Hien M. Nguyen
Carl Johnson/Pfizer Professor of Organic Chemistry
B.S. Tufts University, 1996
Ph.D. University of Illinois at Urbana-Champaign, 2003
NIH Postdoctoral Fellow, Stanford University, 2003 - 2006
Chem 337 and 341
Hien M. Nguyen was born in Ho Chi Minh City (Saigon), Vietnam. Prof. Nguyen came to the US in 1989 and first settled with his family in Boston, Massachusetts. He graduated with honors from Tufts University in Medford, Massachusetts where he majored in chemistry and conducted research with Professor Marc d'Alarcao. Hien left Boston and moved to attend the University of Illinois at Urbana-Champaign, and he subsequently joined the group of the late David Y. Gin. His PhD thesis focused on developing new carbohydrate methodologies for efficient assembly of complex oligosaccharides. As an NIH postdoctoral fellow in the group of Prof. Barry Trost at Stanford University, Prof. Nguyen pursued training in the area of transition-metal catalysis. Prof. Nguyen began his independent career in 2006 and was promoted with tenure at the University of Iowa. In 2018, he relocated to Wayne State University as the Carl Johnson/Pfizer Endowed Chair and Professor of Chemistry.
Professor Nguyen's research group is focused on new catalytic carbohydrate reaction methods, fluorination and radiofluorination chemistry, as well as chemical biology of heparan sulfate and heparanase.
1) Catalytic Methods for Stereoselective 1,2-Cis Glycosylation
The field of glycoscience has burgeoned in the last several decades, leading to the identification of many oligosaccharides and glycoconjugates which could serve critical roles in a wide range of biological processes. This rapid growth of knowledge about the function of carbohydrates has attracted increasing attention from biological, pharmacological, and medicinal researchers. Meeting their research demands require access to significant quantities of well-defined bioactive carbohydrates. This has prompted resurgence in synthetic interest, with a particular focus on new approaches to construct glycosidic bond. Despite the numerous elegant strategies and methods developed for the formation of glycosidic bonds, stereoselective construction of alpha- and beta-glycosides remains challenging.
We have recently developed novel nickel-catalyzed 1,2-cis-2-amnio 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 at the newly formed glycosidic bond. In addition, the
methods are mild and conducted under operationally simple protocol utilizing sub-stoichiometric amounts of nickel
catalyst. The utility of the nickel-catalyzed 1,2-cis-2-amino glycosylation methods have been applied to the synthesis
of heparin oligosaccharides, tumor-associated mucin TN-antigen, GPI anchors, and mycothiol.
Currently, we are also developing a series of predictable and stereoselective methods for the construction of the
challenging 1,2-cis glycosidic bonds via either photoinduced copper catalysis or organocatalysis (using nitrogen-
containing heterocycles as catalysts). The newly developed chemistry is an entirely new mechanistic approach to
glycosidation and utilizes the bench-stable catalysts under mild and operationally simple conditions. In addition,
this new chemistry does not rely on the nature of the C(2)-protecting or directing groups to control formation of
the 1,2-cis glycosidic bond.
2) Chemical Biology of Heparan Sulfate and Heparanase
Heparanase, a beta-endo-glucuronidase, cleaves heparan sulfate (HS) chains at the specific intra-chain sites in
the extracellular matrix (ECM). This enzyme is regarded as a regulator of aggressive tumor behavior as clinical
studies have showed that raised heparanase levels correlated with increased tumor size, amplified angiogenesis,
enhanced metastasis, inflammation, and poor prognosis. As such, heparanase is a leading target for the treatment
of cancers and other diseases. Interaction of heparanase with HS is regulated by specific substrate N- and
O-sulfation patterns. Although the crystal structure of human heparanase has been recently resolved, a systematic
understanding of how this enzyme reads the sulfation pattern of HS substrates at each subsites of heparanase and
selects favorable hydrolysis sites remains lacking. This difficulty is due to lack of technology for preparing
specific and defied sulfated oligosaccharides. In addition, carbohydrate-based heparanase inhibitors have been
developed, but none is translated into clinical use. These inhibitors are heparin-modified molecules, therefore,
heterogeneous in size and sulfation patterns, which can lead to unforeseen adverse effects.
