One-pot Diels–Alder cycloaddition/gold(I)-catalyzed 6-endo-dig cyclization for the synthesis of the complex bicyclo[3.3.1]alkenone framework

The rapid synthesis of bicyclo[m.n.1]alkanone cores possessing quaternary carbon centers adjacent to a bridged ketone represents a significant synthetic challenge. This type of architectural feature is embedded in various complex biologically active compounds such as hyperforin and garsubellin A. Herein, we report a highly diastereoselective one-pot Diels–Alder reaction/Au(I)-catalyzed carbocyclization to generate bicyclo[3.3.1]alkanones in yields ranging from 48–93%.


S3
aqueous layer was extracted with ethyl acetate (3x), and the combined organic phases were dried over anhydrous magnesium sulphate, filtered and concentrated.
The crude oil was distilled under reduced pressure and purified by chromatography (10% EtOAc:hexanes) to give 14.48 g (83%) of 8 as a clear yellow oil. Spectral data is in accordance with reported data and full characterization is available through the literature [1].
The reaction mixture was allowed to reflux overnight and was then quenched with NaHCO 3 saturated solution, and the aqueous phase was extracted with DCM (3x).
The organic phases were then combined and concentrated. The resulting mixture was filtered through a small silica pad and washed with solution of 7% EtOAc in hexanes and concentrated again. The crude enol ether 10 (209 mg, 46%) was then directly used for the next reaction.

4-Methylenenon-1-en-8-yn-5-one (B)
To a solution of homoallylphosphonate (5 g, 26 mmol,) in THF (50 mL) at −78 °C, under an argon atmosphere, was added dropwise a solution of n-BuLi (2.45 M in hexanes, 12.74 mL, 31.2 mmol). The reaction mixture was stirred for 3 h and then a solution of methyl pent-4-ynoate (4.38 g, 39 mmol) in THF (10mL) was added to the prepared mixture. After 1 h, the temperature was raised to rt. The reaction was quenched with a saturated solution of NH 4 Cl. The mixture was extracted three times with Et 2 O, washed with water and concentrated at reduced pressure to furnish the S7 diethyl 5-oxonon-1-en-8-yn-4-ylphosphonate (A) as a brown oil. The crude product was taken into the next step without further purification.
The mixture was extracted with Et 2 O (3x), dried over MgSO 4 and then concentrated.

General procedure for the formation of dienes 16, 19-22 and 32-35
To a solution of enone (1 mmol) in DCM (5 mL) was added Et 3 N (3 mmol) and TIPSOTf (2 mmol). The solution was then heated at reflux overnight. The reaction was quenched with a saturated solution of NaHCO 3 . The aqueous phase was extracted with DCM (2x), the organic phases were combined and dried over MgSO 4 .

General procedure for the Diels-Alder reaction/gold cyclization process
Diene (1 equiv) was charged into a microwave quartz tube (the tube was washed in a base bath and dried). N-phenylmaleimide (2 equiv) was added and then toluene (0.1 M) was added. The mixture was heated to 150 °C at 300 W in the microwave for 2 h. After cooling down to rt, catalyst 6 (5 mol%) was added to the mixture with a minimal amount of acetone to solubilize the catalyst. After stirring overnight, the S16 solution was concentrated and purified by flash chromatography (25-40% EtOAc in hexanes) to afford the desired ketone.