Total Synthesis of Viniferifuran, Resveratrol-Piceatannol Hybrid, Anigopreissin A and Analogues - Investigation of Demethylation Strategies

Abstract

Resveratrol-based natural products constitute a valuable source of unique compounds with diverse biological activities. In this report we investigate demethylation strategies to minimize formation of cyclized and dimerized products during the synthesis of viniferifuran and analogues. We found that boron trichloride/tetra-n-butylammonium iodide (BCl₃/TBAI) is typically more effective than boron tribromide (BBr₃). Based on these findings we carried out the first syntheses of dehydro-δ-viniferin, resveratrol-piceatannol hybrid and anigopreissin A. In addition, we have developed a short and efficient route to viniferifuran that was obtained in 13% yield over six steps.

Keywords: demethylation; natural products; polyphenols; resveratrol oligomers; stilbenoids; total synthesis.

Figure 1

Selected natural and non‐natural resveratrol dimers and the stilbenoid diptoindonesin G.

Scheme 1

Modified synthetic route to viniferifuran. Reagents and conditions: a) LiAlH₄ (3 equiv.), THF, 0 °C, 10 min. b) Dess–Martin periodinane (1.2 equiv.), DCM, 0 °C, 1 h, 80–90%, 2 steps. c) ArBr or ArI (1.5–2 equiv.), Pd(OAc)₂ (0.1 equiv.), PCy₃⋅HBF₄ (0.2 equiv.), K₂CO₃ (1.5 equiv.), PivOH (3 equiv.), 100 °C, 20 h, 74%. d) ArBr (1.5–2 equiv.), PdCl(C₃H₅)dppb (0.05 equiv.), KOAc (2 equiv.), DMA, 150 °C, 20 h, 60%. e) Phosphonate derivatives (1.5 equiv.), NaH (3 equiv.), THF, 120 °C, MWI, 30 min, 80%. f) BCl₃, TBAI, DCM, 0 °C to room temperature, 6 h, 23% (HPLC).

Scheme 2

Modified synthetic route to viniferifuran. Reagents and conditions: a) ArBr or ArI (1.5–2 equiv.), Pd(OAc)₂ (0.1 equiv.), PCy₃⋅HBF₄ (0.2 equiv.), K₂CO₃ (1.5 equiv.), PivOH (3 equiv.), 100 °C, 20 h, 35–74%. b) ArBr (1.5–2 equiv.), PdCl(C₃H₅)(dppb) (0.05 equiv.), KOAc (2 equiv.), DMA, 150 °C, 20 h, 47–60%. c) Phosphonate derivatives (1.5 equiv.), NaH (3 equiv.), THF, 120 °C, MWI, 30 min, 52–82%. d) BCl₃, TBAI, DCM, 0 °C to room temperature, 6 h.

Scheme 3

Alternative routes for the synthesis of viniferifuran and analogues. Reagents and conditions: a) Phosphonate derivatives (1.5 equiv.), NaH (3 equiv.), THF, 120 °C, MWI, 30 min, 60–80%. b) BBr₃ (9–12 equiv.), DCM, −78 °C to room temperature, 6 h. c) Ac₂O, THF, Et₃N, room temperature, overnight, 38–62%, 2 steps. d) NBS (3 equiv.), pTsOH, room temperature, 24–48 h. e) KOH, MeOH, 0 °C, 30 min, 15–30%, 2 steps. f) PdCl₂(dppf)⋅DCM (5% mol), boronic acid (1.5–2 equiv.), Na₂CO₃, DME/H₂O (1/1), 70 °C, MWI, 30 min, 41–76%. g) 4‐Bromoanisole (2 equiv.), Pd(OAc)₂ (0.1 equiv.), PCy₃⋅HBF₄ (0.2 equiv.), K₂CO₃ (1.5 equiv.), PivOH (3 equiv.), 100 °C, 20 h, 25–36%. h) Styrene derivatives (1.2 equiv.), Pd(OAc)₂ (0.1 equiv.), dppp (0.1 equiv.), Et₃N, DMF, 120 °C, 20 h, 25–64%.

Scheme 4

Total synthesis of anigopreissin A, resveratrol‐piceatannol hybrid and dehydro‐δ‐viniferin. Reagents and conditions: a) PdCl₂(PPh₃)₂ (5% mol), CuI (3% mol), ethynylanisole (1.2–1.5 equiv.), Et₃N/THF (2/1), MWI, 40 °C, 30 min then CH₃CN, 100 °C, MWI, 30 min, 74–90%. b) MeI, K₂CO₃, DMF, room temperature, overnight, 77%. c) NIS (1 equiv.), pTsOH cat., CH₃CN, room temperature, overnight, 59%. d) PdCl₂(dppf)⋅DCM (5% mol), 3,5‐dimethoxyphenylboronic acid (1.5 equiv.), K₂CO₃, DME/H₂O (4/1), 80–100 °C, MWI, 30 min, 83–91%. e) Phosphonate derivatives (1.5 equiv.), NaH (3 equiv.), THF, 120 °C, MWI, 30 min, 58–84%. f) BBr₃, DCM, −78 °C to room temperature, 6 h. g) BCl₃, TBAI, DCM, 0 °C to room temperature, 6 h. h) NBS (1.1 equiv.), DCM, room temperature, overnight, 50%. i) PdCl₂(PPh₃)₂ (5% mol), CuI (3% mol), 4‐ethynylanisole (1.2–1.5 equiv.), Et₃N/THF (2/1), MWI, 40 °C, 30 min then 1‐iodo‐3,5‐dimethoxybenzene (1.5 equiv.), CH₃CN, 100 °C, MWI, 30 min, 25% 33+60% 32. j) 1‐Bromo‐3,5‐dimethoxybenzene (1.5 equiv.), PdCl(C₃H₅)dppb (5% mol), KOAc (2 equiv.), DMA, 150 °C, 20 h, 60%.