Stereoselective Synthesis of Tricyclic Pyranoxepin Derivatives by Ruthenium-Catalyzed Enyne Metathesis/Diels-Alder Reaction

Abstract

Synthesis of tricyclic oxepin-annulated pyrone derivatives has been achieved by the ring-closing enyne metathesis using the first-generation Grubbs’ catalyst under a nitrogen atmosphere. The Diels-Alder reaction of these cyclized products with the dienophile proceeded smoothly to afford the tricyclic compounds in ­excellent yield.

Key words

pyrone - oxepin - heterocycles - ruthenium - ring-closing metathesis - enyne metathesis - Diels-Alder reactions

References

• 1a Mors WB. Gottlieb OR. Djerassi C. J. Am. Chem. Soc.  1957,  79:  4507 
• 1b McGahren WJ. Ellestad GA. Morton GO. Kunstman MP. Mullen P. J. Org. Chem.  1973,  38:  3542 
• 1c Irschik H. Gerth K. Hofle G. Kohl W. Reichenbach H. J. Antibiot.  1983,  36:  1651 
• 1d Sparace SA. Mudd JB. Bruke BA. Aasan AJ. Phytochemistry  1984,  23:  2499 
• 1e Mori K. Otsuka T. Oda M. Tetrahedron Lett.  1984,  40:  2929 
• 1f Prasad JVN. Pavolovsky P. Para KS. Ellsworth EL. Tummino PJ. Nouhan C. Ferguson D. Bioorg. Med. Chem. Lett.  1996,  6:  1113 
• 1g Prasad JVN. Para KS. Lunney EA. Ortwine DE. Dunbar JB. Ferguson D. Tummino PJ. Hupe D. Bradley BD. J. Am. Chem. Soc.  1994,  116:  6989 
• 2 Bravo P. Frigerio M. Ticozzi C. J. Heterocycl. Chem.  1988,  25:  647 
• 3a Schuster M. Blechert S. Angew. Chem., Int. Ed. Engl.  1997,  36:  2036 
• 3b Grubbs RH. Chang S. Tetrahedron  1998,  54:  4413 
• 3c Armstrong SK. J. Chem. Soc., Perkin Trans. 1  1998,  371 
• 3d Schrock RR. Tetrahedron  1999,  55:  8141 
• 3e Deiters A. Martin SF. Chem. Rev.  2004,  104:  2199 
• 4a Diver TA. Giessert A. Chem. Rev.  2004,  104:  1317 
• 4b Mori M. J. Synth. Org. Chem. Jpn.  1998,  56:  115 
• 4c Hoye TR. Donaldson SM. Vos TJ. Org. Lett.  1999,  1:  277 
• 4d Mori M. Topics in Organometallic Chemistry   Vol. 1:  Fürstner A. Springer-Verlag; Berlin, Heidelberg: 1998.  p.133 
• 4e Timmer MSM. Ovaa H. Filippov DV. Vander Marel GA. Van Boom JH. Tetrahedron Lett.  2001,  42:  8231 
• 4f Clark JS. Hamelin O. Angew. Chem. Int. Ed.  2000,  39:  372 
• 4g Renaud J. Graf CD. Oberer L. Angew. Chem. Int. Ed.  2000,  39:  3101 
• 4h Bentz D. Laschat S. Synthesis  2000,  1766 
• 4i Fürstner A. Szillat H. Stelzer F. J. Am. Chem. Soc.  2000,  122:  6785 
• 5 Schwab P. France MB. Ziller JW. Grubbs RH. Angew. Chem., Int. Ed. Engl.  1995,  34:  2039 
• 6a Moreno-Manas M. Ribas J. Virgili A. J. Org. Chem.  1988,  53:  5328 
• 6b Manger MC. Ollis WD. Sutherland IO. J. Chem. Soc., Chem. Commun.  1967,  577 
• 6c Majumdar KC. Ghosh S. Monatsh. Chem.  2002,  133:  1317 
• 8a Schurer SC. Blechert S. Chem. Commun.  1999,  1203 
• 8b Zheng G. Dougherty TJ. Pandey RK. Chem. Commun.  1999,  2469 
• 8c Smulic JA. Diver ST. Tetrahedron Lett.  2001,  42:  171 
• 9a Mori M. Sakakibara N. Kinoshita A. J. Org. Chem.  1998,  63:  6082 
• 9b Kotha S. Sreenivasachary N. Chem. Commun.  2000,  503 
• 9c Kotha S. Sreenivasachary N. Brahmachary E. Eur. J. Org. Chem.  2001,  787 

