The development of new reactions for organic synthesis is at the core of health related fields such as drug discovery, process chemistry, natural products synthesis and biologically inspired molecular design. While the state of the art is such that remarkably complex molecules can be synthesized given ample time and skilled personnel, there persists a need for tandem reactions that couple simple partners to selectively produce complex products. The goal of this research program is to harness the unusual reactivity of high strain molecules to quickly generate molecules that are rich in stereochemical complexity and structural diversity. These 'strain assisted' reactions include directed nucleophilic addition/capture sequences and cycloaddition reactions of cyclopropenes and bicyclobutanes. In order for the methodology to have broad utility, it is explicitly necessary to develop asymmetric and enantioselective syntheses and reactions. While the exploratory stages of any program in synthetic methodology rely on screening, the refinement stage of each method will rely heavily on mechanistic analysis. The applications of this research are threefold: 1) the development of new synthetic methods that will have broad utility because they address fundamental, unsolved problems; 2) the development of unnatural amino acids with applications in environmentally responsive biomaterials; 3) the use of strained molecules in the syntheses of alkaloids with all-carbon quaternary centers and in the synthesis of pycnocomolide - a 12-deoxy-16-hydroxyphorbol natural product that is a potent activator of PKC and a target as a cancer drug. The syntheses of computationally designed pycnocomolide analogs are also proposed.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM068640-05
Application #
7450856
Study Section
Medicinal Chemistry Study Section (MCHA)
Program Officer
Schwab, John M
Project Start
2004-07-05
Project End
2009-09-29
Budget Start
2008-07-01
Budget End
2009-09-29
Support Year
5
Fiscal Year
2008
Total Cost
$250,558
Indirect Cost
Name
University of Delaware
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
059007500
City
Newark
State
DE
Country
United States
Zip Code
19716
Taylor, Michael T; Fox, Joseph M (2015) Biosynthesis of the C15-acetogenin laurepoxide may involve bromine-induced skeletal rearrangement of a ?4-oxocene precursor. Tetrahedron Lett 56:3560-3563
Darko, Ampofo; Wallace, Stephen; Dmitrenko, Olga et al. (2014) Conformationally Strained trans-Cyclooctene with Improved Stability and Excellent Reactivity in Tetrazine Ligation. Chem Sci 5:3770-3776
Selvaraj, Ramajeyam; Fox, Joseph M (2013) trans-Cyclooctene--a stable, voracious dienophile for bioorthogonal labeling. Curr Opin Chem Biol 17:753-60
Xie, Xiaocong; Li, Yi; Fox, Joseph M (2013) Selective syntheses of ?(?,?) and ?(?,?) butenolides from allylic cyclopropenecarboxylates via tandem ring expansion/[3,3]-sigmatropic rearrangements. Org Lett 15:1500-3
Panish, Robert; Chintala, Srinivasa R; Boruta, David T et al. (2013) Enantioselective synthesis of cyclobutanes via sequential Rh-catalyzed bicyclobutanation/Cu-catalyzed homoconjugate addition. J Am Chem Soc 135:9283-6
Fisher, Laural A; Smith, Natalee J; Fox, Joseph M (2013) Chiral cyclopropenyl ketones: reactive and selective Diels-Alder dienophiles. J Org Chem 78:3342-8
Hassink, Matthew D; Fox, Joseph M (2012) Functionalized Cyclopropenes and Methylenecyclopropenes from Dianions of 3-Hydroxymethylcyclopropenes. Synthesis (Stuttg) 44:2843-2850
Tarwade, Vinod; Selvaraj, Ramajeyam; Fox, Joseph M (2012) Facially selective Cu-catalyzed carbozincation of cyclopropenes using arylzinc reagents formed by sequential I/Mg/Zn exchange. J Org Chem 77:9900-4
Boruta, David T; Dmitrenko, Olga; Yap, Glenn P A et al. (2012) Rh(2)(S-PTTL)(3)TPA-A Mixed Ligand Dirhodium(II) Catalyst for Enantioselective Reactions of ?-Alkyl-?-Diazoesters. Chem Sci 3:1589-1593
DeAngelis, Andrew; Dmitrenko, Olga; Fox, Joseph M (2012) Rh-catalyzed intermolecular reactions of cyclic ýý-diazocarbonyl compounds with selectivity over tertiary C-H bond migration. J Am Chem Soc 134:11035-43

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