Synthetic approaches to N(delta)-methylated L-arginine, N(omega)-hydroxy-L-arginine, L-citrulline, and N(delta)-cyano-L-ornithine.
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.
Schade
Dennis
D
Department of Pharmaceutical Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76-78, D-24118 Kiel, Germany.
Töpker-Lehmann
Katrin
K
Kotthaus
Jürke
J
Clement
Bernd
B
D001120:Arginine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D001896:Boron Compounds / Q000138:chemical synthesis / Q000737:chemistry; D002956:Citrulline / Q000138:chemical synthesis* / Q000737:chemistry; D015394:Molecular Structure; D009952:Ornithine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry; D010081:Oxazolone / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry
D001896:Boron Compounds; C527584:delta-cyano-L-ornithine; C461065:trifluoromethyloxazolinone; D010081:Oxazolone; D002956:Citrulline; C068309:N(omega)-hydroxyarginine; C027742:delta-N-methylarginine; D001120:Arginine; D009952:Ornithine