Hyperbranched Polyester Supported Disaccharide Synthesis: The Effect of Loading Level on Glycosylation Efficiency

Abstract

The efficiency of glycosylation of glycosyl acceptors supported on a hyperbranched polyester (Boltorn H-50) by an activated trichloroacetamidate donor was investigated as a function of the polymer loading. Loading of the hyperbranched polyester with an o-nitrobenzyl photolabile linker at 25% loading capacity (corresponding to 1.36 mmol/g) and using five equivalents of the glycosyl donor was optimal for quantitative transformation (>98%) at both the mono- and disaccharide stage. The disaccharide product obtained under these optimized conditions was isolated in 16% yield over five steps.

Key words

carbohydrates - glycosylations - polymers - dendrimers - solid-phase

References

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  Manufacturer specifications for Boltorn H-40: 64 terminal OH groups, nominal M _W 7,316 and PDI 1.8; Boltorn H-50: 128 terminal OH groups, nominal M _W 14,600 and PDI 2.0.

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  The disaccharide yield is comparable with yields obtained previously utilizing the UV light cleavage protocol (ref. 9).

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16

Representative Experimental Procedures.
Compound 17. The glycosyl acceptor 5 (25% loading capacity, 1.36 mmol/g; 0.33 g, 0.45 mmol, 100 mol%) and the glycosyl donor 12 (1.27 g, 2.25 mmol, 500 mol%) were dissolved in dry THF (4.5 mL). After a homogeneous solution had formed, BF₃·OEt₂ (90 µL, 102 mg, 0.72 mmol, 160 mol%) was added and the solution was stirred for 30 min. The solution was concentrated in vacuo and then precipitated with MeOH (50 mL). After centrifugation, decantation of the supernatant, rinsing of the polymer mass with MeOH (3 × 10 mL) and drying under high vacuum, compound 17 (0.275 g, 0.23 mmol, 50%) was obtained. ¹H NMR (500 MHz, CDCl₃): δ = 0.08 (s, 6 H), 0.91 (s, 9 H), 4.95-5.42 (m, 5 H), 7.95 (br s, 1 H), 8.32 (br s, 1 H), 8.67 (br s, 1H).
Compound 25. To a solution of 17 (0.275 g, 0.225 mmol, 100 mol%) in THF, HF·pyridine (0.5 mL, 0.5 g, 5.0 mmol, 222 mol%) was added and the solution stirred for 12 h. The mixture was diluted with EtOAc (15 mL) and washed with H₂O (5 mL), 10% H₂SO₄ (5 mL) and sat. NaHCO₃ (5 mL). After drying (MgSO₄) and evaporation of the solvent, compound 21 was obtained as yellow foam and used directly for the next step. The monosaccharide donor 21 was glycosylated using the glycosyl donor 12 (0.64 g, 1.13 mmol, 500 mol%), BF₃·OEt₂ (45 µL, 51 mg, 0.36 mmol, 160 mol%), and dry THF (2.5 mL) as described for 17 above. The polymer-immobilized disaccharide 25 was isolated after precipitation into MeOH (25 mL). ¹H NMR (500 MHz, CDCl₃): δ = 0.09 (s, 3 H), 0.10 (s, 3 H), 1.28 (s, 9 H), 4.80-5.45 (m, 10 H), 7.95 (br s, 1 H), 8.32 (br s, 1 H), 8.67 (br s, 1 H). Disaccharide 29. Compound 25 (as obtained from the previous step) was dissolved in dry THF (2.5 mL) in a quartz vessel, purged with Ar for 10 min, then irradiated with UV light (350 nm) for 48 h. The solution was evaporated and the crude mixture applied directly onto a silica gel column. After chromatography (hexanes-EtOAc, 2:1), compound 29 (50 mg, 0.072 mmol, 32% from 21) was isolated as colorless oil. Major anomer (α,α): ¹H NMR (400 MHz, CDCl₃): δ = -0.04 (s, 3 H), -0.02 (s, 3 H), 0.84 (s, 9 H), 1.91 (s, 3 H), 1.92 (s, 3 H), 1.96 (s, 3 H), 1.98 (s, 3 H), 2.05 (s, 3 H), 2.08 (s, 3 H), 3.48 (m, 1 H), 3.62-3,82 (m, 5 H), 4.16 (m, 1 H), 4.75 (d, J = 1.6 Hz, 1 H), 5.13-5.28 (m, 5 H). ¹³C NMR (100 MHz, CDCl₃): δ = -5.01, -4.95, 18.8, 21.1, 21.1, 21.2, 21.2, 21.2, 21.2, 26.3, 62.9, 66.9, 67.2, 67.7, 69.3, 69.6, 69.7, 70.1, 70.4, 71.9, 92.5 (¹ J _C-H = 172.6 Hz), 97.7 (¹ J _C-H = 170.1 Hz), 170.1, 170.2, 170.3, 170.5, 170.6, 170.7. Anal. Calcd for C₃₀H₁₇O₁₇Si: C, 50.84; H, 6.83. Found: C, 50.72; H, 6.64.

17

In contrast, benzyl-protected oligosaccharides loaded on acetate-capped Boltorn polyesters at comparable loading levels were completely insoluble in MeOH (ref. 9). Such behavior is in agreement with the notion that the terminal groups largely determine the solubility properties of dendrimers and hyperbranched polymers.