Synthesis and interest in medicinal chemistry of β-phenylalanine derivatives (β-PAD): an update (2010–2022)

β-Phenylalanine derivatives (β-PAD) represent a structural family of therapeutic interest, either as components of drugs or as starting materials for access to key compounds. As scaffolds for medicinal chemistry work, β-PAD offer the advantage of great diversity and modularity, a chiral pseudopeptidic character that opens up the capacity to be recognized by natural systems, and greater stability than natural α-amino acids. Nevertheless, their synthesis remains a challenge in drug discovery and numerous methods have been devoted to their preparation. This review is an update of the access routes to β-PAD and their various therapeutic applications. β-phenylalanine derivatives (β-PAD) are part of natural or synthetic compounds where they exploit an analogy with natural α-aminoacids to confer them biologic activities and better druggability. β-PAD are also useful scaffolds for pharmacomodulation in the synthesis of drug candidates. Historical β-PAD synthesis pathways are reviewed with a focus on the Knoevenagel/Rodionow-Johnson reaction. Metallocatalytic and asymmetric syntheses have been developed to increase the diversity of β-PAD. Many enzymes have been explored as biocatalysts to improve yield and enantioselectivity. Recently, new β-PAD access methods have been developed for the synthesis of a wide variety of compounds of therapeutic interest. Among them, metal-free and green methods have emerged as potential low-cost and sustainable processes for industrial production. Biocatalytic pathways remain challenging and novel methods need to be developed to facilitate access to enantiomerically pure β-PAD.