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 Prof. Dr. Thomas Nugent
Prof. Dr. Thomas Nugent
Prof. Dr.
Professor of Chemistry
Life Sciences & Chemistry

Campus Ring 1 28759 Bremen Germany

Fax: 
+49 421 200-3102
Email: 
t.nugent [at] jacobs-university.de
Office: 
Research III, Room 113
Research Interests: 

The Nugent group is interested in the synthesis of organic molecules of consequence, that is, those having an immediate societal impact (pharmaceutical and natural product drugs) and those containing challenging architectural features. These molecules require many chemical operations to synthesize (build) them and sometimes require years of research to do so. 
More often than not, a specific sequence of chemical operations (multistep organic synthesis) may only be accomplished when new synthetic methods (single organic transformations) are developed.  In particular synthetic methods based on enantioselective catalysis, employing transition metals (organometallic catalysts) or organic catalysts, are at the forefront of our modern know-how in synthetic organic chemistry. 
Development of these reactions is important because they enable the transformation of inexpensive prochiral (i.e. without handedness) organic starting materials into high value chiral (i.e. with handedness) synthons.  These chiral synthons (building blocks) allow the efficient synthesis of pharmaceutical and natural product drugs to occur and are consequently a major focus of our research efforts.

Current Research
Over the last five years the research group has focused on stepwise efficient mild methods for the synthesis of chiral molecules that can facilitate pharmaceutical drug and/or natural product synthesis. From these efforts two main areas of research have evolved:

  • Organocatalysis Research
    Organocatalysis is an exciting expanding field of research whose current challenges are of three main types: new catalyst templates, tandem reactions, and new reaction types. Our first contributions have come in the form of designing and introducing new organocatalyst templates, in particular using self-assembled catalysts based on amino acids (Michael and Mannich reactions) or with picolylamine catalysts (aldol and Michael reactions).
    • Noncovalent Organocatalysts
       In situ assembled catalysts represent a promising new avenue of research within the field organocatalysis. Here we show the first synergistic use of an amino acid, a hydrogen bond donor, and a base to form an active organocatalyst. Importantly, this tricomponent (ternary) catalyst system has provided a diverse array of difficult to access chiral quaternary carbon containing compounds, e.g., Michael (additions to nitroalkenes and maleimides) and Mannich reaction products (see below). Of particular note, all of these reactions have set new benchmarks for every measureable category concerning the shown reactions (December 2011), e.g., catalyst loading, stoichiometry of the starting materials, product yield, stereoselectivity, and reaction time.
    • Diamine Organocatalysts
      Although pyridine based diamine organocatalysts have been previously examined, none are currently known to be exceptional catalysts. We introduced the 2-picolylamine catalyst template and have established the chiral versions as very promising new organocatalysts. PicAm-2, which exhibits a lone stereogenic center, was identified as allowing fast and highly stereoselective anti-aldol product formation at a low catalyst loading (5 mol %) in brine.
      Aldol reactions of cyclohexanone with ortho-, meta-, or para-substituted benzaldehydes are good for establishing the potential usefulness of a new catalyst, but the products themselves lack the functional group diversity of drug-like building blocks. Our examination of functionalized ketones allowed us to realize the inherent high value of our new organocatalyst template. Notably the results achieved below, for the N-Boc-piperidone and 4-ketalcyclohexanone based products (bottom line of structures), are the best achieved to date (yield, dr, and ee) at a 5 mol% catalyst loading.
  • Chiral Amine Synthesis
    Chiral amines are powerful pharmacophores for defining new pharmaceutical drugs, which is perhaps unsurprising due to their combination of high density structural information with biologically relevant hydrogen bonding capabilities. Chiral amine-based pharmaceutical drugs and alkaloid natural products overwhelmingly contain secondary or tertiary amines, but introducing nitrogen in these forms is not yet feasible. To overcome this problem, chiral primary amines are the building blocks that medicinal chemists often seek out for drug candidate development.
    • Chiral primary amines are currently the reliable building blocks that chemists often turn to during the synthetic planning of an alkaloid, while medicinal chemists require them because they hold greater diversification potential verses secondary or tertiary chiral amine building blocks for drug candidate development (see marketed drugs below).
      The synthesis of most chiral primary amines continues to be challenging. This is especially so when framed in the context of reaction step economy from commodity chemicals, e.g., from aliphatic or aromatic based prochiral ketones. In response to this shortcoming, we have developed robust procedures permitting access to chiral primary amines in one-step or two-step methods from ketones and aldehdyes. The two step methods are as depicted below.
      The above noted methods are of practical value to organic chemists because they do not require a glovebox or specialized techniques and are stepwise efficient. Furthermore, the phenylethylamine (PEA or α-MBA) auxiliary is inexpensive and used on an industrial scale in either enantiomeric form, allowing access to both enantiomeric forms of the desired amine.
      For specific chiral amine examples and the strategies employed, follow the hyperlinks in the ovals below.

