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Synthesis and biological activity of alpha-galactosyl ceramide KRN7000 and galactosyl (alpha1-->2) galactosyl ceramide.

Veerapen N, Brigl M, Garg S, Cerundolo V, Cox LR, Brenner MB, Besra GS - Bioorg. Med. Chem. Lett. (2009)

Bottom Line: We herein report a faster and less cumbersome synthesis of the biologically attractive, alpha-galactosyl ceramide (alpha-GalCer), known as KRN7000, and its analogues.More importantly, the use of a silicon tethered intramolecular glycosylation reaction gave easy access to the diglycosyl ceramide Gal(alpha1-->2)GalCer, which has been shown to require uptake and processing to the biologically active alpha-GalCer derivative.

View Article: PubMed Central - PubMed

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

ABSTRACT
We herein report a faster and less cumbersome synthesis of the biologically attractive, alpha-galactosyl ceramide (alpha-GalCer), known as KRN7000, and its analogues. More importantly, the use of a silicon tethered intramolecular glycosylation reaction gave easy access to the diglycosyl ceramide Gal(alpha1-->2)GalCer, which has been shown to require uptake and processing to the biologically active alpha-GalCer derivative.

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Reagents and conditions: (a) PhSH, DMF, Cs2CO3, 75%; (b) (CH3)2Si(Cl)2, Pyridine, CH2Cl2, quant; (c) 5, Pyridine, DMF, 72%; (d) NIS, CH3NO2, 66%; (e) NaOMe/MeOH, quant; (f) H2, Pd/C, MeOH, 80%; (g) C25H51COCl, THF, NaOAc, 75%.
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fig4: Reagents and conditions: (a) PhSH, DMF, Cs2CO3, 75%; (b) (CH3)2Si(Cl)2, Pyridine, CH2Cl2, quant; (c) 5, Pyridine, DMF, 72%; (d) NIS, CH3NO2, 66%; (e) NaOMe/MeOH, quant; (f) H2, Pd/C, MeOH, 80%; (g) C25H51COCl, THF, NaOAc, 75%.

Mentions: Scheme 3 illustrates our novel strategy to synthesise α-GalCer and its derivatives. Silicon tethered intramolecular glycosylation20 is a particularly attractive method for generating glycosidic bonds stereoselectively, but not attempted by many research groups due to the difficulty in handling and relative instability of the silylene-tethered sugar derivative. However, successful examples have been reported and we were motivated by Bols21 work on the synthesis of disaccharides containing α-galactosyl linkages. Hence, 3, 4, 6-tri-O-acetylgalactopyranosyl chloride (7)22 was obtained from β-d-galactopyranose pentaacetate and converted to the corresponding thioglycoside 8 by reacting with thiophenol in the presence of caesium carbonate. The tethered compound 9 was then synthesised following the procedure described by Bols.21 Rearrangement of the silylene 9, catalyzed by N-iodosuccinimide (NIS) in anhydrous nitromethane at 80 °C,21 yielded the desired product 10 along with some small amounts of 5 after 2 h. It was observed that by careful monitoring and quenching of the reaction as soon as compound 9 was consumed, helped in minimizing the regeneration of phytosphingosine derivative 5 and hence enhanced the yield of the glycosylated product. Methanolysis, followed by hydrogenation of the azide then afforded compound 2. Finally, N-acylation with the fully saturated fatty acid, hexacosanoic acid, was achieved via reaction of the corresponding acid chloride with the free amine 2 in a 1:1 mixture of THF and saturated sodium acetate solution. Target compound 1 was obtained as a white solid after concentration of the organic phase and purification of the residue by flash chromatography. The spectroscopic data of the latter were consistent with the literature.14


Synthesis and biological activity of alpha-galactosyl ceramide KRN7000 and galactosyl (alpha1-->2) galactosyl ceramide.

Veerapen N, Brigl M, Garg S, Cerundolo V, Cox LR, Brenner MB, Besra GS - Bioorg. Med. Chem. Lett. (2009)

Reagents and conditions: (a) PhSH, DMF, Cs2CO3, 75%; (b) (CH3)2Si(Cl)2, Pyridine, CH2Cl2, quant; (c) 5, Pyridine, DMF, 72%; (d) NIS, CH3NO2, 66%; (e) NaOMe/MeOH, quant; (f) H2, Pd/C, MeOH, 80%; (g) C25H51COCl, THF, NaOAc, 75%.
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getmorefigures.php?uid=PMC2722241&req=5

fig4: Reagents and conditions: (a) PhSH, DMF, Cs2CO3, 75%; (b) (CH3)2Si(Cl)2, Pyridine, CH2Cl2, quant; (c) 5, Pyridine, DMF, 72%; (d) NIS, CH3NO2, 66%; (e) NaOMe/MeOH, quant; (f) H2, Pd/C, MeOH, 80%; (g) C25H51COCl, THF, NaOAc, 75%.
Mentions: Scheme 3 illustrates our novel strategy to synthesise α-GalCer and its derivatives. Silicon tethered intramolecular glycosylation20 is a particularly attractive method for generating glycosidic bonds stereoselectively, but not attempted by many research groups due to the difficulty in handling and relative instability of the silylene-tethered sugar derivative. However, successful examples have been reported and we were motivated by Bols21 work on the synthesis of disaccharides containing α-galactosyl linkages. Hence, 3, 4, 6-tri-O-acetylgalactopyranosyl chloride (7)22 was obtained from β-d-galactopyranose pentaacetate and converted to the corresponding thioglycoside 8 by reacting with thiophenol in the presence of caesium carbonate. The tethered compound 9 was then synthesised following the procedure described by Bols.21 Rearrangement of the silylene 9, catalyzed by N-iodosuccinimide (NIS) in anhydrous nitromethane at 80 °C,21 yielded the desired product 10 along with some small amounts of 5 after 2 h. It was observed that by careful monitoring and quenching of the reaction as soon as compound 9 was consumed, helped in minimizing the regeneration of phytosphingosine derivative 5 and hence enhanced the yield of the glycosylated product. Methanolysis, followed by hydrogenation of the azide then afforded compound 2. Finally, N-acylation with the fully saturated fatty acid, hexacosanoic acid, was achieved via reaction of the corresponding acid chloride with the free amine 2 in a 1:1 mixture of THF and saturated sodium acetate solution. Target compound 1 was obtained as a white solid after concentration of the organic phase and purification of the residue by flash chromatography. The spectroscopic data of the latter were consistent with the literature.14

Bottom Line: We herein report a faster and less cumbersome synthesis of the biologically attractive, alpha-galactosyl ceramide (alpha-GalCer), known as KRN7000, and its analogues.More importantly, the use of a silicon tethered intramolecular glycosylation reaction gave easy access to the diglycosyl ceramide Gal(alpha1-->2)GalCer, which has been shown to require uptake and processing to the biologically active alpha-GalCer derivative.

View Article: PubMed Central - PubMed

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

ABSTRACT
We herein report a faster and less cumbersome synthesis of the biologically attractive, alpha-galactosyl ceramide (alpha-GalCer), known as KRN7000, and its analogues. More importantly, the use of a silicon tethered intramolecular glycosylation reaction gave easy access to the diglycosyl ceramide Gal(alpha1-->2)GalCer, which has been shown to require uptake and processing to the biologically active alpha-GalCer derivative.

Show MeSH