Prof. Dr. Thomas Nugent

Back row (left to right): Thomas Nugent, Ruslan Levochkin (B.Sc. student), Sofiia-Stefaniia Zhylinska (B.Sc. student), Nilesh Shitole (Ph.D. student),
Front row (left to right): Aida Hilawe Lakew (B.Sc. student), Fathima Shakira Mohamed Nazar (B.Sc. student), Kateryna Lagunova (B.Sc. student), Kritika Brahmanand Dwivedi (Ph.D. student).
In total we originate from: Ethiopia, India, Russia, Sri Lanka, Ukraine, and the USA.

Pharmaceutical and natural product drug candidates are developed to improve and extend human and animal health, but they will not become marketed drugs if an efficient synthesis is not available. Our entry point is to devise syntheses that are more efficient than currently known. As a consequence, students in the Nugent research group are exposed to inventive new strategies to shorten the synthesis of complex chiral organic molecules. In parallel, the devised synthetic route should allow previously inaccessible analogs to be synthesized for medicinal chemistry evaluation. Recent successful examples from our research group include syntheses of (R)-Pristiq (antidepressant) and a highly enantioenriched Alzheimer drug candidate (GSM-1). Our current focus is on the morphine family of analgesics and includes a short synthesis of morphine.

The insight and creativity required for efficient drug synthesis often relies on one or two critical enantioselective catalytic methodologies. For this reason, we also engage in methodological studies wherein a transition metal catalyst or organocatalyst transforms an inexpensive prochiral starting material into a high value chiral building block. Examples from our group are methods for enantioenriched amine synthesis, regio-, chemo-, and enantioselective aldol reactions, expanded substrate breadth for enantioselective Michael reactions, chiral enolate reactions, etc.

Current Research (2017-2023):

• Natural Product / Pharmaceutical Drug Synthesis
  • Short synthesis of morphine and new analogs (2023-continuous)
  • Step efficient synthesis (2017)
    • Shortest enantioselective synthesis of (R)-Pristiq (commonly prescribed antidepressant)
  • First enantioselective synthesis of Alzheimer research drugs (2016)
    • g-secretase modulators
      • Highest yielding synthesis of Merck Sharp & Dohme’s top research drug candidate
      • Medicinal chemistry opportunities
• In Water Reaction Concepts
  • Discovery of new chemoselectivity: aldol versus Knoevenagel reactions (2021 & 2023)
  • Host-guest chemistry: cucurbituril based reaction rate acceleration (2022)
• Enantioselective Organocatalysis
  • Enamine based bifunctional catalyst concepts (2017)
    • Salt bridge transition state organizing principles
    • Hydrogen bond transition state organizing principles
• Enantioselective Organocatalysis (continued)
  • Site-Selectivity within di- and triketones (2021)
    • Highly selective mono-aldolization
    • Desymmetrization
    • Access to new aldol diastereomers
  • Michael substrate expansion: acidic spectator group tolerance (2017)
    • Carboxylic acids
    • Aniline-based amides
    • Catechols and phenols

• Postdoctoral fellowship, University of Liverpool, Liverpool, Great Britain (1996-1997)

• Professor's Social Involvement Award (Student government awarded in 2005)

• Teacher of the Year 2016 (within the Natural Science programs)

• Teacher of the Year 2020 (within the Natural Science programs)

Book (editor)

• Chiral Amine Synthesis. Methods, Developments and Applications; Nugent, T. C. Ed.; Wiley-VCH: Weinheim, 2010.

Book Chapters

• Nugent, T. C. Asymmetric Reductive Amination. In Chiral Amine Synthesis. Methods, Developments and Applications, Nugent, T. C. Ed.; Wiley-VCH: Weinheim, 2010, p. 225-245.
   
• Nugent, T. C. Chiral Amine Synthesis – Strategies, Examples, and Limitations. In Process Chemistry in the Pharmaceutical Industry, Second Edition: Challenges in an Ever-Changing Climate, Braish, T. F.; Gadamasetti, K. Eds.; CRC Press-Taylor and Francis Group: New York, 2008, p. 137-156.

Manuscripts

*Corresponding author

31. T. C Nugent*, N. N. Shitole, Aromatic Functionalized Indanones and Indanols: Broad Spectrum Intermediates for Drug Candidate Diversification, Organics 2024, 5, 263–276. https://doi.org/10.3390/org5030014 Distinction: Selected for the cover page.

