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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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
Selvaraj, Ramajeyam; Fox, Joseph M (2013) trans-Cyclooctene--a stable, voracious dienophile for bioorthogonal labeling. Curr Opin Chem Biol 17:753-60
Hassink, Matthew; Liu, Xiaozhong; Fox, Joseph M (2011) Copper-catalyzed synthesis of 2,4-disubstituted allenoates from ?-diazoesters. Org Lett 13:2388-91
Xie, Xiaocong; Yang, Zhe; Fox, Joseph M (2010) Stereospecific synthesis of alkylidenecyclopropanes via sequential cyclopropene carbomagnesation/1,3-carbon shift. J Org Chem 75:3847-50
DeAngelis, Andrew; Taylor, Michael T; Fox, Joseph M (2009) Unusually reactive and selective carbonyl ylides for three-component cycloaddition reactions. J Am Chem Soc 131:1101-5
Tarwade, Vinod; Liu, Xiaozhong; Yan, Ni et al. (2009) Directed carbozincation reactions of cyclopropene derivatives. J Am Chem Soc 131:5382-3
DeAngelis, Andrew; Dmitrenko, Olga; Yap, Glenn P A et al. (2009) Chiral crown conformation of Rh(2)(S-PTTL)(4): enantioselective cyclopropanation with alpha-alkyl-alpha-diazoesters. J Am Chem Soc 131:7230-1
Panne, Patricia; DeAngelis, Andrew; Fox, Joseph M (2008) Rh-catalyzed intermolecular cyclopropanation with alpha-alkyl-alpha-diazoesters: catalyst-dependent chemo- and diastereoselectivity. Org Lett 10:2987-9
DeAngelis, Andrew; Panne, Patricia; Yap, Glenn P A et al. (2008) Rh-catalyzed formation of dioxolanes from alpha-alkyl diazoesters: diastereoselective cycloadditions of carbonyl ylides with selectivity over beta-hydride elimination. J Org Chem 73:1435-9
Blackman, Melissa L; Royzen, Maksim; Fox, Joseph M (2008) Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity. J Am Chem Soc 130:13518-9

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