A Solid-Phase Synthetic Route to Unnatural Amino Acids with Diverse Side-Chain Substitutions

Reacting imine derivatives of resin-bound amino acids with α,ω-dihaloalkanes provides highly versatile intermediates to racemic α,α-disubstituted amino acids with a wide variety of side-chain functionality. Two strategies were developed to convert the intermediate ω-chloro or ω-bromo derivatives to the desired products. Together, they allow the creation of amino acids with diverse functionalities (ω-chlorides, nitriles, azides, acetates, thioacetates, thioethers, secondary and tertiary aliphatic amines, and anilines) placed at varying chain lengths (2−5) from the α-center of the amino acid.