Gregory K. Friestad

Gregory K. Friestad
Associate Professor
Phone: 
319-335-1364
Office: 
E455 CB
Divisions: 
Biosketch: 
  • B.S., Bradley University (1990)
  • Ph.D., University of Oregon (1995)
  • NIH Postdoctoral Fellowship, University of Pennsylvania (1995-1998)
  • Visiting Professor and JSPS Fellowship, Kobe Pharmaceutical University (2003)
  • Visiting Professor, University of Wisconsin-Madison (2005)
Keywords: 

Synthetic methodology and natural product synthesis, emphasizing chiral amines, stereoselective carbon-carbon bond constructions, radical addition reactions, organometallic reagents, and asymmetric catalysis.

Research Interests: 

Organic synthesis is crucial to biomedical research and nanotechnology because organic chemists design and provide new substances with the improved properties needed to achieve the amazing advances we see in these areas. Fundamental basic research in organic chemistry allows us to make new substances more efficiently, and with less environmental impact.

Researchers in the Friestad Group address problems in synthetic methodology and natural product synthesis, with special emphasis on efficiency by developing useful carbon-carbon bond constructions. Our primary synthetic targets are biologically active substances which have significant potential either as biological probes in health sciences research or as lead compounds for development of new disease therapies. Students develop new synthetic methods and apply them to natural product targets, routinely using research instrumentation such as nuclear magnetic resonance (NMR) and high-performance liquid chromatography (HPLC). Such projects, combining the depth of methodology research with the breadth of total synthesis training, are outstanding preparation for industrial or academic research. Friestad Group alumni have careers in pharmaceutical companies both big and small, as well as teaching and research positions in academia.

Specific projects we have developed involve reaction methodology at the interface with organometallic chemistry, ranging from organosilicon and organotransition metal chemistry to free radical reactions. We've developed silicon-tethered diastereoselective radical cyclizations leading to amino alcohols. We've designed and implemented a novel chiral N-acylhydrazone motif for asymmetric addition reactions which provides for excellent enantioselectivity from chiral auxiliaries or catalysts. Our chiral N-acylhydrazones have proved to be broadly useful acceptors for additions of alkyl radicals and a wide range of nucleophiles including hydride and allylsilane reagents. We found that photolysis of Mn2(CO)10 enables radical addition to chiral N-acylhydrazones using a broad range of precursors, including primary alkyl halides and multifunctional compounds. This method is now in use for synthesis of complex natural product targets.

 New Synthetic Methods and Applications

Recent Publications: 
  • Cullen, S. T. J.; Friestad, G. K. "Alkyl radical addition to aliphatic and aromatic N-acylhydrazones using an organic photoredox catalyst." Organic Letters 2019, 21, 8290-8294. PDF: doi 10.1021/acs.orglett.9b03053.

  • Friedrich, R. M.; Bell, J. Q.; Garcia, A.; Shen, Z.; Friestad, G. K. "Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Preparation and Coupling of C15–C25 and C26–C40 Fragments of Tetrafibricin." Journal of Organic Chemistry 2018, 83, 13650-13669.  (Featured Article)  PDF: doi.org/10.1021/acs.joc.8b02034

  • Friedrich, R. M.; Sreenilayam, G.; Hackbarth, J.; Friestad, G. K. "Unified Strategy for 1,5,9- and 1,5,7-Triols via Configuration-Encoded 1,5-Polyol Synthesis: Enantioselective Preparation of gamma-Sulfonyl-alpha-silyloxyaldehydes and Iterative Julia–Kocienski Coupling." Journal of Organic Chemistry 2018, 83, 13636-13649.  (Featured Article)  PDF: doi.org/10.1021/acs.joc.8b02033

  • Ibrahim, S. M. S.; Banerjee, K.; Slater, K. A.; Friestad, G. K. "A Tamao-Fleming oxidation route to dipeptides bearing N,O-acetal functionality." Tetrahedron Letters 2017, 58, 4864-4866.  PDF: doi.org/10.1016/j.tetlet.2017.11.036

