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Synthetic Approaches to N δ -Methylated l -Arginine, N ω -Hydroxy- l -arginine, l -Citrulline, and N δ -Cyano- l -ornithine

2008; American Chemical Society; Volume: 73; Issue: 3 Linguagem: Inglês

10.1021/jo702150d

1520-6904

Dennis Schade, Katrin Töpker-Lehmann, Jürke Kotthaus, Bernd Clement,

Polyamine Metabolism and Applications

Nomega-Methylated arginines such as asymmetric dimethyl-L-arginine (ADMA) and monomethyl-l-arginine (NMMA) are known as potent physiological inhibitors of nitric oxide synthases (NOSs). To explore a possible physiological and pharmaceutical relevance of N(delta)-methylated analogues, a synthetic scheme had to be developed that would not lead to N(delta)-methyl-L-arginine only but also to its presumed metabolites of NOS catalysis. Two basic synthetic approaches have been pursued to obtain N(delta)-methylated derivatives of L-ornithine, L-citrulline, L-arginine, and N(omega)-hydroxy-L-arginine. A first attempt utilized conventionally protected L-ornithine, i.e., the tert-butyl ester and Boc-amine, and led to three end compounds in excellent yields. Simultaneous protection of the alpha-amino acid moiety by formation of boroxazolidinones, particularly by employing 9-borabicyclo[3.3.1]nonane (9-BBN-H), proved to be a convenient option to perform side chain modifications and led to all of the desired end compounds. Additionally, enantiomeric excess (ee, %) of crucial synthetic intermediates and end compounds was determined by chiral HPLC.