Highly Practical Methodology for the Synthesis ofd- andl-α-Amino Acids,N-Protected α-Amino Acids, andN-Methyl-α-amino Acids

Abstract

Full details are provided for an exceedingly practical method to synthesize d- and l-α-amino acids, N-protected α-amino acids, and N-methyl-α-amino acids, employing as a key step the asymmetric alkylation of pseudoephedrine glycinamide (1) or pseudoephedrine sarcosinamide (2). Practical procedures for the synthesis of 1 and 2 from pseudoephedrine and glycine methyl ester or sarcosine methyl ester, respectively, are presented. Optimum protocols for the enolization and subsequent alkylation of 1 and 2 are described. Alkylation reactions of 1 and 2 are found to be quite efficient with a wide range of alkyl halide substrates, and the products are formed with high diastereoselectivity. The products of these alkylation reactions are hydrolyzed efficiently and with little to no racemization simply by heating in water or water−dioxane mixtures. This protocol provides an exceedingly practical method for the preparation of salt-free α-amino acids of high enantiomeric purity. Alternatively, the alkylation products may be hydrolyzed in high yield and with little to no racemization by heating with aqueous sodium hydroxide. The alkaline hydrolyzate can then be treated with an acylating reagent to provide directly highly enantiomerically enriched N-protected derivatives such as N-Boc and N-Fmoc. Key features necessary for the successful execution of these experimental procedures are identified.