Research in our group focuses the development of novel methodologies for the stereoselective synthesis of complex oligosaccharides and the enantioselective construction of nitrogen and fluorine-containing compounds that possess significant bioactivity utilizing 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. Recently, we have developed a rapid and mild conditions for fluorine-18 incorporation into small organic molecules for potential use as PET radiotracers. For each of the above projects, we team up with collaborators at the University of Iowa College of Medicine, the University of Iowa PET Imaging Center, the University of Alabama, Northwestern University, and the University of North Carolina for biological studies.

NEW METHODS FOR 1,2-CIS-2-AMINOSUGARS AND SYNTHESIS AND BIOLOGICAL STUDIES OF BIOACTIVE OLIGOSACCHARIDES

One facet of our research program involves the development of a series of new methodologies, allowing for the efficient assembly of complex carbohydrate molecules which can be explored as potential therapeutics against cancers, bacterial infections, tuberculosis, and anticoagulation. In particular, we exploit the nature of transition metals as the catalyst to selectively promote the formation of high purity 1,2-cis-2-aminosugars, one of the most important classes of naturally occurring complex carbohydrates and glycoproteins. Progress toward understanding the specific roles that glycoproteins play in biochemical processes is hampered by low isolation yields, inconsistent composition, and the lack of purity of these materials. In many cases, high purity 1,2-cis-2-aminosugars can only be obtained by chemical synthesis. We have developed an innovative method for the synthesis of 1,2-cis-2-aminosugars that utilizes nickel catalysts to direct the coupling. 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. The utility of the nickel catalyzed 1,2-cis-2-amino glycosylation method is currently applicable to the synthesis of a number of biologically active complex carbohydrates. Representative molecules include:  1) mycothiol, which is a low molecular weight thiol present in mycobacterium tuberculosis, is a potential target for the development of new treatment against tuberculosis; 2) heparin and heparan sulfate  oligomers which prevents blood clotting with minimal side effect and can be used as potent inhibitors of heparanase; 3) heptasaccharide N-linked glycan which is important for the adherence of Campylobacter jejuni to the surface of human host cells and plays a crucial role of the protein glycosylation system in the pathogenesis of C. jejuni; 4) Natural zwitterionic polysaccharide PS A1 has been demonstrated as potential novel vaccine adjuvants. The chemical biology studies of the bioactive oligosaccharides and their corresponding analogues are done in collaboration with Prof. Jon Houtman and Prof. Steve Varga at the University of Iowa College of Medicine and Prof. Jian Liu at UNC-Chapel Hill.

 

References:

1) McKay, M. J.; Nguyen, H. M. “Recent Advances in Transition Metal-Catalyzed Glycosylation.” ACS Catalysis 2012, 2, 1563-1595.

2) Mensah, E. A.; Yu, F.; Nguyen, H. M. “Nickel-Catalyzed Alpha- Coupling with C(2)-N-Substituted Benzylidene Trichloroacetimidates for the Formation of 1,2-cis-2-Amino Glycosides. Applications to the Synthesis of Heparin Disaccharides, Alpha-GalNAc, and GPI Anchor Pseudodisaccharides.” J. Am. Chem. Soc. 2010, 132, 14288-14302.

3) Mensah, E. A.; Nguyen, H. M. “Nickel-Catalyzed Formation of Alpha-2-Deoxy-2-Amino-Glycosides.” J. Am. Chem. Soc. 2009, 131, 8778-8780.

4) Yu, F.; Nguyen, H. M. “Studies on the Selectivity Between Nickel-Catalyzed 1,2-Cis-2-Amino Glycosylation of Hydroxyl Groups of Thioglycoside Acceptors with C(2)-Substituted Benzylidene N-Phenyl Trifluoroacetimidates and Intermolecular Aglycon Transfer of the Sulfide Group.” J. Org. Chem. 2012, 77, 7330-7343.

5) 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.

6) 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.

 

NITROGEN-SUBSTITUTED QUARTERNARY CENTERS

Many practical and elegant routes to the synthesis of amine-containing compounds have been developed. There are, however, limited approaches available for the asymmetric synthesis of alpha, alpha-disubstituted amines, the class of nitrogen-substituted quaternary centers. Transition metal-catalyzed substitution of primary and secondary allylic carbonates or acetates has been utilized for the preparation of chiral alpha-substituted N-arylamines. We have developed the dynamic kinetic asymmetric transformations (DYKAT) of racemic tertiary allylic imidates with anilines utilizing Hayashi’s bicyclo[2.2.2]-octadiene ligand-ligated rhodium catalyst. The method allows for the preparation of alpha, alpha-disubstituted allylic N-arylamines in good yields and with excellent regio- and enantioselectivity.  The ability of the rhodium-catalyzed DYKAT of racemic tertiary allylic imidates is currently applying to the synthesis of a number of bioactive natural products. Representative targets includes: 1) myriocin, which is one of the most potent immunosuppressant natural products, inhibits serine palmitoyltransferase, an enzyme in the biosynthesis of sphingolipid; 2) manzacidins exhibit useful activities as alpha-adrenoreceptor blockers, actomyosin ATPase activators, and serotonin antagonists. However, these compounds have only been preliminarily tested due to their limited quantities from natural sources;  3) BIRT-377, a potent inhibitor of cell adhesion molecule-1(ICAM-1) and lymphocyte function-associated antigen. Thus, BIRT-377 could play a vital function in the treatment of various inflammatory and immune disorders, and 4) pactamycin, a highly potent antitumor and antibacterial antibiotic isolated from Streptomyces pactum var. pactum.  Jogyamycin and TM-026 were isolated via biosynthesis and genetic engineering studies. While TM-026 exhibited potent antimalarial activity, jogyamycin displayed antibacterial activity.

