Total Synthesis and Stereochemical Confirmation of 2,5-Diaryl-3,4-dimethyltetrahydrofuran Lignans: (+)-Fragransin A₂, (+)-Galbelgin, (+)-Talaumidin, (-)-Saucernetin and (-)-Verrucosin

Abstract

A new ring closure to tetrasubstituted tetrahydrofurans from the intramolecular attack of an OMOM ether onto a benzylic mesylate proceeds through a quinonoid intermediate or by direct S_N2 displacement. The synthesis of diastereomeric biologically active natural lignans is described utilizing this general methodology.

lignans - tetrahydrofurans - quinonoid intermediate - ­cycloetherification - enantioselective synthesis

References and Notes

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Data of (+)-Fragransin A₂ (1).
Mp 198-200 °C (Lit. [3a] 200-202 °C); [α]_D +77.7 (c 1.0, CHCl₃) [Lit. [3a] +79.0 (c 0.84, CHCl₃)]. IR (thin film): 3428, 2957, 2926, 1515, 1272, 1034 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 6.85-6.98 (m, 6 H), 5.58 (s, 2 H), 4.65 (d, 2 H, J = 9.2 Hz), 3.94 (s, 6 H), 1.76-1.82 (m, 2 H), 1.06 (d, 6 H, J = 6.0 Hz) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 146.2, 144.7, 134.0, 119.0, 113.6, 108.0, 88.0, 55.6, 50.6, 13.47 ppm. HRMS: m/z calcd for C₂₀H₂₅O₅ [M + H]⁺: 345.1698; found: 345.1696.

<A NAME="RS18006ST-18">18</A>

Data of (+)-Galbelgin ( 2).
Mp 140-142 °C (Lit. [4c] 141-142 °C); [α]_D +83.4 (c 0.47, CHCl₃) [Lit. [4c] -85.1 (c 0.047, CHCl₃) for (-)-galbelgin]. IR (thin film): 2957, 2929, 1515, 1263, 1028 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 6.84-7.01 (m, 6 H), 4.68 (d, 2 H, J = 9.2 Hz), 3.93 (s, 6 H), 3.90 (s, 6 H), 1.78-1.87 (m, 2 H), 1.07 (d, 6 H, J = 5.6 Hz) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 148.6, 148.0, 134.5, 118.2, 110.4, 108.7, 88.0, 55.54, 55.52, 50.6, 13.5 ppm. HRMS: m/z calcd for C₂₂H₂₉O₅ [M + H]⁺: 373.2009; found: 373.2014.

<A NAME="RS18006ST-19">19</A>

Data of (+)-Talaumidin ( 3).
Colorless oil; [α]_D +76.0 (c 0.5, CHCl₃) [Lit. [9] -81.8 (c 0.43, CHCl₃) for (-)-talaumidin]. ¹H NMR (400 MHz, CDCl₃): δ = 6.77-6.97 (m, 6 H), 5.96 (s, 2 H), 5.57 (br s, 1 H), 4.63 (d, 2 H, J = 8.8 Hz), 3.93 (s, 6 H), 1.74-1.82 (m, 2 H), 1.05 (d, 3 H, J = 5.6 Hz), 1.04 (d, 3 H, J = 6.0 Hz) ppm. ¹³C NMR (400 MHz, CDCl₃): δ = 147.4, 146.6, 146.2, 144.7, 136.2, 133.7, 119.3, 119.0, 113.6, 108.1, 107.6, 106.2, 100.6, 88.1, 87.8, 55.6, 50.8, 50.5, 13.45, 13.43 ppm. HRMS: m/z calcd for C₂₀H₂₃O₅ [M + H]⁺: 343.1540; found: 343.1553.

<A NAME="RS18006ST-20">20</A> Evans DA. Rieger DL. Biodeau MT. Urpi F. J. Am. Chem. Soc.  1991,  113:  1047 

<A NAME="RS18006ST-21">21</A>

Data of (-)-Verrucosin ( 4).
Colorless oil; [α]_D -16.14 (c 0.96, CHCl₃) [Lit. [3a] +14.8 (c 1.38, CHCl₃) for (+)-verrucosin]. IR (thin film): 3435, 2937, 2963, 1510, 1266, 1033 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 6.81-7.07 (m, 6 H), 5.62 (s, 1 H), 5.56 (s, 1 H), 5.14 (d, 1 H, J = 8.6 Hz), 4.42 (d, 1 H, J = 9.3 Hz), 3.94 (s, 3 H), 3.88 (s, 3 H), 2.19-2.31 (m, 1 H), 1.76-1.86 (m, 1 H), 1.08 (d, 3 H, J = 6.5 Hz), 0.68 (d, 3 H, J = 7.0 Hz) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 146.1, 145.8, 144.8, 144.2, 132.9, 132.4, 119.5, 118.9, 113.8, 113.5, 109.4, 109.3, 87.0, 82.8, 55.50, 55.46, 47.3, 45.6, 14.6, 14.5 ppm. HRMS: m/z calcd for C₂₀H₂₅O₅ [M + H]⁺: 345.1698; found: 345.1693.

<A NAME="RS18006ST-22">22</A>

Data of (-)-Saucernetin ( 5).
Mp 77-79 °C (Lit. [6c] 78-80 °C); [α]_D -44.2 (c 0.5, CHCl₃) [lit. [6c] +48.1 (c 0.5, CHCl₃)]. IR (thin film): 2957, 2926, 1515, 1272, 1033 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 6.85-6.90 (m, 6 H), 5.47 (d, 2 H, J = 6.0 Hz), 3.92 (s, 6 H), 3.90 (s, 6 H), 2.25-2.32 (m, 2 H), 0.71 (d, 6 H, J = 6.4 Hz). ¹³C NMR (400 MHz, CDCl₃): δ = 148.2, 147.5, 133.6, 118.0, 110.3, 109.1, 83.1, 55.5, 43.7, 14.4 ppm. HRMS: m/z calcd for C₂₂H₂₉O₅ [M + H]⁺: 373.2009; found: 373.2014.