New Reactivity, Catalysis, Organic Synthesis, and Macromolecules

Our research program aims to discover new chemical reactivity and to develop its practical applications in organic synthesis, chemical biology, and materials science. Catalytic processes are the focus of our work because they often offer many variables for optimization to make them useful on both laboratory and industrial scales. We use a variety of techniques to interrogate catalytic systems of interest and understand the dynamic changes that affect structure and performance of a catalyst.

Our studies produced several practical and widely utilized processes. Among them is the Copper-Catalyzed Azide-Alkyne Cycloaddition (CuAAC), the sister ruthenium-catalyzed reaction, and catalytic reactions of azavinyl carbenes, a novel carbene species. The aqueous variant of CuAAC we discovered has found many applications in organic synthesis, in in vitro and in vivo imaging, and in materials science, both in academia and in industry. It has become the most utilized and well-known click reaction (and is often called click chemistry). It has also provided fundamental insights into the structure and reactivity of multinuclear acetylide complexes. We are currently pursuing a number of interdisciplinary projects with scientists at TSRI and well beyond its walls.

Kwok, S.W., Zhang, L., Grimster, N.P., Fokin, V.V. Catalytic Asymmetric Transannulation of NH-1,2,3-Triazoles with Olefins. Angew. Chem., Int. Ed. 2014, Ahead of Print. doi:10.1002/anie.201306706

Sit, R.K., Fokin, V.V., Amitai, G., Sharpless, K.B., Taylor, P., Radic, Z. Imidazole Aldoximes Effective in Assisting Butyrylcholinesterase Catalysis of Organophosphate Detoxification. J. Med. Chem. 2014, 57, 1378-1389. doi:10.1021/jm401650z

Chuprakov, S., Worrell, B.T., Selander, N., Sit, R.K., Fokin, V.V. Stereoselective 1,3-Insertions of Rhodium(II) Azavinyl Carbenes. J. Am. Chem. Soc. 2014, 136, 195-202. doi:10.1021/ja408185c

Worrell, B.T., Ellery, S.P., Fokin, V.V. Copper(I)-Catalyzed Cycloaddition of Bismuth(III) Acetylides with Organic Azides: Synthesis of Stable Triazole Anion Equivalents. Angew. Chem., Int. Ed. 2013, 52, 13037-13041. doi:10.1002/anie.201306192 (C&EN News of the Week; TSRI News&Views)

Sanphanya, K., Wattanapitayakul, S.K., Phowichit, S., Fokin, V.V., Vajragupta, O. Novel VEGFR-2 Kinase Inhibitors Identified by the Back-to-Front Approach. Bioorg. Med. Chem. Lett. 2013, 23, 2962-2967. doi:10.1016/j.bmcl.2013.03.042

Worrell, B.T., Malik, J.A., Fokin, V.V.Direct Evidence of a Dinuclear Copper Intermediate in Cu(I)-Catalyzed Azide-Alkyne Cycloadditions. Science (Washington, DC, U. S.) 2013, 340, 457-460. doi: 10.1126/science.1229506

Rillahan, C.D., Schwartz, E., Rademacher, C., McBride, R., Rangarajan, J., Fokin, V.V., Paulson, J.C. On-Chip Synthesis and Screening of a Sialoside Library Yields a High Affinity Ligand for Siglec-7. ACS Chem. Biol. 2013, 8, 1417-1422. doi:10.1021/cb400125w

Radic, Z., Sit, R.K., Garcia, E., Zhang, L., Berend, S., Kovarik, Z., Amitai, G., Fokin, V.V., Barry Sharpless, K., Taylor, P. Mechanism of Interaction of Novel Uncharged, Centrally Active Reactivators with OP-hAChE Conjugates. Chem.-Biol. Interact. 2013, 203, 67-71. doi:10.1016/j.cbi.2012.08.014

