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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM080337-05
Application #
7821337
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Hagan, Ann A
Project Start
2007-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2012-04-30
Support Year
5
Fiscal Year
2010
Total Cost
$291,555
Indirect Cost
Name
Emory University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
066469933
City
Atlanta
State
GA
Country
United States
Zip Code
30322
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
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
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
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
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

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