  • Friedrich, R. M.; Friestad, G. K. "Access to an anti,syn-1,5,7-Triol by Configuration-Encoded 1,5-Polyol Synthesis: The C15–C25 Fragment of Tetrafibricin." European Journal of Organic Chemistry 2017, 1961-1964.  PDF:  doi.org/10.1002/ejoc.201700373

  • Friestad; G. K.; Banerjee, K.; Marié, J.-C.; Mali, U.; Yao, L. “Stereoselective Access to Tubuphenylalanine and Tubuvaline: Improved Mn-Mediated Radical Additions and Assembly of A Tubulysin Tetrapeptide Analog” Journal of Antibiotics 2016, 69, 294-298.   PDF:  doi.org/10.1038/ja.2016.7

  • Slater, K. A.; Friestad, G. K. “Mn-Mediated Radical-Ionic Annulations of Chiral N-Acylhydrazones.” Journal of Organic Chemistry 2015, 80, 6432-6440.  PDF: doi.org/10.1021/acs.joc.5b00863

  • Friestad, G. K. "Control of Asymmetry in the Radical Addition Approach to Chiral Amine Synthesis" In Topics In Current Chemistry: Stereoselective Formation of Amines; Li, W.; Zhang, X., Eds.; Springer-Verlag: Berlin, 2014, vol. 343, pp. 1-32.

  • Xu, X.; Friestad, G. K.; Yao, L."Recent Advances in the Synthesis of Tubulysins" Mini-Reviews in Medicinal Chemistry 2013, 13, 1572-1578.  PDF: doi.org/10.2174/13895575113139990063

  • Friestad, G. K.; Sreenilayam, G.; Cannistra, J. C.; Slominski, L. M. "Preparation of Enol Ester Epoxides and Their Ring-Opening to alpha-Silyloxyaldehydes." Tetrahedron Letters 2012, 53, 5064-5067.  PDF: doi.org/10.1016/j.tetlet.2012.06.142

  • Friestad, G. K. "Asymmetric Radical Addition to Chiral Hydrazones." In Topics In Current Chemistry: Radicals in Synthesis III; Gansauer A.; Heinrich, M., Eds., Springer-Verlag: Berlin, 2012, vol. 320, pp. 61-92

  • Friestad, G. K. "Organomanganese-Mediated Radical Reactions." In The Chemistry of Organo-Manganese Compounds; Marek, I.; Rappoport, Z., Eds.; Wiley: Chichester, United Kingdom, 2011, pp. 559-584.  [PDF]

  • Friestad, G. K.; Ji, A.; Korapala, C. S.; Qin, J.  "Intermolecular Radical Addition to N-Acylhydrazones as a Stereocontrol Strategy for Alkaloid Synthesis: Formal Synthesis of Quinine." Organic and Biomolecular Chemistry 2011, 4039-4043.   [PDF]

  • Friestad, G. K.; Sreenilayam, G. "1,5-Polyols: Challenging Motifs for Configurational Assignment and Synthesis." Pure and Applied Chemistry 2011, 83, 461-478.  [PDF]

  • Friestad, G.K.; Ji, A.; Baltrusaitis, J.; Korapala, C.S.; Qin, J.  Scope of Stereoselective Mn-Mediated Radical Addition to Chiral Hydrazones and Application in a Formal Synthesis of Quinine. Journal of Organic Chemistry 2012, 77, 3159-3180.

  • Friestad, G.K.; Sreenilayam, G.  Versatile Configuration-Encoded Strategy for Rapid Synthesis of 1,sd5-Polyol Stereoisomers. Organic Letters 2010, 12, 5016-5019.

  • Friestad, G. K.; Lee, H. J. "Trans-2,5-Disubstituted Tetrahydrofurans via Additions of Carbon Nucleophiles to the Strained Bicyclic Acetal 2,7-Dioxabicyclo[2.2.1]heptane." Organic Letters 2009, 11, 3958-3961.

