A Generic and Reproducible Route to Homo- and Heteroannular Bicyclic β-Diketones via Knochel-Type 1,4-Conjugate Additions to α,β-Unsaturated Cycloalkenones

Abstract

A generic and reproducible method for the preparation of homo- and heteroannular bicyclic β-diketones is reported. The method employs the copper acetate mediated 1,4-conjugate addition of organozinc derivatives of iodopropionate and iodobutanoate esters to α,β-unsaturated cycloalkenones, followed by intramolecular Dieckmann condensation.

Key words

annulation - enzymes - bicyclic compounds - ketones - cyclisations

References and Notes

• 1 Kel’in AV. Curr. Org. Chem.  2003,  7:  1691 
• 2 Kel’in AV. Maioli A. Curr. Org. Chem.  2003,  7:  1855 
• 3 Grogan G. Biochem. J.  2005,  388:  721 
• 4 Grogan G. Graf J. Jones A. Parsons S. Turner NJ. Flitsch SL. Angew. Chem. Int. Ed.  2001,  40:  1111 
• 5 Leonard PM. Grogan G. J. Biol. Chem.  2004,  279:  31312 
• 6 Asoka M. Ohkubo T. Itahana H. Kosaka T. Takei H. Tetrahedron  1995,  51:  3115 
• 7 Cheney DL. Paquette LA. J. Org. Chem.  1989,  54:  3334 
• 8 Eaton PE. Mueller RH. Carlson GR. Cullison DA. Cooper GF. Krebs E. J. Am. Chem. Soc.  1977,  99:  2751 
• 9 Bal S. Marfat A. Helquist P. J. Org. Chem.  1982,  47:  5045 
• 10 Duthaler RO. Maienfisch P. Helv. Chim. Acta  1984,  67:  856 
• 11 Engling G. Emrick T. Hellmann J. McElroy E. Brandt M. Reingold ID. J. Org. Chem.  1994,  59:  1945 
• 12 Muthusamy S. Babu SA. Gunanathan C. Synth. Commun.  2001,  31:  1205 
• 13 Brattesani RN. Heathcock CH. J. Org. Chem.  1975,  40:  2165 
• 14 Padwa A. Hornbuckle SF. Zhang Z. Zhi L. J. Org. Chem.  1990,  55:  5297 
• 15 Knochel P. Yeh MCP. Berk SC. Talbert J. J. Org. Chem.  1988,  53:  2390 
• 17 Hu Y. Yu J. Yang S. Wang J.-X. Yin Y. Synth. Commun.  1998,  2793 

16

Procedure for Copper-Mediated 1,4-Conjugate Addition Using CuCN - for the Synthesis of 3-(3-Oxo-cyclopentanyl)propionic Acid Methyl Ester (7), the Precursor of Bicyclo[3.3.0]octane-2,8-dione (1).
A suspension of zinc (1.5 g, 23 mmol) in THF (2 mL) containing dibromoethane (0.09 mL) was heated to 65 °C for 1 min then allowed to cool back to 25 °C under nitrogen. The suspension was stirred at 25 °C for a further 10 min then chlorotrimethylsilane (0.09 mL) was added. After 15 min at 25 °C a solution of ethyl iodopropionate (5 g, 22 mmol) in THF (10 mL) was added dropwise at 30 °C. After addition the reaction mixture was stirred at 35-40 °C for 12 h. The solution was then cooled to -10 °C and added to a solution of CuCN (1.7 g, 19 mmol) and LiCl (1.7 g, 39 mmol, dried at 150 °C for 1 h) in THF (20 mL). The resulting solution was stirred at 0 °C for 10 min then cooled to -78 °C. A solution of cyclopentenone (1.53 g, 16 mmol) and chlorotrimethyl silane (4.86 g, 38 mmol) in Et₂O (10 mL) was added slowly to the prepared copper reagent. The solution was stirred at -78 °C for 3 h then allowed to warm to r.t. and stirred for a further 12 h. The reaction was quenched with aq NH₄Cl (9 mL) and NH₃ (1 mL). The aqueous phase was extracted with Et₂O (3 × 15 mL). Combined organic extracts were washed with H₂O (15 mL) and brine (15 mL), dried over anhyd MgSO₄, filtered and the solvent evaporated under reduced pressure to give crude product, which was purified by flash column chromatography on silica using PE-EtOAc (9:1) as the eluant to yield the conjugate addition product 7 in 44% yield. Spectroscopic data were in agreement with the literature.¹⁰ Procedure for Copper-Mediated 1,4-Conjugate Addition Using Cu(OAc) ₂ - for the Synthesis of 3-(3-Oxo-cyclopentanyl)propionic Acid Methyl Ester (7), the Precursor of Bicyclo[3.3.0]octane-2,8-dione (1).
This followed the method of Hu.¹⁷ A suspension of zinc (3.4 g, 52 mmol) in THF (4 mL) containing 1,2-dibromoethane (0.09 mL) was heated to 65 °C for 1 min then allowed to cool back to 25 °C under nitrogen. The suspension was stirred at 25 °C for a further 10 min then TMSCl (0.09 mL) was added. After 15 min at 25 °C a solution of iodo compound (11.4 g, 50 mmol) in THF (10 mL) was added dropwise. After addition the reaction mixture was stirred at 35-40 °C for 12 h. The solution was then cooled to -18 °C and added to a solution of Cu(OAc)₂ (4.8 g, 26 mmol) and LiCl (2.2 g, 52 mmol; both dried at 150 °C for 1 h) in THF (20 mL). The resulting solution was stirred at -18 °C for 10 min. A solution of cyclopentenone (2.3 g, 24 mmol) and TMSCl (6 mL) in Et₂O (10 mL) was added slowly to the prepared copper reagent. The solution was stirred at -18 °C for 1 h then allowed to warm to r.t. and stirred for a further 12 h. The reaction was quenched with aq NH₄Cl (15 mL). The aqueous phase was extracted with Et₂O (3 × 20 mL). Combined organic extracts were washed with sodium water (20 mL) and brine (20 mL), dried (MgSO₄), filtered and solvent evaporated under reduced pressure to give crude product. Purification by flash column chromatography on silica (PE-EtOAc, 9:1) gave pure product. Spectroscopic data were in agreement with the literature.¹⁰ Cyclisation of Conjugate Addition Product to Diketone 1. Solid MeONa (459 mg, 8.5 mmol) was suspended in dry Et₂O (30 mL) under nitrogen. The reaction mixture was cooled to 10-15 °C with cold H₂O. A solution of keto ester 7 (1.30 g, 7.1 mmol) in dry Et₂O (10 mL) was added dropwise in 10 min. The reaction was left to stir for 22 h, and then quenched with aq K₂HPO₄ (11 g in 40 mL). The ether layer was separated and the aqueous layer extracted with EtOAc (3 × 25 mL). Organic phases were combined and washed the aq (NH₄)₂SO₄ (20 mL), dried (MgSO₄) and the solvent removed under reduced pressure to give the crude product (yellow oil). Purification by flash column chromatography on silica (PE-EtOAc, 1:1) gave diketone 1 (870 mg, 89%). Spectroscopic data were in accordance with the literature.¹⁰