HIGHLY PRACTICAL METHODOLOGY FOR THE SYNTHESIS OF D-ALPHA-AMINO-ACIDSAND L-ALPHA-AMINO-ACIDS, N-PROTECTED ALPHA-AMINO-ACIDS, AND N-METHYL-ALPHA-AMINO ACIDS

Full details are provided for an exceedingly practical method to synth esize D- and L-cr-amino acids, N-protected alpha-amino acids, and N-me thyl-alpha-amino acids, employing as a key step the asymmetric alkylat ion of pseudoephedrine glycinamide (1) or pseudoephedrine sarcosinamid e (2). Practical procedures for the synthesis of 1 and 2 from pseudoep hedrine and glycine methyl ester or sarcosine methyl ester, respective ly, are presented. Optimum protocols for the enolization and subsequen t 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 sub strates, and the products are formed with high diastereoselectivity. T he products of these alkylation reactions are hydrolyzed efficiently a nd with little to no racemization simply by heating in water or water- dioxane mixtures. This protocol provides an exceedingly practical meth od for the preparation of salt-free alpha-amino acids of high enantiom eric purity. Alternatively, the alkylation products may be hydrolyzed in high yield and with little to no racemization by heating with aqueo us sodium hydroxide. The alkaline hydrolyzate can then be treated with an acylating reagent to provide directly highly enantiomerically enri ched N-protected derivatives such as N-Boc and N-Fmoc. Key features ne cessary for the successful execution of these experimental procedures are identified.