Copper-Catalyzed Enantioselective Tandem Conjugate Addition/N-Nitroso Aldol Reaction

Abstract

The first enantioselective tandem conjugate addition/N-nitroso aldol reaction catalyzed by copper and phosphoramidite is presented. The reactions proceeded smoothly furnishing the α-hydroxyamino carbonyl compounds in good yields with high enantioselectivity up to 95% ee.

tandem conjugate addition - N-nitroso aldol reaction - α-hydroxyamino carbonyl compounds - enantioselective - monophosphoramidite

References and Notes

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Copper-Catalyzed Enantioselective Tandem Conjugate Addition/ N -Nitroso-Aldol Reaction: Typical Procedure: Under an Ar atmosphere, a solution of Cu(OTf)₂ (3.6 mg, 0.010 mmol) and the monodentate phosphoramidite (0.020 mmol) in toluene (1 mL) was stirred at r.t. for 1 h. The colorless solution was cooled (-20 °C) and the ketone (0.50 mmol) and the diethylzinc solution (1.2 equiv) in hexane (1.0 M, 0.6 mL, 0.6 mmol) were added. After 3 h at -20 °C, PhNO (80.2 mg, 0.75 mmol, 1.5 equiv) in anhyd toluene (1.5 mL) was added. After stirring the mixture for 18 h, sat. aq NH₄Cl (10 mL) was added to the reaction mixture, and then the reaction mixture was extracted with EtOAc (3 × 10 mL). The combined organic phases were washed with brine and dried over Na₂SO₄. The solvent was then removed under vacuum. After purification by flash chromatography on silica gel (PE-EtOAc, 200:1), the addition product 2a was obtained in 86.4% yield as a 2:1 diastereomeric mixture. IR (KBr): 3413, 2956, 2825, 2871, 1677, 1637, 1594, 1489, 1452, 1377, 1362, 1257, 1222 cm^-1. MS: m/z = 345 [M⁺], 240 (47), 226 (80), 104 (53), 91 (44), 77 (100). 2a ^¹ (minor isomer); yellow solid; mp 117.9-119.6 °C. ¹H NMR (300 MHz, CDCl₃): δ = 0.78 (t, J = 7.3 Hz, 3 H), 1.82 (m, J = 7.3 Hz, 1 H), 2.43 (m, J = 7.3 Hz, 1 H), 3.50 (m, J = 10.3 Hz, 1 H), 5.27 (d, J = 10.3 Hz, 1 H), 6.79 (t, J = 7.1 Hz, 1 H), 6.97-7.34 (m, 15 H). ¹³C NMR (75 MHz, CDCl₃): δ = 11.7, 22.7, 48.2, 70.9, 114.9, 121.4, 126.9, 127.9, 128.1, 128.3, 128.4, 128.9, 129.1, 133.0, 137.2, 139.6, 151.3, 205.8. 2a ^² (major isomer): yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 0.72 (t, J = 7.2 Hz, 3 H), 1.62 (m, J = 7.2 Hz, 2 H), 3.61 (m, 1 H), 5.4 (d, J = 9.7 Hz, 1 H), 6.79 (t, J = 7.1 Hz, 1 H), 6.97-7.34 (m, 15 H). ¹³C NMR (75 MHz, CDCl₃): δ = 12.3, 26.2, 47.4, 71.5, 115.5, 121.5, 126.7, 128.3, 128.4, 128.5, 128.6, 128.8, 133.8, 137.8, 141.5, 151.2, 203.7.
The enantiomeric excess of 2a was determined according to the following procedure: EtOH (20 mL) and HCl (2 M, 20 mL) were added to 2a at r.t. and the mixture was stirred for 2 d. The solvent was evaporated under vacuum and to the residue was added H₂O (10 mL) and the resulting mixture was extracted with EtOAc (3 × 10 mL). The combined organic phase was washed with brine and dried over Na₂SO₄. The solvent was then removed under vacuum. Purification by flash chromatography on silica gel afforded 3a (PE-EtOAc, 200:1). IR (KBr): 3514, 3419, 2957, 2926, 2871, 1677, 1595, 1488, 1452, 1446, 1258, 1223, 1211, 750, 768, 696, 685 cm^-1. MS: m/z = 363 [M⁺], 258 (100), 244 (39), 105 (23), 91 (30), 77 (40). 3a ^¹ : yellow solid; mp 99.1-102.5 °C. ¹H NMR (300 MHz, CDCl₃): δ = 0.67 (t, J = 7.3 Hz, 3 H), 1.75 (m, 2 H), 2.99 (q, J = 4.8 Hz, 1 H), 4.75 (d, J = 9.2 Hz, 1 H), 5.03 (q, J = 4.6 Hz, 1 H), 6.36 (q, J = 6.7 Hz, 2 H), 6.98 (q, J = 6.7 Hz, 2 H), 7.20-7.26 (m, 5 H), 7.43-7.48 (m, 2 H), 7.54-7.57 (m, 1 H), 7.85-7.88 (q, J = 10.0 Hz, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 12.1, 22.5, 50.9, 64.5, 115.4, 122.9, 127.1, 128.4, 128.7, 128.9, 129.1, 133.6, 135.8, 146.6, 200.6.
3a ^² : yellow oil. ¹H NMR (300 MHz, CDCl₃): δ = 0.84 (t, J = 7.3 Hz, 3 H), 1.90 (m, 2 H), 3.09 (m, 1 H), 4.31 (d, J = 9.2 Hz, 1 H), 5.16 (q, J = 4.4 Hz, 1 H), 6.57 (q, J = 6.8 Hz, 2 H), 6.98 (m, 2 H), 7.04 (q, J = 6.8 Hz, 2 H), 7.22-7.26 (m, 3 H), 7.48-7.62 (m, 3 H), 7.92-7.95 (m, 2 H). ¹³C NMR (75 MHz, CDCl₃): δ = 12.5, 25.4, 50.8, 62.9, 115.4, 122.9, 127.2, 128.4, 128.4, 128.7, 129.0, 129.1, 133.6, 136.0, 138.8, 146.4, 199.9. Enantiomeric excess: 87%, 87%, determined by chiral HPLC analysis [Daicel Chiralcel AS; hexane-i-PrOH = 99:1, flow = 1.0 mL/min, t _R (3a ^¹ ) = 12.49 min, 18.19 min; t _R (3a ^² ) = 13.95 min, 22.65 min].

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Crystal data of 3c: C₂₃H₂₁ClFNO, MW = 381.86, orthorhombic, space group P2(1)2(1)2(1), a = 9.682(2), b = 19.389(3), c = 21.673(4) Å, α = 90°, β = 90°, γ = 90°, V = 4068.5(13) ų, T = 296(2) K, Z = 8, D _c = 1.247 mg/m³, µ = 0.208 mm^-1, λ = 0.71073 Å, F(000) = 464, crystal size: 0.60 × 0.50 × 0.36 mm³, 9078 reflections collected, 7582 independent reflections [R(int) = 0.0203]; refinement method: full-matrix least-squares on F²; goodness-of-fit on F ^² = 0.804, final R indices [I > 2σ(I)] R1 = 0.0419, wR2 = 0.0853 (CCDC no. 618359).