Synthesis 2018; 50(07): 1546-1554
DOI: 10.1055/s-0036-1589148
© Georg Thieme Verlag Stuttgart · New York

Synthesis of Novel Oxazolyl Amino Acids and Their Use in the Parallel Synthesis of Disubstituted Oxazole Libraries

Siva Murru
a  University of Louisiana Monroe, 700 University Avenue, Monroe, Louisiana, 71209, USA   Email:
Ramesh Bista
a  University of Louisiana Monroe, 700 University Avenue, Monroe, Louisiana, 71209, USA   Email:
Adel Nefzi*
b  Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St Lucie, Florida 34987, USA   Email:
› Author Affiliations
The authors would like to thank the State of Florida Funding, NIH (1R21CA191351-01A1 Nefzi/Piedrafita), NIH (1R01AI105836-01A1, Nefzi/Piedrafita), and Louisiana Biomedical Research Network (Murru) for providing generous financial support.
Further Information

Publication History

Received: 06 November 2017

Accepted after revision: 14 November 2017

Publication Date:
19 January 2018 (online)


Novel chiral oxazolyl alanine and homologues are synthesized and utilized as building blocks for the solid-phase parallel synthesis of novel trifunctional oxazole small molecules in good to excellent overall yields and with high purity. The orthogonal deprotection strategy of oxazolyl amino acids, prepared from serine methyl ester and amino acids such as aspartic and glutamic acids, allows multiple sites of diversification to make a variety of pharmacologically relevant small molecules. The general nature of this approach allows the preparation of a large number of small molecules and peptidomimetics.

