Cooperative activation of cyclobutanones and olefins leads to bridged ring systems by a catalytic [4 + 2] coupling

Abstract

Bridged ring systems are widely found in natural products, and successful syntheses of them frequently feature intramolecular Diels-Alder reactions. These reactions are subclassified as either type I or type II depending on how the diene motif is tethered to the rest of the substrate (type I are tethered at the 1-position of the diene and type II at the 2-position). Although the type I reaction has been used with great success, the molecular scaffolds accessible by the type II reactions are limited by the strain inherent in the formation of an sp(2) carbon at a bridgehead position. Here, we describe a complementary approach that provides access to these structures through the C-C activation of cyclobutanones and their coupling with olefins. Various alkenes have been coupled with cyclobutanones to provide a range of bridged skeletons. The ketone group of the products serves as a convenient handle for downstream functionalization.

Figure 1. The challenge of bridged-ring synthesis

a, Selected alkaloid natural products with bridged-ring substructures. b, Comparison of the type II IMDA reaction - which is synthetically limited by the incipient strain in an unsaturated bridgehead carbon - and the approach described in this work. c, Previous work on metal-catalysed C−C activation of cyclobutanones towards coupling and potential challenges due to the decarbonylation of the ketones.

Figure 2. Proposed catalytic cycle

The key features include using metal-ligand cooperative activation of cyclobutanones and in situ carbonyl group protection to avoid decarbonylation.

Figure 3. Potentials and applications in bridged-ring synthesis

a, Construction of fused-bridged tricyclic structures. b, Potentials for developing an enantioselective transformation. c, Use of the carbonyl group in the product as a handle to access ring-contracted and expanded bridged rings.