7

Typical Procedure for the Enyne RCM.
To a solution of substrate 4d (68.9 mg, 0.2 mmol) in dry degassed CH₂Cl₂ (8 mL) under N₂ was added catalyst A (15 mg) and the reaction was stirred at r.t. for 8 h. After the removal of the solvent, the residue was purified by flash column chromatography on silica gel (PE-EtOAc, 4:1) to give 5d in 90% yield. Compound 5a: yield 82%; sticky liquid. IR (neat): ν_max = 1704, 1665, 1568 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.13 (s, 3 H), 3.47 (d, J = 6.55 Hz, 2 H), 4.99 (s, 2 H), 5.09 (d, J = 10.8 Hz, 1 H), 5.25 (d, J = 17.5 Hz, 1 H), 5.60 (s, 1 H), 6.24 (t, J = 6.55 Hz, 1 H), 6.29 (dd, J = 17.5 Hz, J = 10.8 Hz, 1 H). MS: m/z = 204 [M⁺]. Anal. Calcd for C₁₂H₁₂O₃: C, 70.59; H, 5.88. Found: C, 70.73; H, 5.72%.
Compound 5d: yield 90%; light-yellow solid, mp 112 °C. IR (KBr): ν_max = 1698, 1658, 1568, 1491 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.13 (s, 3 H), 3.51 (d, J = 6.64 Hz, 2 H), 4.66 (s, 2 H), 5.07 (s, 2 H), 5.38 (s, 1 H), 5.41 (s, 1 H), 5.60 (s, 1 H), 6.39 (t, J = 6.64 Hz, 1 H), 6.82 (d, J = 8.88 Hz, 1 H), 7.21 (d, J = 8.88 Hz, 2 H). MS: m/z = 344, 346 [M⁺]. Anal. Calcd for C₁₉H₁₇O₄Cl: C, 66.18; H, 4.93. Found: C, 65.98; H, 5.17%.

10

Procedure for the Diels-Alder Reactions. A solution of 5d (17.2 mg, 0.05 mmol) and dimethylfumarate (14.4 mg, 0.1 mmol) in toluene was heated at 100 °C for 4 h. After removal of the solvent the residue was purified by flash column chromatography on silica gel (PE-EtOAc, 3:1) to give 6d in 95% yield. Compound 6d: yield 95%; white solid, mp 118-119 °C. IR (KBr): ν_max = 1736, 1703, 1655, 1580 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.15 (s, 3 H), 2.44-2.48 (m, 1 H), 2.58-2.69 (m, 3 H), 2.95-3.05 (m, 3 H), 3.67 (s, 3 H), 3.76 (s, 3 H), 4.39 (d, J = 11.2 Hz, 1 H), 4.47 (d, J = 11.2 Hz, 1 H), 4.79 (d, J = 13.6 Hz, 1 H), 5.04 (d, J = 13.6 Hz, 1 H), 5.65 (s, 1 H), 6.79 (d, J = 8.8 Hz, 2 H), 7.22 (d, J = 8.8 Hz, 2 H). ¹³C NMR (125 MHz, CDCl₃): δ = 19.93, 27.11, 31.09, 41.86, 42.76, 47.74, 52.57, 52.69, 67.37, 69.49, 101.93, 102.54, 116.32, 126.79, 129.90, 130.79, 133.98, 157.35, 159.99, 166.12, 168.50, 174.01, 175.07. MS: m/z = 488, 490 [M⁺]. Anal. Calcd for C₂₅H₂₅O₈Cl: C, 61.41; H, 5.12. Found: C, 61.68; H, 5.30%.
Compound 6e: yield 96%; white solid, mp 125 °C. IR (KBr): ν_max = 1736, 1704, 1650, 1580 cm^-1. ¹H NMR (400 MHz, CDCl₃): δ = 2.15 (s, 3 H), 2.41-2.47 (m, 1 H), 2.58-2.68 (m, 3 H), 2.93-3.02 (m, 3 H), 3.67 (s, 3 H), 3.76 (s, 3 H), 4.39 (d, J = 11.5 Hz, 1 H), 4.48 (d, J = 11.5 Hz, 1 H), 4.79 (d, J = 13.4 Hz, 1 H), 5.05 (d, J = 13.4 Hz, 1 H), 5.65 (s, 1 H), 6.78 (d, J = 8.6 Hz, 1 H), 7.21-7.25 (m, 2 H). MS: m/z = 522, 524, 526 [M⁺]. Anal. Calcd for C₂₅H₂₄O₈Cl₂: C, 57.36; H, 4.59. Found: C, 57.66; H, 4.44%.