Efficient Lewis Acid Mediated Epoxyolefin Cyclizations with Pyrones as Terminators in Liquid SO₂ as a Solvent

Abstract

Lewis acids like BF₃·OEt₂, TiCl₄, ZnCl₂·OEt₂, ZnI₂, and InCl₃ in liquid SO₂ as a solvent at low temperatures have been found to be highly efficient in epoxyolefin cyclizations with pyrones as terminators.

epoxides - Lewis acids - cyclizations - heterocycles - ­pyrones - sulfur dioxide

References and Notes

1a Review: Shiomi K. Tomoda H. Otoguro K. Omura S. Pure Appl. Chem.  1999,  71:  1059 

1b Omura S. Tomoda H. Kim YK. Nishida H. J. Antibiot.  1993,  46:  1168 

1c Kim YK. Tomoda H. Nishida H. Sunazuka T. Obata R. Omura S. J. Antibiot.  1994,  47:  154 

2

Compounds 1 refer to enantiomers and compounds 2-16 to racemates.

3 Tomoda H. Tabata N. Nakata Y. Nishida H. Kaneko T. Obata R. Sunazuka T. Omura S. J. Org. Chem.  1996,  61:  882 

4 Sliskovic DR. White AD. Trends Pharmacol. Sci.  1991,  12:  194 

5 Sunazuka T. Omura S. Chem. Rev.  2005,  105:  4559 

6a Parker KA. Resnick L. J. Org. Chem.  1995,  60:  5726 

6b Smith AB. Kinsho T. Sunazuka T. Omura S. Tetrahedron Lett.  1996,  37:  6461 

7 A different approach, the cationic cyclization with alkenes as initiators and pyrones as terminators has been studied also; Leutbecher H. Ph.D. Thesis   Universität Hohenheim; Germany: 2007.  p.paper in preparation 

8a Van Tamelen EE. Curphey TJ. Tetrahedron Lett.  1962,  3:  121 

8b Hanzlik RP. Organic Syntheses, Coll. Vol. VI   John Wiley and Sons; New York: 1988.  p.560 

9a Lygo B. Tetrahedron Lett.  1994,  35:  5073 

9b Lygo B. Tetrahedron  1995,  51:  12859 

10

Schmidt, D.; Beifuss, U., unpublished results.

11a Cervelló J. Marquet J. Moreno-Mañas M. J. Chem. Soc., Chem. Commun.  1987,  644 

11b Cervelló J. Marquet J. Moreno-Mañas M. Tetrahedron Lett.  1987,  28:  3715 

11c Marquet J. Moreno-Mañas M. Prat M. Tetrahedron Lett.  1989,  30:  3105 

11d Cervelló J. Marquet J. Moreno-Mañas M. Tetrahedron  1990,  46:  2035 

12a Schmidt D. Conrad J. Klaiber I. Beifuss U. Chem. Commun.  2006,  4732 

12b Schmidt D. Conrad J. Klaiber I. Mika S. Beifuss U. Synlett  2007,  333 

13 Corey EJ. Keck GE. Székely I. J. Am. Chem. Soc.  1977,  99:  2006 

14a Ireland RE. Dawson MI. Bordner J. Dickerson RE. J. Am. Chem. Soc.  1970,  92:  2568 

14b Sharpless KB. J. Am. Chem. Soc.  1970,  92:  6999 

14c Van der Gen A. Wiedhaup K. Swoboda JJ. Dunathan HC. Johnson WS. J. Am. Chem. Soc.  1973,  95:  2656 

15 Johnson WS. Berner D. Dumas DJ. Nederlof PJR. Welch J. J. Am. Chem. Soc.  1982,  104:  3508 

16a Muntyan GE. Kurbanov M. Smit VA. Semenovskii AV. Kucherov VF. Izv. Akad. Nauk. SSSR, Ser. Khim.  1973,  633 

16b Mustafaeva MT. Smit VA. Semenovskii AV. Kucherov VF. Izv. Akad. Nauk. SSSR, Ser. Khim.  1973,  1151 

