Molecular Diversity

, Volume 18, Issue 4, pp 701–719 | Cite as

Catalytic enantioselective diversity-oriented synthesis of a small library of polyhydroxylated pyrans inspired from thiomarinol antibiotics

Full-Length Paper


A small library of 30 thiomarinol analogues was successfully synthesised using as a key step–a catalytic enantioselective tandem oxa[4+2] cycloaddition/aldehyde allylboration methodology. With this method, highly substituted \(\alpha \)-hydroxyalkyl dihydropyrans were assembled in a single three-component reaction utilizing three different enol ethers and a wide variety of aldehydes, such as aromatic, heteroaromatic, unsaturated and aliphatic aldehydes. In a second operation, a mild and direct method for reducing an acetal unit in the \(\alpha \)-hydroxyalkyl dihydropyrans was optimised without the need for protecting a nearby hydroxyl group. This procedure facilitated the synthetic sequence, which was completed by a dihydroxylation of the residual olefin of \(\alpha \)-hydroxyalkyl 2\(H\)-pyrans to provide the desired library of dihydroxylated pyran analogues reminiscent of the thiomarinol antibiotics. The relative stereochemistry of the resulting library compounds was demonstrated by X-ray crystallography on one of the analogues.

Graphical Abstract


Allylboration ATP mimics Combinatorial library  Enantioselective catalysis Hetero-Diels–Alder cycloaddition Pyrans 



The authors thank the Natural Sciences and Engineering Research Council (NSERC) of Canada and the University of Alberta for financial support of this research.

Supplementary material

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ESM 1 (PDF 19,012 kb)


