Among the most ubiquitous scaffolds in medicinal chemistry, biological chemistry, and glycobiology are ?-substituted amines and ethers. The goal of the proposed research program is to define a general and modular catalytic strategy that enables the enantioselective synthesis of these structural motifs, including those imbedded within heterocyclic frameworks, in much the same way that cross coupling serves as an all-purpose and powerful protocol for the assembly of Csp2-Csp2 bonds. To achieve this goal, we will exploit the ability of low-valent transition metal catalysts to undergo oxidative addition to iminium and oxocarbenium ions and show that this underutilized activation mode offers a versatile entry to alkyl cross-coupling reactions. In this contribution, we will pursue catalyst design and development for enantioselective arylation, heteroarylation, and alkylation of readily available and stable N,O-acetals and acetals using organoboronate and organozinc reagents (Specific Aim 1). The substituted dihydroquinolines, piperidines, chromenes, and pyrans that we will obtain from these studies constitute the core structural elements of small molecules that exhibit an array of pharmacological activities.
In Specific Aim 2, we will develop a new class of stable Ni precatalyst that is easily activated to Ni(0) and enables more efficient and convenient Suzuki-Miyaura cross-coupling reactions. Reaction development will also demonstrate that the iminium/oxocarbenium ion activation mode facilitates unprecedented bond constructions with simple feedstock chemicals such as electron-deficient olefins and carbon dioxide for the synthesis of allylic ethers, allylic amines, and ?-amino acids (Specific Aim 3).

Public Health Relevance

The goal of the proposed research is to establish a new cross-coupling methodology for the synthesis of single enantiomer ?-substituted amines and ethers. In so doing, the research will directly impact the biomedical mission of the NIH by providing efficient and selective access to some of the most ubiquitous chemical scaffolds in human medicines and biologically active small molecules.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
1R01GM100985-01A1
Application #
8580437
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Lees, Robert G
Project Start
2013-07-01
Project End
2018-03-31
Budget Start
2013-07-01
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$293,603
Indirect Cost
$103,603
Name
Princeton University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
002484665
City
Princeton
State
NJ
Country
United States
Zip Code
08544
Shields, Jason D; Ahneman, Derek T; Graham, Thomas J A et al. (2014) Enantioselective, nickel-catalyzed Suzuki cross-coupling of quinolinium ions. Org Lett 16:142-5
Zuo, Zhiwei; Ahneman, Derek T; Chu, Lingling et al. (2014) Dual catalysis. Merging photoredox with nickel catalysis: coupling of ?-carboxyl spĀ³-carbons with aryl halides. Science 345:437-40