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J Org Chem. 2008 Feb 1;73(3):1025-30. doi: 10.1021/jo702150d. Epub 2008 Jan 8.

Synthetic approaches to N(delta)-methylated L-arginine, N(omega)-hydroxy-L-arginine, L-citrulline, and N(delta)-cyano-L-ornithine.

Author information

1
Department of Pharmaceutical Chemistry, Pharmaceutical Institute, Christian-Albrechts-University of Kiel, Gutenbergstrasse 76-78, D-24118 Kiel, Germany.

Abstract

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.

PMID:
18179234
DOI:
10.1021/jo702150d
[Indexed for MEDLINE]

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