Selective Cationic Cyclizations with α-Pyrones as Terminators

Heiko Leutbecher; Dietmar Schmidt; Jürgen Conrad; Uwe Beifuss

doi:10.1055/s-2007-986660

LETTER

Selective Cationic Cyclizations with α-Pyrones as Terminators

Heiko Leutbecher, Dietmar Schmidt, Jürgen Conrad, Uwe Beifuss*
Bioorganische Chemie, Institut für Chemie, Universität Hohenheim, Garbenstr. 30, 70599 Stuttgart, Germany
Fax: +49(711)45922951; e-Mail: ubeifuss@uni-hohenheim.de;

Abstract

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Abstract

The process of the cationic olefin cyclization of 3-substituted 4-hydroxy-2H-pyran-2-ones 3 that may produce both trans- and cis-pyrano[4,3-b]chromen-1-ones (4) and trans- and cis-pyrano[2,3-b]chromen-4-ones (5) can be efficiently controlled by properly choosing reagents and reaction conditions. The highly selective formation of trans-4 can be achieved with Et₂AlCl as a Lewis acid. Preferred formation of cis-4 is observed with PTSA under microwave conditions at high temperatures. PTSA and low temperatures produce cis-5 in excess.

Key words

Lewis and Brønsted acid catalysis - cyclization - diastereoselectivity - heterocycles

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References

References and Notes

<A NAME="RG18507ST-1">1</A> Sunazuka T. Omura S. Chem. Rev. 2005, 105: 4559

<A NAME="RG18507ST-2">2</A> Phipps RK. Petersen BO. Christensen KB. Duus J. Frisvad JC. Larsen TO. Org. Lett. 2004, 6: 3441

<A NAME="RG18507ST-3A">3a</A> Parker KA. Resnick L. J. Org. Chem. 1995, 60: 5726

<A NAME="RG18507ST-3B">3b</A> Smith AB. Kinsho T. Sunazuka T. Omura S. Tetrahedron Lett. 1996, 37: 6461

<A NAME="RG18507ST-4">4</A> Schmidt D. Leutbecher H. Conrad J. Klaiber I. Mika S. Greiner G. Beifuss U. Synlett 2007, 1725

<A NAME="RG18507ST-5A">5a</A> Majumdar KC. Basu PK. Roy B. Synth. Commun. 2003, 33: 3621

<A NAME="RG18507ST-5B">5b</A> Majumdar KC. Ghosh S. Monatsh. Chem. 2002, 133: 1317

<A NAME="RG18507ST-5C">5c</A> Majumdar KC. Sarkar S. Tetrahedron 2002, 58: 8501

<A NAME="RG18507ST-6A">6a</A> Majumdar KC. Biswas P. Choudhury PK. Synth. Commun. 2000, 30: 4047

<A NAME="RG18507ST-6B">6b</A> Ahluwalia VK. Arora KK. Mukherjee I. Heterocycles 1984, 22: 223

<A NAME="RG18507ST-7">7</A> Bravo P. Arnone A. Tiozzi C. Cavicchio G. Marchetti V. Gazz. Chim. Ital. 1988, 118: 263

<A NAME="RG18507ST-8">8</A> Cervello J. Marquet J. Moreno-Mañas M. Tetrahedron 1990, 46: 2035

<A NAME="RG18507ST-9">9</A> Crombie BS. Smith C. Varnavas CZ. Wallace TW. J. Chem. Soc., Perkin Trans. 1 2001, 206

