The Development of Zinc and Zinc/Copper Reagents for the Synthesis of Enantiomerically Pure Amino Acids

Abstract: The application of organometallic chemistry to the synthesis of highly functionalised target compounds has seen very significant advances in the last 15 years. In particular, the realisation that carbon-zinc bonds are compatible with many functional groups has transformed the general perception of the utility of organozinc compounds. This review describes the development of synthetic methods for the preparation of a wide variety of unnatural amino acids using organozinc and zinc/copper reagents derived from simple, readily available amino acids such as serine, aspartic acid and glutamic acid. In the case of serine, standard protection of the amino acid functionality, followed by conversion of the free alcohol into an iodide, yields a stable crystalline compound that may be converted into the corresponding alkylzinc iodide by treatment with suitably activated zinc metal. This alkylzinc iodide, formed without loss of stereochemical integrity, can react under palladium catalysis with many electrophiles (including iodoaromatics and acid chlorides) to give a wide variety of useful products. Examples from several other laboratories of the applications of the method to the preparation of phenylalanine derivatives are discussed. Extension of this approach to alkyl iodides derived from aspartic acid and glutamic acid leads to a further array of a-, p- and y-amino acids. Some key observations about the stability of these reagents, especially those bearing a P-amido group, have lead to the optimisation of the process, specifically in terms of the use of dipolar aprotic solvents.