Synlett 2013; 24(3): 343-346
DOI: 10.1055/s-0032-1318117
© Georg Thieme Verlag Stuttgart · New York

Stereocontrolled Synthesis of 5′- and 6′-Epimeric Analogues of Muraymycin Nucleoside Antibiotics

Anatol P. Spork
University of Paderborn, Department of Chemistry, Warburger Str. 100, 33 098 Paderborn, Germany   Fax: +49(5251)603245   Email: [email protected]
Christian Ducho*
University of Paderborn, Department of Chemistry, Warburger Str. 100, 33 098 Paderborn, Germany   Fax: +49(5251)603245   Email: [email protected]
› Author Affiliations
Further Information

Publication History

Received: 30 October 2012

Accepted after revision: 07 January 2013

Publication Date:
23 January 2013 (online)


Naturally occurring nucleoside antibiotics, for example, Streptomyces-produced muraymycins, represent a promising class of potential lead structures for the development of novel antimicrobial agents. The efficient preparation of muraymycin analogues is an essential prerequisite for detailed structure–activity relationship (SAR) studies, particularly with respect to the variation of the stereochemistry in a controlled manner. In this work, stereoselective syntheses of 5′- as well as 6′-epimers of muraymycins are reported. The obtained target structures also represent useful probes for the elucidation of the biosynthesis of muraymycins and related nucleoside antibiotics.

Supporting Information

  • References and Notes

    • 1a Taubes G. Science 2008; 321: 356
    • 1b Cooper MA, Shlaes D. Nature (London) 2011; 472: 32
  • 2 Walsh C. Nat. Rev. Microbiol. 2003; 1: 65

    • MraY as a potential drug target:
    • 3a Dini C. Curr. Top. Med. Chem. 2005; 5: 1221
    • 3b Bugg TD. H, Lloyd AJ, Roper DI. Infect. Disord.: Drug Targets 2006; 6: 85

      Selected biochemical investigations on MraY including methodology for activity assays:
    • 4a Lloyd AJ, Brandish PE, Gilbey AM, Bugg TD. H. J. Bacteriol. 2004; 186: 1747
    • 4b Bouhss A, Crouvoisier M, Blanot D, Mengin-Lecreulx D. J. Biol. Chem. 2004; 279: 29974
    • 4c Stachyra T, Dini C, Ferrari P, Bouhss A, van Heijernoort J, Mengin-Lecreulx D, Blanot D, Biton J, Le Beller D. Antimicrob. Agents Chemother. 2004; 48: 897
    • 4d Ma Y, Münch D, Schneider T, Sahl H.-G, Bouhss A, Ghoshdastider U, Wang J, Dötsch V, Wang X, Bernhard F. J. Biol. Chem. 2011; 286: 38844
    • 4e Shapiro AB, Jahić H, Gao N, Hajec L, Rivin O. J. Biomol. Screen. 2012; 17: 662

