Synlett 2009(9): 1506-1510  
DOI: 10.1055/s-0029-1217167
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

A Simple Synthesis of Imide-Dipeptides

Damei Kea,b, Chuanlang Zhan*a, Xiao Lia,b, Alexander D. Q. Lic, Jiannian Yao*a
a Beijing National Laboratory of Molecular Science (BNLMS), Laboratory of Photochemistry, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, P. R. of China
Fax: +86(10)82616517; e-Mail: [email protected]; e-Mail: [email protected];
b Graduate School, Chinese Academy of Sciences, Beijing 100039, P. R. of China
c Department of Chemistry, Washington State University, Pullman, Washington 99164, USA
Further Information

Publication History

Received 2 February 2009
Publication Date:
13 May 2009 (online)

Abstract

We report a simple approach to synthesize a new class of imide-dipeptides. This approach is mild, and the starting materials are the easily accessible amino acid derivatives. The imide-dipeptides were synthesized from the coupling of an amide and a 4-nitrophenyl activating ester of an amino acid. The acidic proton of the first amide was removed by 1 equivalent of n-butyl lithium to afford the corresponding amide anion which then reacted with the activating ester to give the desired imide derivatives.

    References and Notes

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13

A Typical Procedure to Synthesize the Imide-dipeptides
The amide (1.1 mmol) of an N-Boc-l-amino acid was dissolved in distilled THF (10 mL). Then, n-BuLi (1.1 equiv, 1.5 mM in hexane) was added at -76 ˚C. One hour later, the reaction mixture was injected into 4-nitrophenyl N-Boc-l-amino acid ester (1.0 mmol) in distilled THF (10 mL) and stirred overnight at r.t. The mixture was then refluxed for another 3 h. After removal of solvents, the residue was applied to chromatography to yield desired imide-dipeptides as a white solid.
Imide-dipeptide (1a)
After removal of solvents, the residue was applied to chromatography by using PE-EtOAc (4:1) as eluents to yield 1a as a white solid (200 mg, 0.56 mmol, 56%, R f = 0.2). ¹H NMR (400 MHz, CDCl3, 16.7 mM): δ = 9.21 (s, 1 H, imide NH), 5.02 (d, 2 H, carbamate NH, ³ J = 6.7 Hz), 4.57-4.52 (m, 2 H, α-proton, ³ J HN α= 8.0 Hz), 1.45 (s, 18 H, Boc H), 1.27 (t, 6 H, β-H of Ala, ³ J = 6.8 Hz) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 171.9, 154.5, 98.6, 79.6, 27.2, 16.5 ppm. ESI-MS: m/z = 359, 382 [+ Na+].
Imide-dipeptide (1b) After removal of solvents, the residue was applied to chromatography by using PE-EtOAc (3:1) as eluents to yield 1b as a white solid (300 mg, 0.68 mmol, 68%, R f = 0.2). ¹H NMR (400 MHz, CDCl3, 10 mM): δ = 9.02 (s, 1 H, imide NH), 4.89 (d, 2 H, carbamate NH, ³ J = 7.7 Hz), 4.57 (br s, 2 H, α-protons), 1.74-1.60 (m, 4 H, β-H of Leu, ³ J = 5-7 Hz), 1.47-1.40 (m, 2 H, γ-H of Leu, ³ J = 4.8 Hz), 1.45 (s, 18 H, Boc H), 0.98-0.94 (q, 12 H, δ-H of Leu, ³ J = 6.5, 5.2 Hz) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 173.3, 156.0, 80.6, 54.0, 40.7, 28.4, 24.9, 23.3, 21.5 ppm. ESI-MS: m/z = 443, 466 [+ Na+].
