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.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Exploratory Grants (P20)
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Special Emphasis Panel (ZGM1)
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University of Delaware
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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
Cobb, Kelsey M; Rabb-Lynch, Javon M; Hoerrner, Megan E et al. (2017) Stereospecific, Nickel-Catalyzed Suzuki-Miyaura Cross-Coupling of Allylic Pivalates To Deliver Quaternary Stereocenters. Org Lett 19:4355-4358
Lambert, William D; Scinto, Samuel L; Dmitrenko, Olga et al. (2017) Computationally guided discovery of a reactive, hydrophilic trans-5-oxocene dienophile for bioorthogonal labeling. Org Biomol Chem 15:6640-6644
Vulovic, Bojan; Watson, Donald A (2017) Heck-like Reactions Involving Heteroatomic Electrophiles. European J Org Chem 2017:4996-5009
Guo, Chen; Kim, Heejae; Ovadia, Elisa M et al. (2017) Bio-orthogonal conjugation and enzymatically triggered release of proteins within multi-layered hydrogels. Acta Biomater 56:80-90
Rezazadeh, Sina; Devannah, Vijayarajan; Watson, Donald A (2017) Nickel-Catalyzed C-Alkylation of Nitroalkanes with Unactivated Alkyl Iodides. J Am Chem Soc 139:8110-8113
Urello, Morgan A; Kiick, Kristi L; Sullivan, Millicent O (2017) ECM turnover-stimulated gene delivery through collagen-mimetic peptide-plasmid integration in collagen. Acta Biomater 62:167-178
Wolfe, Aaron J; Si, Wei; Zhang, Zhengqi et al. (2017) Quantification of Membrane Protein-Detergent Complex Interactions. J Phys Chem B 121:10228-10241
Basch, Corey H; Liao, Jennie; Xu, Jianyu et al. (2017) Harnessing Alkyl Amines as Electrophiles for Nickel-Catalyzed Cross Couplings via C-N Bond Activation. J Am Chem Soc 139:5313-5316
Gietter-Burch, Amber A S; Devannah, Vijayarajan; Watson, Donald A (2017) Trifluoromethylation of Secondary Nitroalkanes. Org Lett 19:2957-2960

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