Asymmetric diels-alder cycloaddition of 1-aminocyclohexadiene to chiral acrylate:: Synthesis of enantiopure bridgehead-aminobicyclo[2.2.2]octane-2-carboxylic acid derivatives

The acrylate derivative of the (R)-4-(3-hydroxy-4,4-dimethyl-2-oxopyrrolidin-1-yl)benzoic acid benzyl ester (R)-2 reacted with 1-(benzyloxycarbonylamino)cyclohexadiene 3 under microwave irradation in solvent-free conditions to yield [4+2] cycloadducts in good yields (91%), The reaction proceeded with moderate endo selectivity (67%) and good facial selectivity (90%). The major cycloadducts were isolated and transformed to afford three enantiopure bicyclic beta-amino acids: (1S,2R,4R)-1-(benzyloxycarbonylamino)bicyclo[2.2.2]oct-5-ene-2-carboxylic acid [(1S,2R,4R)-4], (1R,2R,4S)-1-(benzyloxycarbonylamino)bicyclo[2.2.2]oct-5-ene-2-carboxylic acid [(1R,2R,4S)-5] and (R)-1-aminobicyclo[2.2.2]octane-2-carboxylic acid [(R)-6]. This work has led to the preparation of these enantiopure bicyclic beta-amino acids and provides a rare example of an asymmetric Diels-Alder reaction by microwave activation.