Imide-dipeptide (1c) After removal of solvents, the residue was applied to chromatography by using PE-EtOAc (5:1) as eluents to yield 1c as a white solid (290 mg, 0.65 mmol, 65%, R f = 0.2). ¹H NMR (400 MHz, CDCl3): δ = 9.13 (s, 1 H, imide NH), 7.19-7.16 (m, 6 H, phenyl H, ³ J = 6.0 Hz), 7.01-7.00 (d, 4 H, phenyl H, ³ J = 6.4 Hz), 4.94 (d, 2 H, carbamate NH, ³ J = 8.0 Hz), 4.57 (q, 2 H, α-protons, ³ J = 8.2 Hz), 3.01 (d, 4 H, BnCH2, ³ J = 6.0 Hz), 1.45 (s, 18 H, Boc H) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 174.0, 156.0, 139.5, 128.7, 127.6, 126.2, 80.6, 54.5, 37.8, 28.4 ppm. ESI-MS: m/z = 511, 534 [+ Na+].
Imide-dipeptide (1d) After removal of solvents, the residue was applied to chromatography by using PE-EtOAc (3:1) as eluents to yield 1d as a white solid (400 mg, 0.54 mmol, 54%, R f = 0.2). ¹H NMR (400 MHz, CDCl3): δ = 8.96 (s, 1 H, imide NH), 7.35-7.26 (m, 10 H, phenyl H, ³ J = 6.0 Hz), 5.15 (s, 2 H, Cbz NH), 5.06 (s, 4 H, BnCH2), 4.95 (s, 2 H, carbamate NH), 4.30 (m, 2 H, α-protons, ³ J = 8.0 Hz), 3.11 (m, 4 H, CH2, ³ J = 6.0 Hz), 1.79 (br s, 2 H, CH2), 1.65 (m, 2 H, CH2, ³ J = 7.9 Hz), 1.47-1.32 (m, 8 H, CH2, ³ J = 7.4 Hz), 1.45 (s, 18 H, Boc H) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 173.9, 156.0, 141.1, 128.6, 128.2, 80.6, 66.6, 53.4, 41.0, 32.0, 29.4, 28.4, 22.5 ppm. ESI-MS: m/z = 741, 764 [+ Na+].
Imide-dipeptide (1e) After removal of solvents, the residue was applied to chromatography by using PE-EtOAc (4:1) as eluents to yield 1e as a white solid (430 mg, 0.68 mmol, 68%, R f = 0.2). ¹H NMR (400 MHz, CDCl3, 10 mM): δ = 9.09 (s, 1 H, imide NH), 7.29-7.13 (m, 10 H, phenyl H), 5.22 (s, 1 H, Cbz NH), 5.06 (m, 1 H, carbamate NH, overlapping, ³ J = 7.2 Hz), 5.03 (s, 2 H, BnCH2), 4.91 (s, 1 H, carbamate NH), 4.73 and 4.67 (br s, 1 H, α-protons), 4.46 (br s, 1 H, α-protons), 3.11 (s, 2 H, CH2), 3.11 (br s, 1 H, BnCH2, overlapping), 2.85 (br s, 1 H, BnCH2), 1.74 (br s, 2 H, CH2), 1.47 (m, 4 H, CH2, ³ J = 6.4 Hz), 1.29 and 1.20 (s, 18 H, Boc H) ppm.¹³C NMR (100 MHz, CDCl3): δ = 172.7, 171.9, 156.7, 155.9, 155.4, 136.5, 135.8, 129.4, 128.6, 128.5, 128.1, 127.1, 80.4, 66.7, 56.3, 55.1, 40.1, 37.5, 31.0, 29.2, 28.3, 22.4 ppm. ESI-MS: m/z = 626, 749 [+ Na+].
Imide-dipeptide (1f) After removal of solvents, the residue was applied to chromatography by using PE-EtOAc (5:1) as eluents to yield 1f as a white solid (290 mg and 310 mg, 0.56 mmol and 0.60 mmol, 56% and 60%, R f = 0.2). ¹H NMR (400 MHz, CDCl3): δ = 8.89-8.82 (d, 1 H, imide NH), 7.35-7.17 (m, 10 H, phenyl H), 5.29 (s, 1 H, Cbz NH), 5.05 (s, 2 H, BnCH2), 5.00 (d, 1 H, carbamate NH, ³ J = 8.4 Hz), 5.00 (m, 1 H, α-protons, overlapping), 4.57 (m, 1 H, α-protons, ³ J = 8.2 Hz), 3.11 (m, 1 H, BnCH2), 2.85 (m, 1 H, BnCH2), 1.74-1.60 (m, 2 H, β-H of Leu, ³ J = 5-7 Hz), 1.47-1.40 (m, 1 H, γ-H of Leu, ³ J = 4.8 Hz), 1.45 (s, 9 H, Boc H), 0.98-0.88 (q, 6 H,
δ-H of Leu, ³ J = 6.5, 5.2 Hz) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 174.0, 173.3, 156.2, 156.0, 141.1, 140.3, 129.5, 128.7, 128.6, 128.5, 128.2, 127.1, 80.6, 66.0, 54.9, 54.0, 40.7, 37.8, 28.4, 24.9, 23.3, 22.2 ppm. ESI-MS: m/z = 511, 534 [+ Na+].

