Thieme Chemistry Journals Awardees – Where Are They Now? ­Ribosylation of an Acid-Labile Glycosyl Acceptor as a Potential Key Step for the Synthesis of Nucleoside Antibiotics

Dedicated to Professor Joachim Thiem on the occasion of his birthday.

Abstract

Naturally occurring nucleoside antibiotics (e.g., muraymycins and caprazamycins) represent attractive lead structures for the development of urgently needed novel antibacterial agents. One major challenge in the total synthesis of muraymycins, caprazamycins, and their analogues is the efficient construction of the densely functionalized aminoribosylated uridine-derived core unit. In order to avoid tedious protecting-group manipulations, we have aimed to conduct the aminoribosylation step with an acid-labile glycosyl acceptor. Therefore, different glycosylation approaches have been studied, with pentenyl glycosides giving the best results.

Key words

natural products - antibiotics - nucleosides - glycosylation - ribosylation - pentenyl glycosides

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• 25 Synthesis of Protected Ribosylated (5′S,6′S)-GlyU 4To a solution of the glycosyl donor β-18 (20.1 mg, 64.5 μmol) and the (5′S,6′S)-GlyU-derived acceptor 2 (35.6 mg, 48.4 μmol) in CH₂Cl₂ (3 mL) with freshly activated molecular sieves (4 Å), NIS (18.9 mg, 83.9 μmol) was added at r.t. under exclusion of light. Over 10 min, TESOTf (5.8 μL, 26 μmol, 1% solution in CH₂Cl₂) was added dropwise. The reaction mixture was stirred at r.t. for 15 min before ice (5 g) was added and the mixture was allowed to warm to r.t. again. It was then diluted with CH₂Cl₂ (70 mL) and the organic layer was washed with 10% Na₂S₂O₃ solution (1 × 70 mL), sat. NaHCO₃ solution (1 × 70 mL), and brine (1 × 70 mL). The organic layer was dried over Na₂SO₄, and the solvent was evaporated under reduced pressure. The resultant crude product was purified by column chromatography (PE–EtOAc, 75:25 → 70:30) to give 4 (16.6 mg, 36%, 58% brsm) as a colorless solid; mp 72 °C. TLC: R_f = 0.28 (i-hexane–EtOAc, 7:3). [α]_D ²⁰ –7.0 (c 0.7, CHCl₃). ¹H NMR (500 MHz, CDCl₃): δ = 0.07 (s, 3 H, SiCH₃), 0.08 (s, 3 H, SiCH₃), 0.09 (s, 3 H, SiCH₃), 0.13 (s, 3 H, SiCH₃), 0.83 (t, J = 7.5 Hz, 3 H, 1^iv-H), 0.88 (t, J = 7.5 Hz, 3 H, 5^iv-H), 0.90 (s, 9 H, SiC(CH₃)₃), 0.90 (s, 9 H, SiC(CH₃)₃), 1.45 (s, 9 H, OC(CH₃)₃), 1.53 (q, J = 7.4 Hz, 2 H, 2^iv-H), 1.66 (dq, J = 7.4, 1.8 Hz, 2 H, 4^iv-H), 3.55 (dd, J = 13.0, 4.0 Hz, 1 H, 5′′′-H_a), 3.72 (dd, J = 13.0, 3.9 Hz, 1 H, 5′′′-H_b), 3.94 (dd, J = 5.7, 4.1 Hz, 1 H, 3′-H), 4.13 (dd, J = 5.7, 2.3 Hz, 1 H, 4′-H), 4.16 (dd, J = 4.1, 3.6 Hz, 1 H, 2′-H), 4.31–4.34 (m, 1 H, 4′′′-H), 4.39 (dd, J = 2.3, 1.9 Hz, 1 H, 5′-H), 4.48 (d, J = 6.3 Hz, 1 H, 2′′′-H), 4.51 (dd, J = 9.2, 1.9 Hz, 1 H, 6′-H), 4.64 (dd, J = 6.3, 1.4 Hz, 1 H, 3′′′-H), 4.97 (d, J = 12.1 Hz, 1 H, 1′′-H_a), 5.14 (s, 1 H, 1′′′-H), 5.24 (d, J = 12.1 Hz, 1 H, 1′′-H_b), 5.44 (d, J = 3.6 Hz, 1 H, 1′-H), 5.60 (dd, J = 8.2, 2.1 Hz, 1 H, 5-H), 6.15 (d, J = 9.2 Hz, 1 H, 6′-NH), 7.24–7.36 (m, 5 H, aryl-H), 7.82 (d, J = 8.2 Hz, 1 H, 6-H), 8.02 (d, J = 2.1 Hz, 1 H, 3-NH). ¹³C NMR (126 MHz, CDCl₃): δ = –4.9, –4.8, –4.2, –3.9, 7.6, 8.5, 18.1, 18.2, 26.0, 26.0, 28.1, 28.9, 29.4, 53.5, 56.5, 67.0, 71.5, 74.8, 77.8, 81.8, 82.7, 85.3, 86.0, 86.4, 90.6, 101.1, 112.3, 117.9, 128.3, 128.4, 127.7, 136.8, 140.8, 149.9, 156.4, 162.9, 168.8. HRMS (ESI⁺): m/z calcd for C₄₅H₇₃N₆O₁₃Si₂: 961.4769 [M + H]⁺; found: 961.4778. IR (ATR): ν = 2930, 2857, 2104, 1685, 1457, 1253, 1160, 1059, 835, 775 cm^–1. UV (MeCN): λ_max = 261 nm.
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