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Synlett 2006(6): 877-880  
DOI: 10.1055/s-2006-939044
LETTER
© Georg Thieme Verlag Stuttgart · New York

A General and Facile Synthetic Approach to N α-Boc Ureidoalanine Derivatives

Hanbing Teng, Yunjiao He, Lamei Wu, Jiangtao Su, Xichun Feng, Guofu Qiu, Shucai Liang, Xianming Hu*
State Key Laboratory of Virology, College of Pharmacy, Wuhan University, Wuhan 430072, P. R. of China
Fax: +86(27)68754629; e-Mail: xmhu@whu.edu.cn;
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Publication History

Received 14 December 2005
Publication Date:
14 March 2006 (online)

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Abstract

We report a new and facile synthetic approach to N α-Boc ureidoalanine derivatives from commercially available Boc-l-aspartic acid. Not only N′-substituted but also N′,N′-disubstituted ureidoalanine derivatives may be obtained by this method. The key aspect of this method is the employment of a 5-oxazolidinone to provide proper protection of the α-nitrogen of l-aspartic acid. This ensures successful obtainment of the corresponding isocyanate by a Curtius rearrangement.

Key words

ureidoalanine - amino acids - protecting groups - 5-oxazolidinone - Curtius rearrangement

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Typical Procedure for the Preparation of Compounds 9.
Compound 7 (10 mmol) was dissolved in dry THF (30 mL) and cooled to -15 °C. After addition of EtOCOCl (11 mmol) and NMM (12 mmol), the mixture was stirred for 20 min. A solution of NaN3 (25 mmol) in H2O (5 mL) was added and stirred for 1 h at -10 °C. The solution was then diluted with H2O and extracted with EtOAc (150 mL). The organic layers were washed with brine (2 × 10 mL), dried over Na2SO4 and concentrated under reduced pressure to give crude acyl azide. This crude acyl azide can be further purified by a flash column chromatography (PE-EtOAc, 2:1, R f = 0.7). Purified acyl azide was dissolved in toluene (30 mL) and the resulting solution was heated to 75 °C under stirring. After gas evolution had stopped the toluene was removed under reduced pressure to afford isocyanate 8 as clear oil. This isocyanate 8 was directly used in the next step without further purification. Amine (8 mmol) was added to a stirred suspension of isocyanate in CH2Cl2 (40 mL) at r.t. (when highly reactive amines are used, they should be dissolved in solvent and added dropwise). The solvent was removed under reduced pressure when the reaction was complete (detected by TLC) and the products were purified by a column chromatography.
Compound 9a: white foam; R f = 0.3 (EtOAc). [α]D 20 +65.8 (c 1, MeOH). 1H NMR (300 MHz, CDCl3): δ = 1.48 (s, 9 H), 3.62-3.82 (m, 2 H), 4.21 (br s, 1 H), 5.05 (s, 2 H, NH2), 5.19 (d, 1 H, J = 3.9 Hz), 5.38 (br s, 1 H), 5.90 (br s, 1 H, NH). 13C NMR (150 MHz, CDCl3): δ = 28.24, 40.22, 56.09, 78.43, 82.53, 152.12, 159.29, 171.99. MS: m/z = 259 [M+]. Anal. Calcd for C10H17N3O5: C, 46.33; H, 6.61; N, 16.21. Found: C, 46.57; H, 6.56; N, 16.11.
Compound 9h: white foam; R f = 0.6 (PE-EtOAc, 1:1); [α]D 20 +114.4 (c 1, MeOH). 1H NMR (300 MHz, CDCl3): δ = 1.48 (s, 9 H), 3.24 (s, 3 H), 3.58-3.76 (m, 1 H), 4.19 (s, 1 H), 4.64-4.80 (m, 1 H, NH), 5.09 (d, 1 H, J = 3.6 Hz), 5.38 (br s, 1 H), 7.21-7.42 (m, 5 H). 13C NMR (150 MHz, CDCl3): δ = 28.44, 37.50, 40.95, 55.05, 78.28, 82.51, 127.54, 127.83, 130.30, 143.09, 152.27, 157.09, 171.96. MS: m/z = 349 [M+]. Anal. Calcd for C17H23N3O5: C, 58.71; H, 6.70; N, 12.25. Found: C, 58.44; H, 6.64; N, 12.03.
Compound 9k: white foam; R f = 0.4 (PE-EtOAc, 1:1); [α]D 20 +140.2 (c 1, MeOH). 1H NMR (300 MHz, CDCl3): δ = 1.46 (s, 9 H), 3.50-3.72 (m, 2 H), 4.15-4.26 (m, 3 H), 5.06 (br s, 1 H), 5.32 (br s, 1 H), 5.53-5.64 (m, 2 H, NH), 7.19-7.25 (m, 5 H). 13C NMR (150 MHz, CDCl3): δ = 27.19, 39.29, 43.16, 54.51, 77.29, 81.31, 126.07, 126.28, 127.45, 138.36, 151.06, 157.33, 170.94. MS: m/z = 349 [M+]. Anal. Calcd for C17H23N3O5: C, 58.44; H, 6.64; N, 12.03. Found: C, 58.63; H, 6.34; N, 11.96.

