The discovery and development of effective chemical therapeutics for human disease is limited by the shortcomings of synthetic chemistry that make investigating important chemical structures difficult. In particular, the clinical potential of many complex polycyclic structures is under-explored due to a lack of methods for their preparation. Bridging this gap will allow many new structures to be synthesized rapidly, leading to an increased rate at which new therapeutics are discovered. Our long-term goal is to make significant contributions to both chemistry and medicine by developing general synthetic methods to construct biologically active complex polycyclic structures. The overall objective of our current research is to develop the oxidative coupling of silicon-tethered enolates as a powerful method to prepare complex structures that contain contiguous stereocenters. The paucity of available methods limits the use of such structures in chemical library synthesis and makes the efficient preparation of clinically relevant natural products difficult. Our rationale for investigating silyl bis-enol ethers is that they can mediate the coupling of two different chemical fragments and simultaneously control the stereochemical outcome of bond formation, thereby affording concise syntheses of complex structures.
The Specific Aims of this proposal are: 1. Develop and utilize silyl bis-enol ether-based oxidation as a powerful new method to construct contiguous stereocenters;2. Develop multicomponent coupling processes for rapid generation of complex bioactive molecules;and 3. Develop new oxidative bond-forming reactions that extend beyond enol-enol coupling. This proposed research is innovative because the silicon-tether acts to control both heterocoupling vs. homocoupling, and stereoselectivity for oxidative enolate bond formation. The development of techniques for fashioning quaternary stereocenters, vicinal stereoarrays, and tandem multicomponent coupling sequences will generate complexity efficiently. Additional research into Lewis base activation will provide enantioselective methods for preparing these structures. The invention of new oxidative bond-forming reactions will expand the usefulness of the silicon-tether concept to a wealth of challenging compounds. The expected outcomes of this research will be the concise synthesis of many medicinally important structures that are of significant challenge to current methods. This proposed research is significant for human health because it is expected to provide complex polycyclic structures in quantities that will ensure their utilization in discovering new chemical therapeutics.

Public Health Relevance

This proposed research will generate new methods to prepare biologically important polycyclic molecules. The synthesis of these unexplored structures will have an important positive impact on human health by allowing in-depth biological studies, and thus unearth new drug candidates and biological targets for combating diseases such as cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM085322-05
Application #
8474634
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2009-06-01
Project End
2014-05-31
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
5
Fiscal Year
2013
Total Cost
$268,927
Indirect Cost
$79,768
Name
Northwestern University at Chicago
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
160079455
City
Evanston
State
IL
Country
United States
Zip Code
60201
Jones, Brian T; Avetta, Christopher T; Thomson, Regan J (2014) Total Synthesis of Propolisbenzofuran B. Chem Sci 5:1794-1798
Jones, Brian T; Hu, Dennis X; Savoie, Brett M et al. (2013) Elimination of butylcycloheptylprodigiosin as a known natural product inspired by an evolutionary hypothesis for cyclic prodigiosin biosynthesis. J Nat Prod 76:1937-45
Larson, Reed T; Clift, Michael D; Thomson, Regan J (2012) Total synthesis of the Galbulimima alkaloid (-)-GB17. Angew Chem Int Ed Engl 51:2481-4
Guo, Fenghai; Konkol, Leah C; Thomson, Regan J (2011) Enantioselective synthesis of biphenols from 1,4-diketones by traceless central-to-axial chirality exchange. J Am Chem Soc 133:18-20
Konkol, Leah C; Jones, Brian T; Thomson, Regan J (2009) Oxidative carbon-carbon bond formation via allyldimethylsilyl enol ethers. Org Lett 11:5550-3
Clift, Michael D; Thomson, Regan J (2009) Development of a merged conjugate addition/oxidative coupling sequence. Application to the enantioselective total synthesis of metacycloprodigiosin and prodigiosin R1. J Am Chem Soc 131:14579-83