Skip to main content

Advertisement

SpringerLink
Log in

Semisynthetic preparation of leucomycin derivatives: Introduction of aromatic side chains by reductive amination

  • Short communication
  • Published:
Molecular Diversity Aims and scope Submit manuscript

Abstract

A small library of leucomycin A7 derivatives was prepared by NaCNBH3/ZnCl2-mediated reductive amination of the C18 aldehyde moiety with a variety of lipophilic benzylamines and tested for antibiotic activity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abbreviations

Bnz:

benzyl

BOC:

tert-butyloxycarbonyl

br:

broad

Cy:

cyclohexyl

DCC:

dicyclohexyl carbodiimide

DCM:

methylene chloride

DMAP:

4-N,N-dimethylaminopyridine

NHS:

N-hydroxysuccinimide

NP:

normal phase

TEA:

triethylamine

TLC:

thin-layer chromatography

References

  1. Bryskier, A.J., Butzler, J.-P., Neu, H.C. and Tulkens, P.M., Macrolides: Chemistry, Pharmacology and Clinical Uses, Arnette Blackwell, Paris, 1993.

    Google Scholar 

  2. Schönfeld, W. and H.A. Kirst (Eds.), Macrolide Antibiotics, Birkhäuser, Basel, 2002.

    Google Scholar 

  3. Elliott, R.L., Pireh, H., Griesgraber, G., Nilius, A.M., Ewing, P.J., Bui, M.H., Raney, P.M., Flamm, R.K., Kim, K., Henry, R.F., Chu, D.T.W., Plattner, J.J. and Or, Y.S., Anhydrolide macrolides. 1. Synthesis and antibacterial activity of 2,3-anhydro-6-O-methyl-11,12-carbamate erythromycin a analogues, J. Med. Chem., 41 (1998) 1651.

    Google Scholar 

  4. Denis, A., Agouridas, C., Auger, J.M., Benedetti, Y., Bonnefoy, A., Bretin, F., Chantot, J.F., Dussarat, A., Fromentin, C., Gouin-D’Ambrièrsa, S., Lachaud, S., Laurin, P., Le Martret, O., Loyau, V., Tessot, N., Pejac, J.-M. and Perron, S., Synthesis and antibacterial activity of Hmr 3647 – A new ketolide highly potent against erythromycin-resistant and susceptible pathogens, Bioorg. Med. Chem. Lett., 9 (1999) 3075–3080.

    Google Scholar 

  5. Phan, L.T., Clark, R.F., Rupp, M., Or, Y.S., Chu, D.T.W. and Ma, Z., Synthesis of 2-fluoro-6-O-propargyl-11,12-carbamate ketolides. A novel class of antibiotics, Org. Lett., 2 (2000) 2951–2954.

    Google Scholar 

  6. Denis, A., Bretin, F., Fromentin, C., Bonnet, A., Piltan, G., Agouridas, C. and Bonnefoy, A., Β-Ketoester chemistry and ketolides. Synthesis and antibacterial activity of 2-halogeno, 2-methyl and 2,3-enol-ether ketolides, Bioorg. Med. Chem. Lett., 10 (2000) 2019-2022.

    Google Scholar 

  7. Clark, R.F., Ma, Z., Wang, S., Griesgraber, G., Tufano, M., Yong, H., Li, L., Zhang, X., Nilius, A., Chu, D.T.W. and Or, Y.S., Synthesis and antibacterial activity of novel 6-O-substituted erythromycin a derivatives, Bioorg. Med. Chem. Lett., 10 (2000) 815–819.

    Google Scholar 

  8. Shengxi, C., Xiandong, X. and Lanxiang, Y., 3-Keto-9-O-substituted oxime derivatives of 6-O-methyl erythromycin a synthesis and in vitro activity, J. Antibiot., 54 (2001) 506–509.

    Google Scholar 

  9. Fardis, M., Ashley, G.W., Carney, J.R. and Chu, D.T., Synthesis of 14,15-dehydroerythromycin a ketolides: Effects of the 13-substituent on erythromycin tautomerism, J. Antibiot., 54 (2001) 278–284.

    Google Scholar 

  10. Denis, A., Pejac, J.-M., Bretin, F. and Bonnefoy, A., Synthesis of 9-oxime-11,12-carbamate ketolides through a novel N-deamination reaction of 11,12-hydrazonocarbamate ketolide, Bioorg. Med. Chem. Lett, 11 (2003) 2389–2394.

    Google Scholar 

  11. Keyes, R.F., Carter, J.J., Englund, E.E., Daly, M.M., Stone, G.G., Nilius, A.M. and Ma, Z., Synthesis and antibacterial activity of 6-O-arylbutynyl ketolides with improved activity against some key erythromycin-resistant pathogens, J. Med. Chem., 46 (2003) 1795–1798.

