New Generation of Modular Nucleophilic Glycine Equivalents for the General Synthesis of α-Amino Acids

A review of the advances in the synthesis of sterically constrained alpha-amino acids, specifically the preparation of optically active beta-substituted pyroglutamic acids via the homologation of a new generation of modular nickel(II)-complexed glycine equivalents, is herein presented. Following a brief overview of the general methods for the preparation of alpha-amino acids, paying close attention to the homologation of achiral glycine equivalents, the majority of this review is dedicated to the accomplishments of a new generation of modularly designed nucleophilic glycine equivalents. As one will see from this review, the key advantage of this new series of glycine equivalents is that the physical and chemical properties of these compounds can be altered to fit the requirements of the homologation technique desired. This modular approach has already been exploited to fine-tune the nickel(II)-complexed glycine equivalent for the asymmetric synthesis of a variety of beta-substituted pyroglutamic acids via its Michael addition reaction with various (S)-3-(E)-enoyl-4-phenyloxazolidin-2-ones. 1 Introduction 2 Literature Examples of Achiral Glycine Equivalents 3 Picolinic Acid-Schiff Base Derived Achiral Glycine Equivalents 4 Modular Design of Achiral Nucleophilic Glycine Equivalents 5 Rational Control of Physicochemical Properties and Reactivity in a Series of Modular Nucleophilic Glycine Equivalents 6 Application of Modular Nucleophilic Glycine Equivalents for the General Asymmetric Synthesis of beta-Substituted Pyroglutamic Acids 7 Disassembly of the Michael Addition Products, Isolation of the Target alpha-Amino Acids, and Recycling of the Starting Compounds 8 Elaboration of beta-Substituted Pyroglutamic Acids into Various Sterically Constrained C-5- and C-6-alpha-Amino Acids 9 Summary