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Synlett 2009(3): 407-410  
DOI: 10.1055/s-0028-1087538
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

One-Pot Synthesis of Ureido Peptides and Urea-Tethered Glycosylated Amino Acids Employing Deoxo-Fluor and TMSN3

H. P. Hemantha, G. Chennakrishnareddy, T. M. Vishwanatha, V. V. Sureshbabu*
Peptide Research Laboratory, Department of Studies in Chemistry, Central College Campus, Dr. B. R. Ambedkar Veedhi, Bangalore University, Bangalore 560001, India
Fax: +91(80)22292848; e-Mail: hariccb@rediffmail.com;
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Publication History

Received 10 November 2008
Publication Date:
21 January 2009 (online)

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Abstract

A facile one-pot procedure for the synthesis of urea-linked peptidomimetics and neoglycopeptides under Curtius rearrangement conditions employing Deoxo-Fluor and TMSN3 is described. The method is efficient and circumvents the isolation of acyl azide and isocyanate intermediates. The rearrangement of the in situ generated acyl azide via the acyl fluoride was carried out under ultrasonication followed by amine capture to insert a urea bond. The protocol worked well with all the common N-urethane-protected amino acids and also with a sugar-6-acid.

Key words

peptidomimetics - neoglycopeptides - ureido linkage - acyl fluoride - Deoxo-Fluor

    References and Notes

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29

Typical Experimental Procedure for 2a
To a stirred solution of Fmoc-Ala-OH (1 mmol) in dry CH2Cl2, Et3N (2 mmol) and Deoxo-Fluor (1.4 mmol) were added at 0 ˚C. After the addition of TMSN3 (1.3 mmol), the reaction mixture was subjected to ultrasonication. After 10 min, H-Leu-OMe (1.5 mmol) was added, and the ultrasonication was continued until completion of the reaction. The reaction mixture was evaporated, hexane was added, and the residue was filtered. It was washed with H2O, hexane, and dried under vacuum. Finally, the compound was recrystallized using DMSO-H2O to afford the urea as a colorless crystalline solid.

30

Selected Spectroscopic Data
Fmoc-Val-ψ(NH-CO-NH)-Leu-OBzl (2b): white solid, mp 184 ˚C. ¹H NMR (300 MHz, DMSO): δ = 0.92 (12 H, m), 1.32-1.85 (4 H, m), 3.10 (2 H, s), 3.70-3.80 (2 H, m), 4.20 (1 H, t), 4.42 (2 H, m), 5.10 (1 H, d), 6.60-6.70 (2 H, m), 7.20-7.85 (13 H, m). ¹³C NMR (200 MHz, DMSO): δ = 18.5, 19.5, 22.0, 23.1, 24.5, 29.2, 40.3, 47.2, 59.0, 66.6, 120.0, 125.1, 126.5, 127.0, 127.2, 128.4, 129.3, 137.6, 141.2, 144.0, 155.4, 156.8, 176.4. HRMS: m/z calcd for C33H39N3NaO5: 580.2787; found: 580.2774 [M + Na].
Z-Gly-ψ(NH-CO-NH)-Val-OMe (2d): Off-white solid, mp 159 ˚C. ¹H NMR (300 MHz, DMSO): δ = 0.93 (6 H, d), 3.14 (1 H, m), 3.58 (3 H, s), 4.51 (3 H, m), 5.30 (2 H, s), 6.10 (2 H, m), 6.48 (1 H, t), 7.20-7.40 (5 H, m). ¹³C NMR (200 MHz, DMSO): δ = 17.1, 31.1, 52.1, 56.2, 57.8, 65.4, 127.1, 127.2, 128.5, 141.2, 156.8, 157.5, 171.6. HRMS: m/z calcd for C16H23N3NaO5: 360.1535; found: 360.1513 [M + Na].
Boc-Glu(OBzl)-ψ(NH-CO-NH)-Ile-OMe (2e): solid, mp 138 ˚C. ¹H NMR (300 MHz, DMSO): δ = 0.91 (6 H, d), 1.30-1.45 (11 H, s), 1.65 (1 H, m), 2.55 (2 H, m), 2.90 (2 H, m), 3.65 (3 H, s), 3.80-3.90 (2 H, m), 5.15 (2 H, s), 5.30 (1 H, d), 6.35 (1 H, d), 6.50 (1 H, d), 7.30-7.40 (5 H, m). ¹³C NMR (200 MHz, DMSO): δ = 22.1, 23.1, 24.7, 28.6, 37.9, 39.7, 419, 50.9, 51.7, 61.9, 63.1, 78.7, 126.7, 127.6, 128.9, 137.7, 155.3, 156.8, 157.5, 178.1. HRMS: m/z calcd for C24H37N3NaO7: 502.2529; found: 502.2543 [M + Na].
Fmoc-Val-ψ(NH-CO-NH)-2,3,4,6-tetra-O-acetyl-β-d-glucopyranoside (3a): white solid, mp 179 ˚C. ¹H NMR (300 MHz, DMSO): δ = 0.93 (6 H, d), 1.95 (12 H, s), 3.12 (1 H, m), 4.30-4.45 (3 H, m), 4.67 (2 H, d), 4.90-5.20 (5 H, m), 5.40 (1 H, m), 5.70 (2 H, br), 6.90-7.50 (8 H, m). ¹³C NMR (200 MHz, DMSO): δ = 15.1, 20.8, 21.1, 33.2, 47.5, 59.7, 67.8, 68.0, 69.1, 69.2, 73.0, 74.8, 81.0, 126.8, 128.2, 128.4, 128.6, 141.3, 142.5, 156.0, 158.1, 170.7. HRMS: m/z calcd for C34H41N3NaO12: 706.2588; found: 706.2601 [M + Na].
(1,2),(3,4)-Diacetylgalactopyranosyl-6-NH-CO-NH-Phe-OMe (4b): solid, mp 104 ˚C. ¹H NMR (300 MHz, DMSO): δ = 1.25 (12 H, s), 3.21 (2 H, d), 3.85 (3 H, s), 4.30-4.53 (3 H, m), 4.80 (1 H, m), 5.50-5.70 (2 H, m), 6.31 (2 H, s), 7.10-7.40 (5 H, m). ¹³C NMR (200 MHz, DMSO): δ = 23.5, 34.2, 50.8, 54.2, 67.4, 69.2, 76.8, 77.9, 89.2, 107.6, 113.5, 125.4, 126.7, 127.8, 137.0, 157.2, 171.8. HRMS: m/z calcd for C22H30N2NaO8: 473.1900; found: 473.1918 [M + Na].