Ferrier Rearrangement of 1,2-Dihydropyrans with Organozinc Species in Toluene/n-Dibutyl Ether

Abstract

Herein, we report the catalyst-free addition of organozinc species to glycal derivatives and dihydropyrans in a toluene/n-dibutyl ether solvent mixture via a Ferrier rearrangement at room temperature. This methodology requires only a slight excess of the nucleophile and leads preferentially to the C-glycoside α-anomer. Various 1,2-dihydropyrans were assessed with a range of nucleophiles (aryl, alkynyl, alkyl) yielding the desired C-glycosides in good yield and diastereoselectivity up to 20:1.

Key words

Ferrier - rearrangement - C-glycosides - glycal - dihydropyran - organozinc species - solvent effect

• References and Notes

• 1 New address: School of Chemistry, University of Manchester, Oxford Road, Manchester M13 9PL, UK.
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• 11 General Procedure for the Synthesis of Dihydropyrans 6a–c, 7a–g, and 8a,b A 25 mL Schlenk tube was equipped with magnetic agitation under inert atmosphere (N₂). The corresponding iodo compound (1.1 equiv) was dissolved in toluene (4 L/mol). After cooling the mixture to 0 °C with an ice-bath, n-BuLi (1.15 equiv, 25% w/w in heptane) was added over 5 min. After 20 min, ZnBr₂·LiBr (1.15 equiv, 32% w/w in DBE) was added over 5 min at 0 °C. After 20 min, a toluene solution of glycal substrate (1.0 equiv, 1 L/mol) was added at 0 °C. The reaction was stirred at r.t. and followed by TLC until starting material was completely consumed (1–5 h). After completion, the reaction medium was quenched with saturated NH₄Cl (aq) (4 L/mol) for 30 min, and phases were separated. The aqueous phase was extracted three times with EtOAc. All organic layers were combined and dried over Na₂SO₄, filtered, and finally put under reduced pressure to remove volatile materials. The diastereomeric ratio was determined from the crude mixture based on the ¹H NMR spectrum analysis. After evaporation, purification on silica gel by flash column chromatography afforded the desired product. (2S,6S)-2-[(Benzyloxy)methyl]-6-[4-(benzyloxy)phenyl]-3,6-dihydro-2H-pyran (6a) 248 mg isolated (69% yield – 0.93 mmol scale); colorless oil. Major Diastereomer R_f = 0.12 (60:40 CH₂Cl₂/heptane). ¹H NMR (360 MHz, CDCl₃): δ = 7.48–7.28 (m, 12 H), 7.01–6.94 (m, 2 H), 6.09–6.03 (m, 1 H), 6.03–5.97 (m, 1 H), 5.31–5.26 (m, 1 H), 5.08 (s, 2 H), 4.53 (s, 2 H), 3.87–3.79 (m, 1 H), 3.59–3.45 (m, 2 H), 2.30–3.18 (m, 1 H), 2.08–1.99 (m, 1 H). ¹³C NMR (90 MHz, CDCl₃): δ = 158.4, 138.4, 137.0, 133.4, 129.4, 128.6, 128.3, 127.9, 127.7, 127.6, 127.5, 127.4, 125.3, 114.5, 73.7, 73.2, 72.8, 70.0, 67.6, 27.4. Minor Diastereomer R_f = 0.15 (60:40 CH₂Cl₂/heptane). ¹H NMR (360 MHz, CDCl₃): δ = 7.47–7.26 (m, 12 H), 7.00–6.91 (m, 2 H), 5.97–5.90 (m, 1 H), 5.77–5.72 (m, 1 H), 5.21–5.16 (m, 1 H), 5.07 (s, 2 H), 4.67–4.53 (m, 2 H), 4.08–3.49 (m, 1 H), 3.68–3.49 (m, 2 H), 2.25–2.12 (m, 1 H), 2.12–2.00 (m, 1 H). ¹³C NMR (90 MHz, CDCl₃): δ = 158.4, 138.4, 137.1, 133.9, 130.3, 128.6, 128.5, 128.3, 127.9, 127.7, 127.5, 127.4, 124.1, 114.8, 77.1, 73.7, 73.4, 73.3, 70.0, 27.7. HRMS: m/z calcd for C₂₆H₂₇O₃ [M + H]⁺: 387.1954; found: 387.1956.