30. H. Al Beiruty, S.-S. Zhylinska, N. Kutateladze, H. K. T. Cheong, J. A. Ñíguez, S. J. Burlingham, X. Marset, G. Guillena, R. Chinchilla, D. A. Alonso*, and T. C. Nugent*, Enantioselective Catalytic Aldol Reactions in the Presence of Knoevenagel Nucleophiles: A Chemoselective Switch Optimized in Deep Eutectic Solvents Using Mechanochemistry, Molecules 2024, 29, 4. (published December 19, 2023) https://doi.org/10.3390/molecules29010004

29. Invited contribution to a Special Collection on ‘Organocatalysis’: T. C. Nugent*, A. E. de Vos, I. Hussain, H. A. E. D. Hussein, F. Goswami, A 2000 to 2020 Practitioner’s Guide to Chiral Amine Based Enantioselective Aldol Reactions: Ketone Substrates, Best Methods, in Water Reaction Environments, and Defining Nuances, Eur. J. Org. Chem. 2022, 7, e202100529. https://doi.org/10.1002/ejoc.202100529

28. F. N. Tehrani, K. I. Assaf*, R. Hein, Casper M. E. Jensen, T. C. Nugent, W. M. Nau*, Supramolecular Catalysis of a Catalysis-Resistant Diels-Alder Reaction: Almost Theoretical Acceleration of Cyclopentadiene Dimerization inside Cucurbit[7]uril, ACS Catalysis 2022, 12, 2261−2269. https://doi.org/10.1021/acscatal.1c05659

27. T. C. Nugent*, F. Goswami, S. Debnath, I. Hussain, H. A. E. D. Hussein, A. Karn, and S. Nakka, Harnessing Additional Capability from in Water Reaction Conditions: Aldol versus Knoevenagel Chemoselectivity, Adv. Synth. Catal. 2021, 363, 3539-3545. https://doi.org/10.1002/adsc.202100301

26. A. Sadiq and T. C. Nugent*, Catalytic Access to Succinimide Products Containing Stereogenic Quaternary Carbons, ChemistrySelect 2020, 5, 11934-11938. https://doi.org/10.1002/slct.202003664

25. T. C. Nugent*, H. A. E. D. Hussein, S. Ahmed, F. T. Najafian, I. Hussain, T. Georgiev, M. K. Al-Joumhawy, Carboxylate Salt Bridge-Mediated Enamine Catalysis: Expanded Michael Reaction Substrate Scope and Facile Access to Antidepressant (R)-Pristiq, Adv. Synth. Catal. 2017, 359, 2824-2831. https://doi.org/10.1002/adsc.201700801

24. T. C. Nugent*, P. Spiteller, I. Hussain, H. A. E. D. Hussein, F. T. Najafian, A Catalyst-Directed Remote Stereogenic Center Switch During the Site-Selective Aldol Desymmetrization of Cyclohexanone-Based Diketones, Adv. Synth. Catal. 2016, 358, 3706-3713. https://doi.org/10.1002/adsc.201600833

23. T. C. Nugent*, F. T. Najafian, H. A. E. D. Hussein, I. Hussain, Beyond Chemoselectivity: Catalytic Site-Selective Aldolization of Diketones and Exploitation for Enantioselective Alzheimer Drug Candidate Synthesis, Chem. Eur. J. 2016, 22, 14342-14348. https://doi.org/10.1002/chem.201602900

22. T. C. Nugent*, R. V. Williams*, A. Dragan, A. A. Méndez, A. V. Iosub, An investigation of the observed, but counterintuitive, stereoselectivity noted during chiral amine synthesis via N-chiral-ketimines, Beilstein J. Org. Chem. 2013, 9, 2103-2112.

21. T. C. Nugent*, S. M. Marinova, Step Efficient Access to Chiral Primary Amines, Synthesis 2013, 45, 153-166.

20. T. C. Nugent*, A. Bibi, A. Sadiq, M. Shoaib, M. N. Umar, F. N. Tehrani, Chiral Picolylamines for Michael and Aldol Reactions: Probing Substrate Boundaries, Org. Biomol. Chem. 2012, 10, 9287-9294.

19. T. C. Nugent*, A. Sadiq, A. Bibi, T. Heine, L. L. Zeonjuk N. Vankova, B. S. Bassil, Noncovalent Bifunctional Organocatalysts: Powerful Tools for Contiguous Quaternary-Tertiary Stereogenic Carbon Formation, Scope, and Origin of Enantioselectivity, Chem. Eur. J. 2012, 18, 4088-4098.

18. T. C. Nugent*, D. E. Negru, M. El-Shazly, D. Hu, A. Sadiq, A. Bibi, M. N. Umar, Sequential Reductive Amination-Hydrogenolysis: A One-Pot Synthesis of Challenging Chiral Primary Amines, Adv. Synth. & Catal. 2011, 353, 2085-2092.

17. T. C. Nugent*, M. Shoaib, A. Shoaib, Practical access to highly enantioenriched quaternary carbon Michael adducts using simple organocatalysts, Org. Biomol. Chem. 2011, 9, 52-56.

