Project Summary/Abstract
The efficient production of small organic molecules and chemical processes impacts pharmaceutical
research, both drug discovery and process chemistry. Chiral compounds make up a substantial portion
of bioactive small organic molecules. Their enantioselective synthesis minimizes use of chiral
separation technology, which can be time and resource intensive, and the production of undesired
enantiomers, which are often considered chemical waste. New copper-catalyzed alkene
difunctionalization reactions that enable efficient and stereoselective synthesis of chiral amine
derivatives and ethers, predominantly saturated heterocycles, are being developed. The products of
these reactions readily map on to structures contained in bioactive organic small molecules such as
natural products and pharmaceuticals. In Objective 1, reactions involving the propagation of chirality,
initiated by enantioselective copper-catalyzed reactions, are being explored. This new synthesis
approach can provide an unconventional, yet streamlined route to complex and potentially bioactive
molecules. In Objective 2, a new synthesis of enantioenriched oxygen heterocycles functionalized with
a pendant carbon-carbon double bond is being explored. Application of this strategy in the efficient
synthesis of bioactive natural products is proposed. One natural product synthesis will complete its
structural assignment, while another will provide an authentic sample for bioactivity profiling. In
Objective 3, our new aerobic enantioselective alkene aminooxygenation reaction will be applied to the
synthesis of drug analogs aimed at increased stability and selectivity in biological settings. In Objective
4, we outline plans to develop a catalytic enantioselective reaction for the synthesis of amine derivatives
with bioactivities related to a range of disease states including cancer and diabetes. Mechanistic
aspects of the reactions developed in Objectives 1-4 will be explored, which will enable their rational
optimization and predictable application. Development of these chemical transformations will enable
their use in in drug discovery and chemical biology applications. Lessons learned in reaction
engineering for efficiency and selectivity should be applicable to the invention and development of
related useful chemical processes. The inclusion of select biochemical analysis of a subset of small
molecules made in this project will give insight into their potential as therapeutic agents.