The goal of this proposal is to design new Ti-catalyzed oxidative nitrene transfer reactions to rapidly, modularly, and selectively assemble pyrrole derivatives and difunctionalize alkynes. The rationale for developing Ti-catalyzed nitrene transfer is that Ti is earth-abundant and generally biocompatible, which obviates the need for efficient catalyst removal and recovery in fine chemical synthesis. Furthermore, early transition metals can often access different structures and elementary reaction steps than late transition metals, opening up new bond forming strategies that may be complementary or orthogonal to existing technology. The first phase of research concerns developing generalizable [2+2+1] pyrrole syntheses from alkynes and diazenes that are chemo- and regioselective. Using preliminary data gained in our laboratory on Ti-catalyzed [2+2+1] reactions, we will explore empirical catalyst and substrate effects on regioselectivity, use kinetic and mechanistic insight to design new catalyst systems with improved selectivity and milder reaction conditions, and engineer systems for the efficient, selective, and modular production of high value bioactive targets such as the statin Lipitor. The second phase of the proposed research will expand upon our mechanistic understanding of [2+2+1] pyrrole catalysis and other preliminary results from our laboratory to design related Ti-catalyzed tandem bond forming reactions that incorporate different unsaturated coupling partners. This phase will result in catalytic methods for the synthesis of other N-heterocycles from simple alkyne starting materials and for the oxidative difunctionalization of alkynes. Relevance to public health. Nitrogen heterocycles constitute the single most prevalent class of functional groups in FDA-approved small-molecule drugs: 59% of all unique small molecule drugs contain at least one N- heterocycle. Pyrroles care an important class within this group, and have broad bioactivity. Although many multicomponent reactions to form pyrroles exist, the development of a general synthetic method remains an unmet challenge due to the unique reactivity profile of the pyrrole unit. By designing general methods to pyrroles and related heterocycles, synthetic chemists will have rapid and convergent access to diverse and novel molecular architectures and building blocks that will ultimately allow for widespread distribution of new small molecule drug-like architectures to the biomedical community

Public Health Relevance

Pyrroles constitute an important class of bioactive natural products and FDA-approved drugs: for example, HMG-CoA-reductase inhibitor Atorvastatin (Lipitor) is the best-selling drug of all time and has significantly helped in cardiovascular disease prevention, whereas Sunitinib, a receptor tyrosine kinase inhibitor, is a promising second line therapy for renal cell carcinoma and gastrointestinal stromal tumors. Despite their ubiquity, pyrroles are often challenging to synthesize and the realization of a general method of synthesis from simple starting materials remains an unmet challenge. The objective of this proposal is to design a general synthesis of pyrroles from simple alkynes, which will allow synthetic chemists to access diverse molecular building blocks that will ultimately allow for widespread distribution of new small molecule drug-like architectures to the biomedical community.

National Institute of Health (NIH)
National Institute of General Medical Sciences (NIGMS)
Unknown (R35)
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Special Emphasis Panel (ZRG1-CB-B (50)R)
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Lees, Robert G
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University of Minnesota Twin Cities
Schools of Arts and Sciences
United States
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Pearce, Adam J; See, Xin Yi; Tonks, Ian A (2018) Oxidative nitrene transfer from azides to alkynes via Ti(ii)/Ti(iv) redox catalysis: formal [2+2+1] synthesis of pyrroles. Chem Commun (Camb) 54:6891-6894
Chiu, Hsin-Chun; Tonks, Ian A (2018) Trimethylsilyl-Protected Alkynes as Selective Cross-Coupling Partners in Titanium-Catalyzed [2+2+1] Pyrrole Synthesis. Angew Chem Int Ed Engl 57:6090-6094
See, Xin Yi; Beaumier, Evan P; Davis-Gilbert, Zachary W et al. (2017) Generation of TiII Alkyne Trimerization Catalysts in the Absence of Strong Metal Reductants. Organometallics 36:1383-1390
Davis-Gilbert, Zachary W; Tonks, Ian A (2017) Titanium redox catalysis: insights and applications of an earth-abundant base metal. Dalton Trans 46:11522-11528
Davis-Gilbert, Zachary W; Yao, Letitia J; Tonks, Ian A (2016) Ti-Catalyzed Multicomponent Oxidative Carboamination of Alkynes with Alkenes and Diazenes. J Am Chem Soc 138:14570-14573