To address these challenges, we are developing a new modular chemical approach for the parallel combinatorial
synthesis of a library of HS oligosaccharides, representing all possible O- and N-sulfation motifs. Our
strategy provides a systematic understanding of substrate specificity for heparanase and how this enzyme
selects favorable cleavage site. Furthermore, this study provides an attractive starting point for the design
and development of heparanase-inhibiting sulfated oligosaccharides of high efficacy and clinical applicability.
3) Nucleophilic Fluorination and Radiofluorination for PET Imaging
Over the past decade, fluorine-containing molecules have become increasingly important in several fields
including medicinal chemistry, positron emission tomography (PET) imaging, agriculture, and materials science.
The introduction of carbon-fluorine bonds into organic molecules can lead to improved bioavailability and, in turn,
the efficacy of fluorinated drug candidates over their non-fluorinated parent compounds by affecting a wide variety
of properties including pKa, lipophilicity, metabolic stability, and binding affinity. Roughly 30% of agrochemicals
and 20% of pharmaceutical targets currently on the market contain at least one fluorine atom. As such, numerous
methods have been developed to address the unmet challenges previously associated with the syntheses of aryl
fluorides and enantioenriched aliphatic fluorides via nucleophilic fluorination. Allylic fluorides are biologically
important and can be found in many pharmaceuticals and PET radiotracers. However, catalytic asymmetric methods for
the direct nucleophilic incorporation of fluoride into allylic systems remain underdeveloped.
Our program involves the discovery of new methods for the regio- and enantioselective synthesis of allylic fluorides
via iridium-catalyzed fluorination of trichloroacetimidate substrates. In 2011, we have developed a branched-selective
fluorination of allylic trichloroacetimidates utilizing [IrCl(COD)]2 and Et3N·3HF. Recently, we extend the method to
the dynamic kinetic asymmetric transformations of racemic allylic trichloroacetimidate substrates catalyzed a chiral
diene-ligated iridium catalyst to allylic fluorides with excellent levels of asymmetric induction (90-97% ee).
Recently, we have developed a rapid incorporation of fluorine-18 into allylic systems of organic molecules utilizing
iridium catalyst in a combination with [18F]KF.kryptofix complex for use as PET tracers. Under our radiofluorination
conditions, the use of [18F]KF.kryptofix allows 18F-incorporation into allylic systems within 5-10 minutes at room
temperature with excellent radiochemical yield and specific activity. We continue our efforts by applying this
reaction to the radiochemical synthesis of [18F]-labeled PET imaging agents. In addition, we explore the use of allylic
[18F]fluorides generated as [18F]-based reagents for utilization in site-specific modification of the peptides and
Sletten, E. T.; Loka, R. S.; Yu, F.; Nguyen, H. M. "Glycosidase Inhibitors from Multivalent Presentation of Heparan Sulfate Saccharides on Bottlebrush Polymer." Biomacromolecules 2017, 18, 3387-3399.
Loka, R. S.; Yu, F.; Sletten, E. T.; Nguyen, H. M. "Design, Synthesis, and Evaluation of Heparan Sulfate Mimicking Glycopolymers for Inhibiting Heparanase Activity." Chem. Commun. 2017, 53, 9163-9166.
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.
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.
Zhang, Q.; Nguyen, H. M. "Rhodium-Catalyzed Regioselective Ring Opening of Vinyl Epoxides with Et3N·3HF: Formation of Allylic Fluorohydrins." Chem. Sci. 2014, 5, 291-296.
McConnell, M. S.; Yu, F.; Nguyen, H. M. "Nickel-Catalyzed alpha-Glycosylation of C(1)-Hydroxyl Group of Inositol Acceptors: A Formal Synthesis of Mycothiol." Chem. Commun. 2013, 49, 4313-4315.
Topczewski, J. J.; Tewson, T. J.; Nguyen, H. M. "Iridium-Catalyzed Allylic Fluorination of Trichloroacetimidates." J. Am. Chem. Soc. 2011, 133, 19318-19321.
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 Oligosaccharides, GPI Anchor Pseudodisaccharides, and alpha-GalNAc." J. Am. Chem. Soc. 2010, 132, 14288-14302.