Ethyl 2-O-benzyl-3-O-(2-naphthylmethyl)-4-O-(9-fluorenylmethoxycarbonyl)-6-O-levulinoyl-1-thio-beta-D-glucopyranoside

Ethyl 2-O-benzyl-3-O-(2-naphthylmethyl)-4-O-(9-fluorenylmethoxycarbonyl)-6-O-levulinoyl-1-thio-β-D-glucopyranoside

Ethyl 2-O-benzyl-3-O-(2-naphthylmethyl)-4-O-(9-fluorenylmethoxycarbonyl)-6-O-levulinoyl-1-thio-β-D-glucopyranoside is a multifunctional thioglycoside building block engineered for controlled glycosylation in complex carbohydrate synthesis. Its design integrates orthogonal protecting groups to enable sequential deprotection and stereoselective coupling.

Core Structure

• Scaffold: β-D-glucopyranoside with an ethylthio (–SEt) group at the anomeric (C1) position, serving as a thioglycosyl donor activated by thiophilic promoters (e.g., NIS/AgOTf).

Protecting Groups

1. C2: Benzyl ether (–OBn)
   • Acid-stable and removable via hydrogenolysis (H₂/Pd-C), providing compatibility with base-sensitive groups like Fmoc.
2. C3: 2-Naphthylmethyl ether (–O-2-Nap)
   • Acid-labile (e.g., cleaved by TFA) with enhanced steric bulk compared to benzyl, directing glycosylation stereochemistry via steric hindrance.
3. C4: 9-Fluorenylmethoxycarbonyl (Fmoc)
   • Base-labile (e.g., piperidine/DMF), ideal for solid-phase synthesis workflows.
4. C6: Levulinoyl ester (–OLv)
   • Base-sensitive, removable under mild conditions (e.g., hydrazine) without affecting other groups.

Synthetic Utility

• Orthogonal Deprotection:
  • Step 1: Fmoc cleavage (base) exposes C4-OH for glycosylation.
  • Step 2: Levulinoyl removal (base) unmasks C6-OH.
  • Step 3: Benzyl/2-Nap deprotection (acid/hydrogenolysis) finalizes glycan assembly.
• Reactivity: The ethylthio donor’s activation under mild conditions ensures compatibility with sensitive protective groups. The 2-naphthylmethyl group enhances α/β selectivity through steric effects.

Characterization

• NMR: Distinct downfield shifts for Fmoc aromatic protons (~7.1–7.8 ppm), Lev carbonyl (~172 ppm), and benzyl/naphthylmethyl signals.
• MS: ESI-MS confirms molecular weight (expected [M+Na]⁺ ~950–1000 Da).

Applications

• Automated Glycan Assembly (AGA): Fmoc compatibility supports solid-phase synthesis of glycans for therapeutic and diagnostic purposes
• Complex Oligosaccharides: Enables regioselective glycosylation for biologically relevant glycoconjugates, such as protozoan surface glycans.

This compound exemplifies advanced strategies in carbohydrate chemistry, balancing reactivity, steric control, and orthogonal deprotection for precision in glycan synthesis.

Citations:

1. https://onlinelibrary.wiley.com/doi/10.1002/ajoc.201900397
2. https://repositorio.ul.pt/bitstream/10451/58145/1/TM_Eduardo_Sousa.pdf
3. https://pmc.ncbi.nlm.nih.gov/articles/PMC5301963/
4. https://pmc.ncbi.nlm.nih.gov/articles/PMC9182441/
5. https://www.mdpi.com/1420-3049/23/7/1712
6. https://onlinelibrary.wiley.com/doi/abs/10.1002/9783527697014.ch3
7. https://onlinelibrary.wiley.com/doi/10.1002/9783527697014.ch5
8. https://pubs.acs.org/doi/10.1021/acs.orglett.6b02241