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

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

Ethyl 2-O-benzoyl-3-O-(2-naphthylmethyl)-4-O-(9-fluorenylmethoxycarbonyl)-6-O-benzyl-1-thio-β-D-glucopyranoside is a strategically protected thioglycoside optimized for stereocontrolled glycosylation in carbohydrate synthesis. Its design leverages orthogonal protecting groups to enable precise regioselective deprotection during oligosaccharide assembly.

Core Structure

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

Protecting Groups

1. C2: Benzoyl ester (–OBez)
   • Acts as a participating group via neighboring group participation (NGP) to enforce β-selectivity during glycosylation.
   • Removable under basic (e.g., NaOMe/MeOH) or acidic (e.g., hydrazine) conditions.
2. C3: 2-Naphthylmethyl ether (–O-2-Nap)
   • Acid-labile (e.g., cleaved by TFA) with enhanced steric bulk compared to benzyl groups, providing stability during base-sensitive reactions.
3. C4: 9-Fluorenylmethoxycarbonyl (Fmoc)
   • Base-labile (e.g., piperidine/DMF), ideal for solid-phase synthesis workflows.
4. C6: Benzyl ether (–OBn)
   • Acid-stable but removable via hydrogenolysis (H₂/Pd-C), offering orthogonal compatibility with Fmoc and benzoyl groups.

Synthetic Utility

• Orthogonal Deprotection Strategy:
  • Step 1: Fmoc removal (base) → exposes C4-OH for glycosylation.
  • Step 2: Benzoyl cleavage (base/acid) → unmask C2-OH for further coupling.
  • Step 3: Benzyl/2-Nap removal (acid/hydrogenolysis) → finalize glycan assembly.
• Glycosylation Control: The C2 benzoyl ensures β-selectivity via NGP, while the ethylthio donor enables activation under mild conditions.

Characterization

• NMR: 1H^1 \text{H}1H and 13C^13 \text{C}13C NMR confirm substitution patterns (e.g., downfield shifts for benzoyl carbonyl at ~167 ppm, Fmoc aromatic protons at 7.1–7.8 ppm).
• MS: ESI-MS validates molecular weight (expected [M+Na]⁺ ~900–950 Da).

Applications

• Oligosaccharide Synthesis: Used to build branched or sterically hindered glycans via sequential glycosylation.
• Solid-Phase Platforms: Fmoc compatibility supports automated glycomimetic synthesis.

This compound exemplifies advanced protecting group tactics in carbohydrate chemistry, balancing reactivity, selectivity, and orthogonal deprotection for complex glycan construction.

Citations:

1. https://pmc.ncbi.nlm.nih.gov/articles/PMC6259426/
2. https://pmc.ncbi.nlm.nih.gov/articles/PMC8423405/
3. https://pmc.ncbi.nlm.nih.gov/articles/PMC9506437/
4. https://pubs.rsc.org/en/content/articlehtml/2023/ob/d3ob00817g
5. https://pubs.acs.org/doi/10.1021/ed074p1297
6. https://onlinelibrary.wiley.com/doi/10.1002/9783527697014.ch5
7. https://par.nsf.gov/servlets/purl/10157801
8. https://onlinelibrary.wiley.com/doi/abs/10.1002/9783527697014.ch3