Hien M. Nguyen
- B.S., Tufts University (1996)
- Ph.D., University of Illinois at Urbana-Champaign (2003)
- NIH Postdoctoral Fellow, Stanford University (2004-2006)
Organic Chemistry, Transition-Metal Catalysis, Chemical Biology, Polymer Chemistry, Nucleophilic Fluorination and Radiofluorination, Transition-Metal-Catalyzed 1,2-Cis Glycosylation, Photoredox Catalysis, Heparin and Heparan Sulfate Oligosaccharides, PS A1 Immunostimulants, and Carbohydrate-Functionalized Polymers.
My laboratory is focused on the development of novel methods for the stereoselective synthesis of complex oligosaccharides and the enantioselective construction of fluorine-containing compounds that possess significant bioactivity utilizing novel transition-metal-catalyzed processes. The bioactive molecules obtained will set the stage for subsequent biological studies as well as the design and development of related structural analogs. For each of the projects, we have teamed up with the collaborators here at the University of Iowa Carver College of Medicine, Northwestern University, and the University of North Carolina - Chapel Hill.
1) New Approaches to Stereoselective 1,2-Cis Glycosylation
We have developed novel transition-metal-catalyzed stereoselective glycosylation methods for combining a wide variety of different classes of monosaccharides to produce oligosaccharides bearing 1,2-cis-2-aminosugar motifs in excellent yield and selectivity. The method relies on the nature of the catalyst rather than protecting groups on the substrate to control the selectivity, is broadly applicable to a wide range of substrates, and provides the coupling products in high yields and with excellent selectivity. In addition, the methods are mild and conducted under operationally simple protocol utilizin sub-stoichiometric amounts of nickel catalyst. The nickel-catalyzed 1,2-cis-2-amino glycosylation methodologies have been applied to the synthesis and chemical biology of heparin and heparan sulfate oligosaccharides (anticoagulant and anticancer), tumor-associated mucin TN-antigen, GPI anchors, and mycothiol. Currently, we are designing and synthesizing heparan-sulfate oligosaccharide-functionalized polymers for potential use for heparanase inhibitors (this project is in collaboration with Prof. Jian Liu at UNC-Chapel Hill) and PS A1 analogs as potential immunostimulants (this project is in collaboration with Prof. Jon Houtman and Prof. Steve Varga here in the Department of Microbiology Carver College of Medicine).
Currently, we are also developing a series of predictable and stereoselective methods for the construction of the challenging beta-mannosides, alpha-1,2-cis glycosides, and alpha sialosides via the merger of photoredox catalysis with transition-metal catalysis. This chemistry is an entirely new approach to glycosidation and utilizes the bench-stable catalysts under mild and operationally simple conditions.
2) Nucleophilic Fluorination and Radiofluorination
Our second research program involves the discovery of new methods for the regio- and enantioselective synthesis of fluorine-containing compounds via transition-metal-catalyzed fluorination of trichloroacetimidate substrates. In 2011, we have developed a branched-selective fluorination of allylic trichloroacetimidates utilizing [IrCl(COD)]2 and Et3N.3HF. In 2015, we extended the fluorination process to the enantioselective variant. Employing a chiral diene-ligated iridium catalyst resulted in allylic fluorides with 90–97% ee.
Recently, we have developed a rapid incorporation of fluorine-18 into allylic systems of organic molecules utilizing [IrMeO(COD)]2 in a combination with [18F]KF.kryptofix complex for potential use as PET tracers. [18F]fluorine-containing compounds play a prominent role in positron emission tomography (PET) imaging, one of the most rapidly growing areas of non-invasive medical imaging. Fluorine-18 appears to be the most ideal isotope for PETimaging due to its low energy positron emission, ease of preparation, and ideal half-life (110 min). Use of [18F]KF.kryptofix allows 18F-incorporation into allylic systems in 5- 10 minutes with excellent radiochemical yield and specific activity. We continue our efforts by applying this reaction to the synthesis of nitric oxide synthase inhibitors and [18F]-labeled PET imaging agents of these inhibitors for detecting neurological disorders. This project is done in collaboration with 1) Prof. David Dick here at the University of Iowa College of Medicine PET Imaging Center and 2) Prof. Richard Silverman in the Department of Chemistry at Northwestern University.
