Download PDF
Synlett 2010(18): 2797-2801  
DOI: 10.1055/s-0030-1258993
LETTER
© Georg Thieme Verlag Stuttgart ˙ New York

Transannular [4C+3C]-Cycloaddition Reactions of Oxyallyl Cation to Furan

Benjamin W. Gung*, Ryan Conyers
Department of Chemistry & Biochemistry, Miami University, Oxford, OH 45056, USA
Fax: +1(513)5295715; e-Mail: gungbw@muohio.edu;
Further Information

Publication History

Received 26 March 2010
Publication Date:
08 October 2010 (online)

    Permissions and Reprints All articles of this category

Abstract

For the first time, successful transannular [4+3]-cyclo­addition reactions based on an oxyallyl cation intermediate are reported. The key steps involve the synthesis of the macrocyclic precursor and the transanuular [4C+3C]-cycloaddition step.

Key words

transannular - cycloaddition - oxyallyl - macrocycle - acyloin reaction

30

Synthesis and Spectroscopic Data for Selected Compounds
2,5-Di(hex-5-enyl)furan (6)
To a round-bottom flask equipped with a stirring bar under an atmosphere of nitrogen was added 2-hex-5-enyl-furan (3.84 g, 25.5 mmol) in freshly distilled THF (28 mL). The solution was cooled to 0 ˚C and n-BuLi (1.6 M in hexane, 21.0 mL, 33.2 mmol) was added dropwise and stirred at this temperature for 2 h. The reaction was then cooled to -78 ˚C and 1-bromo-5-hexene (5.42 g, 33.2 mmol) was added as a solution in anhydrous THF (17 mL) dropwise by syringe. The reaction was then warmed to 0 ˚C for 1 h and then allowed to warm to r.t. overnight. The reaction was quenched with sat. NaCl solution, and the aqueous layer was extracted with Et2O. The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (2% EtOAc-hexanes) and provided 5.78 g (97%) of a yellow oil. ¹H NMR (500 MHz, CDCl3): δ = 1.42-1.47 (4 H, m), 1.60-1.66 (4 H, m), 2.05-2.10 (4 H, m), 2.57 (4 H, t, J = 7.5 Hz), 4.93-5.02 (4 H, m), 5.76-5.82 (2 H, m), 5.84 (2 H, s). ¹³C NMR (125 MHz, CDCl3): δ = 27.6, 27.9, 28.5, 33.5, 105.0, 114.4, 138.8, 154.4. LC-MS: m/z calcd for C16H24O: 232.2; found: 233.1 [M + H].
6-[5-(6-Hydroxyhexyl)furan-2-yl]hexan-1-ol (11a) To a round-bottom flask equipped with a stirring bar under an atmosphere of nitrogen was added 2,5-di(hex-5-enyl)furan (4.15 g, 17.9 mmol) in Et2O (134 mL). The solution was cooled to 0 ˚C, and BH3˙SMe2 (2 M in THF, 21.5 mL, 42.9 mmol) was added. The reaction was allowed to warm to r.t. and stirred at this temperature until disappearance of starting material as indicated by TLC. The reaction was then cooled to 0 ˚C and NaOH (3 M, 24 mL, 71.5 mmol) and H2O2 (30%, 24 mL) were added dropwise sequentially. The reaction was warmed to r.t. for 15 min then refluxed until complete conversion into alcohol as indicated by TLC. The reaction was quenched with ice cold H2O and extracted with Et2O. Combined organic layers were washed with sat. NaHCO3 and sat. NaCl solution, then dried over MgSO4, filtered, and concentrated. The residue was purified by silica gel chromatography (20-50% EtOAc-hexanes) and provided 3.49 g (73%) of a white waxy solid. ¹H NMR (500 MHz, CDCl3): δ = 1.37-1.42 (8 H, m), 1.45 (2 H, br s), 1.54-1.60 (4 H, m), 1.60-1.66 (4 H, m), 2.57 (4 H, t, J = 7.5 Hz), 3.64 (4 H, t, J = 6.5 Hz), 5.84 (2 H, s). ¹³C NMR (125 MHz, CDCl3): δ = 25.5, 28.0, 28.1, 28.9, 32.7, 63.0, 105.0, 154.5. LC-MS: m/z calcd for C16H28O3Na: 291.2; found: 291.2 [M + Na].
