The goal of the proposed research is to develop selective methods for organic synthesis with strained molecules and rhodium carbenoids.
The specific aims of the proposal are:
Aim 1 is to develop stereoselective transformations of strained three-membered ring compounds. Modes of reactivity that will be explored will include carbometallation reactions, cycloaddition reactions, and transition metal catalyzed rearrangements. Of particular interest is the unusual ability of strained molecules to control the stereochemical outcome of such reactions.
Aim 2 is to develop ligands that expand the types of diazo compounds that can be utlized in Rh-carbenoid chemistry. Because Rh-carbeniods are critical to the synthesis of cyclopropenes and cyclopropanes, addressing the limitations of the chemistry of Rh-carbenes is a fundamental component to advancing the utility strained molecules in synthesis. Of particular interest is the development of ligands that facilitate reactions of ?-alkyldiazo compounds, which are susceptible to ?-hydride elimination. With insight from computational studies, catalysts will be designed that can navigate away from undesired reaction pathways and provide desired products with maximum selectivity.
Aim 3 is to develop general, stereoselective methods for the synthesis of medium ring trans-cycloalkenes. Also developed will be new stereospecific reaction chemistry that transfers the planar chirality of the alkene to newly created stereocenters in products. Reactions to be studied include transannular cyclization reactions, and intramolecular cycloaddition reactions. Applications will include the development of a unified approach to the synthesis of a family of naturally occuring pyrrolizidine alkaloids.

Public Health Relevance

Organic synthesis plays a central role in the advancement of human health, and the increasing complexity of small molecule targets has required increasingly sophisticated methodology for organic synthesis. Synthetic methodology has been cited by former NIH director Elias Zerhouni as being """"""""the number one stumbling block"""""""" for the biological sciences. The objective of this proposal is to develop methodologies that will overcome existing limitations in organic synthesis, and thereby accelerate the process of drug discovery.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
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University of Delaware
Schools of Arts and Sciences
United States
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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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