A sequential diversification approach for the synthesis of various multi‐substituted β‐keto amide derivatives based on a simple and readily available dioxinone scaffold was developed. The process involves: (1) nucleophilic addition of the scaffold to an aldehyde, and a subsequent one‐pot dehydration; (2) palladium‐catalysed cross‐coupling of the scaffold with either an arylboronic acid pinacol ester, or CO and an aliphatic amine; and (3) nucleophilic addition of either an aliphatic amine or an arylamine, or a hetero‐Diels–Alder reaction of isocyanate/isothiocyanate, with an acylketene generated in situ from the dioxinone scaffold.

An asymmetric total synthesis of ent-pyripyropene A was achieved by a convergent synthetic route. We used our originally developed Ti(III) -catalyzed radical cyclization to construct an AB-ring portion that consisted of a trans-decalin skeleton with five contiguous stereogenic centers. The coupling between the AB-ring and the DE-ring portions, and a subsequent C-ring cyclization, led to the total synthesis of ent-pyripyropene A. An evaluation of the insecticidal activity of ent-pyripyropene A against two aphid species revealed that ent-pyripyropene A was 35-175 times less active than naturally occurring pyripyropene A. This result indicated that the biological target of pyripyropene A recognizes the absolute configuration of pyripyropene A.

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