<A NAME="RG18507ST-10">10</A> Lygo B. Tetrahedron 1995, 51: 12859

Experimental Procedure and Selected Analytical Data for (5a RS ,9a SR )-3,5a,9,9-tetramethyl-5a,6,8,9,9a,10-hexahydro-1 H ,7 H -pyrano[4,3- b ]chromen-1-one ( cis -4a)
A mixture of 4-hydroxy-6-methyl-3-(2,6,6-trimethyl-cyclohex-1-enylmethyl)-2H-pyran-2-one (3a, 100 mg, 0.38 mmol) and PTSA (68 mg, 0.39 mmol) in anhyd toluene (8 mL) was refluxed for 3 h. The reaction mixture was concentrated in vacuo. The residue was then solved in Et₂O (30 mL) and washed with a sat. NaHCO₃ solution (20 mL) and brine (15 mL), dried over MgSO₄, and concentrated in vacuo. Purification of the crude product by silica gel flash chromatography (Et₂O-PE, 1:1) gave 58 mg (58%) of a yellow pale oil. Crystallization from PE gave pure cis-4a. ¹H NMR (500 MHz, C₆D₆): δ = 0.71 [s, 3 H, 9-CH₃ ₍ _ax)], 0.74 [s, 3 H, 9-CH₃ ₍ _eq)], 0.89 [s, 3 H, 5a-CH₃ ₍ _eq)], 0.94 [td, J = 13.6, 3.6 Hz, 1 H, 8-H₍ _ax)], 1.02 [td, J = 13.8, 4.3 Hz, 1 H, 6-H₍ _ax)], 1.03 [d, J = 8.1 Hz, 1 H, 9a-H₍ _ax)], 1.20 [m, 2 H, 7-H₍ _eq), 8-H₍ _eq)], 1.53 (s, 3 H, 3-CH₃), 1.70 [qt, J = 13.7, 3.5 Hz, 1 H, 7-H₍ _ax)], 1.85 [m, 1 H, 6-H₍ _eq)], 2.46 [ddd, J = 18.3, 8.0, 0.8 Hz, 1 H, 10-H₍ _ax _′)], 2.73 [d, J = 18.4 Hz, 1 H, 10-H₍ _eq _′)], 5.30 (d, J = 0.8 Hz, 1 H, 4-H). ¹³C NMR (75 MHz, C₆D₆): δ = 18.1 (C-7), 18.6 (C-10), 19.2 (3-CH₃), 21.3 [9-CH₃ ₍ _ax)], 26.8 [5a-CH₃ ₍ _eq)], 32.0 [9-CH₃ ₍ _eq)], 33.9 (C-9), 38.9 (C-6), 41.4 (C-8), 43.6 (C-9a), 78.3 (C-5a), 98.3 (C-10a), 99.9 (C-4), 159.8 (C-3), 163.7 (C-1 or C-4a), 163.8 (C-1 or C-4a). MS (EI, 70 eV): m/z (%) = 262 (48) [M⁺], 247 (9) [M⁺ - CH₃], 219 (7), 193 (10), 139 (100), 123 (53), 109 (29), 81 (22), 43 (92). HRMS (EI, 70 eV): m/z calcd for C₁₆H₂₂O₃: 262.15689; found: 262.15631 [M⁺].

Experimental Procedure and Selected Analytical Data for (5a RS ,9a SR )-2,6,6,9a-tetramethyl-5a,6,7,8,9,9a-hexahydro-4 H ,5 H -pyrano[2,3- b ]chromen-4-one ( cis -5a)
A mixture of 4-hydroxy-6-methyl-3-(2,6,6-trimethyl-cyclohex-1-enylmethyl)-2H-pyran-2-one (3a, 15 mg, 0.057 mmol) and PTSA (30 mg, 0.17 mmol) in toluene (1.5 mL) was heated to 45 °C for 24 h. The solvent was evaporated in vacuo. The residue was solved in TBME (30 mL) and washed with a sat. NaHCO₃ solution (3 × 20 mL) and brine (15 mL). The organic extract was dried over MgSO₄ and concentrated in vacuo. NMR spectroscopic data of cis-5a were deduced from the instable crude product. ¹H NMR (500 MHz, C₆D₆): δ = 0.72 [s, 3 H, 6-CH₃ ₍ _A)], 0.74 [s, 3 H, 6-CH₃ ₍ _B)], 0.90 (s, 3 H, 9a-CH₃), 0.90 [td, J = 14.0, 4.3 Hz, 1 H, 7-H₍ _ax)], 0.97 [d, J = 7.7 Hz, 1 H, 5a-H₍ _ax)], 0.98 [td, J = 13.9, 4.4 Hz, 1 H, 9-H₍ _ax)], 1.12-1.20 [m, 1 H, 8-H₍ _eq)], 1.20-1.26 [m, 1 H, 7-H₍ _eq)], 1.44 (s, 3 H, 2-CH₃), 1.68 [qt, J = 13.8, 3.7 Hz, 1 H, 8-H₍ _ax)], 1.76-1.86 [m, 1 H, 9-H₍ _eq)], 2.48 [dd, J = 17.8, 8.0 Hz, 1 H, 5-H₍ _ax _′)], 2.89 [d, J = 17.8 Hz, 1 H, 5-H₍ _eq _′)], 5.93 (s, 1 H, 3-H). ¹³C NMR (125 MHz, C₆D₆): δ = 17.2 (C-5), 17.9 (C-8), 18.3 (2-CH₃), 21.0 [6-CH₃ ₍ _A)], 26.4 (9a-CH₃), 31.9 [6-CH₃ ₍ _B)], 33.7 (C-6), 38.4 (C-9), 41.1 (C-7), 43.7 (C-5a), 82.3 (C-9a), 98.7 (C-4a), 112.4 (C-3), 160.1 (C-2), 163.1 (C-10a), 179.2 (C-4).

