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.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM063540-12
Application #
8654340
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2001-09-01
Project End
2016-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
12
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Utah
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
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
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
Xu, Liping; Zhang, Xin; McCammant, Matthew S et al. (2016) Mechanism and Selectivity in the Pd-Catalyzed Difunctionalization of Isoprene. J Org Chem :
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
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
Hilton, Margaret J; Cheng, Bin; Buckley, Benjamin R et al. (2015) Relative reactivity of alkenyl alcohols in the palladium-catalyzed redox-relay Heck reaction. Tetrahedron 71:6513-6518
McCammant, Matthew S; Sigman, Matthew S (2015) Development and Investigation of a Site Selective Palladium-Catalyzed 1,4-Difunctionalization of Isoprene using Pyridine-Oxazoline Ligands. Chem Sci 6:1355-1361
Saini, Vaneet; O'Dair, Mark; Sigman, Matthew S (2015) Synthesis of highly functionalized tri- and tetrasubstituted alkenes via Pd-catalyzed 1,2-hydrovinylation of terminal 1,3-dienes. J Am Chem Soc 137:608-11
Zhang, Chun; Santiago, Celine B; Kou, Lei et al. (2015) Alkenyl carbonyl derivatives in enantioselective redox relay Heck reactions: accessing α,β-unsaturated systems. J Am Chem Soc 137:7290-3
Zhang, Chun; Santiago, Celine B; Crawford, Jennifer M et al. (2015) Enantioselective Dehydrogenative Heck Arylations of Trisubstituted Alkenes with Indoles to Construct Quaternary Stereocenters. J Am Chem Soc 137:15668-71

Showing the most recent 10 out of 67 publications