Identification of a common Diels–Alder pattern in three classes of bioactive natural products led us to study the synthesis and cycloaddition of a new class of cyclic dienes readily available from β,γ-unsaturated lactams. A practical and readily scalable route to the parent p-methoxybenzyl-protected 6- and 7-membered β,γ-unsaturated lactams was developed. These were readily transformed into the corresponding O-silylated dienes, which were reacted with dimethyl and diethyl fumarate to yield stereoselectively highly functionalized bicyclic adducts. These exhibited unexpected and versatile transformations upon acid hydrolysis depending on the nature of the dienophile substituents and the acid catalyst. All reactions have been performed on multigram quantities. These transformations provide a convenient, economical, and easily scalable pathway for the rapid construction of functionally and stereochemically dense privileged scaffolds for the construction of libraries of natural products-inspired molecules of pharmacological relevance.
This work was generously supported by the Institut Servier (fellowships to E.B., K.H.V.R., A.L., C.S., S.C., E.P.), the former Rhône–Poulenc‐Rorer (fellowship to L.T.) and IECB. We thank Frédéric Rosu and Estelle Morvan for their experimental help (MS and NMR).
- molecular diversity
- natural products
- pattern recognition