Paul Helquist

Paul Helquist

Synthetic Organic Chemistry Drug Discovery for Rare Diseases


Professor, University of Notre Dame
Professor, State University of New York at Stony Brook
Associate Professor, State University of New York at Stony Brook
Assistant Professor, Department of Chemistry, State University of New York at Stony Brook
Postdoctoral Fellow, Harvard University
Ph.D. in Organic Chemistry, Cornell University
B.A. in Chemistry, University of Minnesota, Duluth

Selected Awards

2020, 2009
Joyce Award for Excellence in Undergraduate Teaching
Tage Erlander Guest Professor of the Swedish National Research Council, University of Gothenburg and University of Stockholm
Faculty Award, University of Notre Dame
2005, 2002
Kaneb Teaching Award

Research Interests

Professor Helquist's research group is concerned with two broad areas: (1) the development of new methods in synthetic organic chemistry, including the preparation, structural study, and applications of new transition metal organometallic complexes as catalysts and reagents for asymmetric synthesis; and (2) the structure, synthesis, mechanism of action, and pharmaceutical development of biologically active compounds including antibiotics and antitumor agents, many of which have their origins as natural products. Often we take advantage of the interface between these two areas by applying some of our new methods, reagents, and catalysts in the synthesis of targeted natural products.

We have developed numerous synthetic methods employing iron, nickel, copper, rhodium, palladium, titanium, zirconium, magnesium, lithium, zinc, and samarium compounds as reagents or catalysts. We have employed many of these methods in the synthesis of complex natural products. Coupled with this organometallic work is the rational design of chiral transition metal catalysts through use of molecular mechanics computational techniques. Through use of this approach, we have succeeded in obtaining metal complexes that can be employed in metal-catalyzed reactions to give products with >99% enantiomeric excess.

In the area of total synthesis, our laboratory studies compounds that show promise of being developed into clinically useful antibiotics and anti-cancer agents. For several of the compounds that we study, the full structures have not been determined previously, and we therefore begin our work by employing high-field NMR and molecular mechanics computational techniques to determine the full, three-dimensional structures of these compounds. In the course of then pursuing total syntheses of these compounds, we often develop new methods. With synthetic materials in hand, we study structure-activity relationships and mechanisms of action. We employ this knowledge to obtain modified forms of the natural products to improve therapeutic properties, leading to the development of new pharmaceutical products. Some of our most recent derivatives are highly potent antibiotics that are active against a range of bacteria that are resistant to other classes of antibiotics.

Recent Publications

  • Wahlers, J.; Margalef, J.; Hansen, E.; Bayesteh, A.; Helquist, P.; Dieguez, M.; Pamies, O.; Wiest, O. and Norrby, P. O. "Proofreading Experimentally Assigned Stereochemistry through Q2MM Predictions in Pd-Catalyzed Allylic Aminations" 2021 Nature Communications, 12 (1), 6719. DOI: 10.1038/s41467-021-27065-2.
  • Pipalia, N. H.; Saad, S. Z.; Subramanian, K.; Cross, A.; Al-Motawa, A.; Garg, K.; Blagg, B.; Neckers, L.; Helquist, P.; Wiest, O.; Ory, D. S. and Maxfield, F. R. "HSP90 Inhibitors Reduce Cholesterol Storage in Niemann-Pick Type C1 Mutant Fibroblasts" 2021 Journal of Lipid Research, 62, 100114. DOI: 10.1016/j.jlr.2021.100114.
  • Cruz, D. L.; Pipalia, N.; Mao, S.; Gadi, D.; Liu, G.; Grigalunas, M.; O'Neill, M.; Quinn, T. R.; Kipper, A.; Ekebergh, A.; Dimmling, A.; Gartner, C.; Melancon, B. J.; Wagner, F. F.; Holson, E.; Helquist, P.; Wiest, O. and Maxfield, F. R. "Inhibition of Histone Deacetylases 1, 2, and 3 Enhances Clearance of Cholesterol Accumulation in Niemann-Pick C1 Fibroblasts" 2021 ACS Pharmacology & Translational Science, 4 (3), pp.1136-1148. DOI: 10.1021/acsptsci.1c00033.
  • Quinn, T. R.; Steussy, C. N.; Haines, B. E.; Lei, J. P.; Wang, W.; Sheong, F.; Stauffacher, C. V.; Huang, X. H.; Norrby, P. O.; Helquist, P. and Wiest, O. "Microsecond Timescale MD Simulations at the Transition State of PmHMGR Predict Remote Allosteric Residues" 2021 Chemical Science, 12 (18), pp.6413-6418. DOI: 10.1039/d1sc00102g.
  • Wahlers, J.; Maloney, M.; Salahi, F.; Rosales, A. R.; Helquist, P.; Norrby, P. O. and Wiest, O. "Stereoselectivity Predictions for the Pd-Catalyzed 1,4-Conjugate Addition using Quantum-Guided Molecular Mechanics" 2021 Journal of Organic Chemistry, 86 (8), pp.5660-5667. DOI: 10.1021/acs.joc.1c00136.
  • Work, E. M.; Ferraudi, G.; Kiefer, L.; Liu, G.; Grigalunas, M.; Bhardwaj, A.; Kaur, R.; Dempsey, J. M.; Wustner, D.; Helquist, P. and Wiest, O. "Design, Synthesis, and Evaluation of a Luminescent Cholesterol Mimic" 2021 Journal of Organic Chemistry, 86 (2), pp.1612-1621. DOI: 10.1021/acs.joc.0c02460.

Contact Information

  • Professor; Associate Chair
  • Office: 385 Stepan Chemistry Hall
  • Phone: 574-631-7822
  • Send an email

Primary Research Areas

Research Specialties