A Rapid Total Synthesis of (±)-Sylvone

Abstract

We report a convergent and diastereoselective synthesis of (±)-sylvone that utilizes a diastereoselective [1,3] ring contraction.

Key words

ring contraction - [1,3] rearrangement - 1,3-dioxepin - tetrahydrofuran - sylvone

References and Notes

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• 11 For a procedure to prepare 6, see: Scannell RT. Stevenson R. J. Heterocycl. Chem.  1980,  17:  1727 

10

2-(3,4-Dimethoxyphenyl)-4,7-dihydro[1,3]dioxepine (5): ¹H NMR (400 MHz, CDCl₃): δ = 7.08-7.02 (2 H, m), 6.84 (1 H, d, J = 8.1 Hz), 5.79 (1 H, s), 5.75 (2 H, s), 4.41-4.19 (4 H, m), 3.88 (3 H, s), 3.86 (3 H, s). ¹³C NMR (100 MHz, CDCl₃): δ = 149.2, 148.9, 131.8, 130.2, 118.9, 110.8, 109.7, 102.3, 64.7, 56.1. IR (NaCl dep. from CHCl₃): 2942, 2837, 1516, 1259, 1160, 777 cm^-1.

12

Vinyl iodide 6 is consumed in these reactions. Small amounts of dioxepin 5 could be re-isolated (ca. 20%).

13

2-(3,4-Dimethoxyphenyl)-5-[1-(3,4,5-trimethoxy-phenyl)vinyl]-4,5-dihydro[1,3]dioxepine (7): ¹H NMR (400 MHz, CDCl₃): δ = 7.08-7.02 (2 H, m), 6.84 (1 H, d, J = 8.3 Hz), 6.62 (2 H, s), 6.53 (1 H, dd, J = 7.5, 3.0 Hz), 5.49 (1 H, s), 5.38 (1 H, s), 5.19 (1 H, s), 5.01 (1 H, d, J = 7.3 Hz), 4.23 (1 H, d, J = 11.5, 4.5 Hz), 3.94-3.82 (16 H, m), 3.38 (1 H, dd, J = 11.1, 11.1 Hz). ¹³C NMR (100 MHz, CDCl₃): δ = 153.3, 149.6, 149.1, 148.4, 145.3, 138.2, 136.9, 131.6, 118.7, 114.2, 113.3, 110.9, 109.0, 106.4, 103.9, 74.4, 61.1, 56.4, 56.2, 56.1, 46.9. IR (NaCl dep. from CHCl₃): 2937, 2836, 1645, 1411, 1128, 732 cm^-1. HRMS (+TOF MS): m/z calcd for C₂₄H₂₉O₇ [M + H]⁺: 429.1908; found: 429.1893.

14

Procedure for the Stereoselective Ring Contraction of 7
A flame-dried round-bottomed flask was purged with argon then charged with propionitrile (0.1 M with respect to 1,3-dioxepin) and 0.1 equiv of TMSOTf. The solution was cooled to -78 °C. A separate flame-dried round-bottomed flask was purged with argon and charged with propionitirile (0.1 M with respect to 1,3-dioxepin) and 1 equiv of 7. The solution was then cooled to -78 °C. The solution containing 7 was transferred via cannula to the solution containing Lewis acid at an approximate rate of 1 mL/min. The solution was allowed to mix for 1 h at -78 °C. When the reaction was complete the Lewis acid was quenched with 1 equiv of Et₃N and subsequently poured into sat. aq NaHCO₃. The aqueous layer was extracted with Et₂O (3 ×), then the organic layer was dried with MgSO₄. After filtration the solvent removed in vacuo and the crude product was carried through the remainder of the synthetic steps to afford (±)-sylvone 1.

15

(±)-Sylvone (1)
¹H NMR (400 MHz, CDCl₃): δ = 7.41 (2 H, s), 6.84 (3 H, m), 5.03, (1 H, d, J = 6.0 Hz), 4.43 (1 H, dd, J = 7.9, 7.9 Hz), 4.31 (1 H, ddd, J = 7.7, 5.8, 2.8 Hz), 4.24 (1 H, dd, J = 8.1, 5.8 Hz), 3.96-3.77 (15 H, m), 3.41 (2 H, d, J = 6.4 Hz), 2.89 (1 H, ddd, J = 6.2, 6.0, 2.8 Hz), 1.40 (1 H, br s). ¹³C NMR (100 MHz, CDCl₃): δ = 198.7, 153.3, 149.1, 148.4, 142.9, 131.5, 130.6, 117.9, 111.2, 108.9, 106.4, 81.5, 69.1, 62.1, 61.1, 56.4, 56.0, 56.0, 49.9, 48.9. IR (NaCl dep. from CHCl₃): 3516, 2941, 1673, 1516, 1127, 731 cm^-1. MS (EI⁺): m/z calcd for C₂₃H₂₈O₈ [M + H]⁺: 433.2; found: 433.3.