    Google Scholar 

  12. Zhao, Y., You, Q. and Shen, W., A novel bicyclic ketolide derivative, Bioorg. Med. Chem. Lett., 13 (2003) 1805–1807.

    Google Scholar 

  13. Hranjec, M., Starcevi’c, K., Zamola, B., Mutak, S., Derek, M. and Karminski-Zamola, G., New amidino-benzimidazolyl derivatives of tylosin and desmycosin, J. Antibiot., 55 (2002) 308–314.

    Google Scholar 

  14. Mandic, Z., Naranda, A., Novak, P., Brajsa, K., Derek, M. and Ivekovic, D., New derivatives of tylosin: Chemical and electrochemical oxidation products of desmycosin, J. Antibiot., 55 (2002) 807–813.

    Google Scholar 

  15. Kurihara, K.-I., Ajito, K., Shibahara, S., Ishizuka, T., Hara, O., Araake, M. and Omoto, S., Cladinose analogues of sixteen-membered macrolide antibiotics. I. Synthesis of 4-O-alkyl-L-cladinose analogues via glycosylation, J. Antibiot., 49 (1996) 582–592.

    Google Scholar 

  16. Kurihara, K.-I., Ajito, K., Shibahara, S., Hara, O., Araake, M., Omoto, S. and Inouye, S., Cladinose analogues of sixteen-membered macrolide antibiotics VI. Synthesis of metabolically programmed, highly potent analogues of sixteen-membered macrolide antibiotics, J. Antibiot., 51 (1998) 771–785.

    Google Scholar 

  17. Furuuchi, T., Kurihara, K.-I., Yoshida, T. and Ajito, K., Synthesis and biological evaluation of novel leucomycin analogues at the C-3 position, J. Antibiot., 56 (2003) 399–414.

    Google Scholar 

  18. Akritopoulou-Zanze, I. and Sowin, T.J., Solid-phase synthesis of macrolide analogues, J. Comb. Chem., 3 (2001) 301–311.

    Google Scholar 

  19. Kirst, H.A., Toth, E.J., Debono, M., Willard, K.E., Truedell, B.A., Ott, J.L., Counter, F.T., Felty-Duckworth, A.M. and Pekarek, Synthesis and evaluation of tylosin-related macrolides modified at the aldehyde function: A new series of orally effective, antibiotics, J. Med. Chem., 31 (1988) 1631–1641.

    Google Scholar 

  20. Creemer, L.C., Beier, R.C. and Kiehl, D.E., Facile synthesis of tilmicosin and tylosin related haptens for use as protein conjugates, J. Antibiot., 56 (2003) 481–487.

    Google Scholar 

  21. Gebhardt, P., Perner, A. and Gräfe, U., Chromatographia (2004), in press.

  22. Kim, S., Oh, C.H., Ko, J.S.K., Ahn, K.H. and Kim, Y.J., Zinc modified cyanoborohydride as a selective reducing agent, J. Org. Chem., 50 (1985) 1927–1932.

    Google Scholar 

  23. Friedrich-Bochnitschek, S., Waldmann, H. and Kunz, H., Allyl esters as carboxy protecting groups in the synthesis of O-glycopeptides, J. Org. Chem., 54 (1989) 751–756.

    Google Scholar 

  24. Tsuda, Y., Wanaka, K., Tada, M., Okamoto, S., Hijikata-Okunomiya, A. and Okada, Y., Design of plasma kallikrein inhibitors: Functional and structural requirements of plasma kallikrein inhibitors, Chem. Pharm. Bull., 46 (1998) 452–457.

    Google Scholar 

  25. Hinman, C. and Vaughan, K., Active esters of anthranilic acid; N-(O-aminobenzoyloxy)-imides as reagents for O-aminobenzoylation, synthesis, (1980) 719–721.

  26. Kazmirowski, H.G., Neuland, P., Landmann, H. and Markwardt, F., Synthesis of antiproteolytically active derivatives of 4-aminomethylbenzoic acid and of other structurally related compounds, Pharmazie, 22 (1967) 465–470.

    Google Scholar 

  27. Landmann, H., Relations between chemical constitution and anti trypsin activity in p-amino methylbenzoic acid derivatives, Monatsber. Dtsch. Akad. Wiss. Berl., 8 (1966) 943–947.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Hans-Knöll-Institute for Natural Products Research, Beutenbergstr. 11a, 07745, Jena, Germany

    Peter Gebhardt, Udo Gräfe, Ute Möllmann & Christian Hertweck

Authors
  1. Peter Gebhardt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Udo Gräfe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ute Möllmann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Christian Hertweck
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Christian Hertweck.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gebhardt, P., Gräfe, U., Möllmann, U. et al. Semisynthetic preparation of leucomycin derivatives: Introduction of aromatic side chains by reductive amination. Mol Divers 9, 27–32 (2005). https://doi.org/10.1007/s11030-005-1304-z

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11030-005-1304-z

Keywords

Search

Navigation