  1. 1.
    Sutherland R, Boon RJ, Griffin KE, Masters PJ, Slocombe B, White AR (1985) Antibacterial activity of mupirocin (pseudomonic acid), a new antibiotic for topical use. Antimicrob Agents Chemother 27:495–498PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Badder A, Garre C (1887) Title. Corresp Bl Sweiz Aertze 17:385Google Scholar
  3. 3.
    Fuller AT, Mellows G, Woolford M, Banks GT, Barrow KD, Chain EB (1971) Pseudomonic acid—antibiotic produced by Pseudomonas fluorescens. Nature 234:416–416. doi: 10.1038/234416a0 PubMedCrossRefGoogle Scholar
  4. 4.
    Chain EB, Mellows G (1977) Pseudomonic acid. 3. Structure of pseudomonic acid B. J Chem Soc Perkin Trans 1:318–322. doi: 10.1039/p19770000318 CrossRefGoogle Scholar
  5. 5.
    Alexander RG, Clayton JP, Luk K, Rogers NH, King TJ (1978) Chemistry of pseudomonic acid. 1. Absolute configuration of pseudomonic acid A. J Chem Soc Perkin Trans 1:561–565. doi: 10.1039/p19780000561 CrossRefGoogle Scholar
  6. 6.
    Hughes J, Mellows G (1978) Inhibition of isoleucyl transfer ribonucleic acid synthetase in Escherichia coli by pseudomonic acid. Biochem J 176:305–318PubMedPubMedCentralGoogle Scholar
  7. 7.
    Hughes J, Mellows G (1978) Mode of action of pseudomonic acid—inhibition of protein synthesis in Staphylococcus aureus. J Antibiot 31:330–335PubMedCrossRefGoogle Scholar
  8. 8.
    Hughes J, Mellows G, Soughton S (1980) How does Pseudomonas fluorescens, the producing organism of the antibiotic pseudomonic acid A, avoid suicide. FEBS Lett 122:322–324. doi: 10.1016/0014-5793(80)80465-0 PubMedCrossRefGoogle Scholar
  9. 9.
    Silvian LF, Wang J, Steitz TA (1999) Insights into editing from an Ile-tRNA synthetase structure with tRNA(Ile) and mupirocin. Science 285:1074–1077. doi: 10.1126/science.285.5430.1074 PubMedCrossRefGoogle Scholar
  10. 10.
    Class YJ, DeShong P (1995) The pseudomonic acids. Chem Rev 95:1843–1857. doi: 10.1021/cr00038a005 CrossRefGoogle Scholar
  11. 11.
    Clayton JP, Oliver RS, Rogers NP, King TJ (1979) Chemistry of pseudomonic acid 3. Rearrangement of pseudomonic acid A in acid and basic solution. J Chem Soc Perkin Trans I 838–846. doi: 10.1039/p19790000838
  12. 12.
    Shiozawa H, Kagasaki T, Kinoshita T, Haruyama H, Domon H, Utsui Y, Kodama K, Takahashi S (1993) Thiomarinol, a new hybrid antimicrobial antibiotic produced by a marine bacterium fermentation, isolation, structure, and antimicrobial activity. J Antibiot 46:1834–1842PubMedCrossRefGoogle Scholar
  13. 13.
    Stierle DB, Stierle AA (1992) Pseudomonic acid derivatives from a marine bacterium. Experientia 48:1165–1169. doi: 10.1007/BF01948016 CrossRefGoogle Scholar
  14. 14.
    Shiozawa H, Takahashi S (1994) Configurational studies on thiomarinol. J Antibiot 47:851–853PubMedCrossRefGoogle Scholar
  15. 15.
    Shiozawa H, Kagasaki T, Torikata A, Tanaka N, Fujimoto K, Hata T, Furukawa Y, Takahashi S (1995) Thiomarinol B and thiomarinol C, new antimicrobial antibiotics produced by a marine bacterium. J Antibiot 48:907–909PubMedCrossRefGoogle Scholar
  16. 16.
    Gao X, Hall DG (2005) Catalytic asymmetric synthesis of a potent thiomarinol antibiotic. J Am Chem Soc 127:1628–1629. doi: 10.1021/ja042827p PubMedCrossRefGoogle Scholar
  17. 17.
    Marion O, Gao X, Marcus S, Hall DG (2009) Synthesis and preliminary antibacterial evaluation of simplified thiomarinol analogs. Bioorg Med Chem 17:1006–1017. doi: 10.1016/j.bmc.2008.01.001 PubMedCrossRefGoogle Scholar
  18. 18.
    Breinbauer R, Vetter IR, Waldmann H (2002) From protein domains to drug candidates—natural products as guiding principles in the design and synthesis of compound libraries. Angew Chem Int Ed 41:2878–2890. doi: 10.1002/1521-3773(20020816)41:16<2878:AID-ANIE2878>3.0.CO;2-B
  19. 19.