  • Friestad, G. K.; Banerjee, K. "Synthesis of gamma-Amino Esters via Mn-Mediated Radical Addition to Chiral gamma-Hydrazonoesters." Organic Letters 2009, 11, 1095-1098.

  • Friestad, G. K.; Wu, Y. "Intermolecular Non-Reductive Alkylation of Enamides via Radical-Polar Crossover." Organic Letters 2009, 11, 819-822.

  • Friestad, G. K. "Reaction of Acetals with Organometallic Reagents." in Science of Synthesis, Vol. 40a: Compounds with One Saturated Carbon-Heteroatom Bond: Amines and Ammonium Salts, Enders, D.; Shaumann, E., Eds.; Thieme: Stuttgart, Germany, 2009, pp. 91-110.

  • Friestad, G. K. "Addition of Carbanions to Azomethines." in Science of Synthesis, Vol. 40a: Compounds with One Saturated Carbon-Heteroatom Bond: Amines and Ammonium Salts, Enders, D.; Shaumann, E., Eds.; Thieme: Stuttgart, Germany, 2009, pp 305-342.

  • Friestad, G. K.; Jiang, T.; Fioroni, G. M. "Stereocontrol in Radical Mannich Equivalents for Aminosugar Synthesis: Haloacetal and 2-(Phenylthio)vinyl Tethered Radical Additions to alpha-Hydroxyhydrazones." Tetrahedron 2008, 64, 11549-11557.

  • Friestad, G.K.; Ji, A.  Mn-Mediated Coupling of Alkyl Iodides and Ketimines: A Radical Addition Route to alpha,alpha-Disubstituted alpha-Aminoesters. Organic Letters, 2008, 10, 2311-2313.

  • Korapala, C. S.; Qin, J.; Friestad, G. K. "Quinine Synthesis Studies: A Radical-Ionic Annulation via Mn-Mediated Addition to Chiral N-Acylhydrazones" Organic Letters 2007, 9, 4246-4249.

  • Friestad, G. K.; Mathies, A. K. "Effects of alpha-Alkoxy Substitution and Conformational Constraints on 6-exo Radical Cyclizations of Hydrazones via Reversible Thiyl and Stannyl Additions." Tetrahedron 2007, 63, 9373-9381.  (Corrigendum:  Tetrahedron 2007, 63, 13039.)

  • Friestad, G. K.; Jiang, T.; Mathies, A. K. "Enhanced Reactivity in Radical Cyclizations of Hydrazones Using the Silicon-Tethered 1-Bromovinyl Group." Tetrahedron 2007, 63, 3964-3972.

  • Friestad, G. K.; Jiang, T.; Mathies, A. K. "Aldehyde-Selective Wacker Oxidation in a Thiyl-Mediated Vinyl Group Transfer Route to Daunosamine." Organic Letters 2007, 9, 777-780.

  • Friestad, G. K.; Mathies, A. K. "Recent Developments in Asymmetric Catalytic Addition to C=N Bonds." Tetrahedron 2007, 63, 2541-2569.

  • Friestad, G.K.; Qin, J; Suh, Y.; Marié, J.C.   Mn-Mediated Coupling of Alkyl Iodides and Chiral N-Acylhydrazones: Optimization, Scope, and Evidence for a Radical Mechanism. Journal of Organic Chemistry  2006, 71, 7016-7027.

  • Ding, H.; Friestad, G. K. "Strecker Reactions of Chiral N-Acylhydrazones." Heterocycles 2006, 70, 185-199.

  • Friestad, G. K.; Korapala, C. S.; Ding, H.  "Dual Activation in Asymmetric Allylsilane Addition to Chiral N-Acylhydrazones: Method Development, Mechanistic Studies, and Elaboration of Homoallylic Amine Adducts." Journal of Organic Chemistry 2006, 71, 281-289.

  • Ding, H.; Friestad, G. K.  "Asymmetric Addition of Allylic Nucleophiles to Imino Compounds."  Synthesis 2005, 2815-2829.

