Advances in catalytic science and technology enable the preparation of pharmaceutical agents used to treat human disease. This project has the long-term goal of developing a broad class of inexpensive nonmetal catalysts that promote catalytic transformations via formal oxidation state cycling in qualitative analogy to transition metal catalysis. Within this overarching goal, the primary focus of this proposal is the design and application of phosphorus-based catalysts that function in the P(III)?P(V) redox couple. While phosphines are well-established in catalysis as spectator ligands for transition metal catalysis and as nucleophilic catalysts, this research describes innovative phosphorus-based catalysts of novel com- position and structure that explore the structural and electronic conditions required to enable new catalyt- ically-relevant reactivity via reversible P(III)?P(V) oxidation state cycling. The first major effort is the de- velopment of phosphine-catalyzed O-atom transfer methods that result in reductive functionalization of nitroarene compounds through the formation of new carbon-nitrogen bonds. The second major effort is the development of net redox-neutral (cyclo)dehydration reactions that are accomplished by phosphine catalysis in the P(III)?P(V) redox couple. The proposed research is expected to yield new practical cata- lytic methods for the construction of pharmacologically-relevant small molecules that meet the challenges of sustainable synthesis, and an improved fundamental understanding the interplay between structure and reactivity in the p-block that will underpin future development of nonmetals for atom transfer, bond activation, and catalysis. Taken together, these outcomes will advance nonmetal-based redox catalysis as a new and powerful modality in pharmaceutical synthesis.

Public Health Relevance

Innovative homogeneous catalytic methods play an increasingly important role in chemical synthesis of pharmaceuticals. This proposal outlines new reactions based on nonmetal phosphorus-based catalysts that strengthen our ability to access classes of molecules relevant to human health.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Research Project (R01)
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Synthetic and Biological Chemistry B Study Section (SBCB)
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Yang, Jiong
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Massachusetts Institute of Technology
Schools of Arts and Sciences
United States
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Tanushi, Akira; Radosevich, Alexander T (2018) Insertion of a Nontrigonal Phosphorus Ligand into a Transition Metal-Hydride: Direct Access to a Metallohydrophosphorane. J Am Chem Soc 140:8114-8118
Nykaza, Trevor V; Cooper, Julian C; Li, Gen et al. (2018) Intermolecular Reductive C-N Cross Coupling of Nitroarenes and Boronic Acids by PIII/PV?O Catalysis. J Am Chem Soc 140:15200-15205
Nykaza, Trevor V; Ramirez, Antonio; Harrison, Tyler S et al. (2018) Biphilic Organophosphorus-Catalyzed Intramolecular Csp2-H Amination: Evidence for a Nitrenoid in Catalytic Cadogan Cyclizations. J Am Chem Soc 140:3103-3113
Lin, Yi-Chun; Hatzakis, Emmanuel; McCarthy, Sean M et al. (2017) P-N Cooperative Borane Activation and Catalytic Hydroboration by a Distorted Phosphorous Triamide Platform. J Am Chem Soc 139:6008-6016
Nykaza, Trevor V; Harrison, Tyler S; Ghosh, Avipsa et al. (2017) A Biphilic Phosphetane Catalyzes N-N Bond-Forming Cadogan Heterocyclization via PIII/PV?O Redox Cycling. J Am Chem Soc 139:6839-6842
Reichl, Kyle D; Dunn, Nicole L; Fastuca, Nicholas J et al. (2015) Biphilic Organophosphorus Catalysis: Regioselective Reductive Transposition of Allylic Bromides via P(III)/P(V) Redox Cycling. J Am Chem Soc 137:5292-5
Wang, Sunewang Rixin; Radosevich, Alexander T (2015) P(NMe2)3-Mediated Umpolung Alkylation and Nonylidic Olefination of ?-Keto Esters. Org Lett 17:3810-3
Zhao, Wei; Radosevich, Alexander T (2015) Phosphorus(III)-Mediated Reductive Condensation of ?-Keto Esters and Protic Pronucleophiles. Organic Synth 92:267-276