Synthesis of Superarmed Thioglycosides via the Ring Opening of 1,2-Orthoesters

Abstract

Since the advent of the armed–disarmed strategy, thioglycosides have become essential tools in one-pot oligosaccharide synthesis. The continuum of glycosyl donor reactivity has since been expanded to include so-called ‘superarmed’ thioglycoside donors whose reactivity relies on more than just the inductive effects of protecting groups. Here we report a new method for the synthesis of superarmed thioglycosides via the ring opening of 1,2-orthoesters. This method ensures the necessary 1,2-trans stereochemistry, and importantly, makes use of trimethylsilyl thioethers as sulfur nucleophiles to avoid the use of unpleasant free thiols. Ten examples of ethyl and phenyl thioglycosides of mono- and disaccharides were synthesised from their orthoesters using tris(pentafluorophenyl)borane (BCF) as the Lewis acid promoter and were obtained in good yield and purity.

Key words

thioglycoside - superarmed - BCF - orthoester - stereoselective

Publication History

Received: 21 June 2023

Accepted after revision: 18 July 2023

Accepted Manuscript online:
18 July 2023

Article published online:
20 September 2023

• References and Notes

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• 13a General Procedure for the Formation of Ethyl 2-O-Acetyl Thioglycosides A sugar orthoester (0.20 mmol) was dried under high vacuum for 1 h. The flask was flushed with N₂, and dry CH₂Cl₂ (5 mL) was added. The flask was cooled to 0 °C and (ethylthio)trimethylsilane (72 μL, 0.44 mmol, 2.2 equiv) was added followed by tris(pentafluorophenyl)borane (0.150 g, 0.30 mmol, 1.5 equiv). The mixture was stirred at 0 °C for 5 min. The reaction was neutralised with triethylamine (0.1 mL) and then concentrated in vacuo. The crude mixture was purified by flash chromatography (cHex/EtOAc, 8:1) to give the product as a colorless solid. Compound 6a was obtained as a colorless solid (0.074 g, 0.139 mmol, 70%). ¹H NMR (500 MHz, CDCl₃): δ = 7.38–7.27 (m, 13 H, ArCH), 7.20 (dd, J = 7.3, 2.1 Hz, 2 H, ArCH), 5.06 (dd, J = 10.1, 9.0 Hz, 1 H, H-2), 4.82 (dd, J = 11.1, 7.5 Hz, 2 H, benzyl CH₂), 4.71 (d, J = 11.4 Hz, 1 H, benzyl CH₂), 4.65–4.55 (m, 3 H, benzyl CH₂), 4.38 (d, J = 10.0 Hz, 1 H, H-1), 3.78 (dd, J = 11.1, 2.0 Hz, 1 H, H-6a), 3.75–3.67 (m, 3 H, H-3, H-4, H-6b), 3.52 (ddt, J = 6.7, 4.5, 2.1 Hz, 1 H, H-5), 2.80–2.65 (m, 2 H, SCH₂), 2.00 (s, 3 H,C(O)CH₃), 1.28 (t, J = 7.5 Hz, 3 H, S(CH₂)CH₃) ppm. ¹³C NMR (126 MHz, CDCl₃): δ = 169.8 (C=O), 138.3, 138.3, 138.0 (ArC), 128.6, 128.5, 128.2, 128.0, 127.9, 127.9, 127.8, 127.7 (ArCH), 84.5 (C-3), 83.5 (C-1), 79.6 (C-5), 78.0 (C-4), 75.4 (benzyl CH₂), 75.2 (benzyl CH₂), 73.6 (benzyl CH₂), 71.9 (C-2), 69.0 (C-6), 23.9 (SCH₂), 21.1 (acetyl CH₃), 15.0 (SCH₂ CH₃) ppm.

Spectra matched literature reports:
• 13b Ple K, Chwalek M, Voutquenne-Nazabadioko L. Tetrahedron 2005; 61: 4347
• 14a Ethyl-2-O-benzoyl-3,4,6-tri-O-benzyl-1-thio-β-d-glucopyranoside (9a) Orthoester 4 (0.20 mmol) was dried under high vacuum for 1 h. The flask was flushed with N₂, and dry CH₂Cl₂ (5 mL) was added. The flask was cooled to 0 °C and (ethylthio)trimethylsilane (72 μL, 0.44 mmol, 2.2 equiv) was added followed by tris(pentafluorophenyl)borane (0.150 g, 0.30 mmol, 1.5 equiv). The mixture was brought to rt and stirred for 4 h. The reaction was neutralised with triethylamine (0.1 mL) then concentrated in vacuo. The crude mixture was purified by flash chromatography (cHex/EtOAc, 8:1) to give the product as a colourless solid (0.11 g, 0.18 mmol, 61%). ¹H NMR (400 MHz, CDCl₃): δ = 8.05–8.00 (m, 2 H, ArH), 7.57 (t, J = 7.4 Hz, 1 H, ArH), 7.47–7.41 (m, 2 H, ArH), 7.37–7.26 (m, 8 H, ArH), 7.21–7.17 (m, 2 H, ArH), 7.16–7.08 (m, 5 H, ArH), 5.31 (dd, J = 10.0, 8.9 Hz, 1 H, H-2), 4.82 (d, J = 10.9 Hz, 1 H, benzyl CH₂), 4.74 (d, J = 11.1 Hz, 1 H, benzyl CH₂), 4.66 (d, J = 11.1 Hz, 1 H, benzyl CH₂), 4.63 (d, J = 12.0 Hz, 1 H, benzyl CH₂), 4.61–4.55 (m, 2 H, benzyl CH₂), 4.53 (d, J = 10.1 Hz, 1 H, H-1), 3.84 (t, J = 8.9 Hz, 1 H, H-3), 3.81–3.71 (m, 3 H, H-4, H6a+b), 3.60–3.55 (m, 1 H, H-5), 2.73 (qd, J = 12.3, 7.4 Hz, 2 H, SCH₂), 1.24 (t, J = 7.5 Hz, 3 H, SCH₂CH₃) ppm. ¹³C NMR (101 MHz, CDCl₃): δ = 165.4 (C=O), 138.3, 138.1, 137.9 (ArC), 133.3 (ArCH), 130.1 (ArC), 130.0, 128.6, 128.5, 128.5, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8, 127.8 (ArCH, 84.5 (C-3), 83.6 (C-1), 79.7 (C-5), 78.1 (C-4), 75.4 (benzyl CH₂), 75.3 (benzyl CH₂), 73.6 (benzyl CH₂), 72.6 (C-2), 69.1 (C-6), 24.0 (SCH₂), 15.1 (SCH₂ CH₃) ppm.

Spectra match literature reports:
• 14b Poulsen LT, Heuckendorff M, Jensen HH. Org. Biomol. Chem. 2018; 16: 2269