Synthesis of Sugar-Lysine Chimera with Integrated gluco-Configured 1,3-Hydroxyamine Motif

Abstract

The paper describes the synthesis of glucose-configured sugar-lysine chimeras in which the side chain of lysine is conformationally constrained via incorporation into a d-glucose scaffold. Key step in the synthesis is a high-yielding, reductive ring opening of an exocyclic glucose-derived epoxide to form an α-hydroxyester that can be converted into chimeric sugar-lysine analogues. To demonstrate the use of these novel chimeric sugar-lysine building blocks in peptide coupling, we replaced d-lysine in the antimicro­bial dipeptide sequence kW by a d-glucose-d-lysine chimera.

sugar-lysine chimera - reductive ring opening - epoxides

References and Notes

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16

Synthetic Procedures for Compounds 12-17.
Synthesis of Compounds 12-15.
Ester 11 (60 mg, 0.16 mmol) was treated with LiOH (7 mg, 0.31 mmol) for 8 h at r.t. in aq THF (1:1), and then acidified with formic acid (100 µL). The solution was extracted with EtOAc (6 × 10 mL) and the combined organic layer solvent was dried (Na₂SO₄) and concentrated to afford inseparable mixture of crude acids 12 and 13 (59 mg, quant.), which was treated with Cs₂CO₃ (61 mg, 0.18 mmol) and MeI (30 µL, 0.48 mmol) in DMF. The reaction was worked up with H₂O and extracted with EtOAc (4 × 15 mL); the combined organic phases were dried (Na₂SO₄) and concentrated. The crude was acetylated by dissolving it in a 1:1 mixture containing Ac₂O (0.5 mL) and pyridine (0.5 mL). The crude mixture was purified by the flash chromatography (EtOAc-hexane, 1:2) to afford compound 14 (61 mg, 80%) and 15 (15 mg, 20%). Compound 14 was identical to the product obtained by acetylation of compound 11.
Synthesis of Compound 16.
Acid 12 (46 mg, 0.12 mmol) was dissolved in MeOH (4 mL) and hydrogentated for 20 min using 20 wt% Pd/C. The solution was filtered and the solvent was evaporated in vacuo. The solid residue was dissolved in aq acetone (3 mL, 1:1) and treated with 9-fluorenylmethyl pentafluorophenyl carbonate (91 mg, 0.24 mmol) and NaHCO₃ (31 mg, 0.37 mmol) for 4 h at r.t. Then, H₂O (10 mL) was added and the aqueous layer was extracted with EtOAc (6 × 10 mL). Finally, the solvent was dried (Na₂SO₄) and concentrated. The crude product was purified by flash column chromatography (MeOH-EtOAc, 1:1) to afford compound 16 (45 mg, 63%).
Synthesis of Compound 17. To the mixture of Fmoc-Trp(Boc)-OH (205 mg, 0.39 mmol) and benzylamine (165 µL, 1.51 mmol) in DMF (5 mL) was added TBTU (249 mg, 0.77 mmol) and DIPEA (340 µL, 1.95 mmol). The reaction was stirred for 2 h at r.t. The solvent was removed in vacuo and the residue was purified by flash column silica gel chromatography (2:1, hexane-EtOAc) to yield the Fmoc-Trp(Boc)-NHBn (151 mg, 63%). The solution of Fmoc-Trp(Boc)-NHBn (151 mg, 0.25 mmol) and piperidine (0.5 mL) in DMF (2 mL) was stirred for 1 h at r.t. The solvent was removed in vacuo and