Download PDF
Synlett 2007(2): 0273-0277  
DOI: 10.1055/s-2007-968012
LETTER
© Georg Thieme Verlag Stuttgart · New York

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

Yan-Jun Xua,b, Quan-Zhong Liu*a, Lin Dongb
a College of Chemistry and Chemical Engineering, China West Normal University, Nanchong 637002, P. R. of China
b Key Laboratory for Asymmetric Synthesis and Chirotechnology of Sichuan Province and Union Laboratory of Asymmetric Synthesis, Chengdu Institute of Organic Chemistry, Chinese Academy of Sciences, Chengdu 610041, P. R. of China
e-Mail: quanzhongliu@cwnu.edu.cn;
Further Information

Publication History

Received 18 July 2006
Publication Date:
24 January 2007 (online)

    Permissions and Reprints All articles of this category

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.

Key words

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

19

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].

20

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) Å3, 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).