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Synthesis and biological activity of alpha-L-fucosyl ceramides, analogues of the potent agonist, alpha-D-galactosyl ceramide KRN7000.

Veerapen N, Reddington F, Bricard G, Porcelli SA, Besra GS - Bioorg. Med. Chem. Lett. (2010)

Bottom Line: Activation of iNKT cells is known to lead to the production of cytokines that can help alleviate or exacerbate these conditions. alpha-Galactosyl ceramide (alpha-GalCer) is a known agonist of iNKT cells and it is believed that its fucosyl counterpart might have similar immunogenic properties.The key challenge in the synthesis of the target molecules involved the stereoselective synthesis of the alpha-glycosidic linkage.Of the methods examined, the per-TMS-protected glycosyl iodide donor was completely alpha-selective, and could be scaled up to provide gram quantities of the azide precursor 11, from which a range of N-acylated alpha-L-fucosyl ceramides were readily obtained and evaluated for ex vivo expansion of human iNKT cells.

View Article: PubMed Central - PubMed

Affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

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(a) NIS/TfOH, CH2Cl2, −78 °C to −20 °C, 68%; (b) NaOMe/MeOH, 92%; (c) H2, Pd, 76%.
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fig3: (a) NIS/TfOH, CH2Cl2, −78 °C to −20 °C, 68%; (b) NaOMe/MeOH, 92%; (c) H2, Pd, 76%.

Mentions: With both the acceptor and donor in hand, we then proceeded to the critical glycosylation reaction. Interestingly, NIS/TfOH activation of 1 g of the thioglycoside 6 (Scheme 2) in anhydrous CH2Cl2 at −78 °C afforded the glycosylated compound 8, almost exclusively as the α-anomer (α:β ratio = 9:1), in 68% yield after 2 h. Our results show a definite improvement in selectivity from the previously reported syntheses. Because the formation of the α-anomer is favoured by the anomeric effect, we rationalise that the latter is a governing factor under our reaction conditions. Both the lower temperature and the different reactivity of the acceptor 7 could potentially influence the stereoselectivity of the glycosylation reaction. These factors will have to be more thoroughly investigated in a later study. Subsequent Zemplen’s deprotection of the benzoate protecting groups produced the azide intermediate in quantitative yields. Tandem hydrogenation of the azido group and hydrogenolysis of the benzyl ethers in methanol then produced the amine 9 as a white solid, which exhibited spectroscopic data consistent with the literature.25


Synthesis and biological activity of alpha-L-fucosyl ceramides, analogues of the potent agonist, alpha-D-galactosyl ceramide KRN7000.

Veerapen N, Reddington F, Bricard G, Porcelli SA, Besra GS - Bioorg. Med. Chem. Lett. (2010)

(a) NIS/TfOH, CH2Cl2, −78 °C to −20 °C, 68%; (b) NaOMe/MeOH, 92%; (c) H2, Pd, 76%.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2957807&req=5

fig3: (a) NIS/TfOH, CH2Cl2, −78 °C to −20 °C, 68%; (b) NaOMe/MeOH, 92%; (c) H2, Pd, 76%.
Mentions: With both the acceptor and donor in hand, we then proceeded to the critical glycosylation reaction. Interestingly, NIS/TfOH activation of 1 g of the thioglycoside 6 (Scheme 2) in anhydrous CH2Cl2 at −78 °C afforded the glycosylated compound 8, almost exclusively as the α-anomer (α:β ratio = 9:1), in 68% yield after 2 h. Our results show a definite improvement in selectivity from the previously reported syntheses. Because the formation of the α-anomer is favoured by the anomeric effect, we rationalise that the latter is a governing factor under our reaction conditions. Both the lower temperature and the different reactivity of the acceptor 7 could potentially influence the stereoselectivity of the glycosylation reaction. These factors will have to be more thoroughly investigated in a later study. Subsequent Zemplen’s deprotection of the benzoate protecting groups produced the azide intermediate in quantitative yields. Tandem hydrogenation of the azido group and hydrogenolysis of the benzyl ethers in methanol then produced the amine 9 as a white solid, which exhibited spectroscopic data consistent with the literature.25

Bottom Line: Activation of iNKT cells is known to lead to the production of cytokines that can help alleviate or exacerbate these conditions. alpha-Galactosyl ceramide (alpha-GalCer) is a known agonist of iNKT cells and it is believed that its fucosyl counterpart might have similar immunogenic properties.The key challenge in the synthesis of the target molecules involved the stereoselective synthesis of the alpha-glycosidic linkage.Of the methods examined, the per-TMS-protected glycosyl iodide donor was completely alpha-selective, and could be scaled up to provide gram quantities of the azide precursor 11, from which a range of N-acylated alpha-L-fucosyl ceramides were readily obtained and evaluated for ex vivo expansion of human iNKT cells.

View Article: PubMed Central - PubMed

Affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

Show MeSH
Related in: MedlinePlus