Miyamoto, Y., Kalisiak, J., Korthals, K., Lauwaet, T., Cheung, D.Y., Lozano, R., Cobo, E.R., Upcroft, P., Upcroft, J.A., Berg, D.E., Gillin, F.D., Fokin, V.V., Sharpless, K.B., Eckmann, L. Expanded Therapeutic Potential in Activity Space of Next-Generation 5-Nitroimidazole Antimicrobials with Broad Structural Diversity. Proc. Natl. Acad. Sci. U. S. A. 2013, 110, 17564-17569, S17564/17561-S17564/17127. doi:10.1073/pnas.1302664110

Malysheva, Y.B., Buchvalova, S.Y., Svirshchevskaya, E.V., Fokin, V.V., Fedorov, A.Y. Negishi Cross-Coupling Reaction as a Route to Isocombretastatins. Synlett 2013, 24, 1772-1776. doi:10.1055/s-0033-1339334

Zibinsky, M., Fokin, V.V. Sulfonyl-1,2,3-Triazoles: Convenient Synthones for Heterocyclic Compounds. Angew. Chem., Int. Ed. 2013, 52, 1507-1510. doi:10.1002/anie.201206388

Kovarik, Z., Macek, N., Sit, R.K., Radic, Z., Fokin, V.V., Barry Sharpless, K., Taylor, P. Centrally Acting Oximes in Reactivation of Tabun-Phosphoramidated AChE. Chem.-Biol. Interact. 2013, 203, 77-80. doi:10.1016/j.cbi.2012.08.019

Fraser, B.H., Hamilton, S., Krause-Heuer, A.M., Wright, P.J., Greguric, I., Tucker, S.P., Draffan, A.G., Fokin, V.V., Sharpless, K.B. Synthesis of 1,4-Triazole Linked Zanamivir Dimers as Highly Potent Inhibitors of Influenza A and B. MedChemComm 2013, 4, 383-386. doi:10.1039/c2md20300f

Chuprakov, S., Kwok, S.W., Fokin, V.V. Transannulation of 1-Sulfonyl-1,2,3-Triazoles with Heterocumulenes. J. Am. Chem. Soc. 2013, 135, 4652-4655. doi:10.1021/ja400350c

Yamauchi, J.G., Gomez, K., Grimster, N., Dufouil, M., Nemecz, A., Fotsing, J.R., Ho, K.-Y., Talley, T.T., Sharpless, K.B., Fokin, V.V., Taylor, P. Synthesis of Selective Agonists for the a7 Nicotinic Acetylcholine Receptor with in Situ Click-Chemistry on Acetylcholine-Binding Protein Templates. Mol. Pharmacol. 2012, 82, 687-699. doi:10.1124/mol.112.080291

Worrell, B.T., Hein, J.E., Fokin, V.V. Halogen Exchange (Halex) Reaction of 5-Iodo-1,2,3-Triazoles: Synthesis and Applications of 5-Fluorotriazoles. Angew. Chem., Int. Ed. 2012, 51, 11791-11794. doi:10.1002/anie.201204979

Selander, N., Worrell, B.T., Fokin, V.V. Ring Expansion and Rearrangements of Rhodium(II) Azavinyl Carbenes. Angew. Chem., Int. Ed. 2012, 51, 13054-13057. doi:10.1002/anie.201207820

Selander, N., Worrell, B.T., Chuprakov, S., Velaparthi, S., Fokin, V.V. Arylation of Rhodium(II) Azavinyl Carbenes with Boronic Acids. J. Am. Chem. Soc. 2012, 134, 14670-14673. doi:10.1021/ja3062453

Selander, N., Fokin, V.V. Rhodium(II)-Catalyzed Asymmetric Sulfur(VI) Reduction of Diazo Sulfonylamidines. J. Am. Chem. Soc. 2012, 134, 2477-2480. doi:10.1021/ja210180q

Sanphanya, K., Wattanapitayakul, S.K., Prangsaengtong, O., Jo, M., Koizumi, K., Shibahara, N., Priprem, A., Fokin, V.V., Vajragupta, O. Synthesis and Evaluation of 1-(Substituted)-3-Prop-2-Ynylureas as Antiangiogenic Agents. Bioorg. Med. Chem. Lett. 2012, 22, 3001-3005. doi:10.1016/j.bmcl.2012.02.029