The design of new synthetic methods has a broad impact on biomedical research. Many factors are involved in the selection of a compound as a potential drug candidate, but one that is critical, but not always articulated, is whether or not a potential target is accessible. If a compound cannot be made in a practical way either through synthesis or from biological sources, then 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. The central goal of this research program is to develop new strategic reactions that will have broad impact in organic synthesis. Rhodium-stabilized carbenoids containing both donor and acceptor groups are capable of a range of synthetically useful transformations. This proposal focuses on a new direction of study of donor/acceptor carbenoids, namely enantioselective transformations of rhodium-bound zwitterionic intermediates. The full scope of these new synthetic methods will be explored and then applied to the synthesis of biologically relevant natural products and important pharmaceutical drug scaffolds.

Public Health Relevance

Broader Significance: This research program is directed towards the development of new synthetic methods with broad application for streamlining schemes for the stereoselective synthesis of natural products and pharmaceutical targets. The approach is likely to generate synthetic methods that can have a major impact on changing the type of strategies that are used in synthesis compared to studies aimed at improving established reactions. The research group is broadly collaborative and the training environment is ideal for graduate students and post docs who are interested in careers in the pharmaceutical industry or academia.

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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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
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
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
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
Qin, Changming; Davies, Huw M L (2013) Silver-catalyzed vinylogous fluorination of vinyl diazoacetates. Org Lett 15:6152-4
Lian, Yajing; Davies, Huw M L (2012) Rh2(S-biTISP)2-catalyzed asymmetric functionalization of indoles and pyrroles with vinylcarbenoids. Org Lett 14:1934-7
Li, Zhanjie; Boyarskikh, Vyacheslav; Hansen, Jorn H et al. (2012) Scope and mechanistic analysis of the enantioselective synthesis of allenes by rhodium-catalyzed tandem ylide formation/[2,3]-sigmatropic rearrangement between donor/acceptor carbenoids and propargylic alcohols. J Am Chem Soc 134:15497-504
Li, Zhanjie; Parr, Brendan T; Davies, Huw M L (2012) Highly stereoselective C-C bond formation by rhodium-catalyzed tandem ylide formation/[2,3]-sigmatropic rearrangement between donor/acceptor carbenoids and chiral allylic alcohols. J Am Chem Soc 134:10942-6

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