16. T. C. Nugent*, M. N. Umar, A. Bibi, Picolylamine as an Organocatalyst Template for Highly Diastereo- and Enantioselective Aqueous Aldol Reactions, Org. Biomol. Chem. 2010, 8, 4085-4089.

15. T. C. Nugent*, M. El-Shazly, Chiral Amine Synthesis – Recent Developments and Trends for Enamide Reduction, Reductive Amination, and Imine Reduction, Adv. Synth. & Catal. 2010, 352, 753-819.

14. T. C. Nugent*, M. El-Shazly, V. N. Wakchaure, Ytterbium Acetate Promoted Asymmetric Reductive Amination: Significantly Enhanced Stereoselectivity, J. Org. Chem. 2008, 73, 1297-1305.

13. T. C. Nugent*, A. Ghosh, Selective Synthesis of Unnatural a-, b-, and g-Amino Esters, Eur. J. Org. Chem. 2007, 3863-3869.

12. V. N. Wakchaure, R. R. Mohanty, A. J. Shaikh, T. C. Nugent*, A One-Pot Asymmetric Sequential Amination-Alkylation Reaction: Expedient Synthesis of a-Alkyl,-Alkyl Substituted Chiral Amines, Eur. J. Org. Chem. 2007, 959-964.

11. T. C. Nugent*, A. K. Ghosh, V. N. Wakchaure, R. R. Mohanty, Asymmetric Reductive Amination: Convenient Access to Enantioenriched Alkyl-Alkyl or Aryl-Alkyl Substituted a-Chiral Primary Amines, Adv. Synth. & Catal. 2006, 348, 1289-1299.

10. T. C. Nugent*, R. Seemayer, An Efficient Enantiopure Synthesis of a Pivotal Precursor to Substance P Antagonists, Org. Process Res. Dev. 2006, 10, 142-148.

9. T. C. Nugent*, V. N. Wakchaure, A. K. Ghosh, R. R. Mohanty, Evolution of Ti(OiPr)4 and Raney-Nickel for the Asymmetric Reductive Amination of Prochiral Ketones, Org. Lett. 2005, 7, 4967-4970. 

Manuscript publications prior to my independent career as a professor are found below.

8. J. J. Chen*, T. C. Nugent, C. V. Lu, S. Kondapally, P. Giannousis, Y. Wang, J. T. Wilmot, Rapid Improvement of a Reductive Sulfonylation Using Design of Experiment Methods, Org. Process Res. Dev. 2003, 7, 313-317.

7. T. C. Nugent, T. Hudlicky*, Chemoenzymatic Synthesis of all Four Stereoisomers of Sphingosine From Chlorobenzene: Glycosphingolipid Precursors, J. Org. Chem. 1998, 63, 510-520.

6. B. M. Adger, J. V. Barkley, S. Bergeron, M. W. Cappi, B. E. Flowerdew, M. P. Jackson, R. McCague, T. C. Nugent, S. M. Roberts*, Improved Procedure for Juliá-Colonna Asymmetric Epoxidation of a,b-Unsaturated Ketones: Total Synthesis of Diltiazem and Taxol Side Chain, J. Chem. Soc., Perkin Trans. 1 1997, 3501-3507.

5. P. A. Bentley, S. Bergeron, M. W. Cappi, D. E. Hibbs, M. B. Hursthouse, T. C. Nugent, R. Pulido, S. M. Roberts*, Asymmetric Epoxidation of Enones Employing Polymeric a-Amino Acids in Non-Aqueous Media, J. Chem. Soc., Chem. Commun. 1997, 739-740.

4. M. G. Banwell, N. Haddad, T. Hudlicky*, T. C. Nugent, M. F. Mackay, S. L. Richard, Regio- and Stereo-Chemical Outcomes in the Nucleophilic Ring Cleavage Reactions of Monoepoxides Derived from cis-1,2-Dihydrocatechols, J. Chem. Soc., Perkin Trans. 1 1997, 1779-1791.

3. T. Hudlicky*, T. C. Nugent, W. Griffith, Chemoenzymatic Synthesis of D-erythro-C18- and L-threo-C18-sphingosines, J. Org. Chem. 1994, 59, 7944-7946.

2. T. Hudlicky*, M. G. Natchus, T. C. Nugent, Improved Practical Synthesis of a Prostaglandin and Carbocyclic Nucleoside Synthon, Synth. Comm. 1992, 22, 151-157.

1. T. Hudlicky*, H. Luna, H. F. Olivo, C. Anderson, T. C. Nugent, J. D. Price, Biocatalysis as a Strategy in the Exhaustive Enantiocontrolled Synthesis of Conduritols, J. Chem. Soc., Perkin Trans. 1 1991, 2907-2917.
 

• American Chemical Society (ACS)
• Gesellschaft Deutscher Chemiker (GDCh)