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.

β-苯丙氨酸衍生物（β-Phenylalanine derivatives，以下简称β-PAD）是一类兼具治疗研究价值的结构家族，既可作为药物成分，亦可作为关键化合物合成的起始原料。作为药物化学研究的核心骨架，β-PAD具备多重优势：结构多样性与模块化程度高，具有手性伪肽特性，可被天然生物系统识别，且稳定性优于天然α-氨基酸。然而，β-PAD的合成仍是药物研发领域的一大挑战，目前已有诸多方法致力于其制备。本综述旨在更新β-PAD的合成路径及其各类治疗应用的研究进展。β-PAD亦是天然或合成化合物的组成部分，通过模拟天然α-氨基酸的结构特征，赋予其生物活性与更优的成药性。同时，β-PAD也是药物候选分子合成过程中用于药效团修饰的实用骨架。本文综述了经典的β-PAD合成路径，重点聚焦于诺文葛尔（Knoevenagel）/罗季奥诺夫-约翰逊（Rodionow-Johnson）反应。为拓展β-PAD的结构多样性，研究者已开发出金属催化与不对称合成方法。诸多酶类被开发为生物催化剂，以提升合成产率与对映选择性。近年来，研究者开发出新型β-PAD合成方法，用于制备各类具有治疗价值的化合物。其中，无金属绿色合成法已成为具备工业化应用潜力的低成本、可持续化生产路径。但生物催化路径仍存在诸多挑战，亟需开发新型方法以便捷获取对映体纯的β-PAD。