18

Typical Procedure for the Preparation of Compounds 10. Compound 9 (5 mmol) was dissolved in MeOH (20 mL) and 1 N NaOH (10 mL) was added. The mixture was stirred at r.t. till TLC indicated 9 was exhausted. Then, MeOH was removed under reduced pressure and the solution was washed with EtOAc (2 × 10 mL). The aqueous solution was then acidified to pH 2 with 1 N HCl and extracted with EtOAc (4 × 20 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated to give 10.
Compound 10a: white foam; yield 90%; [α]D 20 -13.2 (c 1, MeOH). 1H NMR (300 MHz, CDCl3): δ = 1.43 (s, 9 H), 3.49-3.74 (m, 2 H), 4.30 (br s, 1 H), 6.27 (br s, 2 H, NH2), 6.66 (br s, 1 H, NH). 13C NMR (150 MHz, CDCl3): δ = 28.32, 41.86, 54.42, 80.45, 156.22, 161.25, 174.20. MS: m/z = 247 [M+]. Anal. Calcd for C9H17N3O5: C, 43.72; H, 6.93; N, 17.00. Found: C, 43.97; H, 6.68; N, 17.23.
Compound 10h: white foam; yield 92%; [α]D 20 -1.3 (c 1, MeOH). 1H NMR (300 MHz, CDCl3): δ = 1.42 (s, 9 H), 3.25 (s, 3 H), 3.48-3.63 (m, 2 H), 4.20 (br s, 1 H), 5.02 (br s, 1 H, NH), 5.92 (br s, 1 H), 7.23-7.43 (m, 5 H). 13C NMR (150 MHz, CDCl3): δ = 28.51, 37.75, 43.13, 55.18, 80.45, 127.53, 127.95, 130.34, 142.76, 156.39, 158.43, 172.90. MS: m/z = 337 [M+]. Anal. Calcd for C16H23N3O5: C, 56.96; H, 6.87; N, 12.46. Found: C, 60.24; H, 7.16; N, 12.23.
Compound 10k: white foam; yield 95%; [α]D 20 -1.4 (c 1, MeOH). 1H NMR (300 MHz, CDCl3): δ = 1.37 (s, 9 H), 3.45-3.54 (m, 2 H), 4.16-4.30 (m, 3 H), 6.05-6.32 (br, 2 H, NH), 7.21-7.26 (m, 5 H), 8.19 (br, 1 H, NH). 13C NMR (150 MHz, CDCl3): δ = 28.27, 42.33, 44.29, 55.08, 80.53, 127.18 127.35, 128.53, 138.83, 156.37, 159.77, 173.63. MS:
m/z = 337 [M+]. Anal. Calcd for C16H23N3O5: C, 56.96; H, 6.87; N, 12.46. Found: C, 60.17; H, 7.13; N, 12.65.