Tunable Activation of Glycosyl Trichloro- and (N-phenyl)trifluoro­acetimidates with Ytterbium(III) Triflate: One-Pot Synthesis of ­Trisaccharides under Catalytic Conditions

Abstract

A mild promoter such as Yb(OTf)₃ allows selective activation of glycosyl trichloroacetimidate building blocks in the presence of glycosyl (N-phenyl)trifluoroacetimidates with a similar pattern of protecting groups. This selectivity has been exploited in the one-pot assembly of two different trisaccharides in good overall yields. In contrast to other reported procedures, a catalytic amount of promoter is sufficient to trigger both glycosidation steps of the sequential process.

carbohydrates - glycosidations - ytterbium(III) triflate - solvent effects - stereoselectivity

References and Notes

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18 This compound was readily accessed by Zemplen deacetylation of the corresponding 1,6-di-O-acetylated precursor obtained as described in: Lam SN. Gevay-Hague J. Carbohydr. Res.  2002,  337:  1953 

19

Procedure for the Synthesis of Glycosyl ( N -Phenyl)tri-fluoroacetimidates from Diols.
(N-Phenyl)trifluoroacetimidoyl chloride (55 mL, 0.45 mmol) was added at r.t. to a mixture of 2,3,4-tri-O-benzyl-glucopyranose (100 mg, 0.22 mmol) and K₂CO₃ (37 mg, 0.26 mmol) in acetone (2 mL). After ca. 2 h, a few drops of pyridine were added and the mixture was filtered on a short pad of neutral alumina (eluent: CH₂Cl₂). The residue was chromatographed on neutral aluminum oxide I (eluent: PE-EtOAc from 85:15 to 7:3) to yield 5 (91 mg, yield 66%) as an oil. An analogous procedure was adopted for the synthesis of 8 (38% over two steps).
Spectroscopic data of 5 (β-anomer): ¹H NMR (300 MHz, CDCl₃): δ = 7.60-6.80 (aromatic protons), 5.75 (1 H, br s, H-1), 5.00-4.40 (benzyl CH₂), 4.00-3.20 (6 H). ¹³C NMR (50 MHz, CDCl₃): δ = 143.3, 138.3, 137.8, 137.6, 129.3-127.8, 126.2, 124.4, 120.6, 119.3, 97.0 (C-1), 84.3, 81.0, 76.7, 76.0, 75.6, 75.2, 75.1, 61.4.
Spectroscopic data of 8 (α-anomer): ¹H NMR (300 MHz, CDCl₃): δ = 7.50-6.80 (aromatic protons), 6.42 (1 H, br s, H-1), 4.95-4.55 (benzyl CH₂), 4.08 (1 H, td, J _2,3 = 3.3 Hz, J _3,OH = J _3,4 = 9.3 Hz, H-3), 4.00-3.70 (5 H), 2.45 (d, 3-OH). ¹³C NMR (50 MHz, CDCl₃): δ = 143.4, 138.1, 138.0, 137.1, 128.7-127.5, 124.4, 120.6, 119.4, 94.7 (C-1), 76.0, 75.6, 75.1, 73.8, 73.4, 72.8, 71.3, 68.6.

20

Procedure for the One-Pot Synthesis of 6.
Trichloroacetimidate 2 (38 mg, 56 mmol) and trifluoro-acetimidate 5 (25 mg, 40 mmol) were co-evaporated three times in anhyd toluene and then, after the addition of freshly activated acid-washed molecular sieves, dissolved in MeCN (0.5 mL). The mixture was cooled at -30 °C and then a solution of Yb(OTf)₃ (0.7 mg, 1.2 mmol) in pivalonitrile (30 mL) was added. After consumption of the trichloro-acetimidate donor (1 h), a solution of acceptor 1 (13 mg, 56 mmol) in MeCN (0.9 mL) and a further aliquot of Yb(OTf)₃ (1.6 mg, 2.8 mmol) in pivalonitrile (70 mL) were added and the mixture was allowed to warm spontaneously to r.t. A few drops of pyridine were added and the mixture was filtered on a short pad of silica gel. The residue was chromatographed on a silica gel column eluted with PE-EtOAc mixtures to yield trisaccharide 6 (27 mg, 55% yield) slightly contaminated by minor amounts of anomers.
Spectroscopic data of 6: ¹H NMR (400 MHz, CDCl₃): δ = 7.40-7.22 (aromatic protons), 5.75 (1 H, d, J _1,2 = 4.8 Hz, H-1 Gal), 5.10-4.40 (16 H), 4.43 and 4.41 (2 H, 2 × d, J _1,2 = 7.2 Hz, 2 × H-1 Glc), 4.28 (1 H, dd, J _2,3 = 2.4 Hz, H-2 Gal), 4.25-3.40 (15 H), 1.50, 1.38, 1.30, 1.22 (12 H, 4 × s, acetonides CH₃). ¹³C NMR (50 MHz, CDCl₃): δ = 138.7, 138.6, 138.5, 138.2, 128.3-127.7, 109.3, 108.5, 104.4, 104.0, 96.3, 84.8, 84.5, 81.8, 81.5, 78.0, 77.8, 77.3, 77.1, 76.5, 75.7, 75.6, 75.0, 74.8, 74.7, 74.6, 74.2, 73.5, 71.3, 70.7, 70.5, 70.0, 68.9, 68.6, 67.4, 26.1, 25.9, 25.0, 24.4.

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23

Procedure for the One-Pot Synthesis of 7. Trichloroacetimidate 9 (58 mg, 85 mmol) and trifluoro-acetimidate 8 (37 mg, 60 mmol) were coevaporated three times in anhyd toluene and then, after the addition of freshly activated acid washed molecular sieves, dissolved in 4:1 toluene-Et₂O (0.5 mL). The mixture was cooled at
-10 °C and then a solution of Yb(OTf)₃ (1.2 mg, 1.7 mmol) in dioxane (100 mL) was added. After consumption of the trichloroacetimidate donor (ca. 30 min), a solution of acceptor 10 (41 mg, 84 mmol) in 4:1 toluene-Et₂O (1.2 mL) and a further aliquot of Yb(OTf)₃ (2.8 mg, 4.0 mmol) in dioxane (230 mL) were added and the mixture was allowed to warm spontaneously to r.t. After ca. 3 h, a few drops of pyridine were added and the mixture was filtered on a short pad of silica gel. The residue was chromatographed on a silica gel column eluted with PE-EtOAc mixtures to yield trisaccharide 7 (34 mg, 40% yield) as an oil.
Spectroscopic data of 7: ¹H NMR (400 MHz, CDCl₃): δ = 7.40-6.90 (aromatic protons), 5.83 (1H, m, -CH₂CH=CH₂), 5.25-5.22 (2 H, H-1 and -CH₂CH=CH_trans), 5.20 (1 H, d, J _1,2 = 1.2 Hz, H-1), 5.13 (1 H, br d, J _1,2 = 10.4 Hz,
-CH₂CH=CH_cis), 4.97 (1 H, d, J _1,2 = 1.2 Hz, H-1), 4.90-4.30 (20 H), 4.21 (1 H, dd, J _2,3 = 3.2 Hz, J _3,4 = 8.4 Hz, H-3), 4.15-3.55 (19 H). ¹³C NMR (50 MHz, CDCl₃): δ = 138.9, 138.6, 138.5, 138.4, 138.3, 13.9, 128.3-127.0, 117.1, 99.5, 99.4, 98.2, 80.1, 79.9, 75.5, 75.3, 75.2, 75.0, 74.8, 73.3, 72.6, 72.3, 72.1, 71.8, 69.4, 68.9, 67.8.

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