Synthesis of β,γ-Unsaturated Aliphatic Acids via Ligand-Enabled Dehydrogenation.

Abstract

α,β-Dehydrogenation of aliphatic acids has been realized through both enolate and β-C-H metalation pathways. However, the synthesis of isolated β,γ-unsaturated aliphatic acids via dehydrogenation has not been achieved to date. Herein, we report the ligand-enabled β,γ-dehydrogenation of abundant and inexpensive free aliphatic acids, which provides a new synthetic disconnection as well as a versatile platform for the downstream functionalization of complex molecules at remote γ-sites. A variety of free aliphatic acids, including acyclic and cyclic systems with ring sizes from five-membered to macrocyclic, undergo efficient dehydrogenation. Notably, this protocol features good chemoselectivity in the presence of more accessible α-C-H bonds and excellent regioselectivity in fused bicyclic scaffolds. The utility of this protocol has been demonstrated by the late-stage functionalization of a series of bioactive terpene natural products at the γ-sites. Further functionalization of the β,γ-double bond allows for the installation of covalent warheads, including epoxides, aziridines, and β-lactones, into complex natural product scaffolds, which are valuable for targeted covalent drug discovery.