Selective N-Benzylation of Amino Acids under Homogeneously Catalyzed Hydrogenation Conditions

Abstract

The chemoselective N-benzylation of the α-amino acids l-proline, l-serine and l-threonine is described using a reductive amination procedure with benzaldehyde catalyzed by homogeneous Rh-complexes affording N-benzyl protected amino acids.

Key words

hydrogenation - transition metals - catalysis - amino ­acids

References

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7

( S )- N -Benzylproline. In a typical run, a 50-mL Parr autoclave was charged with 32 mg (0.0345 mmol) of commercial (Ph₃P)₃RhCl complex. Air was evacuated by three vacuum-Ar cycles. A solution of 4.00 g (34.7 mmol) of (S)-Pro in 30.0 mL MeOH (prepared in an Ar atmosphere) was introduced into the autoclave with a needle followed by addition of 5.3 mL (5.57 g, 52.4 mmol) of PhCHO. The autoclave was pressurized with 50 bar of H₂. The reaction mixture was stirred at r.t. for 3 d until uptake of H₂ ceased. The autoclave was opened and the resulted solution evaporated. The residue was triturated under acetone and the solid was filtered and washed twice with acetone. The product was dried on air. Mp 178-179 °C (Lit.⁵ mp 174-175 °C). [α]_D ²⁴ = -27.9 (c 1 in EtOH) [Lit.⁵ [α]_D ²⁰ = -25.8 (c 1 in EtOH)]. Anal. Calcd for C₁₂H₁₅NO₂: C, 70.22; H, 7.37; N, 6.82. Found: C, 70.12; H, 7.34; N, 6.79. ¹H NMR (CD₃OD-CDCl₃): δ = 1.89-2.12 (m, 2 H), 2.13-2.28 (m, 1 H), 2.33-2.49 (m, 1 H), 3.57-3.69 (m, 1 H), 3.89 (dd, 1 H, J = 9.1, 6.6 Hz, α-CH), 4.26 (d, 1 H, J = 12.8 Hz, CH _a H_bPh), 4.45 (d, 1 H, J = 12.8 Hz, CH_a H _b Ph), 7.38-7.54 (m, 5 H, ArH).
( S )- N -Benzylserine. Mp 214-216 °C (decomp.) (Lit.⁸ mp 235-236 °C). [α]_D ²⁴ = 5.6 (c 1 in 6 N HCl)[Lit.⁸ S-isomer [α]_D ²² = 4.9 (c 1 in 6 N HCl), R-isomer [α]_D ²² = -5.5 (c 1 in 6 N HCl)]. Anal. Calcd for C₁₀H₁₃NO₃: C, 61.53; H, 6.71; N, 7.18. Found: C, 61.42; H, 6.43; N, 7.16. ¹H NMR (CD₃OD-DCl conc.): δ = 4.05-4.26 (m, 3 H, α-H and β-H₂-Ser), 4.38 (d, 1 H, J = 13.0 Hz, PhCH _a H_b), 4.42 (d, 1 H, J = 13.0 Hz, PhCH_a H _b ), 7.44-7.52 (m, 3 H, ArH), 7.55-7.63 (m, 2 H, ArH). ¹³C NMR (CD₃OD- DCl conc.): δ = 51.78 (CH₂), 60.42 (CH₂), 62.35 (CH), 131.04 (CH), 131.61 (CH), 132.08 (CH), 132.23 (C), 170.54 (COO).
( S )- N -Benzylthreonine. Mp 237-238 °C. [α]_D ²⁴ = -15.1 (c 1 in 6 N HCl). Anal. Calcd for C₁₁H₁₅NO₃: C, 63.14; H, 7.23; N, 6.69. Found: C, 63.15; H, 7.07; N, 6.67. ¹H NMR (CD₃OD- DCl conc.): δ = 1.35 (d, 3 H, J = 6.5 Hz, Me), 3.72 (d, 1 H, J = 6.5 Hz, α-H), 4.24 (dq, 1 H, J = 6.5, 6.5 Hz, β-H), 4.36 (d, 1 H, J = 13.0 Hz, PhCH _a H_b), 4.42 (d, 1 H, J = 13.0 Hz, PhCH_a H _b ), 7.44-7.52 (m, 3 H, ArH), 7.53-7.60 (m, 2 H, ArH). ¹³C NMR (CD₃OD-DCl conc.): δ = 21.48 (CH₃), 52.32 (CH₂), 66.40 (CH), 67.50 (CH), 131.09 (CH), 131.74 (CH), 131.96 (C), 132.28 (CH), 170.40 (COO).