THE ASYMMETRIC-SYNTHESIS OF ARGININE MIMETICS - DERIVATIVES OF (S)-2-AMIDINOPHENYLALANINE, (S)-3-AMIDINOPHENYLALANINE AND (S)-4-AMIDINOPHENYLALANINE SUITABLE FOR INCORPORATION INTO ENZYME-INHIBITORS AND OR PEPTIDES/

The specific inhibition of trypsin-like serine proteases has become an important therapeutic target. These proteases have been implicated in several physiological and pathophysiological processes, including blo od coagulation, digestion, and inflammation. Proteases of this class c leave polypeptide chains C-terminal to a basic residue (arginine or ly sine). It has been shown that selectivity for a particular serine prot ease can be conferred based upon the structural moiety incorporated in the P-1 position. In this regard, the three isomers (ortho, meta, and para) of amidinophenylalanine represent modified arginine residues an d are important synthetic targets. Herein, a convenient asymmetric syn thesis of (S)-N-alpha-(tert-butyloxycarbonyl)-2-, (S)-N-alpha-(tert-bu tyloxycarbonyl)-3-, and pha-(tert-butyloxycarbonyl)4-amidinophenyl-ala nine N,O-dimethylamides (Weinreb amides) will be described. These deri vatives represent key synthetic intermediates for the synthesis of enz yme inhibitors because the amidine can be readily orthogonally protect ed, while the Weinreb amide is easily converted to a variety of electr ophilic carbonyls via reduction to the corresponding aldehyde or by re action with various lithiated heterocycles. Likewise, the Weinreb amid e can be reduced to the aldehyde and subsequently oxidized to the corr esponding carboxylate, which is suitable for solid- or solution-phase peptide synthetic strategies.