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

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

Ethyl 6-O-(2-chloroacetyl)-4-O-(9-fluorenylmethoxycarbonyl)-2-O-levulinoyl-3-O-(2-naphthylmethyl)-1-thio-β-D-glucopyranoside is a multifunctional thioglycoside engineered for precision in oligosaccharide assembly. Its design incorporates orthogonal protecting groups to enable sequential deprotection and controlled glycosylation.

Structural Breakdown

Core framework:

• β-D-glucopyranose ring with a thioethyl group at the anomeric position (C1), forming a thioglycoside donor for glycosylation reactions.

Protection strategy:

Key Characteristics

• Molecular weight: ~800-850 g/mol (estimated based on substituents)
• Reactivity profile:
  • Thioglycoside activation via NIS/TfOH or other thiophilic promoters
  • Electron-withdrawing esters (levulinoyl, chloroacetyl) moderate donor reactivity compared to benzyl-protected analogs
• Orthogonal deprotection sequence:

1. Fmoc (C4) → 20% piperidine
2. Levulinoyl (C2) → pH 4.5 buffer
3. Chloroacetyl (C6) → 0.1 M thiourea
4. 2-Naphthylmethyl (C3) → H₂/Pd-C

Synthetic Applications

1. Solid-phase oligosaccharide synthesis:
   • Fmoc compatibility allows integration with resin-bound strategies
   • Levulinoyl enables temporary protection during chain elongation
2. Branch-selective functionalization:
   • Chloroacetyl at C6 permits post-glycosylation modifications (e.g., azide substitution)
3. Chemoselective glycosylations:
   • Pair with less reactive acceptors via reactivity tuning from EWG-protected positions

Stability Considerations

• Acid sensitivity: Levulinoyl limits strong acid usage in later synthesis stages
• Base compatibility: Stable to mild bases (e.g., Et₃N) except during Fmoc removal
• Hydrogenolysis constraints: Requires late-stage deprotection of 2-naphthylmethyl to avoid early intermediate exposure

This compound exemplifies modern carbohydrate engineering, combining traditional protecting groups (naphthylmethyl) with photolabile/chemoselective motifs (Fmoc, chloroacetyl) for iterative synthesis of branched glycostructures.

Citations:

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC5301963/
2. https://pubs.rsc.org/en/content/articlehtml/2023/ob/d3ob00817g
3. https://pmc.ncbi.nlm.nih.gov/articles/PMC2677192/
4. https://www.diva-portal.org/smash/get/diva2:318255/FULLTEXT01.pdf
5. https://onlinelibrary.wiley.com/doi/abs/10.1002/9783527697014.ch3
6. https://pubs.acs.org/doi/10.1021/ed074p1297
7. https://onlinelibrary.wiley.com/doi/10.1002/9783527697014.ch5
8. https://par.nsf.gov/servlets/purl/10157801