The asymmetric synthesis of arginine mimetics: derivatives of (S)-2-, 3- and 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 blood coagulation, digestion, and inflammation. Proteases of this class cleave polypeptide chains C-terminal to a basic residue (arginine or lysine). It has been shown that selectivity for a particular serine protease can be conferred based upon the structural moiety incorporated in the P1 position. In this regard, the three isomers (ortho, meta, and para) of amidinophenylalanine represent modified arginine residues and are important synthetic targets. Herein, a convenient asymmetric synthesis of (S)-Nalpha-(tert-butyloxycarbonyl)-2-, (S)-Nalpha-(tert-butyloxycarbonyl)-3-, and (S)-Nalpha-(tert-butyloxycarbonyl)-4-amidinophenyl-alanine N,O-dimethylamides (Weinreb amides) will be described. These derivatives represent key synthetic intermediates for the synthesis of enzyme inhibitors because the amidine can be readily orthogonally protected, while the Weinreb amide is easily converted to a variety of electrophilic carbonyls via reduction to the corresponding aldehyde or by reaction with various lithiated heterocycles. Likewise, the Weinreb amide can be reduced to the aldehyde and subsequently oxidized to the corresponding carboxylate, which is suitable for solid- or solution-phase peptide synthetic strategies.
Kent
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DR
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, Michigan 48105, USA.
Cody
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Doherty
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AM
D000596:Amino Acids / Q000138:chemical synthesis*; D001120:Arginine / Q000031:analogs & derivatives* / Q000737:chemistry; D004151:Dipeptides / Q000737:chemistry*; D010455:Peptides / Q000138:chemical synthesis*; D010649:Phenylalanine / Q000031:analogs & derivatives*; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis*
D000596:Amino Acids; D004151:Dipeptides; D010455:Peptides; D015842:Serine Proteinase Inhibitors; D010649:Phenylalanine; D001120:Arginine