Modular synthesis of α-tertiary amino acids from C–H feedstocks

Abstract

Both linear and cyclic unnatural amino acids (UAAs) play a central role in drug discovery but remain challenging to access from feedstocks. Inspired by terpene biosynthesis, we designed a simple and unified olefin precursor that can be diverged into constrained cyclic motifs, including prolines, azepanes, carbamates, ethers, and lactones. To access this olefin precursor, we exploit the emerging Pd(I/II) cycle and demonstrate a three-component coupling. This visible light-promoted transformation converts readily available C–H donors, 1,3-butadiene, and amidomalonate esters into functionally rich α-tertiary amino acid precursors. We further show how this achiral motif can furnish enantioenriched UAAs through an established Ni-assisted dynamic kinetic resolution. In addition, we build a pyrrolizidine core found in various natural products from simple building blocks, including dichloroethane. Our approach represents a modern twist on the classic amidomalonate synthesis.