1) Zhang, Q.; Stockdale, D. P.; Mixdorf, J. C.; Topczewski, J. J.; Nguyen, H. M.* “Iridium-Catalyzed Enantioselective Fluorination of Racemic. Secondary Trichloroacetimidates.” J. Am. Chem. Soc. 2015, 137, 11912 – 11915.
2) Zhang, Q.; Mixdorf, J. C.; Reynders III, G. J.; Nguyen, H. M. "Rh-Catalyzed Benzylic Fluorination of Trichloroacetimidates with Triethylamine Trihydrofluoride." Tetrahedron. 2015, 71, 5932 – 5938. (Special Issue for Professor Trost 's 2014 Tetrahedron Award).
3) Loka, R.; McConnell, M. S.; Nguyen, H. M. “Studies of Highly-Ordered Heterodiantennary Mannose/Glucose-Functionalized Polymers and Concanavalin A Protein Interactions Using Isothermal Titration Calorimetry.” Biomacromolecules 2015, 16, 4013 – 4021.
4) Yu, F.; McConnell, M. S.; Nguyen, H. M. “Scalable Synthesis of Fmoc-Protected GalNAc-Threonine Amino Acid and TN Antigen via Nickel Catalysis.” Org. Lett. 2015, 17, 2018 – 2021.
5) McKay, M. J.; Park, N. H.; Nguyen, H. M. “Stereoselective Formation of Alpha-Glycosyl Ureas: Scope and Mechanism.” Chem. Eur. J. 2014, 20, 8691 – 8701.
6) Arnold, J. S.; Mwenda, E.; Nguyen, H. M. “Sequential Amination and Hydroacylation Reactions for the Enantioselective Synthesis of Seven-Membered Heterocycles.” Angew. Chem. Int. Ed. 2014, 53, 3688 – 3692.
7) McConnell, M. S.; Yu, F.; Nguyen, H. M.* “Nickel-Catalyzed a-Glycosylation of C(1)-Hydroxyl Group of Inositol Acceptors: A Formal Synthesis of Mycothiol.” Chem. Commun. 2013, 49, 4313 – 4315.
8) Arnold, J. S.; Nguyen, H. M. “Rhodium-Catalyzed Dynamic Kinetic Asymmetric Transformations of Racemic Tertiary Allylic Trichloroacetimidates with Aniline Nucleophiles.” J. Am. Chem. Soc. 2012, 134, 8380 – 8383.
9) McKay, M. J.; Nguyen, H. M.* “Recent Advances in Transition Metal-Catalyzed Glycosylation.” ACS Catalysis 2012, 2, 1563 – 1595.
10) Topczewski, J. J.; Tewson, T. J.; Nguyen, H. M. “Iridium-Catalyzed Allylic Fluorination of Trichloroacetimidates.” J. Am. Chem. Soc. 2011, 133, 19318 – 19321.
11) Mensah, E. A.; Yu, F.; Nguyen, H. M.“Nickel-Catalyzed Stereoselective Glycosylation with C(2)-N-Substituted Benzylidene Glycosyl Trichloroacetimidates for the Formation of 1,2-cis-2-Amino Glycosides. Applications to the Synthesis of Heparin Disaccharides and GPI Anchor Pseudodisaccharides.” J. Am. Chem. Soc. 2010, 132, 14288-14302.
12) Mensah, E. A.; Nguyen, H. M.* “Nickel-Catalyzed Stereoselective Formation of a-2-Deoxy-2-Amino-Glycosides.” J. Am. Chem. Soc. 2009, 131, 8778 – 878010.
13) Mercer, G. J.; Yang, J.; McKay, M. J.; Nguyen, H. M. “Palladium-Catalyzed Rearrangement of Glycal Trichloroacetimidates: Application to the Stereoselective Synthesis of Glycosyl Ureas.” J. Am. Chem. Soc. 2008, 130, 11210-11218.
14) Yang, J.; Cooper-Vanosdell, C.; Mensah, E. A.; Nguyen, H. M. “Palladium-Catalyzed Stereoselective Glycosylation with Glycosyl Trichloroacetimidates” J. Org. Chem., Featured Article, 2008, 73, 794-800.