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

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.

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

References and Notes

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14

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.

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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.

19 Allevi P. Anastasia M. Tetrahedron Lett.  2003,  44:  7663