Ethyl 2-azido-3-O-benzoyl-2-deoxy-4-O-(9-fluorenylmethoxycarbonyl)-6-O-levulinoyl-1-thio-β-D-glucopyranoside

Ethyl 2-azido-3-O-benzoyl-2-deoxy-4-O-(9-fluorenylmethoxycarbonyl)-6-O-levulinoyl-1-thio-β-D-glucopyranoside

Ethyl 2-azido-3-O-benzoyl-2-deoxy-4-O-(9-fluorenylmethoxycarbonyl)-6-O-levulinoyl-1-thio-β-D-glucopyranoside is a synthetic thioglycoside derivative designed for advanced carbohydrate chemistry applications. This compound integrates multiple protecting groups to enable controlled reactivity during oligosaccharide synthesis.

Chemical Structure

The molecule is based on a β-D-glucopyranoside scaffold with the following modifications:

• 1-Thioethyl group: Replaces the anomeric oxygen, forming a thioglycoside linkage that enhances stability and serves as a glycosyl donor in synthetic reactions. Thioglycosides are commonly synthesized using methods such as triflic acid-mediated reactions, which offer efficient synthesis pathways.
• 3-O-benzoyl group: A permanent benzoyl ester protection at position 3, providing stability under acidic/basic conditions and enabling selective deprotection later. Benzoyl groups are widely used in glycosylation reactions due to their ability to participate in neighboring group effects, enhancing the stereoselectivity of glycoside formation.
• 2-Azido group: An azido group at position 2, which can be converted into an amino group under reducing conditions, offering a pathway for further functionalization.
• 4-O-Fmoc group: A 9-fluorenylmethoxycarbonyl (Fmoc) carbonate at position 4, acting as a temporary protecting group cleavable under basic conditions (e.g., piperidine).
• 6-O-levulinoyl group: A levulinoyl ester at position 6, acting as a temporary protecting group that can be cleaved under mild conditions. Levulinoyl groups are used for their ease of removal and ability to participate in glycosylation reactions without affecting the overall reactivity of the glycosyl donor.

Key Properties

• Molecular formula: Estimated to be C29H29N3O8S\text{C}_{29}\text{H}_{29}\text{N}_3\text{O}_8\text{S}C29H29N3O8S based on analogous structures.
• Stereochemistry: β-configuration at the anomeric center (C1), critical for mimicking biological glycosylation patterns.
• Role in synthesis:
  • The thioglycoside moiety facilitates activation via thiophilic promoters (e.g., NIS/TfOH) for glycosylation reactions.
  • Benzoyl group ensures regioselective reactivity, while Fmoc allows orthogonal deprotection for sequential glycosylation.
  • Azido group provides a versatile handle for post-synthetic modifications, such as Staudinger ligation or click chemistry. The choice of protecting groups significantly influences the reactivity and stereoselectivity of glycosylation reactions, as discussed in the context of protecting group strategies.

Applications

This compound is used in solid-phase oligosaccharide synthesis to build complex glycans. Its design supports iterative coupling cycles, where the Fmoc group is selectively removed to expose the 4-OH for subsequent glycosylation. The azido group can be reduced to an amino group, enabling late-stage functionalization. Thioglycosides like this derivative are also explored as metabolic decoys to inhibit glycosylation processes.

Synthetic Considerations

• Preparation: Likely synthesized via sequential protection:
  1. Benzylation of glucose at position 3.
  2. Fmoc protection at position 4.
  3. Levulinoylation at position 6.
  4. Azidation at position 2.
  5. Thioglycoside formation at the anomeric position, which can be achieved using efficient methods like triflic acid-mediated synthesis.
• Stability: Stable under standard glycosylation conditions but sensitive to conditions that cleave the levulinoyl group.

This multifunctional building block exemplifies advanced strategies in glycochemistry, balancing stability and orthogonality for automated glycan assembly.

Citations:

1. https://www.beilstein-journals.org/bjoc/articles/21/27
2. https://pmc.ncbi.nlm.nih.gov/articles/PMC8423405/
3. https://pmc.ncbi.nlm.nih.gov/articles/PMC6259426/
4. https://application.wiley-vch.de/books/sample/3527340106_c01.pdf
5. https://pubs.acs.org/doi/10.1021/acs.orglett.4c04325
6. https://onlinelibrary.wiley.com/doi/full/10.1002%2Fasia.201901621
7. https://pubs.acs.org/doi/10.1021/acs.joc.8b01459