Asymmetric PTC Alkylation of Glycine Imines: Variation of the Imine Ester Moiety

Abstract

Studies into the enantioselective phase-transfer alkylation of a series of glycine imine esters are presented. Using a quaternary ammonium salt catalyst derived from α-methyl-naphthylamine, high enantioselectivities were obtained in reactions involving imines containing tert-butyl, benzhydryl, and benzyl esters. In contrast, a quaternary ammonium salt catalyst derived from dihydrocinchonidine gave highest enantioselectivities with tert-butyl and ethyl esters. Application of the benzhydryl ester alkylation in the preparation of a differentially protected aspartic acid derivative is also presented.

Key words

amino acids - asymmetric alkylation - phase-transfer catalysis - quaternary ammonium salts

References

• For recent reviews covering phase-transfer alkylation of glycine imines see:
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9

Representative Procedure: A solution of salt ent-4 (1.2 mg, 1 mol%) and imine 1b (50 mg, 0.12 mmol) in toluene (4 mL) was cooled to 0 °C, degassed, and placed under an argon atmosphere. tert-Butyl bromoacetate (22 µL, 0.14 mmol) was added followed by degassed 15 M aq KOH (1mL). The resulting mixture stirred at 1500 rpm for 45 min, then diluted with H₂O (5 mL) and extracted with EtOAc (3 × 4 mL). The combined organic extracts were dried (MgSO₄) and concentrated under reduced pressure. Residual tert-butyl bromoacetate was removed under vacuum (1 mm Hg, r.t.) to afford imine 2b′′′ as a colourless oil (64 mg, 100%, 86% ee). ¹H NMR (400 MHz, CDCl₃): δ = 7.62-7.60 (2 H, m, ArH), 7.41-7.23 (16 H, m, ArH), 7.16-7.13 (2 H, m, ArH), 6.89 (1 H, s, OCHPh₂), 4.58 (1 H, dd, J = 7.5, 5.5 Hz, H-2), 2.99 (1 H, dd, J = 15.5, 5.5 Hz, H-3a), 2.85 (1 H, dd, J = 15.5, 7.5 Hz, H-3b), 1.35 (9H, s, t-Bu). ¹³C NMR (100 MHz, CDCl₃): δ = 171.8 (C), 170.0 (C), 139.9 (C), 139.9 (C), 139.6 (C), 136.0 (C), 130.5 (CH), 129.0 (CH), 128.8 (CH), 128.5 (CH), 128.0 (CH), 128.0 (CH), 127.9 (CH), 127.4 (CH), 127.1 (CH), 80.8 (C), 77.5 (CH), 62.3 (CH), 39.5 (CH₂), 28.1 (CH₃). HPLC: Chiralpak AD column (150 × 2.1 mm), hexane/i-propanol (97.5/2.5), 0.2 mL/min, R_t = 13.9 min (R)-isomer, 18.8 min (S)-isomer.
Imine 2b′′′ (38 mg) was then dissolved in THF (1 mL) and treated with 15% aq citric acid (1 mL). The resulting solution was stirred at r.t. for 3 h, then washed with Et₂O (3 × 2 mL). The aqueous layer was basified (sat. aq K₂CO₃) and extracted with CHCl₃ (3 × 5 mL). The combined organic extracts were dried (MgSO₄) and concentrated under reduced pressure to afford amine 5 as a colourless oil (22 mg, 85%). ¹H NMR (400 MHz, CDCl₃): δ = 7.36-7.27 (10 H, m, ArH), 6.92 (1 H, s, OCHPh₂), 3.84 (1 H, dd, J = 6.5, 4.5 Hz, H-2), 2.80 (1 H, dd, J = 16.5, 4.5 Hz, H-3a), 2.72
(1 H, dd, J = 16.5, 6.5 Hz, H-3b), 1.88 (2 H, s, broad, NH₂), 1.38 (9 H, s, t-Bu). ¹³C NMR (100 MHz, CDCl₃): δ = 173.5 (C), 170.3 (C), 139.8 (C), 128.6 (CH), 128.6 (CH), 128.2 (CH), 128.1 (CH), 127.2 (CH), 127.2 (CH), 81.5 (C), 77.8 (CH), 51.6 (CH), 39.8 (CH₂), 28.1 (CH₃)