All microwave-assisted reactions were performed in sealed reaction vessels with a Discover single-mode cavity microwave synthesizer (CEM Corp.), producing continuous irradiation at 2450 MHz.

Experimental Procedure and Selected Analytical Data for (5a RS ,9a RS )-3,5a,9,9-tetramethyl-5a,6,8,9,9a,10-hexahydro-1 H ,7 H -pyrano[4,3- b ]chromen-1-one ( trans -4a)
A two-necked, round-bottom flask (10 mL) with a stirring bar and a rubber septum connected to a vacuum/argon line was flame-dried under vacuum and back-filled with argon (3 times). Then, 600 µL (0.6 mmol) of a 1 M solution of Et₂AlCl in hexane was introduced via syringe through the rubber septum and cooled to 0 °C. Over a period of 10 min a cooled (0 °C) solution of 4-hydroxy-6-methyl-3-(2,6,6-trimethylcyclohex-1-enylmethyl)-2H-pyran-2-one (3a, 50 mg, 0.19 mmol) in anhyd CH₂Cl₂ (5 mL) was added dropwise via an ice cooled syringe. The reaction mixture was poured on 10 g of ice and the aqueous phase sat. with NaCl. The aqueous phase was extracted with Et₂O (2 × 30 mL). The combined organic extracts were washed with a sat. NaHCO₃ solution (15 mL) and with brine (10 mL), dried over MgSO₄, and concentrated in vacuo. The resulting white solid (48 mg, 96%) contained pure trans-4a (90% de). ¹H NMR (300 MHz, C₆D₆): δ = 0.56 [s, 3 H, 9-CH₃ ₍ _ax)], 0.71 [s, 3 H, 9-CH₃ ₍ _eq)], 0.88-1.02 [m, 1 H, 8-H₍ _ax)], 0.94 [s, 3 H, 5a-CH₃ ₍ _ax)], 1.08-1.12 [m, 1 H, 8-H₍ _eq)], 1.10-1.20 [m, 1 H, 7-H₍ _ax)], 1.24 [dd, J = 13.1, 4.4 Hz, 1 H, 9a-H₍ _ax)], 1.24-1.32 [m, 1 H, 7-H₍ _eq)], 1.39 [td, J = 13.0, 4.0 Hz, 1 H, 6-H₍ _ax)], 1.59 (s, 3 H, 3-CH₃), 1.70-1.80 [m, 1 H, 6-H₍ _eq)], 2.06 [dd, J = 16.8, 13.1 Hz, 1 H, 10-H₍ _ax _′)], 2.62 [dd, J = 16.9, 4.7 Hz, 1 H, 10-H₍ _eq _′)], 5.35 (s, 1 H, 4-H). ¹³C NMR (75 MHz, C₆D₆): δ = 18.3 (C-10), 19.3 (3-CH₃ or 5a-CH₃), 19.6 (3-CH₃ or 5a-CH₃), 19.8 (C-7), 20.5 [9-CH₃ ₍ _ax)], 31.9 [(9-CH₃ ₍ _eq)], 33.4 (C-9), 39.5 (C-6), 41.3 (C-8), 47.8 (C-9a), 80.3 (C-5a), 98.5 (C-10a), 100.0 (C-4), 159.9 (C-3), 162.5 (C-4a), 163.9 (C-1). MS (EI, 70 eV): m/z (%) = 262 (95) [M⁺], 247 (17) [M⁺ - CH₃], 219 (13), 193 (16), 139 (100), 123 (87), 109 (46), 81 (23), 43 (47). Anal. Calcd for C₁₆H₂₂O₃ (262.34): C, 73.25; H, 8.45. Found: C, 72.98; H, 8.14.