17

Cyclization of 6 with BF ₃ ·OEt ₂ in SO ₂ (l)
Compound 6 (200 mg) was dissolved in liquid SO₂ (10 mL) at -40 °C and BF₃·OEt₂ (223 µL, 1.107 mmol) was added dropwise at the same temperature. The resulting dark yellow solution was stirred for 2 h and the reaction mixture was allowed to warm to -20 °C. The cooling bath was removed and the excess SO₂ was evaporated by stirring at r.t. The residue was treated with Et₃N (780 µL, 5.56 mmol) followed by MeOH (2 mL) and CH₂Cl₂ (20 mL). After stirring for 10 min the volatiles were removed in vacuo. When the residue was submitted to flash column chromatography (SiO₂, EtOAc) two fractions were isolated: 63 mg crude 7 and 126 mg crude 8; the total yield of 7 and 8 amounted to 95%. Analytically pure samples of 7 and 8 were obtained by semipreparative HPLC.

18

Selected Data for 7
IR (ATR): 3251, 2946, 2410, 1716, 1642, 1578, 1480, 1400, 1390, 1220, 1182, 1126, 1024, 976, 926, 850, 802, 744, 695 cm^-1. UV/Vis (MeCN-H₂O, 1:3): λ_max (log ε) = 236.0 (4.27), 331.0 nm (3.94). ¹H NMR (500 MHz, CD₃OD): δ = 0.94 (s, 3 H, 9′-H₃), 1.16 (s, 3 H, 8′-H₃), 1.36 (s, 3 H, 10′-H₃), 1.68 (dd, 1 H, ³ J _{2 ′ -H,1 ′ -HB} = 13.0 Hz, ³ J _{2 ′ -H,1 ′ -HB} = 4.6 Hz, 2′-H), 1.71-1.74 (m, 1 H, 5′-H_A), 1.80-1.84 (m, 1 H, 4′-H_A), 1.86-1.90 (m, 1 H, 5′-H_B), 2.09-2.12 (m, 1 H, 4′-H_B), 2.36 (dd, 1 H, ² J _{1 ′ -HA,1 ′ -HB} = 16.9 Hz, ³ J _{1 ′ -HA,2 ′ -H} = 13.0 Hz, 1′-H_A), 2.62 (dd, 1 H, ² J _{1 ′ -HB,1 ′ -HA} = 17.3 Hz, ³ J _{1 ′ -HB,2 ′ -H} = 4.6 Hz, 1′-H_B), 3.41 (dd, 1 H, ³ J _{6 ′ -H,5 ′ -HA} = 11.6 Hz, ³ J _{6 ′ -H,5 ′ -HB} = 4.4 Hz, 6-H), 6.89 (s, 1 H, 5-H), 7.73 (dd, 1 H, ³ J _{5 ′′ -H,6 ′′ -H} = 7.9 Hz, ³ J _{5 ′′ -H,4 ′′ -H} = 5.1 Hz, 5′′-H), 8.46 (d, 1 H, ³ J _{6 ′′ -H,5 ′′ -H} = 8.1 Hz, 6′′-H). 8.74 (br s, 1 H, 4′′-H), 9.13 (br s, 1 H, 2′′-H). ¹³C NMR (125 MHz, CD₃OD): δ = 15.04 (C-9′), 18.88 (C-1′), 20.14 (C-10′), 27.89 (C-8′), 28.78 (C-5′), 38.27 (C-4′), 39.69 (C-7′), 47.66 (C-2′), 78.10 (C-6′), 82.00 (C-3′), 101.27 (C-5), 101.59 (C-3), 125.43 (C-5′′), 129.28 (C-1′′), 134.70 (C-6′′), 147.19 (C-2′′), 151.68 (C-4′′), 156.70 (C-6), 165.06 (C-4), 165.78 (C-2). MS (EI, 70 eV): m/z (%) = 341 (38) [M⁺], 323 (4), 308 (9), 256 (11), 202 (100), 148 (26), 121 (47), 106 (59), 78 (42), 43 (41). HRMS (EI, 70 eV): m/z calcd for C₂₀H₂₃NO₄: 341.1627; found: 341.1650.