    • 5a Kimura K.-I, Bugg TD. H. Nat. Prod. Rep. 2003; 20: 252
    • 5b Winn M, Goss RJ. M, Kimura K.-I, Bugg TD. H. Nat. Prod. Rep. 2010; 27: 279
  • 6 McDonald LA, Barbieri LR, Carter GT, Lenoy E, Lotvin J, Petersen PJ, Siegel MM, Singh G, Williamson RT. J. Am. Chem. Soc. 2002; 124: 10260
  • 7 Igarashi M, Nakagawa N, Doi S, Hattori N, Naganawa H, Hamada M. J. Antibiot. 2003; 56: 580
  • 8 Funabashi M, Baba S, Nonaka K, Hosobuchi M, Fujita Y, Shibata T, Van Lanen SG. ChemBioChem 2010; 11: 184
    • 9a Lin Y.-I, Li Z, Francisco GD, McDonald LA, Davis RA, Singh G, Yang Y, Mansour TS. Bioorg. Med. Chem. Lett. 2002; 12: 2341
    • 9b Yamashita A, Norton E, Petersen PJ, Rasmussen BA, Singh G, Yang Y, Mansour TS, Ho DM. Bioorg. Med. Chem. Lett. 2003; 13: 3345
    • 9c Tanino T, Ichikawa S, Al-Dabbagh B, Bouhss A, Oyama H, Matsuda A. ACS Med. Chem. Lett. 2010; 1: 258
    • 9d Tanino T, Al-Dabbagh B, Mengin-Lecreulx D, Bouhss A, Oyama H, Ichikawa S, Matsuda A. J. Med. Chem. 2011; 54: 8421
    • 10a Hirano S, Ichikawa S, Matsuda A. Angew. Chem. Int. Ed. 2005; 44: 1854 ; Angew. Chem. 2005, 117, 1888
    • 10b Hirano S, Ichikawa S, Matsuda A. J. Org. Chem. 2007; 72: 9936
    • 10c Tanino T, Ichikawa S, Shiro M, Matsuda A. J. Org. Chem. 2010; 75: 1366
  • 11 Sarabia et al. were the first to report sulfur ylide reactions with uridine-5′-aldehydes,12a,b initially intended for the synthesis of 5′-epi-muraymycins12b with respect to an incorrect stereochemical assignment for the synthesized epoxides. We have then described an improved version of this methodology12c based on Sarabia’s stereochemical assignment, which we have later corrected based on X-ray crystallography data.12d Sarabia et al. have recently confirmed our stereochemical revision.12e
    • 12a Sarabia F, Martín-Ortiz L, López-Herrera FJ. Org. Lett. 2003; 5: 3927
    • 12b Sarabia F, Martín-Ortiz L. Tetrahedron 2005; 61: 11850
    • 12c Spork AP, Koppermann S, Ducho C. Synlett 2009; 2503
    • 12d Spork AP, Koppermann S, Dittrich B, Herbst-Irmer R, Ducho C. Tetrahedron: Asymmetry 2010; 21: 763
    • 12e Sarabia F, Vivar-García C, García-Ruiz C, Martín-Ortiz L, Romero-Carrasco A. J. Org. Chem. 2012; 77: 1328
  • 13 Cheng L, Chen W, Zhai L, Xu D, Huang T, Lin S, Zhou X, Deng Z. Mol. BioSyst. 2011; 7: 920
  • 14 Kaysser L, Lutsch L, Siebenberg S, Wemakor E, Kammerer B, Gust B. J. Biol. Chem. 2009; 284: 14987
    • 15a Yang Z, Chi X, Funabashi M, Baba S, Nonaka K, Pahari P, Unrine J, Jacobsen JM, Elliott GI, Rohr J, Van Lanen SG. J. Biol. Chem. 2011; 286: 7885
    • 15b Chi X, Pahari P, Nonaka K, Van Lanen SG. J. Am. Chem. Soc. 2011; 133: 14452

      Precedence for epimerization reactions in microbial biosyntheses:
    • 16a Kershaw NJ, Caines ME. C, Sleeman MC, Schofield CJ. Chem. Commun. 2005; 4251
    • 16b Hamed RB, Batchelar ET, Mecinović J, Claridge TD. W, Schofield CJ. ChemBioChem 2009; 10: 246
    • 16c Hamed RB, Gomez-Castellanos JR, Henry L, Ducho C, McDonough MA, Schofield CJ. Nat. Prod. Rep. 2013; 30: 21
  • 17 This is also in good agreement with Sarabia’s recently reported use of the sulfur ylide methodology for the synthesis of 2′′-epi-analogues of liposidomycin and caprazamycin nucleoside antibiotics.12e
    • 18a Spork AP, Ducho C. Org. Biomol. Chem. 2010; 8: 2323
    • 18b Spork AP, Wiegmann D, Granitzka M, Stalke D, Ducho C. J. Org. Chem. 2011; 76: 10083
  • 19 It should be noted that the descriptor of the stereocenter at C-5′ formally changes from R to S or vice versa upon reaction with the nitrogen nucleophile at C-6′ due to altered priorities.
  • 20 Wang Y, Kurosu M. Tetrahedron 2012; 68: 4797
  • 21 Barnard-Britson S, Chi X, Nonaka K, Spork AP, Tibrewal N, Goswami A, Pahari P, Ducho C, Rohr J, Van Lanen SG. J. Am. Chem. Soc. 2012; 134: 18514