THE DEVELOPMENT OF ZINC AND ZINC COPPER REAGENTS FOR THE SYNTHESIS OFENANTIOMERICALLY PURE AMINO-ACIDS/

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 bo nds are compatible with many functional groups has transformed the gen eral perception of the utility of organozinc compounds. This review de scribes 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 s erine, aspartic acid and glutamic acid. In the case of serine, standar d protection of the amino acid functionality, followed by conversion o f the free alcohol into an iodide, yields a stable crystalline compoun d that may be converted into the corresponding alkylzinc iodide by tre atment with suitably activated zinc metal. This alkylzinc iodide, form ed without loss of stereochemical integrity, can react under palladium catalysis with many electrophiles (including iodoaromatics and acid c hlorides) to give a wide variety of useful products. Examples from sev eral other laboratories of the applications of the method to the prepa ration of phenylalanine derivatives are discussed. Extension of this a pproach to alkyl iodides derived from aspartic acid and glutamic acid leads to a further array of alpha-, beta- and gamma-amino acids. Some key observations about the stability of these reagents, especially tho se bearing a P-amido group, have lead to the optimisation of the proce ss, specifically in terms of the use of dipolar aprotic solvents.