6-[5-(6-Oxohexyl)furan-2-yl]hexanal (12a) To a round-bottom flask equipped with a stirring bar under an atmosphere of nitrogen was added 6-[5-(6-hydroxy-hexyl)furan-2-yl]hexan-1-ol (1.02g, 3.79 mmol) and 4-methylmorpholine N-oxide (937 mg, 8.00 mmol) in CH2Cl2 (27 mL). TPAP (133 mg, 0.38 mmol) was then added in one portion. Reaction was stirred at r.t. until disappearance of starting material as indicated by TLC. The solution was then filtered through a pad of silica gel using EtOAc as an eluent and concentrated to provide 450 mg (45%). ¹H NMR (500 MHz, CDCl3): δ = 1.30-1.40 (4 H, m), 1.57-1.68 (8 H, m), 2.41-2.45 (4 H, m), 2.57 (4 H, t, J = 7.5 Hz), 5.84 (2 H, s), 9.76 (2 H, s). ¹³C NMR (125 MHz, CDCl3): δ = 21.8, 27.8, 27.9, 28.6, 43.8, 105.1, 154.2, 202.6. LC-MS: m/z calcd for C16H24O3: 264.2; found: 263.0 [M - H].
6-[5-(5-Methoxycarbonylpentyl)furan-2-yl]hexanoic Acid Methyl Ester (13a) To a round-bottom flask equipped with a stirring bar under an atmosphere of nitrogen was added 6-[5-(6-oxohexyl) furan-2-yl]hexanal (874 mg, 3.31 mmol) in a solution of t-BuOH-H2O (3.5:1). The solution was cooled to 0 ˚C and NaHPO4˙H2O, 2-methyl-2-butene, and NaClO2 were added sequentially. The reaction was allowed to warm to r.t. and stirred for 4.5 h. The reaction was quenched with sat. aq Na2SO3, acidified with 2 N HCl, and extracted five times with EtOAc. The organic layers were washed with sat. NaCl, dried over MgSO4, and concentrated. The crude product was used for the next step without purification. A mixture of crude acid, K2CO3 (4.57 g, 33 mmol), and DMS (1.67 g, 13.2 mmol) were dissolved in anhydrous acetone (17 mL) and refluxed for 2 h. H2O (5 mL) was then added and extracted with Et2O (4 × 10 mL). The combined organic layers were washed with sat. NaCl, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography (10-20% EtOAc-hexanes) and provided 839 mg (78% over 2 steps) of a colorless oil. ¹H NMR (500 MHz, CDCl3): δ = 1.34-1.40 (4 H, m), 1.60-1.69 (8 H, m), 2.31 (4 H, t, J = 7.5 Hz), 2.56 (4 H, t, J = 7.5 Hz), 3.66 (6 H, s), 5.83 (2 H, s). ¹³C NMR (125 MHz, CDCl3): δ = 24.7, 27.7, 27.8, 28.6, 34.0, 105.0, 154.3, 174.1. LC-MS: m/z calcd for C18H28O5Na: 347.2; found: 347.2 [M + Na].
8-Hydroxy-17-oxabicyclo[12.2.1]heptadeca-1(16),14-dien-7-one (14a) To a round-bottom flask equipped with a stirring bar under an atmosphere of nitrogen was added freshly cut Na (402 mg, 17.5 mmol) in toluene (8 mL). Solution was heated to a gentle reflux and dispersed with vigorous stirring. Mixture was cooled to r.t., and TMSCl (2.09 g, 19.2 mmol) was added. The resulting mixture was heated to reflux, and then a few drops of 6-[5-(5-methoxycarbonylpentyl)furan-2-yl]hexanoic acid methyl ester (1.13 g, 3.48 mmol) dissolved in toluene (4 mL) was added. The solution turned a violet color; the remaining mixture of ester was added dropwise over 6 h. The reaction was refluxed for an additional 15 