19

Selected Data for 8
IR (ATR): 3373, 3076, 2943, 2871, 1647, 1561, 1435, 1260, 1164, 1179, 1127, 1026, 931, 812, 702 cm^-1. UV/Vis (MeCN-H₂O, 1:3): λ_max (log ε) = 228 (4.19), 277 nm (3.99). ¹H NMR (500 MHz, CD₃OD): δ = 0.94 (s, 3 H, 9′-H₃), 1.17 (s, 3 H, 8′-H₃), 1.44 (s, 3 H, 10′-H₃), 1.70-1.73 (m, 1 H, 4′-H_B), 1.76 (dd, 1 H, ³ J _{2 ′ -H,1 ′ -HA} = 12.6 Hz, ³ J _{2 ′ -H,1 ′ -HB} = 4.8 Hz, 2′-H), 1.88-1.96 (m, 2 H, 4′-H_A, 5′-H_B), 2.13-2.17 (m, 1 H, 5′-H_A), 2.34 (dd, 1 H, ² J _{1 ′ -HA,1 ′ -HB} = 16.4 Hz, ³ J _{1 ′ -HB,2 ′ -H} = 12.8 Hz, 1′-H_A), 2.71 (dd, 1 H, ² J _{1 ′ -HB,1 ′ -HA} = 16.4 Hz, ³ J _{1 ′ -HB,2 ′ -H} = 4.9 Hz, 1′-H_B), 3.43 (dd, 1 H, ³ J _{6 ′ -H,5 ′ -HA} = 11.7 Hz, ³ J _{6 ′ -H,5 ′ -HB} = 4.1 Hz, 6′-H), 6.92 (s, 1 H, 5-H), 7.71 (dd, 1 H, ³ J _{5 ′′ -H,6 ′′ -H} = 8.1 Hz, ³ J _{5 ′′ -H,4 ′′ -H} = 5.0 Hz, 5′′-H), 8.41 (ddd, 1 H, ³ J _{6 ′′ -H,5 ′′ -H} = 8.2 Hz, ⁴ J _{6 ′′ -H,2 ′′ -H} = 2.1 Hz, ⁴ J _{6 ′′ -H,4 ′′ -H} = 1.5 Hz, 6′′-H), 8.76 (d, 1 H, ³ J _{4 ′′ -H,5 ′′ -H} = 4.3 Hz, 4′′-H), 9.09 (br s, 1 H, 2′′-H). ¹³C NMR (125 MHz, CD₃OD): δ = 15.04 (C-9′), 17.32 (C-1′), 20.09 (C-10′), 27.96 (C-8′), 28.78 (C-5′), 38.02 (C-4′), 39.77 (C-7′), 47.95 (C-2′), 78.00 (C-6′), 86.22 (C-3′), 101.19 (C-3), 110.49 (C-5), 125.53 (C-5′′), 128.74 (C-1′′), 135.15 (C-6′′), 147.44 (C-2′′), 152.37 (C-4′′), 158.62 (C-6), 165.12 (C-2), 182.04 (C-4). MS (EI, 70 eV): m/z (%) = 341 (32) [M⁺], 323 (9), 308 (16), 256 (13), 202 (100), 148 (31), 121 (51), 106 (46), 78 (22), 43 (31). HRMS (EI, 70 eV): m/z calcd for C₂₀H₂₃NO₄: 341.1627; found: 341.1622.

20

Ab initio calculations were performed at the DFT/B3LYP/6-31G level using a GAUSSIAN 03 package.

21 Tago K. Arai M. Kogen H. J. Chem. Soc., Perkin Trans. 1  2000,  2073 

22 Barrero AF. Alvarez-Manzaneda EJ. Palomino PL. Tetrahedron  1994,  50:  13239 

23 Bravo P. Arnone A. Ticozzi C. Cavicchio G. Marchetti V. Gazz. Chim. Ital.  1988,  118:  263