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

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

  • Grigalunas, M.; Wiest, O.; Helquist, P. "Single-Flask Multicomponent Synthesis of Highly Substituted alpha-Pyrones via a Sequential Enolate Arylation and Alkenylation Strategy." Org. Lett. 2016, 18, 5724-5727.
  • Miyake, Y.; Keusch, J. J.; Wang, L.; Saito, M.; Hess, D.; Wang, X.; Melancon, B. J.; Helquist, P.; Gut, H.; Matthias, P. "Structural insights into HDAC6 tubulin deacetylation and its selective inhibition." Nat. Chem. Biol. 2016, 12, 748-+.
  • Lee, J. M.; Zhang, X.; Norrby, P.; Helquist, P.; Wiest, O. "Stereoselectivity in (Acyloxy)borane-Catalyzed Mukaiyama Aldol Reactions." J. Org. Chem. 2016, 81, 5314-5321.
  • Grigalunas, M.; Norrby, P.; Wiest, O.; Helquist, P. "Single-Flask Multicomponent Palladium-Catalyzed alpha,gamma-Coupling of Ketone Enolates: Facile Preparation of Complex Carbon Scaffolds." Angew. Chem. Int. Edit. 2015, 54, 11822-11825.
  • Byrd, K. M.; Arieno, M. D.; Kennelly, M. E.; Estiu, G.; Wiest, O.; Helquist, P. "Design and synthesis of a crosslinker for studying intracellular steroid trafficking pathways." Bioorg. Med. Chem. 2015, 23, 3843-3851.
  • Grigalunas, M.; Ankner, T.; Norrby, P.; Wiest, O.; Helquist, P. "Ni-Catalyzed Alkenylation of Ketone Enolates under Mild Conditions: Catalyst Identification and Optimization." J. Am. Chem. Soc. 2015, 137, 7019-7022.

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