h until most of the starting material was consumed as indicated by TLC. Mixture was filtered and solids were washed with hexane, the combined filtrate, and washings were concentrated. The residue was diluted with THF (12 mL), treated with 1.0 N HCl (5 mL), and refluxed until complete removal of TMS group as indicated by TLC. The reaction was cooled then solid CaCO3 was added, the solution was filtered then extracted with Et2O, washed with sat. NaHCO2 and sat. NaCl, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography (10-20% EtOAc-hexanes) and provided 586 mg (64%) of a yellow oil. ¹H NMR (500 MHz, CDCl3): δ = 1.27-1.33 (4 H, m), 1.33-1.61 (4 H, m), 1.62-1.65 (4 H, m), 1.84-1.86 (2 H, m), 2.53-2.57 (2 H, m), 2.58-2.66 (2 H, m), 3.44 (1 H, d, J = 5.5 Hz), 4.10-4.15 (1 H, m), 5.87 (2 H, s). ¹³C NMR (75 MHz, CDCl3): δ = 22.9, 27.3, 27.4, 27.6, 27.9, 32.5, 37.1, 106.2 (2 × C), 154 (2 × C), 212.7. HRMS: m/z calcd for C16H24O3Na: 287.1623; found: 287.1622 [M + Na].
8-Chloro-17-oxabicyclo[12.2.1]heptadeca-1 (16),14-dien-7-one (10a) To a round-bottom flask equipped with a stirring bar under an atmosphere of nitrogen was added 8-hydroxy-17-oxabicyclo[12.2.1]heptadeca-1 (16),14-dien-7-one (250 mg, 0.95 mmol), and Ph3P (372 mg, 1.42 mmol) in anhydrous MeCN (5 mL) was treated with CCl4 (728 mg, 4.73 mmol). The solution was stirred at r.t. until disappearance of starting material as indicated by TLC. Reaction was then concentrated and purified by silica gel chromatography (5% EtOAc-hexanes) and provided 127 mg (48%) of a colorless oil. ¹H NMR (300 MHz, CDCl3): δ = 1.24-1.31 (6 H, m), 1.57-1.66 (6 H, m), 1.79-1.86 (1 H, m), 1.91-1.96 (1 H, m), 2.55-2.65 (6 H, m), 4.16-4.21 (1 H, dd, J = 5.4 Hz, 8.4 Hz), 5.86 (2 H, s). ¹³C NMR (125 MHz, CDCl3): δ = 0.0, 23.8, 25.3, 27.2, 27.4, 27.6 (2 × C), 27.8, 28.1, 33.6, 38.1, 62.3, 106.2, 106.3, 154.0, 205.8. LC-MS: m/z calcd for C16H23ClO2Na: 305.1; found: 305.1 [M + Na].
Tetracyclic Ketone (15a) To a round-bottom flask equipped with a stirring bar under an atmosphere of nitrogen was added 8-chloro-17-oxabicyclo[12.2.1]heptadeca-1 (16),14-dien-7-one (89 mg, 0.315 mmol) in anhydrous Et2O (1.6 mL) was cooled to -78 ˚C and diluted with 2,2,2-trifluoroethanol (1.6 mL). The solution was stirred for 5 min and Et3N (0.15 mL, 0.945 mmol) was added dropwise. The reaction was allowed to warm to r.t. then heated to 55 ˚C overnight. Reaction was quenched with H2O and extracted with Et2O. Organic layers were combined, dried over MgSO4, and concentrated. The residue was purified by silica gel chromatography (1-2% EtOAc-hexanes) and provided 41 mg (54%) of a white solid; mp 70-72 ˚C. ¹H NMR (500 MHz, CDCl3): δ = 0.90-0.97 (1 H, m), 0.99-1.05 (1 H, m), 1.25-1.47 (4 H, m), 1.64-1.75 (4 H, m) 1.80-1.89 (3 H, m), 1.93-2.09 (4 H, m), 2.34-2.37 (2 H, dd, J = 4.0 Hz, J = 12.5 Hz), 2.64-2.66 (1 H, d, J = 10.0 Hz), 6.14-6.15 (1 H, d, J = 6.0 Hz), 6.22-6.24 (1 H, d, J = 6.0 Hz). ¹³C NMR (125 MHz, CDCl3): δ = 22.0, 22.1, 23.9, 24.0, 24.8, 27.2, 29.1, 34.0, 37.7, 57.1, 60.8, 87.9, 90.1, 134.3, 136.6, 208.1. HRMS: m/z calcd for C16H23O2: 247.1698; found: 247.1693 [M + H].