A Rapid Total Synthesis of (±)-Sylvone

Abstract

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

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

References and Notes

For reviews concerning lignans, see:

1a MacRae WD. Towers GHN. Phytochemistry  1984,  23:  1207 

1b Whiting DA. Nat. Prod. Rep.  1987,  4:  499 

1c Ward RS. Nat. Prod. Rep.  1993,  10:  1 

1d Ward RS. Nat. Prod. Rep.  1995,  12:  183 

1e Ward RS. Nat. Prod. Rep.  1997,  14:  43 

1f Ward RS. Nat. Prod. Rep.  1997,  16:  75 

For reviews on the strategies of oxacycle synthesis, see:

2a Faul MM. Huff BE. Chem. Rev.  2000,  100:  2407 

2b Elliott MC. J. Chem. Soc., Perkin Trans. 1  2002,  2301 

For methods resulting in a total synthesis of a furofuran lignan, see:

3a Takano S. Samizu K. Ogasawara K. Synlett  1993,  785 

3b Akindele T. Marsden SP. Cumming JG. Org. Lett.  2005,  7:  3685 

3c Wardrop DJ. Fritz J. Org. Lett.  2006,  8:  3659 

3d Review: Brown R. Swain NA. Synthesis  2004,  811 

4a Cassidy JH. Marsden SP. Stemp G. Synlett  1997,  1411 

4b Miles SM. Marsden SP. Leatherbarrow RJ. Coates WJ. J. Org. Chem.  2004,  69:  6874 

5a Zhang Y. Reynolds NT. Manju K. Rovis T. J. Am. Chem. Soc.  2002,  124:  9720 

5b Zhang Y. Rovis T. Tetrahedron Lett.  2003,  59:  8979 

5c Nasveschuk CG. Rovis T. Org. Lett.  2005,  7:  2173 

5d Nasveschuk CG. Rovis T. Angew. Chem. Int. Ed.  2005,  44:  3264 

5e Frein JD. Rovis T. Tetrahedron  2006,  62:  4573 

6 Nasveschuk CG. Jui NT. Rovis T. Chem. Commun.  2006,  3119 

7a Banerji A. Sarkar M. Ghosal T. Pal SC. Shoolery JN. Tetrahedron  1984,  40:  5047 

7b Banerji A. Basu S. J. Indian Chem. Soc.  1992,  69:  321 

For reports that discuss the bioactivity of lignans, see:

8a Chen I.-S. Chen J.-J. Duh C.-Y. Tsai I.-L. Phytochemistry  1997,  45:  991 

8b Parmar VS. Jain SC. Bisht KS. Jain R. Taneja P. Jha A. Tyagi OD. Prasad AK. Wengel J. Olsen CE. Boll PM. Phytochemistry  1997,  46:  597 

9a Maioli AT. Civiello RL. Foxman BM. Gordon DM. J. Org. Chem.  1997,  62:  7413 

9b Yoda H. Kimura K. Takabe K. Synlett  2001,  400 

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.

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

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.