An Atom-Efficient Direct Regioselective N(τ)-Allylation of Histidine Deriva­tives

Abstract

Protected N(τ)-allylhistidine has been been prepared by the first direct regioselective allylation procedure using the sterically bulky N(α)-Boc protection group to shield N(π) and thereby inducing regioselectivity. This afforded the N(τ)-allyl protected histidine building block in excellent yields without loss of optical purity.

Key words

histidine - allylation - regioselectivity - amino acid - alkylation

• References and Notes

• 1 Kimbonguila AM, Boucida S, Guibe F, Loffet A. Tetrahedron 1997; 53: 12525
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• 2b Kaur N, Monga V, Jain R. Tetrahedron Lett. 2004; 45: 6883
• 3 Jones JB, Hysert DW. Can. J. Chem. 1971; 49: 3012
• 4 Typical Procedure for the Allylation of N(α)-Boc-histidine Methyl Ester Commercially available N(α)-Boc-histidine methyl ester (1.0 equiv) and Cs₂CO₃ (2.0 equiv) were suspended in acetone, allyl bromide (1.0 equiv) was added, and the reaction mixture was stirred at ambient temperature for 4 h. The reaction mixture was filtered to remove the Cs₂CO₃ and evaporated to afford the crude N(α)-Boc-N(τ)-allylhistidine methyl ester (1) which was purified by flash chromatography on silica gel using EtOAc–heptane mixtures as the eluent. This afforded the desired product as a colorless oil in 96.2% after evaporation of the solvents. Optical purity was determined by HPLC using a Chiralpak IA stationary phase and a 1:1 mixture of EtOH and MeOH as the eluent. ¹H NMR (400 MHz, DMSO-d ₆): δ (major rotamer) = 1.36 (s, 9 H), 2.80 (d, J = 6.5 Hz, 2 H), 3.58 (s, 3 H), 4.22 (q, J = 7.3 Hz, 1 H), 4.55 (d, J = 5.6 Hz, 2 H), 5.03 (dd, J = 1.3, 17.1 Hz, 1 H), 5.17 (dd, J = 1.3, 10.2 Hz, 1 H), 5.90–6.01 (m, 1 H), 6.83 (s, 1 H), 7.13 (d, J = 7.9 Hz, 1 H) 7.52 (s, 1 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ (major rotamer) = 28.1, 29.7, 48.3, 51.6, 53.7, 78.2, 116.8, 117.1, 134.5, 136.9, 137.1, 155.2, 172.5. MS (ES⁺): m/e calcd: 310.18 [M + H]; found: 310.22 [M + H].
• 5 N(α)-Boc-N(τ)-benzylhistidine Methyl Ester ¹H NMR (400 MHz, DMSO-d ₆): δ (major rotamer) = 1.34 (s, 9 H), 2.78 (d, J = 6.5 Hz, 2 H), 3.53 (s, 3 H), 4.21 (q, J = 7.3 Hz, 1 H), 5.13 (s, 2 H), 6.88 (s, 1 H), 7.12 (d, J = 8.0 Hz, 1 H), 7.21 (d, J = 7.5 Hz, 2 H), 7.25–7.37 (m, 3 H), 7.67 (s, 1 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ (major rotamer) = 28.1, 29.7, 49.4, 51.6, 53.7, 78.2, 116.8, 127.3, 127.6, 128.6, 137.1, 137.3, 137.8, 155.2, 172.5. MS (ES⁺): m/e calcd: 360.19 [M + H]; found: 360.24 [M + H].
• 6 N(α)-Boc-N(τ)-propylhistidine Methyl Ester ¹H NMR (400 MHz, DMSO-d ₆): δ (major rotamer) = 0.78 (t, J = 7.4 Hz, 3 H), 1.34 (s, 9 H), 1.66 (sext, J = 7.1 Hz, 2 H), 2.79 (d, J = 6.5 Hz, 2 H), 3.57 (s, 3 H), 3.83 (t, J = 6.5 Hz, 2 H), 4.22 (q, J = 6.9 Hz, 1 H), 6.87 (s, 1 H), 7.09 (d, J = 8.0 Hz, 1 H), 7.51 (s. 1 H). ¹³C NMR (150 MHz, DMSO-d ₆): δ (major rotamer) = 10.7, 23.8, 28.1, 29.7, 47.5, 51.6, 53.8, 78.2, 116.5, 136.8, 136.9, 155.2, 172.5. MS (ES⁺): m/e calcd: 312.19 [M + H]; found: 312.23 [M + H].