  • Friestad, G. K.; Draghici, C.; Soukri, M.; Qin, J. "Radical Addition Approach to Asymmetric Amine Synthesis: Design, Implementation, and Comparison of New Chiral N-Acylhydrazones." Journal of Organic Chemistry 2005, 70, 6330-6338.

  • Friestad, G. K.  "Chiral N-Acylhydrazones: Versatile Imino Acceptors for Asymmetric Amine Synthesis."  European Journal of Organic Chemistry 2005, 3157-3172.

  • Friestad, G. K.; Fioroni, G. M.  "Haloacetal Radical Cyclizations of alpha- and beta-Hydroxyhydrazones."  Organic Letters 2005, 7, 2393-2396.

  • Friestad, G.K.; Deveau, A. M.; Marié, J.C.  Stereoselective Mn-Mediated Coupling of Functionalized Iodides and Hydrazones: A Synthetic Entry to the Tubulysin gamma-Amino Acids.  Organic Letters 2004, 6, 3249-3252.

  • Ding, H.; Friestad, G. K. "Allyltrimethoxysilane Addition to N-Acylhydrazones:  Two Catalytic Methods Employing CuCl and Fluoride." Synthesis 2004, 2216-2221.

  • Friestad, G. K.; Massari, S. E.  "A Silicon Tether Approach for Addition of Functionalized Radicals to Chiral alpha-Hydroxyhydrazones: Diastereoselective Additions of Hydroxymethyl and Vinyl Synthons." Journal of Organic Chemistry 2004, 69, 863-875.

  • Ding, H.; Friestad, G.K.  Trifluoroacetyl-Activated Nitrogen-Nitrogen Bond Cleavage of Hydrazines by Samarium (II) Iodide. Organic Letters 2004, 6, 637-640.

  • Friestad, G.K.; Shen, Y.; Ruggles, E.L.  Enantioselective Radical Addition to N-Acyl-hydrazones Mediated by Chiral Lewis Acids. Angewandte Chemie International Edition 2003, 42, 5061-5063.

  • Friestad, G. K.; Jiang, T.; Fioroni, G. M.  "Tandem Thiyl Radical Addition and Cyclization of Chiral Hydrazones Using a Silicon-Tethered Alkyne." Tetrahedron: Asymmetry 2003, 14, 2853-2856.

  • Qin, J.; Friestad, G. K. "Stereocontrol in Hydride Addition to Ketone-Derived Chiral N-Acylhydrazones." Tetrahedron 2003, 59, 6393-6402.

  • Shen, Y.; Friestad, G. K. "Comparison of Electrophilic Amination Reagents for N-Amination of 2-Oxazolidinones and Application to Synthesis of Chiral Hydrazones." Journal of Organic Chemistry 2002, 67, 6236-6239.

  • Friestad, G.K.; Qin, J.  Intermolecular Alkyl Radical Addition to Chiral N-Acylhydrazones Mediated by Manganese Carbonyl.  Journal of the American Chemical Society  2001, 123, 9922-9923.

  • Friestad, G.K.; Ding, H.   Asymmetric Allylsilane Additions to Enantiopure N-Acylhydrazones with Dual Activation by Fluoride and In(OTf)3Angewandte Chemie International Edition 2001, 40, 4491-4493.

  • Friestad, G. K.  "Addition of Carbon-Centered Radicals to Imines and Related Compounds" Tetrahedron 2001, 57, 5461-5496.

  • Friestad, G. K.; Massari, S. E.  "Diastereoselective Vinyl Addition to Chiral Hydrazones via Tandem Thiyl Radical Addition and Silicon-Tethered Cyclization." Organic Letters 2000, 2, 4237-4240.

  • Friestad, G.K.; Qin, J.   Highly Stereoselective Intermolecular Radical Addition to Aldehyde Hydrazones from a Chiral 3-Amino-2-oxazolidinone. Journal of the American Chemical Society 2000, 122, 8329-8330.

  • Friestad, G. K. "A Silicon Tether Approach for Diastereocontrol in Radical Addition to Chiral Hydrazones."  Organic Letters 1999, 1, 1499-1501.