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Synlett 2010(4): 607-609  
DOI: 10.1055/s-0029-1218391
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Stefanie Roth, Neil R. Thomas*
School of Chemistry, Centre for Biomolecular Sciences, University of Nottingham, University Park, Nottingham NG7 2RD, UK
Fax: +44(115)9513564; e-Mail: neil.thomas@nottingham.ac.uk;
Further Information

Publication History

Received 1 October 2009
Publication Date:
27 November 2009 (online)

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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.

Key words

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

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, Hβ 1), 2.29 (m, 1 H, Hβ 2), 2.92 (s, 3 H, SO2CH3), 4.24 (m, 2 H, Hγ), 4.43 (m, 1 H, Hα), 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 (Cβ), 37.1 (SO2CH3), 50.4 (Cα), 65.8 (Cγ), 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, Hβ 1), 2.08 (m, 1 H, Hβ 2), 3.34 (t, J = 6.7 Hz, 2 H, Hγ), 4.41 (m, 1 H, Hα), 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 (Cβ), 47.6 (Cγ), 51.5 (Cα), 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.

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).