Pilot-Scale Heterocyclic and Carbocyclic Libraries for High Throughout Screening

Summary

Principal Investigator: RICHARD LAROCK
Abstract: The Larock group at Iowa State University will prepare for high throughput screening a large number of libraries of heterocycles and carbocycles expected to exhibit a wide range of biological activity. Three very general synthetic methods primarily developed in the Larock group will be employed. (1) The Pd-catalyzed annulation of alkynes, dienes, alkenes and arynes will be employed to prepare specially diverse libraries of indoles, benzofurans, benzopyrans, coumarins, isocoumarins, phthalides, pyrones, 2-quinolones, pyridines, isoquinolin-1-ones, isoindolin-1-ones, isoquinolines, carbolines, isoindolo[2,1-a]indoles, carbazoles, dibenzofurans and various other heterocycles, plus indenones, indenes, fluoren-9-ones and 9-alkylidene-9Hfluorenes. (2) The cyclization of readily available, functionally-substituted alkynes by halogen, sulfur, selenium and organopalladium electrophiles will be utilized to prepare libraries of medicinally interesting indoles, benzofurans, coumestans, chromones, benzothiophenes, benzoselenophenes, phthalides, isocoumarins, isochromenes, isoquinolines, quinolines, furans, isoxazoles and various spirotrienones. (3) Aryne annulations will be used to prepare xanthones, thioxanthones and acridones. Halogen-containing heterocycles and carbocycles will be further elaborated to more diverse libraries by well known, Pd-catalyzed processes. This methodology is very efficient, tolerates virtually all important organic functional groups, proceeds under mild reaction conditions, affords high yields of very pure compounds, and uses readily available starting materials, reagents and catalysts. Libraries consisting of (20-100 novel, small, densely functionalized, specially diverse compounds will be prepared by this very versatile solution and solid phase chemistry already worked out in the Larock group. Racemic mixtures will be separated by the Armstrong group in Texas and molecular modeling will be carried out by the Lushington group at Kansas University. The resulting libraries will be purified to generally >95% purity using standard laboratory techniques and, if necessary, the high throughput purification techniques available to the PI through the Kansas University Center of Excellence in Chemical Methodologies and Library Development. This methodology will be widely published and the resulting libraries donated to the NIH Molecular Libraries Small-Molecule Repository and the Molecular Libraries Screening Center Network.
Funding Period: 2006-09-15 - 2010-08-31
more information: NIH RePORT

Top Publications

  1. pmc Solution-phase synthesis of a diverse library of benzisoxazoles utilizing the [3 + 2] cycloaddition of in situ-generated nitrile oxides and arynes
    Anton V Dubrovskiy
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    ACS Comb Sci 15:193-201. 2013
  2. pmc Regio- and stereoselective synthesis of cyclic imidates via electrophilic cyclization of 2-(1-alkynyl)benzamides. A correction
    Saurabh Mehta
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Org Chem 77:10938-44. 2012
  3. pmc Synthesis of benzisoxazoles by the [3 + 2] cycloaddition of in situ generated nitrile oxides and arynes
    Anton V Dubrovskiy
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    Org Lett 12:1180-3. 2010
  4. pmc Synthesis of acridines by the [4 + 2] annulation of arynes and 2-aminoaryl ketones
    Donald C Rogness
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Org Chem 75:2289-95. 2010
  5. pmc Synthesis of 2H-indazoles by the [3 + 2] cycloaddition of arynes and sydnones
    Chunrui Wu
    Key Laboratory of Natural Medicine and Immuno Engineering of Henan Province, Henan University, Jinming Campus, Kaifeng, Henan 475004, China PR
    Org Lett 12:2234-7. 2010
  6. pmc Intermolecular C-O addition of carboxylic acids to arynes
    Anton V Dubrovskiy
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    Org Lett 12:3117-9. 2010
  7. pmc Synthesis of dihydrobenzisoxazoles by the [3 + 2] cycloaddition of arynes and oxaziridines
    Arif Kivrak
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
    J Org Chem 75:7381-7. 2010
  8. pmc Solution-phase parallel synthesis of a diverse library of 1,2-dihydroisoquinolines
    Nataliya A Markina
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
    ACS Comb Sci 13:265-71. 2011
  9. pmc Highly substituted lactone/ester-containing furan library by the palladium-catalyzed carbonylation of hydroxyl-substituted 3-iodofurans
    Chul Hee Cho
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
    ACS Comb Sci 13:272-9. 2011
  10. pmc Parallel synthesis of a desketoraloxifene analogue library via iodocyclization/palladium-catalyzed coupling
    Chul Hee Cho
    Department of Chemistry, Iowa State University, Ames, 50011, United States
    ACS Comb Sci 13:501-10. 2011

