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Synlett 2012(6): 948-950  
DOI: 10.1055/s-0031-1290613
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Direct Bifunctional Squaramide-Catalyzed Asymmetric N-Nitroso Aldol Reaction of Tertiary β-Carbonyl Esters

Hong-Jun Yang, Le Dai, Shi-Qiong Yang, Fen-Er Chen*
Fudan-DSM Joint Lab for Synthetic Method and Chiral Technology, Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, P. R. of China
Fax: +86(21)65643811; e-Mail: rfchen@fudan.edu.cn;
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Publication History

Received 31 December 2011
Publication Date:
15 March 2012 (online)

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Abstract

Enantioselective asymmetric N-nitroso aldol reaction of tertiary β-carbonyl esters using the bifunctional squaramide organanocatalysts is described. These adducts have been obtained in moderate yields and with up to 98% ee.

Key words

N-nitroso aldol reaction - bifunctional squaramide catalysts - asymmetric catalysis - β-carbonyl esters - nitrosobenzene

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Typical Experimental Procedure for α-Hydroxy-amination Reaction of β-Carbonyl Esters Using Squaramide Catalyst at Room Temperature: To a solution of squaramide catalyst 3 (5 mol%) in Et2O (1.0 mL) were added nitrosobenzene 2 (0.125 mmol, 1.2 equiv) and β-carbonyl esters 1 (1.0 equiv). The mixture was stirred at r.t. until TLC analysis showed that 1 was completely consumed. The reaction was directly purified by silica gel chroma-tography to afford the desired product 4. Enantiomeric excess was determined by HPLC analysis using AD-H or OJ-H, AS-H column. Benzyl 1-[hydroxy(phenyl)amino]-2-oxocyclopentane-carboxylate (4b): purification by column chromatography on silica gel (PE-EtOAc, 15:1 → 8:1); enantiomeric excess was determined by HPLC; [α]D ²0
-43.44˚ (c = 1.0, CHCl3). IR: 3386, 2961, 2918, 2849, 1759, 1724, 1597, 1491, 1263, 1115, 759, 694 cm-¹. ¹H NMR (400 MHz, CDCl3): δ = 1.26 (t, J = 7.0 Hz, 3 H), 1.89-1.95 (m, 2 H), 2.31-2.42 (m, 3 H), 2.51-2.58 (m, 1 H), 4.25 (q, J = 7.0 Hz, 2 H), 7.01 (t, J = 7.2 Hz, 1 H), 7.07 (d, J = 8.0, 3 H), 7.18 (t, J = 8.0 Hz, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 14.0, 18.6, 29.2, 37.4, 62.3, 80.7, 120.2, 124.1, 128.3, 148.8, 168.6, 209.9. HRMS (ESI): m/z [M + Na]+ calcd for C14H17NO4Na: 286.1055; found: 286.1064. HPLC analysis (Daicel Chiralcel AD-H, 0.46 cm × 25 cm), hexane-i-PrOH (93:7), flow rate: 0.5 mL/min, t R ( minor) = 35.1 min, t R ( major) = 25.9 min, 98% ee.

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To a solution of hydroxyamination adduct 4b (0.125 mmol) in CH2Cl2 (1.0 mL) were added AcOH (0.6 mL) and Zn dust (60 mg) at 0 ˚C. The mixture was stirred vigorously at 30 ˚C. When the reaction was completed, the reaction mixture was treated with sat. aq NaHCO3, and extracted with CH2Cl2. The combined organic layer was washed with brine, dried over anhyd Na2SO4, and concentrated in vacuo. The crude residue was purified by flash column chromatography (15% EtOAc-PE) to afford product 5b. Enantiomeric excess was determined by HPLC; [α]D ²0 34.26˚ (c = 1.0, CHCl3). IR: 3375, 2978, 2919, 1757, 1724, 1603, 1504, 1261, 1221, 1178, 1025, 751, 693 cm-¹. ¹H NMR (400 MHz, CDCl3) :
δ = 1.07 (t, J = 7.6 Hz, 3 H), 2.06-2.27 (m, 3 H), 2.38-2.49 (m, 1 H), 2.55-2.16 (m, 1 H), 3.04-3.15 (m, 1 H), 4.02-4.18 (m, 2 H), 4.76 (s, 1 H), 6.64 (d, J = 8.0 Hz, 2 H), 6.79 (t, J = 7.8 Hz, 1 H), 7.17 (t, J = 7.8 Hz, 2 H). ¹³C NMR (100 MHz, CDCl3): δ = 13.8, 18.3, 34.5, 35.3, 62.0, 70.8, 115.1, 119.0, 129.1, 1445.1, 169.3, 211.2. HRMS (ESI): m/z [M + H]+ calcd for C14H18NO3: 248.1287; found: 248.1286. HPLC analysis (Daicel Chiralcel AD-H, 0.46 cm × 25 cm), hexane-i-PrOH (93:7), flow rate: 0.5 mL/min, t R ( minor) = 14.9 min, t R ( major) = 13.1 min, 98% ee.