N,N′-Carbonyldiimidazole-Mediated DBU-Catalyzed One-Pot Synthesis of Urea-Tethered Glycosyl Amino Acids and Glycoconjugates

Abstract

An efficient, mild, simple, and alternative one-pot protocol for the synthesis of urea-tethered glycosyl amino acids mediated by N,N′-carbonyldiimidazole employing DBU as a catalyst is described. This protocol is also extended for the synthesis of urea-tethered disaccharides and oligosaccharides.

Key words

urea-tethered glycoconjugates - N,N′-carbonyldiimidazole - DBU - base catalysis

References and Notes

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20

The epimerization study was carried out by ^¹H NMR and HPLC analyses of the glycosyl ureas 3k and 3l synthesized by the protocol described below.
Glucosamine (2a),was converted into two epimeric glycosyl ureas 3k and 3l as outlined in Scheme  [³] by coupling separately with l-Ala-OMe (1k) and d-Ala-OMe (1l), respectively. An equimolar mixture of these two epimers was obtained by coupling with the racemic mixture of l- and d-Ala-OMe. The ^¹H NMR spectrum of 3k and 3l contained distinct methyl group doublets at δ = 1.52, 1.54 ppm and δ = 1.55, 1.58 ppm, respectively; whereas the epimeric mixture showed CH₃ group signals at δ = 1.51, 1.54 ppm and δ = 1.56, 1.59 ppm corresponding to two doublets. Additionally, HPLC analysis of the pure l- and d-Ala-OMe-derived glycosyl ureas 3k and 3l showed single peaks at different
t _R values i.e., t _R = 9.23 and t _R = 9.61 (method: gradient 0.1% TFA H₂O-MeCN; MeCN 30-100% in 30 min), respectively.

21

General Procedure for the Preparation of 3a-f
To a suspension of N,N′-carbonyldiimidazole (1.2 mmol) in anhydrous CH₂Cl₂ (10 mL) was added amino acid ester (1.0 mmol) and DBU (0.2 mmol), and the reaction mixture was stirred at ambient temperature for 6-7 min. The glycosyl amine (1.0 mmol) and DBU (0.3 mmol) was then added at 0 ˚C, and the resulting mixture was stirred for about 3 h at 0 ˚C. After completion of the reaction, the resulting solution was diluted with CH₂Cl₂ (10 mL) and washed with citric acid (2 × 10 mL), H₂O (2 × 10 mL), and brine (10 mL). The organic layer was dried over anhyd Na₂SO₄, filtered, and evaporated to obtain the crude product. Pure urea-tethered glycoconjugate was obtained as a solid on column chromatography eluting with EtOAc-hexane (4:6).
The procedure followed for the synthesis of 3g-j is similar to that described above with the only difference being the use of 0.6 mmol DBU during the addition of the second amine component.
Spectroscopic Data for Compound 3a White solid. IR (KBr): ν_max = 3385, 1748, 1655, 1560, 1231 cm^-¹. ^¹H NMR (300 MHz, CDCl₃): δ = 2.00 (s, 3 H), 2.03 (s, 3 H), 2.05 (s, 3 H), 2.07 (s, 3 H), 3.06 (d, 2 H), 3.69 (s, 3 H), 3.77 (ddd, J = 10.0, 4.3, 2.1 Hz, 1 H), 4.10 (dd, J = 12.3, 1.8 Hz, 1 H), 4.29 (dd, J = 12.3, 4.6 Hz, 1 H), 4.71 (q, J = 7.0 Hz, 6.0 Hz, 1 H), 4.88 (t, J = 9.6 Hz, 1 H), 5.10 (t, J = 9.4 Hz, 1 H), 5.15 (t, J = 9.3 Hz, 1 H), 5.12-5.22 (br, 1 H), 5.33 (d, J = 9.6 Hz, 1 H), 5.40-5.53 (br, 1 H), 7.04-7.16 (m, 2 H), 7.22- 7.35 (m, 3 H) ppm. ^¹³C NMR (75 MHz, CDCl₃): δ = 21.0, 21.2, 38.0, 53.1, 54.5, 62.6, 69.5, 70.2, 73.2, 74.3, 81.6, 128.4, 129.1, 130.3, 136.8, 156.5, 169.8, 170.1, 171.0, 171.6, 173.8 ppm.
Spectroscopic Data for Compound 3h White solid. IR (KBr): ν_max = 1669, 1558, 1229 cm^-¹. ^¹H NMR (400 MHz, CDCl₃): δ = 1.31 (s, 3 H), 1.49 (s, 3 H), 2.00 (s, 3 H), 2.02 (s, 3 H), 2.06 (s, 3 H), 2.09 (s, 3 H), 2.14 (s, 3 H), 3.32 (dd, J = 14.6, 5.8 Hz, 1 H), 3.41 (s, 3 H), 3.52 (ddd, J = 15.0, 5.8, 2.6 Hz, 1 H), 3.78 (ddd, J = 10.8, 5.6, 2.4 Hz, 1 H), 3.86 (ddd, J = 10.0, 4.2, 2.2 Hz, 1 H), 4.18 (dd, J = 12.6, 2.0 Hz, 1 H), 4.20 (d, J = 5.8 Hz, 1 H), 4.24 (dd, J = 7.6, 5.5 Hz, 1 H), 4.35 (dd, J = 12.6, 4.0 Hz, 1 H), 4.90 (dd, J = 10.5, 7.5 Hz, 1 H), 4.93 (t, J = 9.5 Hz, 1 H), 4.97 (s, 1 H), 5.12 (t, J = 6.0 Hz, 1 H), 5.15 (t, J = 9.7 Hz, 1 H), 5.19 (t, J = 9.4 Hz, 1 H), 5.36 (t, J = 9.4 Hz, 1 H), 5.47 (br d, J = 9.5 Hz, 1 H) ppm. ^¹³C NMR (100 MHz, CDCl₃): δ = 20.9, 21.5, 21.9, 26.8, 27.9, 42.4, 57.3, 63.9, 68.6, 70.5, 72.1, 73.3, 75.8, 76.7, 77.9, 82.1, 99.6, 110.8, 158.2, 170.4, 170.9, 172.0, 173.9, 174.5 ppm.