Our ability to synthesize carbon-carbon bonds is integral to accessing the important biological activity of myriad organic molecules. Many valuable therapeutic agents exist in non-racemic form comprised of multiple stereogenic elements. Such characteristics highlight the critical need for new chemical reactions that allow chemists to efficiently prepare organic compounds with high levels of selectivity. The focus of this research program involves the development of new stereoselective metal-catalyzed processes for carbon-carbon bond formation via the addition of 1,1-bimetallic nucleophiles to a number of classes of electrophiles. These studies will lead to strategically alternative C-C bond disconnections that deliver important functional molecules in enantiomerically pure form. Many of the reactions described herein do not have existing catalytic protocols. (1) We will develop practical and robust Cu-catalyzed enantio-and diastereoselective alkylations of carbonyls and their derivatives with alkyl boron-containing reagents; these reactions will lead to the synthesis of a range of acyclic hydroxy- and amino-boronates that cannot be easily accessed by others methods. The value of these methods is increased by the installation of a highly versatile stereogenic C-B bond. (2) We will develop general enantioconvergent Cu-catalyzed processes for the addition of a range of alkyl-, alkenyl-, aryl-, allyl- substituted 1,1-heterobimetallic nucleophiles to electron-deficient alkenes. This reaction technology will lead to more efficient ways to synthesize homoallyl alcohols and amines common chemical structures found in bioactive molecules. (3) Reaction development will also demonstrate that 1,1-bimetallic reagents offer unique approaches to substrate-directed stereoselective catalytic reactions. The new catalysts and catalytic methods developed in this program offer unique and selective routes to the enantioselective synthesis of adaptable molecules. Through applications to concise synthesis of pharmacologically active agents, we will demonstrate the utility of our methods, in addition to identifying their limitations.

Public Health Relevance

Advancing human healthcare is directly related to our ability to successfully prepare non-racemic chiral biologically active molecules in efficient and stereoselective ways. The proposed studies will directly address this need by developing catalytic reactions of transformative reagents for the effective preparation of difficult to access chemical structures widespread in pharmaceutical agents.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM116987-04
Application #
9606497
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2016-01-01
Project End
2020-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
4
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
Murray, Stephanie A; Luc, Eugenia C M; Meek, Simon J (2018) Synthesis of Alkenyl Boronates from Epoxides with Di-[B(pin)]-methane via Pd-Catalyzed Dehydroboration. Org Lett 20:469-472
Murray, Stephanie A; Liang, Michael Z; Meek, Simon J (2017) Stereoselective Tandem Bis-Electrophile Couplings of Diborylmethane. J Am Chem Soc 139:14061-14064
Green, Jacob C; Joannou, Matthew V; Murray, Stephanie A et al. (2017) Enantio- and Diastereoselective Synthesis of Hydroxy Bis(boronates) via Cu-Catalyzed Tandem Borylation/1,2-Addition. ACS Catal 7:4441-4445
Murray, Stephanie A; Green, Jacob C; Tailor, Sanita B et al. (2016) Enantio- and Diastereoselective 1,2-Additions to ?-Ketoesters with Diborylmethane and Substituted 1,1-Diborylalkanes. Angew Chem Int Ed Engl 55:9065-9