Alkenes are exceptionally attractive functional groups for synthesis. Newly discovered and significantly improved alkene functionalization reactions can have a direct impact on the efficiency of targeted synthesis. Therefore, the development of selective, practical alkene functionalization reactions is a continuing challenge facing chemists in both academia and industry. In this proposal, we target a new collection of alkene functionalization reactions that exploit Pd(II)-catalysis and its ability to promote both alkene nucleophilic addition reactions and cross-coupling processes to form multiple new C-C, C-H, or C-X bonds across the alkene framework. This reaction method development is coupled to careful mechanistic studies, which are designed to elucidate the fundamental features governing reaction outcomes, as well as to stimulate new reaction development and catalyst design. The current proposal is directed toward the development of new Pd-catalyzed olefin functionalization reactions using both oxidative and classical methods to generate Pd-alkyl intermediates. The reaction development described herein is focused on two significant goals: A) enabling new mechanistically-derived tactics for molecule synthesis by using innovative approaches to functionalize Pd-alkyl intermediates originally derived from an alkene (Aims 1 &2), and B) exploiting our recently developed Heck reactions of electronically non-biased olefins to access important chiral building blocks, while also probing the factors that govern selective Pd-hydride insertion and ?-hydride elimination (Aim 3).

Public Health Relevance

The goal of the proposed research is to develop new palladium-catalyzed alkene functionalization reactions to enable the facile synthesis of biologically-relevant targets and novel small molecules through unique bond disconnections. Advances in the proposed methodology will directly impact the biomedical mission by providing efficient access to derivatives of biologically-active core structures.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Lees, Robert G
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University of Utah
Schools of Arts and Sciences
Salt Lake City
United States
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Patel, Harshkumar H; Prater, Matthew B; Squire Jr, Scott O et al. (2018) Formation of Chiral Allylic Ethers via an Enantioselective Palladium-Catalyzed Alkenylation of Acyclic Enol Ethers. J Am Chem Soc 140:5895-5898
Yuan, Qianjia; Sigman, Matthew S (2018) Palladium-Catalyzed Enantioselective Relay Heck Arylation of Enelactams: Accessing ?,?-Unsaturated ?-Lactams. J Am Chem Soc 140:6527-6530
Chen, Zhi-Min; Nervig, Christine S; DeLuca, Ryan J et al. (2017) Palladium-Catalyzed Enantioselective Redox-Relay Heck Alkynylation of Alkenols To Access Propargylic Stereocenters. Angew Chem Int Ed Engl 56:6651-6654
Avila, Carolina M; Patel, Jigar S; Reddi, Yernaidu et al. (2017) Enantioselective Heck-Matsuda Arylations through Chiral Anion Phase-Transfer of Aryl Diazonium Salts. Angew Chem Int Ed Engl 56:5806-5811
Zhang, Chun; Tutkowski, Brandon; DeLuca, Ryan J et al. (2017) Palladium-Catalyzed Enantioselective Heck Alkenylation of Trisubstituted Allylic Alkenols: A Redox-Relay Strategy to Construct Vicinal Stereocenters. Chem Sci 8:2277-2282
McCammant, Matthew S; Shigeta, Takashi; Sigman, Matthew S (2016) Palladium-Catalyzed 1,3-Difunctionalization Using Terminal Alkenes with Alkenyl Nonaflates and Aryl Boronic Acids. Org Lett 18:1792-5
Xu, Liping; Zhang, Xin; McCammant, Matthew S et al. (2016) Mechanism and Selectivity in the Pd-Catalyzed Difunctionalization of Isoprene. J Org Chem :
Race, Nicholas J; Schwalm, Cristiane S; Nakamuro, Takayuki et al. (2016) Palladium-Catalyzed Enantioselective Intermolecular Coupling of Phenols and Allylic Alcohols. J Am Chem Soc 138:15881-15884
Patel, Harshkumar H; Sigman, Matthew S (2016) Enantioselective Palladium-Catalyzed Alkenylation of Trisubstituted Alkenols To Form Allylic Quaternary Centers. J Am Chem Soc 138:14226-14229
Chen, Zhi-Min; Hilton, Margaret J; Sigman, Matthew S (2016) Palladium-Catalyzed Enantioselective Redox-Relay Heck Arylation of 1,1-Disubstituted Homoallylic Alcohols. J Am Chem Soc 138:11461-4

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