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.
Link to Publisher’s page: Deploying Pictet–Spengler Reactions to Access Constrained Aromatic Amino Acids | The Journal of Organic Chemistry