Detail Information

Publications33

  1. pmc Solution-phase synthesis of a diverse library of benzisoxazoles utilizing the [3 + 2] cycloaddition of in situ-generated nitrile oxides and arynes
    Anton V Dubrovskiy
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    ACS Comb Sci 15:193-201. 2013
    ..These building blocks have been used as the key components of a diverse set of 3,5,6-trisubstituted benzisoxazoles...
  2. pmc Regio- and stereoselective synthesis of cyclic imidates via electrophilic cyclization of 2-(1-alkynyl)benzamides. A correction
    Saurabh Mehta
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Org Chem 77:10938-44. 2012
    ..X-ray crystallography and spectroscopic techniques have been used to characterize the products. A correction is hereby provided in order to rectify the previous misassignment of structure...
  3. pmc Synthesis of benzisoxazoles by the [3 + 2] cycloaddition of in situ generated nitrile oxides and arynes
    Anton V Dubrovskiy
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    Org Lett 12:1180-3. 2010
    ..The reaction scope is quite general, affording a novel, direct route to functionalized benzisoxazoles under mild reaction conditions...
  4. pmc Synthesis of acridines by the [4 + 2] annulation of arynes and 2-aminoaryl ketones
    Donald C Rogness
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Org Chem 75:2289-95. 2010
    ..The reaction of 2-aminoaryl ketones and arynes generated by the treatment of various o-(trimethylsilyl)aryl triflates with CsF results in [4 + 2] annulation to afford substituted acridines in good yields...
  5. pmc Synthesis of 2H-indazoles by the [3 + 2] cycloaddition of arynes and sydnones
    Chunrui Wu
    Key Laboratory of Natural Medicine and Immuno Engineering of Henan Province, Henan University, Jinming Campus, Kaifeng, Henan 475004, China PR
    Org Lett 12:2234-7. 2010
    ..A rapid and efficient synthesis of 2H-indazoles has been developed, which involves the [3 + 2] dipolar cycloaddition of arynes and sydnones. The process proceeds under mild reaction conditions in good to excellent yields...
  6. pmc Intermolecular C-O addition of carboxylic acids to arynes
    Anton V Dubrovskiy
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    Org Lett 12:3117-9. 2010
    ....
  7. pmc Synthesis of dihydrobenzisoxazoles by the [3 + 2] cycloaddition of arynes and oxaziridines
    Arif Kivrak
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
    J Org Chem 75:7381-7. 2010
    ..The resulting halogen-substituted dihydrobenzisoxazoles are readily elaborated to more complex products using palladium-catalyzed crossing-coupling processes...
  8. pmc Solution-phase parallel synthesis of a diverse library of 1,2-dihydroisoquinolines
    Nataliya A Markina
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
    ACS Comb Sci 13:265-71. 2011
    ....
  9. pmc Highly substituted lactone/ester-containing furan library by the palladium-catalyzed carbonylation of hydroxyl-substituted 3-iodofurans
    Chul Hee Cho
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
    ACS Comb Sci 13:272-9. 2011
    ....
  10. pmc Parallel synthesis of a desketoraloxifene analogue library via iodocyclization/palladium-catalyzed coupling
    Chul Hee Cho
    Department of Chemistry, Iowa State University, Ames, 50011, United States
    ACS Comb Sci 13:501-10. 2011
    ..Various hydroxyl-substituted desketoraloxifene analogues 7 were subsequently generated by demethylation with BBr(3)...
  11. pmc Synthesis of 2H-indazoles by the [3 + 2] dipolar cycloaddition of sydnones with arynes
    Yuesi Fang
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, United States
    J Org Chem 76:8840-51. 2011
    ....
  12. pmc Synthesis of benzisoxazolines by the coupling of arynes with nitrones
    Chun Lu
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Org Chem 77:2279-84. 2012
    ..A variety of substituted benzisoxazolines have been synthesized by the [3 + 2] cycloaddition of nitrones and arynes. The reaction scope is broad, the reaction conditions are mild, and the process tolerates a variety of functional groups...
  13. pmc Benzyne click chemistry: synthesis of benzotriazoles from benzynes and azides
    Feng Shi
    Department of Chemistry, Iowa State University, Ames, IA 50010, USA
    Org Lett 10:2409-12. 2008
    ..The reaction scope is quite general, affording a rapid and easy entry to substituted, functionalized benzotriazoles under mild conditions...
