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nugent

Thomas Nugent

Associate Professor of Chemistry
School of Science
Campus Ring 1, 28759 Bremen, Germany
Phone number
+49 421 200-3232
Fax number
+49 421 200-3229
Email Address
tnugent@constructor.university
Office
Research III, Room 113
Research Interests

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

University Education
1991 B.Sc. in Chemistry, Virginia Polytechnic Institute & State University, Blacksburg, Virginia, USA
1995 Ph.D. in Organic Chemistry, Virginia Polytechnic Institute & State University, Blacksburg, Virginia, USA
1996-1997 Postdoctoral Fellow, University of Liverpool, Liverpool, Great Britain
Fellowships and Awards
  • 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)

Research and Teaching Positions
  • Process Research Chemist, Catalytica Fine Chemicals / DSM Pharmaceuticals, Mountain View, California, USA (1998-2000)

  • Process Research Chemist, Pharmacia / Pfizer Corporation, South San Francisco, California, USA (2001-2003)

  • Assistant Professor of Organic Chemistry, International University of Bremen, Bremen, Germany (January 2004)

  • Associate Professor of Organic Chemistry, Jacobs University Bremen gGmbH, Bremen, Germany (September 2017)

  • Associate Professor of Organic Chemistry, Constructor University Bremen, Bremen, Germany (current)

(I have been employed at the same location during all of my professorships, but our university has changed its name three times)

Taught Courses:

Since February 2018 I am the Study Program Chair for the Medicinal Chemistry & Chemical Biology B.Sc. program.

Courses taught since 2018:

Medicinal Chemistry & Chemical Biology (7.5 ECTS)
General Organic Chemistry (5.0 ECTS)
Advanced Organic Chemistry (5.0 ECTS)
Advanced Organic Synthesis (5.0 ECTS)
Seminar (presentation course, 2.5 ECTS)
General and Advanced Organic Chemistry Laboratory (three rotations, each 2.5 ECTS)
(A 5 ECTS course represents 14 weeks of lectures with two 75 minute lectures per week).

Publications

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

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.

Recent Third-Party Funding

 Final Report Date Falling in 2019 to 2024

Funding agency

Reference number

Project title

Funding awarded and status

DFG

NU 235/6-1

The First Regio-, Chemo-, and Stereoselective Mono-a-Functionalization of Achiral Diketone Substrates

(project completed)

119,000.00 €

(two years)

continued as

NU 235/6-2

DFG

NU 235/6-2

Enantioselective Conversion of Achiral Diketones and Triketones for Shortened Bioactive Molecule Synthesis

(project completed)

131,000.00 €

(two years)

Final report:

24 June 2021

DFG

NU 235/7-1

The First Broad Examination of Michael Reactions in the Presence of a Diverse Array of Acidic Spectator Functional Groups – Enantioselective Synthesis

(project completed)

133,000.00 €

(two years)

Final report:

04 March 2019

DFG

NU 235/9-1

Enantioselective Ammonium Enolate Based Michael-Henry and Michael-Henry-Aldol Cascade Reactions: Development, Mechanistic Insight, and Applications for Morphine Family Analgesics (project started January 2023)

222,000.00 €

(three years)

Approved:

28 June 2022

Other Professional Activities
  • American Chemical Society (ACS)
  • Gesellschaft Deutscher Chemiker (GDCh)