Synthesis of Amino Acids With Five‐Membered <i>N</i> ‐Heterocycles in Side Chain

ABSTRACT Unnatural amino acids (UAAs) play a crucial role in advancements in medicinal chemistry and biotechnology. This review focuses on α‐amino acids containing five‐membered N ‐heterocycles in their side chains, including pyrrole, pyrazole, imidazole, 1,2,3‐triazole, 1,2,4‐triazole, and tetrazole derivatives, which are of particular interest as structural analogues of histidine. Based on literature from 1965 to 2024, only 27 amino acids containing unsubstituted 5‐membered N ‐heterocycles in their side chains were reported, among which 12 are the closest unnatural analogues of histidine. In addition, this review outlines strategies for the functionalization of N ‐heterocyclic rings with diverse substituents. Three major strategies to obtain such types of compounds can be highlighted: (1) Construction of a heterocycle onto an amino acid precursor; (2) Transformation of C‐ or N ‐substituents at the N ‐heterocycles to the amino acid side chain; (3) Direct CC or CN bond formation with the N ‐heterocycle. Unnatural histidine analogues represent a neglected subclass of amino acids; therefore, this overview highlights the significance of these compounds in expanding chemical diversity.