Synthetic Organic Chemistry and the Shikimate Pathway: Inhibitors and Intermediates

  • Paul A. Bartlett
Part of the Recent Advances in Phytochemistry book series (RAPT, volume 20)


Scientists have been interested in the shikimate pathway (Fig. 1) for decades, yet it shows no sign of losing this popularity.1,2 Part of the reason for this is that it offers something for everyone. Until quite recently a number of the key intermediates in the sequence had never been synthesized non-enzymatically. The unusual mechanisms of several of the enzymes involved have still not been fully elucidated. And the search for inhibitors of the various steps continues to be spurred by the success of glyphosate as an herbicide.


Shikimic Acid Shikimate Pathway Allylic Bromide Allylic Alcohol Chorismate Mutase 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    HASLAM, E. 1974. The Shikimate Pathway. Wiley-Interscience, New York.Google Scholar
  2. 2.
    GANEM, B. 1978. From glucose to aromatics: Recent development in natural products of the shikimic acid pathway. Tetrahedron 34: 3353–3383.CrossRefGoogle Scholar
  3. 3.
    For a review of early syntheses of shikimate, see Reference 2. For more recent syntheses, see References 4 and 5 and references cited therein.Google Scholar
  4. 4.
    BARTLETT, P.A., L.A. MCQUAID. 1984. Total synthesis of (±)-methyl shikimate and (±)-3-phopsphoshikimic acid. J. Amer. Chem. Soc. 106: 7854–7860.CrossRefGoogle Scholar
  5. 5.
    MIRZA, S., A. VASELLA, 1984. Synthesis of methyl shikimate and of diethyl phosphoshikimate from I)-ribose. Helv. Chim. Acta 67: 1562–1567.CrossRefGoogle Scholar
  6. 6.
    DANISHEFSKY, S., M. HIRAMA, N. FRITSCH, J. CLARDY. 1979. Synthesis of disodium prephenate and disodium epiprephenate. Stereochemistry of prephenic acid and an observation on the base-catalyzed rearrangement of prephenic acid to p-hydroxyphenyllactic acid. J. Amer. Chem. Soc. 101: 7013–7018.CrossRefGoogle Scholar
  7. 7.
    GRAMLICH, W., H. PLIENINGER. 1979. Total synthesis of disodium prephenate. II. Synthesis and stereochemical assignment of disodium prephenate. Chem. Ber. 112: 1571–1584. For a recent synthesis of prephenate, see: Ramage, R., A.M. Macleod. 1984. J. Chem. Soc. Chem. Commun. 1008–1010.CrossRefGoogle Scholar
  8. 8.
    RASTETTER, W.H., T.J. RICHARD, M.D. LEWIS. 1978. 3,5-Dinitroperoxybenzoic acid, a crystalline, storable substitute for peroxytrifluoroacetic acid. J. Org. Chem. 43: 3163–3166.CrossRefGoogle Scholar
  9. 9.
    COBLENS, K.E., V.B. MURALIDHARAN, B. GANEM. 1982. Shikimate-derived metabolites. 12. Stereocontrolled total synthesis of shikimic acid and 6ß-deuterio-shikimate. J. Org. Chem. 47: 5041–5042.CrossRefGoogle Scholar
  10. 10.
    MCKENNA, C.E., J. SCHMIDHAUSER. 1979. Functional selectivity in phosphate ester dealkylation with bromotrimethylsilane. J. Chem. Soc. Chem. Commun. 739.Google Scholar
  11. 11.
    UHLMANN, E., W. PFLEIDERER. 1980. New improvement in oligonucleotide synthesis by use of the p-nitro-phenylethyl phosphate blocking group and its deprotection by DBU or DBN. Tetrahedron Lett. 1181–1184.Google Scholar
  12. 12.
    OVERMAN, L.E., F.M. KNOLL. 1979. Palladium(II)-catalyzed rearrangement of allylic acetates. Tetrahedron Lett. 321–324.Google Scholar
  13. 13.
    GANEM, B., N. IKOTA, V.B. MURALIDHARAN, W.S. WADE, S.D. YOUNG, T.Y. YUKIMOTO. 1982. Total synthesis of (±)-chorismic acid. J. Amer. Chem. Soc. 104: 6787–6788.CrossRefGoogle Scholar
  14. 14.
    DIELS, O., P. FRITZSCHE. 1911. Zur Kenntnis der Azodicarbonsäureester. Chem. Ber. 44: 3018–3027.CrossRefGoogle Scholar
  15. 15.
    TENG, C.Y., Y. YUKIMOTO, B. GANEM. 1985. Shikimate-derived metabolites. 14. Chiral synthesis of (-)-5-enolpyruvylshikimate-3-phosphate. Tetrahedon Lett. 26: 21–24.CrossRefGoogle Scholar
  16. 16.
    DAVIS, B.D., E.S. MINGIOLI. 1953. Aromatic biosynthesis. VII. Accumulation of two derivatives of shikimic acid by bacterial mutants. J. Bacteriol. 66: 129–136.Google Scholar
