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

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.

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

References and Notes

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Utility of commercial activated zinc dust to deprotonate amine hydrochloride salts is documented. Sureshbabu et al. demonstrated the conversion of amino acid/peptide acid ester hydrochloride salts into the corresponding free amines, see:

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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].

31 First, a solution of α-d-galactose (5 mmol) and ZnBr₂ (5.2 mmol) in acetone (20 mL) was stirred for 12 h and filtered. The filtrate was concentrated and after a simple workup, the resulting (1,2),(3,4)-diacetylgalactopyranose was dissolved in MeCN. Then, TEMPO and Na₃PO₄ buffer were added and the reaction mixture was warmed to 35 ˚C. Sodium chlorite and bleach were added, and the reaction mixture was stirred till completion of reaction. A simple workup lead to the isolation of the desired sugar-6-acid. See: Jhao M. Li J. Mano E. Song Z. Tschaen DM. Grabowski EJJ. Reider PJ. J. Org. Chem.  1999,  64:  2564