14

Typical Procedure for the Synthesis of 4-Nitrophenyl N -Boc- l -alanine Ester and N -Boc- l -alanine Amide
N -Boc- l -alanine Acid
l-Alanine (4.5g, 50 mmol) and KOH (3.8 g, 55 mmol) were dissolved in a mixture of H2O (200 mL) and THF (20 mL). Then, di-tert-butyl-dicarbonate (13.0 g, 55 mmol) was added. The resultant solution was allowed to react at 50 ˚C for 2-3 h and at r.t. overnight. Then, 1 M HCl (55 mL) was added dropwise to adjust pH value of the solution to about 5. The solution was extracted with EtOAc (3 × 200 mL) and CH2Cl2 (3 × 200 mL), respectively. The organic phases were mixed and dried with anhyd Na2SO4. The reaction afforded N-Boc-l-alanine acid as an oil-like solid (9 g, 47 mmol, 95%). ¹H NMR (400 MHz, CDCl3): δ = 10.66 (br s, 1 H, acid H), 5.08 (s, 1 H, carbamate H), 4.35 (s, 1 H, α-proton), 1.53 (d, 3 H, CH3, ³ J = 7.6 Hz), 1.45 (s, 9 H, Boc H) ppm. ESI-MS: 188 [- H+], 189, 211 [- H+ and + Na+], 227 [- H+ and
+ K+].
4-Nitrophenyl N -Boc- l -alanine Ester N-Boc-l-alanine acid (1.9 g, 10 mmol), 4-nitrophenol (1.7 g, 12 mmol), and DCC (2.8 g, 12 mmol) were mixed with CH2Cl2 (100 mL). After stirred overnight at r.t., the precipitate was filtered out, and the solvents of the filtration were removed. The resultant residue was applied to flash chromatography with PE-CH2Cl2-EtOAc (10:2:1) as eluents to afford 4-nitrophenyl N-Boc-l-alanine ester as a light yellow solid (2.6 g, 8.4 mmol, 85%, R f = 0.2). ¹H NMR (400 MHz, CDCl3): δ = 8.30 (d, 2 H, phenyl H, ³ J = 9.0 Hz), 7.32 (d, 2 H, phenyl H, ³ J = 9.0 Hz), 5.11 (s, 1 H, carbamate H), 4.54 (t, 1 H, α-proton, ³ J = 7.1, 6.5 Hz), 1.58 (d, 3 H, CH3, ³ J = 7.4 Hz), 1.47 (s, 9 H, Boc H). ¹³C NMR (100 MHz, CDCl3): δ = 171.4, 155.3, 155.2, 145.6, 125.4, 122.4, 80.5, 49.7, 28.4, 18.1. ESI-MS: m/z = 333 [+ Na+].
N - tert -Butoxycarbonyl- l -alanine Amide 4-Nitrophenyl N-Boc-l-alanine ester (2.40 g, 7.7 mmol) was dissolved in MeCN (30 mL) and bubbled by NH3 flow for
4-5 h. After removal of MeCN, the reacted residue was purified with chromatography using PE-CH2Cl2-EtOAc (1:1:1) as eluents to afford N-tert-butoxycarbonyl-l-alanine amide as white solid (1.4 g, 7.4 mmol, 96%, R f = 0.1). ¹H NMR (400 MHz, CDCl3): δ = 6.04 (s, 1 H, amide H), 5.32 (s, 1 H, amide H), 4.89 (s, 1 H, carbamate H), 4.10 (s, 1 H, α-proton), 1.36 (s, 9 H, Boc H), 1.30 (d, 3 H, CH3, ³ J = 7.2) ppm. ¹³C NMR (100 MHz, CDCl3): δ = 171.7, 155.5, 80.3, 49.9, 28.3, 18.2 ppm. ESI-MS: m/z = 211 [+ Na+], 227 [+ K+].