Deploying Pictet-Spengler Reactions to Access Constrained Aromatic Amino Acids

Herein, the synthesis of unusual, conformationally constrained aromatic amino acids is reported using electrocatalysis and Negishi cross-coupling, followed by Pictet-Spengler cyclization, as variants of the tetrahydroisoquinoline-3-carboxylic acid (Tic) residue. Moreover, the experiments were supported by density functional theory (DFT) energy calculations to predict the ease of cyclization, where ΔG^‡ calculations matched the experimental data. Consequently, this study rationalizes the ease of synthesis versus energy barriers encountered when aiming at such N-Fmoc-protected, constrained aromatic amino acids for use in peptidomimetic research.