Many syntheses of drugs and biologically active natural products utilize catalytic cross-coupling reactions as a key step. Cross-coupling reactions often require toxic, expensive, or highly basic reagents to effect formation of organometallic reaction intermediates via transmetalation. The theme of this proposal is the replacement of these undesirable reagents with ubiquitous carboxylic acids. Decarboxylative metalation of carboxylic acid derivatives potentially allows formation of useful organometallic intermediates under mild conditions and produces only non-toxic CO2 as a byproduct. Decarboxylative metalation is being applied to more efficient syntheses of medium- and large-ring ketones, homoallylic amines, functionally differentiated hexadienes, and various biologically important heterocycles including pyridines, azetidines, and piperidines. We have strong preliminary data that demonstrates that enolate, acetylide, amide, allyl, a-amino, and stabilized alkyl nucleophiles can be generated by catalytic decarboxylation of the corresponding carboxylates. We propose to develop synthetic methods based on decarboxylative metalation with a focus on activity, scope, and enantioselectivity. The classes of molecules being targeted for synthetic development have been chosen based on their synthetic flexibility or occurrence as common motifs in natural products and/or Pharmaceuticals. Thus, adaptation of the new strategies developed as a result of this proposal will ultimately contribute to the generation of novel therapeutic reagents to treat human disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM079644-05
Application #
8103270
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2007-07-01
Project End
2012-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$253,861
Indirect Cost
Name
University of Kansas Lawrence
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
076248616
City
Lawrence
State
KS
Country
United States
Zip Code
66045
Grenning, Alexander J; Van Allen, Christie K; Maji, Tapan et al. (2013) Development of asymmetric deacylative allylation. J Org Chem 78:7281-7
Schmitt, Meghan; Grenning, Alexander J; Tunge, Jon A (2012) Intercepted Decarboxylative Allylations of Nitroalkanoates. Tetrahedron Lett 53:4494-4497
Recio 3rd, Antonio; Heinzman, Jeffrey D; Tunge, Jon A (2012) Decarboxylative benzylation and arylation of nitriles. Chem Commun (Camb) 48:142-4
Cattopadhyay, Kalicharan; Recio 3rd, Antonio; Tunge, Jon A (2012) Palladium-catalyzed, pyrrolidine-mediated arylmethylation of ketones and aldehydes with coumarinyl(methyl) acetates. Org Biomol Chem 10:6826-9
Jana, Ranjan; Partridge, James J; Tunge, Jon A (2011) Migratory decarboxylative coupling of coumarins: synthetic and mechanistic aspects. Angew Chem Int Ed Engl 50:5157-61
Grenning, Alexander J; Tunge, Jon A (2011) Deacylative allylation of nitroalkanes: unsymmetric bisallylation by a three-component coupling. Angew Chem Int Ed Engl 50:1688-91
Weaver, Jimmie D; Recio 3rd, Antonio; Grenning, Alexander J et al. (2011) Transition metal-catalyzed decarboxylative allylation and benzylation reactions. Chem Rev 111:1846-913
Jana, Ranjan; Tunge, Jon A (2011) A homogeneous, recyclable polymer support for Rh(I)-catalyzed C-C bond formation. J Org Chem 76:8376-85
Grenning, Alexander J; Tunge, Jon A (2011) Deacylative allylation: allylic alkylation via retro-Claisen activation. J Am Chem Soc 133:14785-94
Weaver, Jimmie D; Ka, Being J; Morris, David K et al. (2010) Stereospecific decarboxylative allylation of sulfones. J Am Chem Soc 132:12179-81

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