The vast majority of medicinally important drugs contain a heterocyclic or carbocyclic ring. The electrophilic cyclization of functionally-substituted alkynes has been little studied, although it would appear to be a very promising route to an extraordinary range of medicinally interesting, functionally-substituted heterocycles and carbocycles. The Larock group has carried out preliminary work suggesting that the electrophilic cyclization of functionally-substituted alkynes readily affords very high yields of a wide variety of halogen-, sulfur- and selenium-substituted benzothiophenes, isoquinolines, benzofurans, and isocoumarins under exceptionally mild reaction conditions. This work will be continued and extended to a wide variety of additional cyclizations including coumestans, furocoumarins, furoflavones, indoles, benzoselenophenes, benzolactams, dihydropyrimidines, 2-furanones, 2-pyrrolinones, benzopyrans, chromones and heteroatom analogues, furans, thiophenes, pyrroles, oxazoles, isoxazoles, pyrazoles, pyridines, quinolines, coumarins, indenes, indenones, naphthols, and phenols. Sequential iodocyclization, Sonogashira coupling and further electrophilic cyclization appears promising as an efficient route to fused polycyclic heterocycles. Analogous cyclizations of functionally-substituted allenes also appear quite promising. The range of electrophiles, which might be employed in these cyclizations, including organopalladium compounds, will also be explored. Subsequent elaboration of the resulting halogen-containing hetero- and carbocycles via palladium-catalyzed processes provides highly, efficient methodology for the construction of pharmaceutically interesting compounds, whose synthesis will be pursued.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM070620-02
Application #
6945402
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2004-09-01
Project End
2008-08-31
Budget Start
2005-09-01
Budget End
2006-08-31
Support Year
2
Fiscal Year
2005
Total Cost
$194,202
Indirect Cost
Name
Iowa State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
005309844
City
Ames
State
IA
Country
United States
Zip Code
50011
Mehta, Saurabh; Waldo, Jesse P; Neuenswander, Benjamin et al. (2013) Solution-phase parallel synthesis of a multisubstituted cyclic imidate library. ACS Comb Sci 15:247-54
Dubrovskiy, Anton V; Jain, Prashi; Shi, Feng et al. (2013) Solution-phase synthesis of a diverse library of benzisoxazoles utilizing the [3 + 2] cycloaddition of in situ-generated nitrile oxides and arynes. ACS Comb Sci 15:193-201
Cho, Chul-Hee; Shi, Feng; Jung, Dai-Il et al. (2012) Solution-phase synthesis of a highly substituted furan library. ACS Comb Sci 14:403-14
Lu, Chun; Markina, Nataliya A; Larock, Richard C (2012) Synthesis of N-acylcarbazoles through palladium-catalyzed aryne annulation of 2-haloacetanilides. J Org Chem 77:11153-60
Lu, Chun; Dubrovskiy, Anton V; Larock, Richard C (2012) Synthesis of benzisoxazolines by the coupling of arynes with nitrones. J Org Chem 77:2279-84
Mehta, Saurabh; Yao, Tuanli; Larock, Richard C (2012) Regio- and stereoselective synthesis of cyclic imidates via electrophilic cyclization of 2-(1-alkynyl)benzamides. A correction. J Org Chem 77:10938-44
Fang, Yuesi; Wu, Chunrui; Larock, Richard C et al. (2011) Synthesis of 2H-indazoles by the [3 + 2] dipolar cycloaddition of sydnones with arynes. J Org Chem 76:8840-51
Cho, Chul-Hee; Jung, Dai-Il; Neuenswander, Benjamin et al. (2011) Parallel synthesis of a desketoraloxifene analogue library via iodocyclization/palladium-catalyzed coupling. ACS Comb Sci 13:501-10
Markina, Nataliya A; Mancuso, Raffaella; Neuenswander, Benjamin et al. (2011) Solution-phase parallel synthesis of a diverse library of 1,2-dihydroisoquinolines. ACS Comb Sci 13:265-71
Cho, Chul-Hee; Larock, Richard C (2011) Highly substituted lactone/ester-containing furan library by the palladium-catalyzed carbonylation of hydroxyl-substituted 3-iodofurans. ACS Comb Sci 13:272-9

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