A Rapid and Diastereoselective Synthesis of 2-Deoxy-2-iodo-α-glycosides and its Mechanism for Diastereoselectivity

Abstract

Reductive deiodination of 2-deoxy-2-iodo-glycoside is an efficient and practical approach for the synthesis of 2-deoxyglycosides, which are moieties of bioactive compounds. However, inseparable diastereoisomers are usually formed in the preparation of 2-deoxy-2-iodo-glycosides via glycosylation of glycals with alcohols using current methods. To overcome this problem, a rapid and diastereoselective transformation of glycals and alcohols into 2-deoxy-2-iodo-α-glycosides enabled by I₂/PhI(OAc)₂ has been developed. 14 glycals, derived from 13 monosaccharides and one disaccharide, diastereoselectively yielded α-glycosides. Only in two cases the diastereoselectivity of the glycosylation was poor. The yields of glycosylation range from 73% to 95%, and the reactions are finished in only five minutes. Investigations for better diastereoselectivity by comparing I₂/Ph(OAc)₂- with I₂/Cu(OAc)₂-mediated glycosylations using UV analysis have been conducted.

Key words

2-deoxy-2-iodo-glycoside - selective glycosylation - glycal - alcohol - iodine - iodobenzene diacetate

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• 10 General Procedures for Preparation of 2-Deoxy-2-iodo-α-glycosides To a solution of glycal (1 mmol), alcohol (10 mmol), and PhI(OAc)₂ (1.2 mmol) in CH₃CN (4 mL) was added I₂ (0.6 mmol), the mixture was stirred at r.t. for 5 min. After addition of EtOAc (50 mL) to the reaction mixture, the organic phase was washed with sat. Na₂S₂O₃, water and brine, dried over anhydrous Na₂SO₄, and concentrated. The residue was further purified by column chromatography to afford final product. Cyclohexyl 3,4,6-Tri-O-acetyl-2-deoxy-2-iodo-α-d-mannopyranoside (2a) 438.5 mg, yield 88%, colorless syrup. ¹H NMR (400 MHz, CDCl₃): δ = 5.37 (t, J = 9.7 Hz, 1 H), 5.32 (s, 1 H), 4.69 (dd, J = 9.4, 4.3 Hz, 1 H), 4.51 (dd, J = 4.2, 0.9 Hz, 1 H), 4.26–4.16 (m, 2 H), 4.16–4.09 (m, 1 H), 3.60 (ddd, J = 13.1, 9.1, 3.8 Hz, 1 H), 2.12 (s, 3 H), 2.10 (s, 3 H), 2.07 (s, 3 H), 1.92–1.84 (m, 2 H), 1.78–1.72 (m, 2 H), 1.59–1.50 (m, 1 H), 1.48–1.37 (m, 1 H), 1.36–1.20 (m, 4 H). ¹³C NMR (101 MHz, CDCl₃): δ = 170.69, 169.87, 169.56, 99.59, 76.92, 69.20, 69.15, 67.86, 62.38, 33.19, 31.59, 30.70, 25.45, 24.10, 23.84, 20.98, 20.73, 20.68. i-Propyl 3,4-Di-O-acetyl-2-deoxy-2-iodo-α-d-arabinopyranoside (2k) 337.2 mg, yield 87%, white solid. ¹H NMR (400 MHz, CDCl₃): δ = 5.53 (s, 1 H), 5.19–5.04 (m, 1 H), 4.87 (d, J = 7.5 Hz, 1 H), 4.16 (dd, J = 7.5, 3.2 Hz, 1 H), 4.02–3.90 (m, 2 H), 3.81 (dd, J = 11.3, 9.4 Hz, 1 H), 2.20 (s, 3 H), 2.03 (s, 3 H), 1.24 (dd, J = 8.1, 6.3 Hz, 6 H). ¹³C NMR (101 MHz, CDCl₃): δ = 169.68, 169.54, 99.64, 72.41, 70.23, 66.67, 61.76, 27.59, 23.29, 21.65, 20.80, 20.71. HRMS: m/z calcd for C₁₂H₂₀O₆IH [M + H⁺]: 387.0299; found: 387.0302.
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• 12 I₂/PhI(OAc)₂-Mediated Glycosylation Glycal (1 mmol), alcohol (10 mmol), I₂ (0.6 mmol), and PhI(OAc)₂ (1.2 mmol) in CH₃CN (4 mL). I₂/Cu(OAc)₂-Mediated Glycosylation Glycal (0.4 mmol), alcohol (0.6 mmol), I₂ (0.6 mmol), molecular sieves 4 Å (0.108 g) and Cu(OAc)₂ (0.6 mmol) in CH₂Cl₂ (4 mL). These reaction solutions (diluted at 30 times by CHCl₃) are measured by UV at 530 nm.
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