A Practical and Efficient Synthetic Route to Dihydropipercide and Pipercide¹

Dihydropipercide 1 and Pipercide 2 are examples of hydrophobic insecticidal isobutylamide derivatives isolated from Piper Nigrum L . which have received synthetic attention over the past decade. Novel structural features combining the N -isobutyldieneamide array, found in related natural products such as Pellitorine, with the 3,4-methylenedioxyphenyl moiety, found in insecticide synergists including Piperonyl Butoxide and Sesamex, render these as attractive targets for synthesis. Although a variety of synthetic routes to related natural products have appeared in the literature, practical methods for the preparation of the title compounds were lacking. Convenient and convergent 10−11-step protocols were developed which provided access to gram quantities of the targets. Methyl 6-oxohexanoate 4 was prepared from cyclohexanone enol acetate 3 via a tandem ozonolysis, methanolysis, hydrolysis process. Subsequent olefination and olefin isomerization steps followed by further elaboration provided the targets 1 and 2 . Noteworthy features of this methodology include the convenient synthesis of oxoester intermediate 4 and the phenythio radical-induced olefin isomerization of intermediate 6 which afforded high yields of >99.5% E -olefin 13 . These are both somewhat uncommon but potentially useful processes which may find further application in organic synthesis.