Enantioselective Nucleophilic Aromatic Substitution Reaction of Azlactones to Synthesize Quaternary α-Amino Acid Derivatives

Abstract

An asymmetric organocatalytic nucleophilic aromatic substitution reaction of azlactones with electron-deficient aryls was established. A variety of α-aryl α-alkyl α-amino acid esters and peptides were obtained in decent yields and stereoselectivities. A new bifunctional catalytic mode involving charge-transfer interaction and hydrogen bonding is proposed to explain the enantioselectivity.

Key words

amino acid esters - peptides - asymmetric catalysis - S_NAr reaction - electron donor–accepter complexes - organocatalysis

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• 13 Chiral Guanidine-Catalyzed Asymmetric S_NAr Reaction; General Procedure A dry tube was charged with G-3 (8.3 mg, 15 mol%), K₃PO₄·H₂O (116 mg, 0.5 mmol), and the appropriate fluoroarene 2 (0.2 mmol). Under a N₂ atmosphere, CHCl₃ (0.3 mL) was added, and the mixture was stirred at 35 °C for 30 min, then cooled to –60 °C for 10 min. The appropriate azlactone 1 (0.1 mmol) was added with stirring, and the mixture was stirred at –60 °C for about 72 h until 1 was fully consumed (TLC). MeOH (1 mL) and DAMP (1.2 mg, 10 mol%) were then added, and the mixture was stirred for about 15 mins at 35 °C. The product was purified by flash column chromatography [silica gel, PE–DCM (1:1)]. Methyl α-(2,4-dinitrophenyl)-N-(4-Fluorobenzoyl)-l-phenylalaninate (3b) White solid; yield: 39.7 mg (85%; 89% ee); mp 186–188 °C; [α]_D ¹⁶ –26.4 (c 0.664, CH₂Cl₂). UPC² (chiral IB-3 column, CO₂ /MeOH = 90:10, flow rate 1.5 mL/min, λ = 254 nm): t _R (minor) = 4.1 min; t _R (major) = 5.3 min. ¹H NMR (400 MHz, CDCl₃): δ = 8.57–8.51 (m, 1 H), 8.46–8.40 (m, 1 H), 8.29–8.21 (m, 1 H), 7.60–7.51 (m, 2 H), 7.32–7.19 (m, 3 H), 7.14–6.93 (m, 5 H), 4.33 (d, J = 18.8 Hz, 1 H), 3.85 (s, 3 H), 3.75 (d, J = 18.8 Hz, 1 H). ¹³C NMR (100 MHz, CDCl₃): δ = 169.4, 166.4 (d, J = 251.7 Hz), 165.6, 148.3, 147.1, 140.3, 133.4, 130.8, 130.1, 129.4 (d, J = 9.1 Hz), 129.2 ( d, J = 3.2 Hz), 128.5, 128.0, 126.4, 119.8, 116.0 (d, J = 22.1 Hz), 64.0, 53.8, 40.5. ¹⁹F NMR (376 MHz, CDCl₃): δ = –106.6. ESI-HRMS: m/z [M + H]⁺ calcd for C₂₃H₁₉FN₃O₇ = 468.1202; found: 468.1191.