Supporting Information

  • References

  • 1 Magrioti V. Moutevelis-Minakakis P. Kokotos G. Synthesis of non-natural amino acids and their applications for the development of medicinally interesting compounds. Essays on Contemporary Peptide Science. Cordopatis P. Research Signpost; India: 2011: 1-17
  • 2 Saladino R. Botta G. Crucianelli M. Mini Rev. Med. Chem. 2012; 12: 277
    • 3a Toy PH. Lam Y. Solid-Phase Organic Synthesis: Concepts, Strategies, and Applications. John Wiley & Sons; Hoboken: 2012
    • 3b Eifler-Lima VL. Graebin CS. Uchoa FD. T. Duarte PD. Correa AG. J. Braz. Chem. Soc. 2010; 21: 1401
    • 3c Krchňák V. Holladay MW. Chem. Rev. 2002; 102: 61
    • 3d Grabowska U. Rizzo A. Farnell K. Quibell M. J. Comb. Chem. 2000; 2: 475
    • 3e Merrifield RB. J. Am. Chem. Soc. 1963; 85: 2149
    • 3f Merrifield B. Science 1986; 232: 341
    • 3g Geysen HM. Meleon RH. Barteling SJ. Proc. Natl. Acad. Sci. U.S.A. 1984; 81: 3998
    • 4a Rohde KH. Michaels HA. Nefzi A. Bioorg. Med. Chem. Lett. 2016; 26: 2206
    • 4b Eans SO. Ganno ML. Mizrachi E. Houghten RA. Dooley CT. McLaughlin JP. Nefzi A. J. Med. Chem. 2015; 58: 4905
    • 4c Murru S. Nefzi A. ACS Comb. Sci. 2014; 16: 39
    • 4d Michaels HA. Velosa DC. Nefzi A. ACS Comb. Sci. 2014; 16: 1
    • 4e Murru S. Dooley C. Nefzi A. Tetrahedron Lett. 2013; 54: 7062
    • 4f Liu A. Nefzi A. J. Comb. Chem. 2010; 12: 566
    • 4g Nefzi A. Appel J. Arutyunyan S. Houghten RA. Bioorg. Med. Chem. Lett. 2009; 19: 5169
    • 5a Chen H. Wang J. Zhou S. Liu H. J. Org. Chem. 2014; 79: 7872
    • 5b Turner CD. Liang HS. Curr. Org. Chem. 2011; 15: 2846
    • 5c Jin Z. Nat. Prod. Rep. 2005; 22: 196
    • 5d Moloney MG. Trippier PC. Yaqoob M. Wang Z. Curr. Drug Discovery Technol. 2004; 1: 181
    • 6a Giddens AC. Boshoff HI. M. Franzblau SG. Barry CE. III. Copp BR. Tetrahedron Lett. 2005; 46: 7355
    • 6b Crank G. Neville M. Ryden R. J. Med. Chem. 1973; 16: 1402
    • 6c Crank G. Foulis MJ. J. Med. Chem. 1971; 14: 1075
    • 7a Allington DR. Rivey MP. Clin. Ther. 2001; 23: 24
    • 7b Brown K. Cavalla JF. Green D. Wilson AB. Nature 1968; 219: 164
    • 8a Ma Z. Cowart DM. Ward BP. Arnold RJ. DiMarchi RD. Zhang L. George GN. Scott RA. Giedroc DP. J. Am. Chem. Soc. 2009; 131: 18044
    • 8b Mennen SM. Blank JT. Tran-Dube MB. Imbriglio JE. Miller SJ. Chem. Commun. 2005; 195
    • 9a Pinto DJ. Smallheer JM. Corte JR. Hu Z. Cavallaro CL. Gilligan PJ. Quan ML. Smith LM. WO2007070826 A1, 2007
    • 9b Campiani G. De Angelis M. Armaroli S. Fattorusso C. Catalanotti B. Ramunno A. Nacci V. Novellino E. Grewer C. Ionescu D. Rauen T. Griffiths R. Sinclair C. Fumagalli E. Mennini T. J. Med. Chem. 2001; 44: 2507
    • 9c Xu Y.-Z. Yuan S. Bowers S. Hom RK. Chan W. Sham HL. Zhu YL. Beroza P. Pan H. Brecht E. Yao N. Lougheed J. Yan J. Tam D. Ren Z. Ruslim L. Bova MP. Artis DR. Bioorg. Med. Chem. Lett. 2013; 23: 3075
    • 9d Zhang W. Liu W. Jiang X. Jiang F. Fu L. Synth. Commun. 2012; 42: 2772
    • 9e Boyd SA. Demeese J. Farouz FS. Gunawardana I. Jacobson IC. Kasar RA. Lehuerou Y. Lupher ML. Mclaughlin M. Miller S. Thomas A. Thorsett ED. Xu R. Yanik M. Zhang G. Patent WO2005016883 A3, 2005
    • 9f Challenger S. Cook AS. Gillmore AT. Middleton DS. Pryde DC. Stobie A. WO2002079143 A1, 2002
    • 9g Glossop MS. Bazin RJ. Dack KN. Fox DN. A. MacDonald GA. Mills M. Owen DR. Phillips C. Reeves KA. Ringer TJ. Strang RS. Watson CA. L. Bioorg. Med. Chem. Lett. 2011; 21: 3406
    • 9h Kolb HC. Sun Q. US 6562944, 2003
    • 10a Brown RD. J. Chem. Soc., Perkin Trans. 1 1998; 3293
    • 10b Baxter AD. Curr. Opin. Chem. Biol. 1997; 1: 79
    • 10c Hermkens PH. H. Ottenheijm HC. J. Rees D. Tetrahedron 1996; 52: 4527
    • 11a Houghten RA. Proc. Natl. Acad. Sci. U.S.A. 1985; 82: 5131
    • 11b Nefzi A. Ostresh JM. Houghten RA. J. Org. Chem. 2004; 69: 3603
    • 12a Li Z. Gever JR. Rao S. Widjaja K. Prusiner SB. Silber BM. ACS Med. Chem. Lett. 2013; 4: 397
    • 12b Helal CJ. Sanner MA. Cooper CB. Gant T. Adam M. Lucas JC. Kang ZJ. Kupchinsky S. Ahlijanian MK. Tate B. Menniti FS. Kelly K. Peterson M. Bioorg. Med. Chem. Lett. 2004; 14: 5521
    • 12c (accessed Dec 15, 2017)
    • 12d Soural M. Bouillon I. Krchnak V. J. Comb. Chem. 2008; 10: 923
  • 13 Kaiser E. Colescott RL. Bossinger CD. Cook PI. Anal. Biochem. 1970; 34: 595