A Concise Route to l-Azidoamino Acids: l-Azidoalanine, l-Azidohomo­alanine and l-Azidonorvaline

Abstract

A simple and highly efficient synthetic route to three homologous azidoamino acids, starting from inexpensive, commercially available, protected natural amino acids is reported. The products can be used to introduce bioorthogonal handles into proteins.

amino acids - azides - bioorganic chemistry - bioorthogonal chemistry - non-canonical

References and Notes

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19

To a solution of alcohol 5 (269 mg, 0.87 mmol, 1.0 equiv)
in CH₂Cl₂ (5 mL) at 0 ˚C, was added Et₃N (288 µL, 2.09 mmol, 2.4 equiv) followed by dropwise addition of methylsulfonyl chloride (81 µL, 1.04 mmol, 1.2 equiv). The ice-bath was removed and the solution was stirred at r.t. for 15 min. Sat. NaHCO₃ (5 mL) was added and the layers were separated. The organic layer was washed with brine (2 × 5 mL) and the combined aqueous layer was back-extracted with CH₂Cl₂ (2 × 10 mL). The combined organic layer was dried over MgSO₄, the solids filtered off and the solvent removed in vacuo. The crude product was purified by column chromatography (silica; PE-EtOAc, 7:3) to give a colourless solid (312 mg, 0.81 mmol, 93%); mp 61-63 C (CHCl₃); [α]_D ^²8 -37.1 (c 0.11, CHCl₃); IR: 3009, 1711, 1500, 1364, 1175 cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 1.39 (s, 9 H, tBu), 2.08 (m, 1 H, H_{β 1}), 2.29 (m, 1 H, H_{β 2}), 2.92 (s, 3 H, SO₂CH₃), 4.24 (m, 2 H, H_γ), 4.43 (m, 1 H, H_α), 5.15 (s, 2 H, CH ₂Ph), 5.26 (bd, J = 7.0 Hz, 1 H, NH), 7.33 (m, 5 H, Ar); ^¹³C NMR (100 MHz, CDCl₃): δ = 28.2 [C(CH₃)₃], 31.8 (C_β), 37.1 (SO₂CH₃), 50.4 (C_α), 65.8 (C_γ), 67.5 (CH₂Ph), 80.3 [C(CH₃)₃], 128.4, 128.5, 128.7, 135.0 (Ar), 155.3 (t -BuOCONHR), 177.5 (CO₂Bn); MS (ESI+): m/z [M + Na]⁺ calcd for C₁₇H₂₅NNaO₇S: 410.1244; found: 410.1225.

20

To a solution of mesylate 6 (222 mg, 0.56 mmol, 1.0 equiv) in anhydrous DMF (2 mL), was added NaN₃ (54 mg, 0.84 mmol, 1.5 equiv) in one portion. The suspension was stirred at 40 ˚C for 4 h, then the solvent was removed in vacuo and the crude product was purified by column chromatography (silica; PE-EtOAc, 4:1). The azide 7 was obtained as a colourless oil (171 mg, 0.51 mmol, 92%); [α]_D ^²8 +2.8 (c 0.71, CHCl₃); IR: 3434, 2981, 2104, 1712, 1499, 1160 cm^-¹; ^¹H NMR (400 MHz, CDCl₃): δ = 1.41 (s, 9 H, tBu), 1.89 (m, 1 H, H_{β 1}), 2.08 (m, 1 H, H_{β 2}), 3.34 (t, J = 6.7 Hz, 2 H, H_γ), 4.41 (m, 1 H, H_α), 5.13 (d, J = 12.3 Hz, 1 H, CH ₂Ph), 5.18 (d, J = 12.3 Hz, 1 H, CH ₂Ph), 5.19 (br s, 1 H, NH), 7.34 (m, 5 H, Ar); ^¹³C NMR (100 MHz, CDCl₃): δ = 28.2 [C(CH₃)₃], 31.7 (C_β), 47.6 (C_γ), 51.5 (C_α), 67.3 (CH₂Ph), 80.2 [C(CH₃)₃], 128.3, 128.5, 128.6, 135.1 (Ar), 155.2 (tBuOCONHR), 171.8 (CO₂Bn); MS (ESI+): m/z [M + Na]⁺ calcd for C₁₆H₂₂N₄NaO₄: 357.1533; found: 357.1522.

21 Felix AM. J. Org. Chem.  1974,  39:  1427 

22

To a solution of protected amino acid 7 (33 mg, 0.1 mmol, 1 equiv) dissolved in anhydrous CH₂Cl₂ (2.5 mL) at -10 ˚C under an N₂ atmosphere, boron tribromide solution (1 M in CH₂Cl₂, 0.5 mL, 0.5 mmol, 5 equiv) was added dropwise over 5 min. The resulting solution was stirred for 1 h at
-10 ˚C and for 2 h at r.t. The reaction was quenched by careful addition of H₂O (2.5 mL), and then the layers were separated. The organic phase was washed with H₂O (3 × 5 mL) and the combined aqueous layer was evaporated to dryness. The crude product was re-dissolved in a minimum amount of ethanol and the pure product 2 was obtained by precipitation at 4 ˚C as a colourless crystalline solid (14 mg, 0.1 mmol, quantitative yield).