College of Pharmacy

A metal-free, tandem approach to the preparation of substituted pyridines:

Uredi, D., Motati, D. R., Watkins, E. B. ChemComm. 2019, 55, 3270-3273.

Pyridines are privileged scaffolds found in numerous natural products and biologically active molecules. Pyridines are also ubiquitous in pharmaceuticals, agrochemicals and in advanced organic materials such as OLEDs and fluorescent sensors. Pyridine and its derivatives have significant applications as organic bases, ligands, catalysts and directing groups in C-H activation reactions.

We recently reported a method for preparing variously substituted pyridine under mild conditions without the need for toxic metals. The products are formed in high yield with absolute regioselectivity.

Additionally, we demonstrated the usefulness of this method by preparing the natural product, (-)-actinidine, a cyclopenta[c]pyridine alkaloid found in the root of Valeriana officinalis and Actinidia polyama.

A metal-free strategy for the synthesis of β-carbolines, γ-carbolines and other fused azaheteroaromatics:

Uredi, D., Motati, D. R., and Watkins, E. B. Org. Lett. 2018, 20, 6336-6339.

Carbolines and fused-pyridine heterocycles are ubiquitous structural motifs prevalent in natural products, pharmaceuticals, agrochemicals, materials and ligand scaffolds, thus highlighting the significance of such structures. Among the isomeric α-, β-, γ-, and σ-carbolines, the most abundant framework in nature is β-carboline. β-Carbolines possess a wide array of pharmacological properties, including anti-inflammatory, anti-Alzheimer, antimalarial, antibacterial, antitumor, anti-HIV activities and others.

We recently reported a method for preparing variously substituted carboline and fused azaheteroaromatics under mild conditions without the need for toxic metals. The products are formed in high yield with absolute selectivity.

This method could easily be applied to the synthesis of a myriad of natural products including the cytocidal β-carbolines, oxopropalines D and G.

Metal-free, regioselective, remote C-H halogenation of 8-substituted quinolines:

Reddy, M. D., Dilipkumar, U., and Watkins, E. B. Chem. Sci. 2018, 9, 1782-1788.

The quinoline framework has received significant attention over the past century due to its frequent occurrence in bioactive natural products, pharmaceuticals, materials and agrochemicals, including the following drugs: chloroquine (E), hydroxychloroquine (F), clioquinol (G), iodoquinol (H), quiniofon (I), mepacrine (J), tafenoquine and primaquine; medicinally important quinoline motifs: antiamyloidogenic agent (A), tumor suppressor (B), ubiquitination inhibitors (C/D), topoisomerase I inhibitor (K), KMD4 inhibitor (L), and bioactive natural products: ammosamides A, B and E (M-O). Additionally, great advancement has been realized in the valuable applications of the quinoline framework as a bidentate directing group in the arena of C-H activation/functionalization processes, after the seminal discovery of 8-aminoquinoline as a bidentate directing group by Daugulis in 2005.

We developed a metal-free C-H activation protocol that allows for the regioselective halogenation of derivatives of 8-aminoquinoline in high yield at room temperature using inexpensive reagents. This method has wide functional group tolerance and allows for isolation of the spent reagent, which can be used to regenerate the active reagent, minimizing cost and waste.

We have demonstrated the power of this new method by preparing the biological active agents, A and B below.

Development of a new bidentate directing group for ortho-C-H functionalization reactions:

Reddy, M. D.; Blanton, A. N.; Watkins, E. B. J. Org. Chem. 2017, 82, 5080-5095.

Transition metal-catalyzed carbon-carbon (C-C) and carbon-heteroatom (C-X) bond formation via C-H bond functionalization has emerged as a powerful and promising synthetic tool in organic synthesis in the past decade. Although various transition metal complexes involving Pd, Ru, Rh, Ni, Co and Cu for C-H bond functionalization have been investigated, Pd-catalyzed reactions to generate C-C and C-X bonds have recently seen tremendous advances due to broad functional group tolerance and the unique reactivity of palladium. The number of reports describing the utility of palladium-catalyzed C-C and C-X bond formation has dramatically increased in recent years. Regioselective C-H functionalization is one of the key challenges in the development of synthetically useful reactions. In this line, substantial progress has been realized using directing group-assisted C-H activation/functionalization. Bidentate directing groups have proven particularly instrumental in position-selective C-H transformations under metal catalysis. The bidentate directing group strongly coordinates the metal with a double coordination strategy and facilitates the C-H functionalization process.

We developed a Pd-catalyzed, highly selective, ortho-monoarylation of benzamides using commercially available N-(2-aminophenyl)acetamide (APA) as a bidentate directing group for the first time and applied this method to the preparation of several natural products of biological interest, urolithins B, M6, and M7.

"Doing research with Dr. Watkins was a truly enlightening experience for me. Coming into pharmacy school, I had a very narrow idea of what the profession of pharmacy encompasses. The drug design and synthesis that goes on in the laboratory is something I never expected to be able to experience, but exposure to the process has taught me so much. Getting to see first-hand how every chemical group is specifically taken into account and adjusted for in the design process made me realize just how unique every drug that comes to market really is. In addition to the theories of drug design that I was exposed to, I also had the opportunity to learn specific techniques and how to utilize the research equipment found in the laboratory. The experience I gained from participating in research with Dr. Watkins was a unique aspect of my pharmacy education and taught me things that will stay with me all throughout my career."

— Diana Barajas, Class of 2021

"Working on a research project with Dr. Watkins was a great experience which I feel helped make me both more proficient in a laboratory setting and a better learner. I was able to reinforce, as well as, see the real-world application of many of the skills and concepts learned from previous labs. Dr. Watkins, along with post-docs, were there to help guide me along and answer any questions I had. I enjoyed having the chance to design our own reaction schemes specific to the project rather than following a standard chemistry lab procedure. Having done research, I also feel I will have an edge in the future when applying to things like residencies or jobs."

— Clint Smith, Class of 2022