, 6 H), 7.61 (d, J = 7.5 Hz, 6 H), 7.32-7.17 (m, 12 H), 7.16 (t, J = 7.3 Hz, 3 H), 7.09 (t, J = 7.3 Hz, 3 H), 6.54 (s, 3 H), 4.98 (s, 3 H), 3.97 (dd, J = 4.6, 9.3 Hz, 3 H), 3.11 (d, J = 12.6 Hz, 3 H), 2.92 (d, J = 12.6 Hz, 3 H), 2.81-2.77 (m, 3 H), 2.30-2.27 (m, 3 H), 1.99-1.93 (m, 3 H), 1.78-1.68 (m, 3 H), 1.65-1.61 (m, 6 H). ¹³C NMR (75 MHz, CDCl₃): δ = 148.1, 146.6, 139.2, 128.1, 128.0, 127.2, 126.3, 126.2, 125.6, 125.5, 77.8, 70.4, 60.2, 55.4, 29.8, 24.1. Anal. Calcd for C₆₀H₆₃N₃O₃: C, 82.44; H, 7.26; N, 4.81. Found: C, 80.81; H, 7.13; N, 4.56; MS (ESI): m/z = 874.7 [M + H⁺]. HRMS-FAB: m/z calcd for C₆₀H₆₄N₃O₃: 874.49419; found: 874.49175 [M + H⁺].

14

Typical Procedure for the Reduction of Prochiral Ketones.
BH₃·SMe₂ (0.3 mL, 2 M solution in THF) was added by syringe to a solution of chiral ligand (0.025 mmol) in dry THF (1.5 mL) under nitrogen at r.t. The mixture was stirred at 50 °C for 30 min. A solution of acetophenone (0.5 mmol) in dry THF (0.5 mL) was added dropwise over a period of 1 h at 50 °C. After 1 h, the reaction mixture was cooled and quenched by dropwise addition of H₂O (5 mL). The product was isolated by extraction with CH₂Cl₂ (3 × 5 mL). The organic phase was dried over anhyd Na₂SO₄. After concen-tration by rotary evaporation, the product was purified by column chromatography on silica gel (PE-EtOAc = 5:1) to afford the corresponding (R)-1-phenylethanol with 96% yield and 94% ee. The enantiomeric excess was determined by HPLC on chiral column. (Daicel Chiralcel OB column, hexane-2-PrOH = 9:1, 1.0 mL/min, 254 nm, t _R,major = 8.54 and t _R,minor = 6.53 min).

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