Effective new strategies for organic synthesis are of great value to biomedical research. Even though it is often argued that any organic compound can be made, in reality the practical accessibility of a potential pharmaceutical target is a major consideration in drug design. Thus, new methodology has the potential of opening up new vistas of chemical structures as viable targets for exploration as pharmaceutical agents. Transition metal-catalyzed reactions have broadly impacted the methods used for the synthesis of pharmaceutical targets. C-H Activation is of considerable current interest because it has the potential of becoming a transforming strategic reaction. This proposal is centered around a recently discovered highly stereoselective rhodium-catalyzed C-H activation process, the combined C-H activation/Cope rearrangement. The hallmark of this C-C bond forming reaction is its remarkable stereoselectivity, with most reactions proceeding in >98% de and >96% ee. The exploration of the full scope of this chemistry will be the focus of this proposal. This C-H functionalization method offers exciting opportunities in organic synthesis but to achieve this, the methodology will need to be extended to a broader range of substrates. Once the foundation chemistry has been established the methodology will be applied to the synthesis of natural products of biomedical interest, the antitubercular agent elisabethin C and the potential anticancer agents sinulobatins B-D and harringtonolide.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
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Synthetic and Biological Chemistry A Study Section (SBCA)
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Hagan, Ann A
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Emory University
Schools of Arts and Sciences
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Davies, Huw M L; Lian, Yajing (2012) The combined C-H functionalization/Cope rearrangement: discovery and applications in organic synthesis. Acc Chem Res 45:923-35
Lian, Yajing; Davies, Huw M L (2011) Combined C-H functionalization/Cope rearrangement with vinyl ethers as a surrogate for the vinylogous Mukaiyama aldol reaction. J Am Chem Soc 133:11940-3
Lian, Yajing; Hardcastle, Kenneth I; Davies, Huw M L (2011) Computationally guided stereocontrol of the combined C-H functionalization/Cope rearrangement. Angew Chem Int Ed Engl 50:9370-3
Lian, Yajing; Davies, Huw M L (2010) Rhodium carbenoid approach for introduction of 4-substituted (Z)-pent-2-enoates into sterically encumbered pyrroles and indoles. Org Lett 12:924-7
Lian, Yajing; Miller, Laura C; Born, Stephen et al. (2010) Catalyst-controlled formal [4 + 3] cycloaddition applied to the total synthesis of (+)-barekoxide and (-)-barekol. J Am Chem Soc 132:12422-5
Nadeau, Etienne; Ventura, Dominic L; Brekan, Jonathan A et al. (2010) Controlling factors for C-H functionalization versus cyclopropanation of dihydronaphthalenes. J Org Chem 75:1927-39
Schwartz, Brett D; Denton, Justin R; Bernhardt, Paul V et al. (2009) Towards the Total Synthesis of 3-Hydroxyvibsanin E. Synthesis (Stuttg) 2009:2840-2846
Schwartz, Brett D; Denton, Justin R; Lian, Yajing et al. (2009) Asymmetric [4 + 3] cycloadditions between vinylcarbenoids and dienes: application to the total synthesis of the natural product (-)-5-epi-vibsanin E. J Am Chem Soc 131:8329-32
Schwartz, Brett D; Denton, Justin R; Davies, Huw M L et al. (2009) Total Synthesis of (±)-Vibsanin E. Aust J Chem 62:980-982
Davies, Huw M L; Denton, Justin R (2009) Application of donor/acceptor-carbenoids to the synthesis of natural products. Chem Soc Rev 38:3061-71

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