High-throughput screening (HTS) of small molecule libraries is a powerful technique to identify new chemical probes and therapeutic leads. However, the stereochemical and molecular diversity of current libraries is lacking. Recognizing that new synthefic methods catalyze discoveries in biomedical research, the long-term goal of this research program is to develop highly efficient methods for the synthesis of biologically active molecules. The objective of this subproject is to establish new enabling reacfion technologies to build novel scaffolds with significant molecular and stereochemical complexity and to exploit these methods to prepare diverse compound libraries. On the basis of strong preliminary results, the new methods for diversity oriented synthesis are proposed in three specific aims: (1) development of copper-catalyzed alkylation of nitroalkanes as a platform for library synthesis;(2) establishment of palladium-catalyzed cross couplings of 0-acylaldoximes to enable preparafion of highly substituted piperidine libraries via an aza-Suzuki/[4+2] cascade strategy;and (3) development of copper-catalyzed arylation of chromene acetals to deliver libraries of a-aryl chromenes. Each of these technologies is innovative, allowing new entries and greafiy facilitated access to complex nitroalkanes, piperidines and chromenes, as well as many derivafives of these highly versatile intermediates. The proposed work is significant, because it will establish new routes for efficient synthesis of bioactive compounds, provide novel libraries to HTS campaigns, and create the synthefic infrastructure and highly interactive collaborafions necessary to not only identify hit compounds, but also to progress these hits into useful chemical probes and leads for therapeufic development.

Public Health Relevance

The proposed research is relevant to public health, because it will enable facile synthesis of scaffolds found in many biologically active compounds. The ulfimate goal of this subproject is to discover new molecular tools to dissect biological pathways associated with human disease and new leads for disease treatments.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Exploratory Grants (P20)
Project #
1P20GM104316-01A1
Application #
8653112
Study Section
Special Emphasis Panel (ZGM1)
Project Start
Project End
Budget Start
2014-09-01
Budget End
2015-05-31
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Delaware
Department
Type
DUNS #
City
Newark
State
DE
Country
United States
Zip Code
19716
Cinderella, Andrew P; Vulovic, Bojan; Watson, Donald A (2017) Palladium-Catalyzed Cross-Coupling of Silyl Electrophiles with Alkylzinc Halides: A Silyl-Negishi Reaction. J Am Chem Soc 139:7741-7744
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