Cross‐Claisen Condensation of N‐Fmoc‐Amino Acids – A Short Route to Heterocyclic γ‐Amino Acids

Abstract

Abstract4‐Amino(methyl)‐1,3‐thiazole‐5‐carboxylic acids (ATCs) are a new class of constrained heterocyclic γ‐amino acids built around a thiazole ring; these compounds are valuable as design mimics of the secondary structures of proteins such as helices, β‐sheets, turns, and β‐hairpins. We report herein a short and versatile chemical route to orthogonally protected ATCs. The synthesis is centered on cross‐Claisen condensations between N‐Fmoc‐amino acids and sterically hindered 1,1‐dimethylallyl acetate. The optimized conditions are compatible with aliphatic, aromatic, acidic, and basic amino acids. The resulting N‐Fmoc‐β‐keto ester intermediates were engaged in a two‐step process to give ATCs in 45–90 % yields. The synthetic protocol provides a highly flexible method for the introduction of a wide variety of lateral chains either on the γ‐carbon atom or on the thiazole core of the γ‐amino acids.