The central goal of this research program is to develop new strategic reactions that will have broad impact in organic synthesis and on the methods used for the synthesis of new pharmaceutical agents. The particular area of emphasis will be on rhodium- stabilized carbenoids containing both donor and acceptor groups, which are capable of a range of synthetically useful transformations. The chemistry of these carbenoids is unusually rich and has resulted in several new strategic reactions for synthesis. In order to develop this chemistry fully it will be necessary to expand the range of donor groups that can be used. The traditional approach to the donor/acceptor carbenes is from diazo compounds, and this limits the type of donor groups to aryl, heteroaryl, and some alkenyl derivatives. In this proposal focuses on the use of N-sulfonyltriazoles to broaden the scope of donor/acceptor carbenes with a particular emphasis on the development of amino- and alkoxy substituted carbene derivatives. It is projected that these studies will result in the development of new synthetic methods that are distinct from those possible with the established rhodium carbenes derived from diazoacetates. These methods will be showcased by their use in the synthesis of biologically relevant natural products and important pharmaceutical drug scaffolds.

Public Health Relevance

The design of new methods for organic synthesis plays an important role in biomedical research. Many factors are involved in the selection of a compound as a potential drug candidate, but one that is crucial is whether or not a potential target is accessibl, because if not, it will never become a viable pharmaceutical agent. Consequently, truly powerful and previously unprecedented synthetic methods can open up vistas of novel structural scaffolds for exploration as potential drug targets.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Lees, Robert G
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Emory University
Schools of Arts and Sciences
United States
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Garlets, Zachary J; Davies, Huw M L (2018) Harnessing the ?-Silicon Effect for Regioselective and Stereoselective Rhodium(II)-Catalyzed C-H Functionalization by Donor/Acceptor Carbenes Derived from 1-Sulfonyl-1,2,3-triazoles. Org Lett 20:2168-2171
Fu, Liangbing; Davies, Huw M L (2017) Scope of the Reactions of Indolyl- and Pyrrolyl-Tethered N-Sulfonyl-1,2,3-triazoles: Rhodium(II)-Catalyzed Synthesis of Indole- and Pyrrole-Fused Polycyclic Compounds. Org Lett 19:1504-1507
Kubiak 2nd, Robert W; Mighion, Jeffrey D; Wilkerson-Hill, Sidney M et al. (2016) Enantioselective Intermolecular C-H Functionalization of Allylic and Benzylic sp(3) C-H Bonds Using N-Sulfonyl-1,2,3-triazoles. Org Lett 18:3118-21
Negretti, Solymar; Cohen, Carolyn M; Chang, Jane J et al. (2015) Enantioselective Dirhodium(II)-Catalyzed Cyclopropanations with Trimethylsilylethyl and Trichloroethyl Aryldiazoacetates. Tetrahedron 71:7415-7420
Parr, Brendan T; Davies, Huw M L (2015) Stereoselective synthesis of highly substituted cyclohexanes by a rhodium-carbene initiated domino sequence. Org Lett 17:794-7
Spangler, Jillian E; Lian, Yajing; Raikar, Sandeep N et al. (2014) Synthesis of complex hexacyclic compounds via a tandem Rh(II)-catalyzed double-cyclopropanation/Cope rearrangement/Diels-Alder reaction. Org Lett 16:4794-7
Parr, Brendan T; Davies, Huw M L (2014) Highly stereoselective synthesis of cyclopentanes bearing four stereocentres by a rhodium carbene-initiated domino sequence. Nat Commun 5:4455
Guzmán, Pablo E; Lian, Yajing; Davies, Huw M L (2014) Reversal of the regiochemistry in the rhodium-catalyzed [4+3] cycloaddition between vinyldiazoacetates and dienes. Angew Chem Int Ed Engl 53:13083-7
Wang, Hengbin; Guptill, David M; Alvarez, Adrian Varela et al. (2013) Rhodium-catalyzed enantioselective cyclopropanation of electron deficient alkenes. Chem Sci 4:2844-2850
Qin, Changming; Davies, Huw M L (2013) Rh2(R-TPCP)4-catalyzed enantioselective [3+2]-cycloaddition between nitrones and vinyldiazoacetates. J Am Chem Soc 135:14516-9

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