Efficient Synthesis of Optically Pure N^ω-Alkylated l-Arginines

Abstract

A number of N^ω-substituted l-arginines have been described to date, particularly with regard to nitric oxide synthase (NOS) modulators. Elaborate multistep syntheses and low yields limit the scope of preparing these modified l-arginines. We describe a synthetic methodology that delivers N^ω-alkylated l-arginine derivatives from protected l-ornithine in a three-step sequence with excellent overall yields (81-90%) and in high purity. Analysis of the synthesized amino acids on a Crownpak Cr(+) column revealed no significant racemization, that is, >99.9% ee for all final compounds.

Key words

nitric oxide - N ^ω-alkyl - l-arginine - NOS - DDAH

References

• 1a Nitric Oxide: Biochemistry, Molecular Biology, and Therapeutic Implications, In Advances in Pharmacology   Vol. 34:  Ignarro L. Murad F. Academic Press; San Diego: 1995. 
• 1b Alderton WK. Cooper CE. Knowles RG. Biochem. J.  2001,  357:  593 
• 2a Beltowski J. Kedra A. Pharmacol. Rep.  2006,  58:  159 
• 2b Cardounel AJ. Cui H. Samouilov A. Johnson W. Kearns P. Tsai AL. Berka V. Zweier JL. J. Biol. Chem.  2007,  282:  879 
• 3 Clement B. Kunze T. Heberling S. Biochem. Biophys. Res. Commun.  2006,  349:  869 
• 4 Boucher JL. Genet A. Vadon S. Delaforge M. Henry Y. Mansuy D. Biochem. Biophys. Res. Commun.  1992,  187:  880 
• 5 Vallance P. Leiper J. Nat. Rev. Drug Discovery  2002,  1:  939 
• 6 Zhang HQ. Dixon RP. Marletta MA. Nikolic D. van Breemen R. Silverman RB. J. Am. Chem. Soc.  1997,  119:  10888 
• 7 Fast WF. Levsky ME. Marletta MA. Silverman RB. Bioorg. Med. Chem.  1997,  5:  1601 
• 8 Rossiter S. Smith CL. Malaki M. Nandi M. Gill H. Leiper JM. Vallance P. Selwood DL. J. Med. Chem.  2005,  48:  4670 
• 9 Hartzoulakis B. Rossiter S. Gill H. O’Hara B. Steinke E. Gane PJ. Hurtado-Guerrero R. Leiper JM. Vallance P. Rust JM. Selwood DL. Bioorg. Med. Chem. Lett.  2007,  17:  3953 
• 10 Cardounel AJ. Cui H. Samouilov A. Johnson W. Kearns P. Tsai AL. Berka V. Zweier JL. J. Biol. Chem.  2007,  282:  879 
• 11 Beltowski J. Kedra A. Pharmacol. Rep.  2006,  58:  159 
• 12 Komori Y. Wallace GC. Fukuto JM. Arch. Biochem. Biophys.  1994,  315:  213 
• 13 Kotthaus J. Schade D. Töpker-Lehmann K. Beitz E. Clement B. Bioorg. Med. Chem.  2008,  16:  2305 
• 14 For a review, see: Katritzky AR. Rogovoy BV. ARKIVOC  2005,  (iv):  49 
• 15 Wagenaar FL. Kerwin JF. J. Org. Chem.  1993,  58:  4331 
• 16 Jia Q. Cai T. Huang M. Li H. Xian M. Poulos TL. Wang PG. J. Med. Chem.  2003,  46:  2271 
• 17 Schade D. Töpker-Lehmann K. Kotthaus J. Clement B. J. Org. Chem.  2008,  73:  1025 
• 18 Bernatowicz MS. Matsueda GR. Synth. Commun.  1993,  23:  657 
• 19 Chen B.-c. Shiu S. Yang D.-y. J. Chin. Chem. Soc.  1998,  45:  549 ; Chem. Abstr. 1998, 129, 276258
• 20 Linton BR. Carr AJ. Orner BP. Hamilton AD. J. Org. Chem.  2000,  65:  1566 
• 21 Martin NI. Woodward JJ. Marletta MA. Org. Lett.  2006,  8:  4035 
• 22 Martin NI. Beeson WT. Woodward JJ. Marletta MA. J. Med. Chem.  2008,  51:  924 
• 23 Kiso Y. Ukawa K. Akita T. J. Chem. Soc., Chem. Commun.  1980,  101 
• 24 Olken NM. Marletta MA. J. Med. Chem.  1992,  35:  1137