  17. 17.
    KHORANA, H.G., A.R. TODD. 1953. Studies on phosphorylation. XI. The reaction between carbodiimides and acid esters of phosphoric acid. A new method for the preparation of pyrophosphates. J. Chem. Soc. 2257–2260.Google Scholar
  18. 18.
    MCGOWAN, D.A., G.A. BERCHTOLD. 1982. Total synthesis of racemic chorismic acid and (-)-5-enolpyruvyl-shikimic acid. J. Amer. Chem. Soc. 104: 7036–7041.CrossRefGoogle Scholar
  19. HOARE, J.H., P.P. POLICASTRO, G.A. BERCHTOLD. 1983. Improved synthesis of racemic chorismic acid. Claisen rearrangement of 4-epi-chorismic acid and dimethyl 4-epi-chorismate. J. Amer. Chem. Soc. 105: 6264–6267.CrossRefGoogle Scholar
  20. 19.
    SOGO, S.G., T.S. WIDLANSKI, J.H. HOARE, C.E. GRIMSHAW, G.A. BERCHTOLD, J.R. KNOWLES. 1984. Stereochemistry of the rearrangement of chorismate to prephe-nate: Chorismate mutase involves a chair transition state. J. Amer. Chem. Soc. 106: 2701–2703.CrossRefGoogle Scholar
  21. 20.
    BARTLETT, P.A., P.M. CHOUINARD. 1983. Stereocontrolled synthesis of (E)- and (Z)-3-deuteriophos-phoenolpyruvate. J. Org. Chem. 48: 3854–3855.CrossRefGoogle Scholar
  22. 21.
    ROSE, I.A. 1975. Preparation of phosphoenolpyruvate and pyruvate specifically labeled with deuterium and tritium. Methods Enzymol. 41B: 110.CrossRefGoogle Scholar
  23. 22.
    HILL, R.K., G.R. NEWKOME. 1969. Stereochemistry of chorismic acid biosynthesis. J. Amer. Chem. Soc. 91: 5893–5894.CrossRefGoogle Scholar
  24. 23.
    WOLFENDEN, R. 1976. Transition state analog inhibitors and enzyme catalysis. Annu. Rev. Biophys. Bioeng. 5: 271–306.CrossRefGoogle Scholar
  25. 24.
    STARK, G.R., P.A. BARTLETT. 1984. Design and use of potent, specific enzyme inhibitors. Pharmacol. Ther. 23: 45–78.CrossRefGoogle Scholar
  26. 25.
    ANDREWS, P.R., G.D. SMITH, I.G. YOUNG. 1973. Transition-state stabilization and enzymic catalysis. Kinetic and molecular orbital studies of the rearrangement of chorismate to prephenate. Biochemistry 12: 3492–3498.CrossRefGoogle Scholar
  27. 26.
    ANDREWS, P.R., E.N. CAIN, E. RIZZARDO, G.D. SMITH. 1977. Rearrangement of chorismate to prephenate. Use of chorismate mutase inhibitors to define the transition state structure. Biochemistry 16: 4848–4852.CrossRefGoogle Scholar
  28. 27.
    CHAO, H.S., G.A. BERCHTOLD. 1981. Inhibition of chorismate mutase activity of chorismate mutase-prephenate dehydrogenase from Aerobacter aerogenes. Biochemistry 21: 2778–2781.CrossRefGoogle Scholar
  29. 28.
    ALSTON, T.A., D.J.T. PORTER, H.J. BRIGHT. 1983. Enzyme inhibition by nitro and nitroso compounds. Accts. Chem. Research 16: 418–424.CrossRefGoogle Scholar
  30. 29.
    FLEET, G.W.J., P.J. HARDING. 1979. Convenient synthesis of bis(triphenylphosphine)-copper(I) tetrahydroborate and reduction of acid chlorides to aldehydes. Tetrahedron Lett. 975–978.Google Scholar
  31. 30.
    EVANS, D.A., L.K. TRUESDALE. 1973. Cyanosilylation of aldehydes and ketones. A convenient route to cyanohydrin derivatives. J. Chem. Soc. Chem. Commun. 55–56.Google Scholar
  32. 31.
    NICOLAOU, K.C. 1981. Organoselenium-induced cyclizations in organic synthesis. Tetrahedron 37: 4097–4109.CrossRefGoogle Scholar
  33. 32.
    AEBISCHER, B., J.H. BIERI, R. PREWO, A. VASELLA. 1982. Synthese von Ketosen durch Kettenverlängerung von 1-Desoxy-l-nitroaldosen. Nucleophile Additionen und Solvolyse von Nitroaethern. Helv. Chim. Acta 65: 2251–2272.CrossRefGoogle Scholar
  34. 33.
    BARTLETT, P.A., C.R. JOHNSON. 1985. An inhibitor of chorismate mutase resembling the transition state conformation. J. Amer. Chem. Soc. 107: 7792–7793.CrossRefGoogle Scholar

Copyright information

© Plenum Press, New York 1986

Authors and Affiliations

  • Paul A. Bartlett
    • 1
  1. 1.Department of ChemistryUniversity of CaliforniaBerkeleyUSA

Personalised recommendations