 

References:

1) Arnold, J. A.; Stone, R. F.; Nguyen, H. M. “Rhodium-Catalyzed Regioselective Amination of Secondary Allylic Trichloroacetimidates with Aromatic Amines.” Org. Lett. 2010, 12, 45804583.

2) Arnold, J. S.; Cizio, G. T.; Nguyen, H. M. “Synthesis of a,a-Disubstituted Allylic Aryl Amines by Rhodium-Catalyzed Amination of Tertiary Allyic Imidates.” Org. Lett. 2011, 13, 5576-5578.

3) Arnold, J. S.; Nguyen, H. M. “Rh-Catalyzed Dynamic Kinetic Asymmetric Transformations of Racemic Tertiary Allylic Imidates with Anilines.” J. Am. Chem. Soc. 2012, 134, 8380-8383.

4) Arnold, J. S.; Cizio, G. T.; Heitz, D. R.; Nguyen, H. M. “Rhodium-Catalyzed Regio- and Enantioselective Amination of Racemic Secondary Allylic Imidates with N-Methyl Anilines.” Chem. Commun. 2012, 48, 11531-11533.

5) Arnold, J. S.; Nguyen, H. M. “Rhodium-Catalyzed Enantioselective Amination of Allylic Trichloroacetimidates.” Synthesis 2013, 45, 2101-2108.

6) Arnold, J. S.; Mwenda, E. E. T.; Nguyen, H. M. “Sequential Amination and Hydroacylation Reactions for the Enantioselective Synthesis of Seven-Membered Heterocycles.” Angew. Chem. Int. Ed. 2014, 53, 3688-3692.

 

FLUORINE-CONTAINING COMPOUNDS FOR PET IMAGING

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. Currently, PET has been widely used in diagnosis of cancers, cardiovascular diseases, early stage neurological disorders and in clinical trials. Measuring physiochemical processes with PET requires imaging agents labeled with positron-emitting radioisotopes. Fluorine-18 (18F) appears to be the most ideal isotope for PET imaging due to its low energy positron emission, ease of preparation, and ideal half life (110 min). The incorporation of fluorine into organic molecules by direct carbon-fluorine bond formation has proven to be quite challenging. We utilize trichloroacetimidates in conjunction with an iridium catalyst and triethylamine-hydrofluoride (Et3N.3HF) reagent to provide allylic fluorides in good yields and with excellent selectivity. The reaction is conducted at room temperature under ambient air and shows considerable functional group tolerance. Use of potassium fluoride-kryptofix complex, the most commonly used source of 18F-fluoride ion in PET imaging, allows 18F-incorporation into allylic electrophiles in 10 minutes. We continue our efforts by developing new strategies which allow rapid and efficient formation of benzylic and alpha-branching allylic C-F bonds. These proposed efforts will deliver suitable synthetic methods for the enantioselective synthesis of alpha-branching heterocyclic and beta-/gama-amino substituted allylic fluorides and the rapid access to [18F]fluorine-containing molecules. The methodologies have potential application in the enantioselective synthesis of potent and selective fluorinated neuronal nitric oxide synthase (nNOs) inhibitors for use in treatment of neurodegenerative diseases and in the preparation of [18F]-containing nNOS inhibitors for utilization as PET radiotracers to monitor Alzheimer’s, Parkinson’s, Huntington’s disease. This project is done in collaboration with Prof. David Dick at the University of Iowa PET Imaging Center and Prof. Silverman at Northwestern University.

 

 

Reference:

1) Topczewski, J. J.; Tewson, T. J.; Nguyen, H. M. “Iridium-Catalyzed Allylic Fluorination of Trichloroacetimidates.” J. Am. Chem. Soc. 2011, 133, 19318-19321.

2) 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.

3) Zhang, Q; Mixdorf, J. C.; Reynders, G. J.; Nguyen, H. M. “Rhodium-Catalyzed Benzylic Fluorination of Trichloroacetimidates with Et3N.3HF.” Tetrahedron. 2015, 71, 5932-5938.

4) 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.