 

University Education: 
1990B.Sc. in Chemistry, Virginia Polytechnic Institute & State University, Blacksburg, Virginia, USA
1995Ph.D. in Organic Chemistry, Virginia Polytechnic Institute & State University, Blacksburg, Virginia, USA
1996-1997Postdoctoral Fellow, University of Liverpool, Liverpool, Great Britain
1998-2000Process Research Chemist, Catalytica Fine Chemicals / DSM Pharmaceuticals, Mountain View, California, USA
2001-2003Process Research Chemist, Pharmacia / Pfizer Corporation, South San Francisco, California, USA
2004 – presentAssistant Professor of Organic Chemistry, Jacobs University Bremen, Germany, Department of Life Sciences & Chemistry, Faculty of Health

 

Fellowships and Awards: 
  • Postdoctoral Fellow, University of Liverpool, Liverpool, Great Britain (1996-1997)
  • Professor's Social Involvement Award (awarded by the student government 2005)
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 (October 2003)
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

  • Nugent, T. C.; Marinova, S. M. Step Efficient Access to Chiral Primary Amines, Synthesis 2013, 45, 153-166.
  • Nugent, T. C., Bibi, A.; Sadiq, A.; Shoaib, M.; Umar, M. N.; Tehrani, F. N. Chiral Picolylamines for Michael and Aldol Reactions: Probing Substrate Boundaries, Org. Biomol. Chem. 2012, 10, 9287-9294.
  • Nugent, T. C.; Sadiq, A.; Bibi, A.; Heine, T.; Zeonjuk L. L.; Vankova, N.; Bassil, B.S. Noncovalent Bifunctional Organocatalysts: Powerful Tools for Contiguous Quaternary-Tertiary Stereogenic Carbon Formation, Scope, and Origin of Enantioselectivity, Chem. Eur. J. 2012, 18, 4088-4098.
  • Nugent, T. C.; Negru, D. E.; El-Shazly, M.; Hu, D.; Sadiq, A.; Bibi, A.; Umar, M. N. Sequential Reductive Amination-Hydrogenolysis: A One-Pot Synthesis of Challenging Chiral Primary Amines, Adv. Synth. Catal. 2011, 353, 2085-2092.
  • Highlighted in Synfacts (2011, 1198)
  • Nugent, T. C.; Shoaib, M.; Shoaib, A. Practical Access to Highly Enantioenriched Quaternary Carbon Michael Adducts Using Simple Organocatalysts,
  • Org. Biomol. Chem. 2011, 9, 52-56.
  • Labeled as a Hot Article.
  • Nugent, T. C.; Naveed Umar, M.; Bibi, A. Picolylamine as an Organocatalyst Template for Highly Diastereo- and Enantioselective Aqueous Aldol Reactions, Org. Biomol. Chem. 2010, 8, 4085-4089.
  • Nugent, T. C.; El-Shazly, M. Chiral Amine Synthesis – Recent Developments and Trends for Enamide Reduction, Reductive Amination, and Imine Reduction, Adv. Synth. Catal. 2010, 352, 753-819.
  • Nugent, T. C.; El-Shazly, M.; Wakchaure, V. N. Ytterbium Acetate Promoted Asymmetric Reductive Amination: Significantly Enhanced Stereoselectivity, J. Org. Chem. 2008, 73, 1297-1305.
  • Nugent, T. C.; Ghosh, A. Selective Synthesis of Unnatural α-, β-, and γ-Amino Esters, Eur. J. Org. Chem. 2007, 3863-3869.
  • Wakchaure, V. N.; Mohanty, R. R.; Shaikh, A. J.; Nugent, T. C. A One-Pot Asymmetric Sequential Amination-Alkylation Reaction: Expedient Synthesis of α-Alkyl,-Alkyl Substituted Chiral Amines, Eur. J. Org. Chem. 2007, 959-964.
