Expedient synthesis of unsaturated amide alkaloids from Piper spp: Exploring the scope of recent methodology

The Sakai aryl aldehyde - cyclic ketone aldol - Grob fragmentation sequence was extended to cinnamaldehyde and cyclohexanone, and the product was elaborated to analogues of the alkaloid piperstachine. The effects of substituents on the reaction involving cinnamaldehyde were studied. The aldol-fragmentation sequence failed with benzaldehyde when cyclooctanone or cyclobutanone was substituted for cyclohexanone or cyclopentanone, and the reasons for this failure were examined. Four-carbon Wittig homologation of the piperonal-cyclobutanone aldol-fragmentation product, a hypothetical route to alkaloids such as retrofractamide A, was thus not viable. Instead, three-carbon homologation of the readily available piperonal-cyclopentanone product, using alkyne chemistry recently disclosed by Lu and Trost, afforded these alkaloids in excellent overall yield. The alkyne isomerization was also used to effect efficient syntheses of pellitorine and several other nonaromatic 2E,4E-dienoic Piper amide alkaloids.