  14. pmc Palladium-catalyzed one-step synthesis of isoindole-1,3-diones by carbonylative cyclization of o-halobenzoates and primary amines
    Shilpa A Worlikar
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Org Chem 73:7175-80. 2008
    ..This methodology provides a good one-step approach to this important class of heterocycles and tolerates a variety of functional groups, including methoxy, alcohol, ketone, and nitro groups...
  15. pmc Parallel synthesis of a multi-substituted benzo[b]furan library
    Chul Hee Cho
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Comb Chem 10:941-7. 2008
    ..The 3-iodobenzofurans are readily prepared in good to excellent yields by the palladium/copper-catalyzed cross-coupling of various o-iodoanisoles and terminal alkynes, followed by electrophilic cyclization with ICl...
  16. pmc A novel synthetic route to 3-sulfenyl- and 3-selenylindoles by n-Bu4NI-induced electrophilic cyclization
    Yu Chen
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    Org Lett 11:173-6. 2009
    ....
  17. pmc Competition studies in alkyne electrophilic cyclization reactions
    Saurabh Mehta
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Org Chem 74:1141-7. 2009
    ....
  18. pmc Solution-phase parallel synthesis of a multi-substituted benzo[b]thiophene library
    Chul Hee Cho
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Comb Chem 11:900-6. 2009
    ..The heteroaromatic carbon-iodine bonds allow further diversification by palladium-catalyzed Suzuki-Miyaura, Sonogashira, Heck, and carboalkoxylation chemistry to give multi-substituted benzo[b]thiophene derivatives...
  19. pmc Synthesis of 3-sulfenyl- and 3-selenylindoles by the Pd/Cu-catalyzed coupling of N,N-dialkyl-2-iodoanilines and terminal alkynes, followed by n-Bu(4)NI-induced electrophilic cyclization
    Yu Chen
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Org Chem 74:6802-11. 2009
    ..In addition, 3-sulfonyl- and 3-sulfinylindoles have also been successfully prepared by facile oxidation of the corresponding 3-sulfenylindoles...
  20. pmc Palladium- and copper-catalyzed solution phase synthesis of a diverse library of isoquinolines
    Sudipta Roy
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Comb Chem 11:1061-5. 2009
    ....
  21. pmc Highly substituted indole library synthesis by palladium-catalyzed coupling reactions in solution and on a solid support
    Shilpa A Worlikar
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Comb Chem 11:875-9. 2009
    ..A diverse 42-member library of highly substituted indoles has been synthesized...
  22. pmc Solution-phase synthesis of a diverse isocoumarin library
    Sujata Roy
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Comb Chem 11:1128-35. 2009
    ..The resulting isocoumarins were further diversified by derivatization of the hydroxyl or bromine groups. A small set of isoquinolinones were also prepared from the corresponding isocoumarins...
  23. pmc A simple and mild synthesis of 1H-isochromenes and (Z)-1-alkylidene-1,3-dihydroisobenzofurans by the iodocyclization of 2-(1-alkynyl)benzylic alcohols
    Raffaella Mancuso
    Dipartimento di Chimica, Universita della Calabria, 87036 Arcavacata di Rende CS, Italy
    J Org Chem 75:897-901. 2010
    ....
  24. pmc Diverse methyl sulfone-containing benzo[b]thiophene library via iodocyclization and palladium-catalyzed coupling
    Chul Hee Cho
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Comb Chem 12:278-85. 2010
    ..The key intermediates for library generation, methyl sulfone-containing 3-iodobenzo[b]thiophenes, are readily prepared by iodocyclization and oxidation methodologies from readily available alkynes...
  25. pmc Iodine/palladium approaches to the synthesis of polyheterocyclic compounds
    Saurabh Mehta
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Org Chem 75:1652-8. 2010
    ..In addition, variations of this strategy afford a variety of linked and fused PHCs...
  26. pmc The synthesis of highly substituted isoxazoles by electrophilic cyclization: an efficient synthesis of valdecoxib
    Jesse P Waldo
    Department of Chemistry, Iowa State University, Ames, Iowa 50011, USA
    J Org Chem 72:9643-7. 2007
    ..The resulting 4-iodoisoxazoles undergo various palladium-catalyzed reactions to yield 3,4,5-trisubstituted isoxazoles, including valdecoxib...