  • Nugent, T. C.; Ghosh, A. K.; Wakchaure, V. N.; Mohanty, R. R. Asymmetric Reductive Amination: Convenient Access to Enantioenriched Alkyl-Alkyl or Aryl-Alkyl Substituted α-Chiral Primary Amines, Adv. Synth. & Catal. 2006, 348, 1289-1299.
  • Nugent, T. C.; Seemayer, R. An Efficient Enantiopure Synthesis of a Pivotal Precursor to Substance P Antagonists, Org. Process Res. Dev. 2006, 10, 142-148.
  • Nugent, T. C.; Wakchaure, V. N.; Ghosh, A. K.; Mohanty, R. R. Evolution of Ti(OiPr)4  Alkoxides and Raney-Nickel for the Asymmetric Reductive Amination of Prochiral Ketones, Org. Lett. 2005, 7, 4967-4970.
  • Chen, J. J.;Nugent, T. C.; Lu, C. V.; Kondapally, S.; Giannousis, P.; Wang, Y.; Wilmot, J. T. Rapid Improvement of a Reductive Sulfonylation Using Design of Experiment Methods, Org. Process Res. Dev.2003, 7, 313-317.
  • Nugent, T. C.; Hudlicky, T. Chemoenzymatic Synthesis of all Four Stereoisomers of Sphingosine From Chlorobenzene: Glycosphingolipid Precursors, J. Org. Chem. 1998, 63, 510-520.
  • Adger, B. M.; Barkley, J. V.; Bergeron, S.; Cappi, M. W.; Flowerdew, B. E.; Jackson, M. P.; McCague, R.; Nugent, T. C.; Roberts, S. M. An Improved Procedure for Juliá-Colonna Asymmetric Epoxidation of α,β-Unsaturated Ketones. Total Synthesis of Diltiazem and Taxol Side Chain, J. Chem. Soc., Perkin Trans. 11997, 3501-3507.
  • Bentley, P. A.; Bergeron, S.; Cappi, M. W.; Hibbs, D. E.; Hursthouse, M. B.; Nugent, T. C.; Pulido, R.; Roberts, S. M. Asymmetric Epoxidation of Enones Employing Polymeric α-Amino Acids in Non-Aqueous Media, J. Chem. Soc., Chem. Commun.1997, 739-740.
  • Banwell, M. G.; Haddad, N.; Hudlicky, T.; Nugent, T. C.; Mackay, M. F.; Richard, S. L. Regio- and Stereo-Chemical Outcomes in the Nucleophilic Ring Cleavage Reactions of Monoepoxides Derived from cis-1,2-Dihydrocatechols, J. Chem. Soc., Perkin Trans. 11997, 1779-1791.
  • Hudlicky, T.; Nugent, T.; Griffith, W. Chemoenzymatic Synthesis of D-erythro-C18– and L-threo-C18-sphingosines, J. Org. Chem.1994, 59, 7944-7946.
  • Hudlicky, T.; Natchus, M. G.; Nugent, T. C. Improved Practical Synthesis of a Prostaglandin and Carbocyclic Nucleoside Synthon, Synth. Comm.1992, 22, 151-157.
  • Hudlicky, T.; Luna, H.; Olivo, H. F.; Anderson, C.; Nugent, T. C.; Price, J. D. Biocatalysis as a Strategy in the Exhaustive Enantiocontrolled Synthesis of Conduritols, J. Chem. Soc., Perkin Trans. 11991, 2907-2917.

Patents

  • Synthesis of Amine Stereoisomers; Nugent, T. C.; Wakchaure, V. N.; Ghosh, A. K.; Mohanty, R. R. (International University Bremen, GmbH), publication number: WO2006030017, 23 March 2006.
  • Process for the Preparation of (S,S)-cis-Phenyl-3-Aminopiperidine; Nugent, T. C.; Seemayer, R.; and Liang, J. (Pfizer Products, Inc. and DSM Pharmaceuticals, Inc.), publication number: WO2004037174, 06 May 2004.
  • Process for the Preparation of (S,S)-cis-2-Benzhydryl-3-benzylaminoquinuclidine; Nugent, T. C.; Seemayer, R. (Pfizer Products, Inc. and DSM Pharmaceuticals, Inc.), publication number: WO2004035575, 29 April 2004.
Other Professional Activities: 
  • American Chemical Society (ACS)
  • Gesellschaft Deutscher Chemiker (GDCh)