the crude product was purified by flash column silica gel chromatography (from EtOAc to 5% MeOH in EtOAc) to afford the NH₂-Trp(Boc)-NHBn (81 mg, 80%). Compound 16 (23 mg, 0.04 mmol) was dissolved in DMF (2 mL) and NH₂-Trp(Boc)-NHBn (72 mg, 0.18 mmol), TBTU (33 mg, 0.10 mmol), and DIPEA (37 µL, 0.21 mmol). The mixture was stirred for 4 h at r.t. before removing the solvent under reduced pressure. The crude product was purified by flash chromatography using EtOAc as eluent to afford 17 (24 mg, 63%).
Characteristic Spectroscopic Data for Compounds 14-17. Compound 14: ¹H NMR (300 MHz, CDCl₃, r.t., TMS): δ = 1.45 (s, 9 H), 2.00 (s, 3 H), 2.02 (s, 3 H), 2.05 (s, 3 H), 3.20-3.33 (m, 2 H), 3.64-3.70 (m, 1 H, H-7), 3.77 (s, 3 H), 3.87 (dd, 1 H, H-3, J = 9.9, 1.7 Hz), 4.66 (dd, 1 H, H-2, J = 9.2, 1.7 Hz), 5.02 (dd, 1 H, H-6, J = 9.3, 9.7 Hz), 5.16 (dd, 1 H, H-5, J = 9.3, 9.1 Hz), 5.25 (dd, 1 H, H-4, J = 9.9, 9.1 Hz), 5.46 (d, 1 H, N-H, J = 9.2 Hz). ¹³C NMR (100 MHz, CDCl₃, r.t.): δ = 20.57, 20.58, 20.66, 28.27 (3 C), 50.83, 52.73, 53.47, 68.77, 69.03, 74.21, 77.77, 78.76, 80.46, 168.78, 168.80, 169.39, 169.51, 170.29. MS (ES): m/z calcd for C₂₀H₃₀N₄NaO₁₁ [M + Na]⁺: 525.18; found: 525.32. Anal. Calcd (%) for C₂₀H₃₀N₄O₁₁: C, 47.81; H, 6.02; N, 11.15. Found: C, 48.08; H, 6.15; N, 10.77.
Compound 15: ¹H NMR (300 MHz, CDCl₃, r.t., TMS): δ = 1.44 (s, 9 H), 1.98 (s, 3 H), 2.03 (s, 3 H), 2.04 (s, 3 H), 3.13-3.29 (m, 2 H, H-8a, H-8b), 3.64-3.71 (m, 1 H, H-7), 3.78 (s, 3 H), 4.16 (dd, 1 H, H-3, J = 9.9, 2.3 Hz), 4.70 (dd, 1 H, H-2, J = 10.5, 2.3 Hz), 5.00 (dd, 1 H, H-6, J = 9.5, 9.5 Hz), 5.06 (dd, 1 H, H-4, J = 9.9, 9.5 Hz), 5.20 (dd, 1 H, H-5, J = 9.5, 9.5 Hz), 5.13 (d, 1 H, N-H, J = 10.5 Hz). ¹³C NMR (100 MHz, CDCl₃, r.t.): δ = 21.23, 21.34 (2 C), 28.88 (3 C), 51.30, 53.02, 53.46, 68.12, 69.84, 74.59, 78.04, 78.47, 79.82, 167.63, 168.12, 168.84, 169.37, 169.72. MS (ES): m/z calcd for C₂₀H₃₀N₄NaO₁₁ [M + Na]⁺: 525.18; found: 525.27. Anal. Calcd (%) for C₂₀H₃₀N₄O₁₁: C, 47.81; H, 6.02; N, 11.15. Found: C, 47.98; H, 6.25; N, 11.55.
Compound 16: ¹H NMR (300 MHz, CD₃OD, r.t., TMS): δ = 1.43 (s, 9 H), 2.98-3.13 (m, 2 H, H-6 and H-8a), 3.18 (m, 1 H, H-7), 3.22-3.44 (m, 2 H, H-3, H-5), 3.62-3.80 (m, 2 H, H-4, H-8b), 4.23 (t, 1 H, J = 6.8 Hz), 4.32-4.48 (m, 3 H), 7.28-7.87 (m, 8 H). ¹³C NMR (100 MHz, CDCl₃, r.t.): δ = 28.88, 43.42, 48.54, 56.37, 67.78, 72.04, 73.14, 79.03, 80.38, 80.76, 82.97, 120.94-128.78 (arom. C), 142.61-145.43 (arom. C), 157.71, 159.12, 169.46. MS (ES): m/z calcd for C₂₈H₃₃N₂O₁₀ [M - H]^-: 557.21; found: 557.09.
Compound 17: ¹H NMR (300 MHz, CDCl₃, r.t., TMS): δ = 1.38 (s, 9 H), 1.63 (s, 9 H), 3.04-3.34 (m, 6 H), 3.37-3.61 (m, 5 H), 3.71-3.83 (m, 1 H), 4.03-4.37 (m, 5 H), 4.45 (dd, 1 H, J = 6.7, 2.2 Hz), 4.75-4.85 (m, 1 H), 5.45-5.56 (br s, 1 H, NH), 6.12-6.29 (br s, 1 H, NH), 6.29-6.46 (br s, 1 H, NH), 6.73-6.91 (m, 2 H), 6.96-7.03 (br, 1 H, NH), 7.08-8.18 (m, 16 H). HRMS (ES): m/z calcd for C₅₁H₅₉N₅NaO₁₂ [M + Na]⁺: 956.40524; found: 956.40537.