    Gao X, Hall DG (2003) 3-Boronoacrolein as an exceptional heterodiene in the highly enantio- and diastereoselective Cr(III)-catalyzed three-component [4+2]/allylboration. J Am Chem Soc 125:9308–9309. doi: 10.1021/ja036368o PubMedCrossRefGoogle Scholar
  20. 20.
    Chavez DE, Jacobsen EN (2005) An efficient, highly diastereo- and enantioselective hetero-Diels–Alder catalyst. Preparation of (2S,6R)-6-(tert-butyldimethyl-siloxymethyl)-2-methoxy-2,5-dihydropyran. Org Synth 82:34Google Scholar
  21. 21.
    Gademann K, Chavez DE, Jacobsen EN (2002) Highly enantioselective inverse-electron-demand hetero-Diels–Alder reactions of alpha, beta-unsaturated aldehydes. Angew Chem Int Ed 41:3059–3061. doi: 10.1002/1521-3773(20020816)41:16<3059:AID-ANIE3059>3.0.CO;2-I
  22. 22.
    Evans DA, Andrews GC, Buckwalter B (1974) Metalated allylic ethers as homoenolate anion equivalents. J Am Chem Soc 96:5560–5561. doi: 10.1021/ja00824a039
  23. 23.
    Yamamoto H, Tsuda M, Sakaguchi S, Ishii Y (1997) Selective oxidation of vinyl ethers and silyl enol ethers with hydrogen peroxide catalyzed by peroxotungstophosphate. J Org Chem 62:7174–7177. doi: 10.1021/jo970440h
  24. 24.
    Gao X, Hall DG, Deligny M, Favre A, Carreaux F, Carboni B (2006) Catalytic enantioselective three-component hetero-[4+2] cycloaddition/allylboration approach to alpha-hydroxyalkyl pyrans: scope, limitations, and mechanistic proposal. Chem Eur J 13:3132–3142. doi: 10.1002/chem.200501197 CrossRefGoogle Scholar
  25. 25.
    Li X, Uchiyama T, Raetz CRH, Hindsgaul O (2003) Synthesis of a carbohydrate-derived hydroxamic acid inhibitor of the bacterial enzyme (LpxC) involved in lipid A biosynthesis. Org Lett 5:539–541. doi: 10.1021/ol027458l PubMedCrossRefGoogle Scholar
  26. 26.
    Rolf D, Gray GR (1982) Reductive cleavage of glycosides. J Am Chem Soc 104:3539–3541. doi: 10.1021/ja00376a065
  27. 27.
    Debenham SD, Toone EJ (2000) Regioselective reduction of 4,6-O-benzylidenes using triethylsilane and \(\text{ BF }_{3}\) center dot \(\text{ Et }_{2}\)O. Tetrahedron: Asymmetry 11:385–387. doi:  10.1016/S0957-4166(99)00584-4 CrossRefGoogle Scholar
  28. 28.
    Lipták A, Jodál I, Nánási P (1975) Stereoselective ring-cleavage of 3-O-benzyl-4,6-O-benzylidenehexopyranoside and 2,3-di-O-benzyl-4,6-O-benzylidenehexopyranoside derivatives with \(\text{ LiAlH }_{4}\)\(\text{ AlCl }_{3}\) reagent. Carbohydr Res 44:1–11. doi:  10.1016/S0008-6215(00)84330-X CrossRefGoogle Scholar
  29. 29.
    Garegg PJ, Hultberg H, Wallin S (1982) A novel, reductive ring-opening of carbohydrate benzylidene acetals. Carbohydr Res 108:97–101CrossRefGoogle Scholar
  30. 30.
    Deninno MP, Etienne JB, Duplantier KC (1995) A method for the selective reduction of carbohydrate 4,6-O-benzylidene acetals. Tetrahedron Lett 36:669–672. doi: 10.1016/0040-4039(94)02348-F CrossRefGoogle Scholar
  31. 31.
    Balakumar V, Aravind A, Baskaran S (2004) A highly regio- and chemoselective reductive cleavage of benzylidene acetals with \(\text{ EtAlCl }_{2}\)\(\text{ Et }_{3}\)SiH. Synlett 647–650: doi: 10.1055/s-2004-817752
  32. 32.
    Zhang HX, Xia P, Zhou WS (2003) Novel asymmetric total synthesis of the natural (+)-6-epicastanospermine. Tetrahedron 59:2015–2020. doi: 10.1016/S0040-4020(02)01258-9 CrossRefGoogle Scholar
  33. 33.
    Deligny M, Carreaux F, Carboni B, Toupet L, Dujardin G (2003) A novel diastereoselective route to alpha-hydroxyalkyldihydropyrans using a hetero Diels–Alder/allylboration sequence. Chem Commun 276–277. doi: 10.1039/b208572k
  34. 34.
    Deligny M, Carreaux F, Toupet L, Carboni B (2003) Efficient asymmetric synthesis of 2,6-disubstituted 2H-dihydropyrans via a catalytic hetero-Diels–Alder/allylboration sequence. Adv Synth Catal 345:1215–1219. doi: 10.1002/adsc.200303127 CrossRefGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.Department of ChemistryUniversity of AlbertaEdmontonCanada

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