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Synlett 2007(16): 2545-2548  
DOI: 10.1055/s-2007-986660
LETTER
© Georg Thieme Verlag Stuttgart · New York

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;
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Publikationsverlauf

Received 13 June 2007
Publikationsdatum:
12. September 2007 (online)

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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

11

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+].

12

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).

13

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.

14

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.