The Type 2 Intramolecular Diels-Alder Reaction: Synthesis and Chemistry of Bridgehead Alkenes

Anti‐Bredt alkenes, bicyclic molecules that contain a bridgehead double bond, were for many years regarded as chemical curiosities. The type 2 intramolecular Diels–Alder (IMDA) reaction provides a one‐step entry into this fascinating class of molecules. The reaction has made available numerous anti‐Bredt alkenes for structural and chemical studies. X‐ray crystallography has revealed the magnitude of the deformations associated with the bridgehead double bond, and rate studies of reactions of bridgehead alkenes have allowed quantification of the kinetic consequences of the torsional distortions. More recently, the type 2 intramolecular Diels–Alder reaction and the resulting anti‐Bredt alkenes have found application in organic synthesis. The constraints resulting from the connectivity in the Diels–Alder precursor creates a strong regio‐ and stereochemical bias in the cycloaddition step. The end result of this bias is the stereoselective synthesis of highly substituted six‐membered rings. The reaction also achieves a facile synthesis of seven‐ and eight‐membered rings in a single step from acyclic precursors. The utility of this reaction has been verified in recent applications of the type 2 IMDA reaction as a key step in the total synthesis of complex natural products. From chemical curiosities to highly sought synthetic building blocks: Anti‐Bredt alkenes are accessible in one step from acyclic precursors by using the type 2 intramolecular Diels–Alder (IMDA) reaction described herein [Eq. (1)]. Unlike with the normal Diels–Alder reaction this variant allows high regio‐ and stereoselectivities. This provided the prerequisite for bridgehead alkenes to play a key role in the synthesis of a large number of complex natural products. Medium‐sized rings are also readily accessible by using this method, and the bridges can be selected such that they can be cleaved after the synthesis.