Additive-Controlled Stereoselective Glycosylations of Oxazolidinone-Protected Glucosamine and Galactosamine Thioglycoside Donors Based on Preactivation Protocol

Abstract

Based on a pre-activation protocol, the stereoselectivity of oxazolidinone-protected amino sugar thioglycoside donors towards glycosylations can be controlled by additives. Either α- or β-selectivity could be obtained by changing additives. 2,4,6-Tri-tert-butylpyrimidine (TTBP) was the best β-directing additive, while thiophene worked as the best α-directing additive. The bifunctional additives such as tetrabutyl ammonium iodide (TBAI) afforded either α- or β-selectivity depending on the amount added. Poor α-­selectivity of some glycosylations without any additives was greatly improved by adding TBAI or thiophene.

Key words

glycosylation - stereoselectivity - preactivation - additive - carbohydrate

References and Notes

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General Procedures for Glycosylations of Donors 1 or 2 with Acceptors 3-8
Tf₂O (8.7 µL, 0.052 mmol, 1.3 equiv) was added to a stirred mixture of donors 1 or 2 (21.2 mg, 0.048 mmol, 1.2 equiv), BSM (11.1 mg, 0.052 mmol, 1.3 equiv), and activated 4 Å MS (300 mg, powder) in CH₂Cl₂ (3 mL) at -73 ˚C under nitrogen atmosphere. The reaction mixture was stirred for 5 min, after loss of the donor detected by TLC, the additive (0.1-2.0 equiv) was added to the mixture. After stirring for 15 min, a solution of the acceptor 3 (15.0 mg, 0.040 mmol, 1.0 equiv) or other acceptors in CH₂Cl₂ (0.2 mL) was added dropwise to the reaction mixture. The mixture was stirred and warmed up to r.t. slowly, quenched by Et₃N (0.1 mL). The precipitate was filtered off, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel to give the products.

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Representative Procedures for Detecting Intermediates after Activation of Donor 1 by Variable Temperature NMR Spectroscopy
To a solution of donor 1 (8.7 mg, 0.02 mmol), BSM (5.1 mg, 0.024 mmol) in CD₂Cl₂ (0.5 mL) in a NMR tube at -60 ˚C, under an argon atmosphere, was added 1.2 equiv of Tf₂O (0.024 mmol, 4.1 µL). The NMR tube was immediately transferred to the pre-cooled NMR probe (-60 ˚C), and ^¹H NMR was recorded. Subsequently the temperature of the probe was raised in 10 ˚C steps with monitoring by ^¹H NMR.

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Product 9 was purified by column chromatography on silica gel (PE-EtOAc, 3:1); R _f  = 0.3 (PE-EtOAc, 1.5:1). ^¹H NMR (400 MHz, CDCl₃): δ = 7.59-7.61 (m, 2 H), 7.33-7.40 (m, 8 H), 6.25 (d, 1 H, J = 2.8 Hz, H-1′), 5.55 (s, 1 H), 5.30 (s, 1 H), 4.70 (d, 1 H, J = 3.6 Hz, H-1), 4.64 (d, 1 H, J = 11.6 Hz), 4.53 (d, 1 H, J = 11.6 Hz), 4.11-4.34 (m, 6 H), 3.77-3.84 (m, 2 H), 3.72 (t, 1 H, J = 10.0 Hz), 3.51-3.56 (m, 2 H), 3.37 (s, 3 H), 2.40 (s, 3 H), 2.08 (s, 3 H), 2.04 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 170.38 (2 C), 169.35, 152.90, 137.54, 137.11, 128.80, 128.62, 128.54, 128.47, 128.05, 126.29, 126.20, 101.14, 97.94, 95.01, 82.39, 78.38, 72.98, 72.07, 72.00, 68.87, 68.03, 65.80, 61.77, 61.54, 56.06, 55.17, 23.80, 20.58, 20.54. ESI-MS: m/z = 686 [M + H]⁺, 703 [M + NH₄]⁺, 708 [M + Na]⁺. Anal. Calcd for C₃₄H₃₉NO₁₄: C, 59.56; H, 5.73; N, 2.04. Found: C, 59.30; H, 5.69; N, 1.97.

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Product 10 was purified by column chromatography on silica gel (PE-EtOAc, 1.5:1); R _f  = 0.1 (PE-EtOAc, 1.5:1). ^¹H NMR (400 MHz, CDCl₃): δ = 7.48-7.50 (m, 2 H), 7.31-7.38 (m, 8 H), 5.59 (s, 1 H), 5.56 (s, 1 H), 5.08 (d, 1 H, J = 7.6 Hz, H-1′), 4.64 (d, 1 H, J = 11.8 Hz), 4.54 (d, 1 H, J = 3.6 Hz, H-1), 4.52 (d, 1 H, J = 12.0 Hz), 4.32 (dd, 1 H, J = 7.6, 12.0 Hz), 4.15-4.24 (m, 3 H), 3.95-4.08 (m, 3 H), 3.63-3.79 (m, 4 H), 3.30 (s, 3 H), 2.38 (s, 3 H), 2.10 (s, 3 H), 1.98 (s, 3 H). ^¹³C NMR (100 MHz, CDCl₃): δ = 171.25, 170.28, 169.33, 153.54, 137.91, 137.35, 128.86, 128.56, 128.18, 128.03, 127.45, 126.04, 103.01, 100.85, 98.25, 80.63, 78.79, 77.23, 76.33, 72.98, 72.23, 68.84, 64.06, 62.53, 61.33, 57.55, 55.22, 25.08, 20.59, 20.56. ESI-MS:
m/z = 686 [M + H]⁺, 703 [M + NH₄]⁺, 708 [M + Na]⁺, 724 [M + K]⁺. Anal. Calcd for C₃₄H₃₉NO₁₄: C, 59.56; H, 5.73; N, 2.04. Found: C, 59.34; H, 5.67; N, 1.96.

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The α-anomers and β-anomers were identified by their ^¹H NMR coupling constants for anomeric protons. For α-anomers, J _1,2 = 2.4-2.8 Hz; for β-anomers, J _1,2 = 7.2-7.6 Hz.