Synthesis of Enantiomerically Pure Dihydrofurans and Dihydropyrans from Common Precursors Using RCM and Tandem RCM-Isomerization

Abstract

Starting from glyceraldehyde, structurally and stereo­chemically diverse dihydrofurans and dihydropyrans with a 1,2-dihydroxyethylene side chain can be accessed in few steps via allyl metal addition, O-allylation and ring-closing metathesis (RCM) or tandem RCM-isomerization, respectively. The synthesis of di­hydrofurans requires a selective double-bond isomerization on the homoallylic alcohol stage, prior to O-allylation and RCM or RCM-isomerization.

Key words

carbohydrates - isomerizations - metathesis - ruthenium - tandem reactions

References and Notes

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32

RCM of dienes 7 has very recently been described in a different context, while our work was in progress. See ref. 30.

49

Synthesis of Cyclic Enol Ethers 9 and 18: To a solution of the corresponding diene (1.0 mmol) in toluene (10 mL) was added [Cl₂(PCy₃)₂Ru=CHPh] (41 mg, 5 mol%). The solution was stirred at 40 °C until the starting material was fully consumed (approximately 30 min, TLC), and 2-propanol (1 mL/mmol) and NaOH (0.25 equiv) were added. The solution was then heated to reflux until the RCM product was completely converted into the enol ether. The reaction mixture was diluted with MTBE and washed with H₂O. The organic layer was separated, dried with MgSO₄, filtered, and evaporated. Column chromatography on silica yielded the dihydropyrans or the dihydrofurans. (R,R)-9: [α]²³ _D -45 (c = 0.9, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 6.41 (d, J = 6.0 Hz, 1 H, H6), 4.69 (m, 1 H, H5), 4.18 (ddd, J = 6.6, 6.6, 6.6 Hz, 1 H, OH₂CCHO), 4.03 (dd, J = 6.6, 8.2 Hz, 1 H, OH ₂CCHO), 3.82 (ddd, J = 2.7, 6.6, 9.3 Hz, 1 H, H2), 3.75 (dd, J = 7.1, 8.2 Hz, 1 H, OH ₂CCHO), 1.90-2.17 (2 H, H4), 1.22-1.78 [12 H, H3, (CH₂)₅]. ¹³C NMR (75 MHz, CDCl₃): δ = 143.6, 110.2, 100.4, 77.0, 75.7, 65.1, 35.9, 34.9, 25.1, 23.9, 23.8, 23.5, 19.4. HRMS: m/z [M⁺ + Na] calcd for C₁₃H₂₀O₃Na: 247.1310; found: 247.1308.
(R,R)-18: [α]²⁴ _D 51 (c = 0.9, CH₂Cl₂). ¹H NMR (300 MHz, CDCl₃): δ = 6.25 (ddd, J = 2.4, 2.4, 2.4 Hz, 1 H, H5), 4.89 (ddd, J = 2.4, 2.4, 2.4 Hz, 1 H, H4), 4.48 (ddd, J = 6.8, 6.8, 10.3 Hz, 1 H, H2), 4.03-4.13 (2 H, OH ₂CCHO), 3.86 (m, 1 H, OH₂CCHO), 2.72 (dddd, J = 2.4, 2.4, 10.3, 15.4 Hz, 1 H, H3), 2.55 (dddd, J = 2.4, 2.4, 6.9, 15.4 Hz, 1 H, H3′), 1.40-1.70 [10 H, (CH₂)₅]. ¹³C NMR (75 MHz, CDCl₃): δ = 144.9, 109.9, 99.3, 81.2, 76.4, 66.5, 36.4, 34.8, 31.7, 25.2, 24.0, 23.8. HRMS: m/z [M + H]⁺ calcd for C₁₂H₁₉O₃: 211.1334; found: 211.1331.