The architectural and functional group complexity of natural products often confers to them unique modes of biological activity and significant therapeutic value. Despite transformative advances in catalytic methods and strategies for constructing highly complex molecules, the practice of total synthesis still remains a laborious and time intensive pursuit. Consequently, such compounds are rarely sought or evaluated as potential therapeutics. Historically, the development of new synthetic methods has had a profound impact on the efficiency of complex molecule synthesis. New reaction classes that lead to fundamentally novel reactivity stand to promote the largest advances in this regard. As a guide, we can look towards Nature?s synthetic strategies that systematically employ C-H oxidation and complexity generating C-C bond forming reactions. This proposal seeks to establish allylic C-H bonds as a new functional group for widespread use in complex molecule synthesis. To achieve this goal we will exploit a highly versatile ?-allyPd intermediate, accessed through allylic C-H cleavage, and develop general strategies by which it can participate in diverse reaction types with consistently high selectivities. Collectively, we expect these Pd(II)-catalyzed allylic C-H functionalization reactions to become fundamental tools for streamlining the synthesis of important structural motifs found in natural products, bioactive compounds, and medicinal agents. Moreover, the general principles that emerge from this approach will be broadly applicable to the field of C-H activation.)

Public Health Relevance

The objective of this research is to discover and develop catalytic reactions that establish the allylic C- H bond as a new functional group for widespread use in the synthesis of structural motifs found in natural products, bioactive compounds, and medicinal agents.)

National Institute of Health (NIH)
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Special Emphasis Panel (ZRG1)
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Lees, Robert G
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University of Illinois Urbana-Champaign
Schools of Arts and Sciences
United States
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Howell, Jennifer M; Liu, Wei; Young, Andrew J et al. (2014) General allylic C-H alkylation with tertiary nucleophiles. J Am Chem Soc 136:5750-4
Bigi, Marinus A; White, M Christina (2013) Terminal olefins to linear ýý,ýý-unsaturated ketones: Pd(II)/hypervalent iodine co-catalyzed Wacker oxidation-dehydrogenation. J Am Chem Soc 135:7831-4
Delcamp, Jared H; Gormisky, Paul E; White, M Christina (2013) Oxidative Heck vinylation for the synthesis of complex dienes and polyenes. J Am Chem Soc 135:8460-3
Jiang, Chao; Covell, Dustin J; Stepan, Antonia F et al. (2012) Sequential allylic C-H amination/vinylic C-H arylation: a strategy for unnatural amino acid synthesis from *-olefins. Org Lett 14:1386-9
Stang, Erik M; White, M Christina (2011) On the macrocyclization of the erythromycin core: preorganization is not required. Angew Chem Int Ed Engl 50:2094-7
Stang, Erik M; White, M Christina (2011) Molecular complexity via C-H activation: a dehydrogenative Diels-Alder reaction. J Am Chem Soc 133:14892-5
Vermeulen, Nicolaas A; Delcamp, Jared H; White, M Christina (2010) Synthesis of complex allylic esters via C-H oxidation vs C-C bond formation. J Am Chem Soc 132:11323-8
Reed, Sean A; Mazzotti, Anthony R; White, M Christina (2009) A catalytic, Bronsted base strategy for intermolecular allylic C-H amination. J Am Chem Soc 131:11701-6
Rice, Grant T; White, M Christina (2009) Allylic C-H amination for the preparation of syn-1,3-amino alcohol motifs. J Am Chem Soc 131:11707-11
Reed, Sean A; White, M Christina (2008) Catalytic intermolecular linear allylic C-H amination via heterobimetallic catalysis. J Am Chem Soc 130:3316-8

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