An Improved Synthesis of β-Cyano-l-Alanine Esters and Amides

Abstract

We have developed a novel, mild, efficient, and scalable protocol for the synthesis of N-protected β-cyano-l-alanine esters or ­amides from N-protected l-asparagin. This protocol avoided the use of toxic or unpleasant reagents and was easy to operate in laboratory.

Key words

l-asparagin - β-cyano-l-alanine - EDC·HCl - DCC

• References and Notes

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• 10 General Procedures for the Synthesis of β-Cyano-l-Alanine Esters and Amides To a stirred solution of N-protected l-asparagin 1a–c (0.10 mmol) and alcohol or amine 2a–n (0.12 mmol) in CH₂Cl₂ (10 mL), EDC·HCl (0.30 mmol), and DMAP (0.02 mmol) were added at 0 °C. This reaction mixture was stirred for 12 h at r.t. Then the reaction mixture was poured in H₂O (10 mL) and extracted with CH₂Cl₂ (20 mL). The organic phase was separated, dried, and subjected to flash column chromatography (EtOAc–hexane, 1: 4) to afford the desired compounds as white solids.
• 11 Selected Spectral Data for Compound Benzyl 2-[(tert-Butoxycarbonyl)amino]-3-cyanopropanoate (4a) Yield: 288 mg (95%); white crystals, mp 131–133 °C. ¹H NMR (300 MHz, CDCl₃): δ = 7.45–7.35 (m, 5 H, ArH), 5.55 (d, J = 6.6 Hz, 1 H, NH), 5.26 (s, 2 H, CH₂), 4.55–4.51 (m, 1 H, COCH), 3.00–2.89 (m, 2 H, CH₂CN), 1.47 [s, 9 H, OC(CH₃)₃]. ¹³C NMR (75 MHz, CDCl₃): δ = 169.13, 155.05, 134.74, 116.54, 81.06, 68.40, 50.53, 28.36, 21.78. ESI-HRMS: m/z [M + Na]⁺ calcd for C₁₆H₂₀N₂O₄ + Na: 327.1321; found: 327.1309.