Efficient Methods for Glycosidations with Glycals - A Key Intermediate for the Synthesis of Mucin Core 1-Type O-Glycan

Abstract

The use of glycals as acceptors in glycosylation reactions is hampered by their sensitivity to acids. We report here on the successful use of mild Lewis acid [Sn(OTf)₂] as catalyst for the glycosylation with O-glycosyl trichloroacetimidates and on the development of this method to construct a key intermediate for the synthesis of mucin type O-glycans. To this end, chemoselective ­nitration of O-glycosylated glycals, stereoselective threonine addition, and reduction of the nitro group to the amino group by an efficient procedure avoiding the use of an expensive catalyst was performed.

Key words

carbohydrates - glycols - glycosylation - Michael additions - glycopeptides - nitro reduction

References

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15

General Procedure for the Glycosylation: A mixture of trichloroacetimidate (4.2 mmol), and galactal (4.7 mmol) in anhyd CH₂Cl₂ (70 mL) was stirred for 1 h at r.t. under dry Ar, then cooled to -20 °C. A solution of 0.1 M Sn(OTf)₂ in MeCN (0.42 mmol) was added, and the mixture was stirred for 10 min at -20 °C. Et₃N was added. Evaporation of the solvent and purification by chromatography on silica gel yielded the target disaccharide.

16

NMR-physical data: 8 [δ (1-Hb) = 4.52, J _1,2 = 8.0 Hz); 10 {δ (1-Hb) = 4.70, J _1,2 = 7.9 Hz, [α]_D +2 (c 0.5, CHCl₃)}; 12 {δ (1-Hb) = 4.90, J _1,2 = 7.9 Hz, [α]_D +24 (c 1.6, CHCl₃)}; 14 {δ (1-Hb) = 4.88, J _1,2 = 8.0 Hz}; 16 {β: δ (1-Hb) = 4.51, J _1,2 = 7.3 Hz, α: δ (1-Hb) = 4.95, J _1,2 = 3.5 Hz}; 18 after debenzylation and peracetylation [δ (1-Hb) = 4.63, J _1,2 = 7.7 Hz]; 20 [δ (1-Hb) = 4.68, J _1,2 = 8.1 Hz]; 22 [δ (1-Hb) = 4.69, J _1,2 = 7.81 Hz); 31 [δ (1-Ha) = 5.43, J _1,2 = 4.8 Hz,
δ (1-Hb) = 4.77, J _1,2 = 7.9 Hz]; 32 [δ (1-Ha) 5.39, J _1,2 =
4.1 Hz, δ (1-Hb) 4.74, J _1,2 = 7.3 Hz]; 33 [δ (1-Ha) = 4.87,
J _1,2 = 3.6 Hz]; 36 [δ (1-Ha) 4.85, J _1,2 = 3.6 Hz].

18

Following one referee, this result may be due to nitration of Fmoc.

20

General Procedure for the Reduction of the Nitro Group: The nitro compound (0.98 mmol) was dissolved in a mixture of THF (75 mL), concd HCl (3 mL), HOAc (16 mL), H₂O (30 mL) and cooled to 0 °C. Zn dust (24 mmol) was added. After stirring for 2 h at 0 °C the Zn was filtrated, the reaction mixture was diluted with CH₂Cl_2, washed with H₂O, sat. aq NaHCO₃, and H₂O, and dried over anhyd MgSO₄. Evaporation of the solvents and conventional acetylation (Ac₂O in pyridine) of the residue followed by concentration of the mixture and purification by chromatography on silica gel afforded the corresponding N-acetamido glycoside.