Abstract: Herein we describe compositions and methods for the synthesis of [2.2.2]-diazabicyclic structures comprising a domino reaction sequence involving aldol condensation, alkene isomerization, and intramolecular hetero-Diels-Alder cycloaddition. Excellent diastereofacial control during the cycloaddition is enforced with a removable chiral phenyl aminal diketopiperazine substituent. The reaction sequence rapidly generates molecular complexity and is competent with both enolizable and non-enolizable aldehyde substrates. This method provides an efficient route to [2.2.2]-diazabicyclic structures, common to bioactive prenylated indole alkaloids such as the brevianamides and stephacidins.

Abstract: Herein we describe compositions and methods for the synthesis of [2.2.2]-diazabicyclic structures comprising a domino reaction sequence involving aldol condensation, alkene isomerization, and intramolecular hetero-Diels-Alder cycloaddition. Excellent diastereofacial control during the cycloaddition is enforced with a removable chiral phenyl aminal diketopiperazine substituent. The reaction sequence rapidly generates molecular complexity and is competent with both enolizable and non-enolizable aldehyde substrates. This method provides an efficient route to [2.2.2]-diazabicyclic structures, common to bioactive prenylated indole alkaloids such as the brevianamides and stephacidins.