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

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

References and notes

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11

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.

12

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.