Synthesis of chiral carbocycles via enantioselective β,γ-dehydrogenation

Abstract

Dehydrogenation of an alkyl group via C–H activation forms a vinyl unit, which can act as a versatile stepping stone for diverse late-stage structural modifications at two adjacent sp3 carbon centres. However, enantioselective dehydrogenation via C–H metalation remains a challenge. Here we describe the realization of palladium-catalysed enantioselective β,γ-dehydrogenation of cycloalkyl amides enabled by chiral oxazoline–pyridone ligands to afford a wide range of highly elaborated carbocycles with exceptional enantioselectivity (>99% e.e.). Notably, the resulting chiral β,γ-unsaturated carbocycles are difficult to access via an inverse electron demand Diels–Alder reaction. Through ligand control, a tandem dehydrogenation and C–H olefination sequence also led to the formation of chiral β-alkylidene-γ-lactams. Remarkably, this catalyst is also compatible with biologically important natural products, including diterpenes and pentacyclic triterpenes, where each enantiomer of our chiral ligand enables site-selective modification at four distinct sites within the E ring. Chiral oxazoline–pyridone ligands enable the enantioselective β,γ-dehydrogenation of cycloalkyl amides, with excellent enantio- and site-selectivity. The palladium-catalysed process provides access to chiral β,γ-unsaturated carbocycles and can also be combined with a C–H olefination step to form chiral γ-lactams.