With this award, the Chemical Synthesis program is supporting the work of Professor Hien Nguyen of the Department of Chemistry at the University of Iowa. Professor Nguyen will explore the development of new methods for the effective preparation of alpha-configured glycosyl ureas and 1,2-cis-2-aminosugars via transition metal catalysis. Successful development of these methods will provide new and efficient approaches for the rapid assembly of a number of complex carbohydrate targets, including potentially glycoconjugate-based tumor-associated antigens, aminoglycoside antibiotics, and anti-tubercular drugs. Specific targets for this project include the glycosyl urea antibiotic cinodine, and glycosylphosphatidyl inositide (GPI) anchor pseudo-oligosaccharides.

The broader impacts of the proposed project will involve training both undergraduate students and graduate students, in continuing to build a program that merges transition-metal-based catalysis with carbohydrate synthesis. In this way, the project will provide multidisciplinary training for these students, including those from groups historically underrepresented in the sciences. There are also important potential scientific broader impacts, as this work is expected to provide new and generalizable methods for stereocontrolled glycosylation and glycoconjugation to the glycoscience community.

Project Report

Our group applies modern organometallic chemistry to solve issues of yield and anomeric selectivity that cannot be achieved under the traditional glycosylation methods. Over the past several years, we have addressed these gaps by developing several methods that utilize transition metals as catalysts to activate carbohydrate trichloroacetimidate electrophiles. The unique nature of the trichloroacetimidate to act as the leaving group and the directing group provides a path to the discovery of new allylic substitution reactions, which will be the objective of this renewed grant application. In this NSF grant, we successfully developed new approaches for the preparation of 1,2-cis-2-aminosugars via nickel-catalyzed a-glycosylation with C(2)-N-substituted benzylideneamino trichloroacetimidate electrophiles. These aminosugars make up one of the most important classes of carbohydrate molecules and play a vital role in a variety of biochemical processes. Our approach to forming 1,2-cis-aminosugars is innovative in that we apply modern organometallic method to solve issues of yield and selectivity that cannot be achieved under the current state-of-the-art methods. Our approach relies on the nickel-ligand complex and the nature of metal-bound functional groups at the C(1)- and C(2)-position on glycosyl donors to control the alpha-selectivity. Our method is broadly applicable and provides highly-yielding and selective products. The synthetic utility of this chemistry was illustrated by the synthesis of mycothiol (a promising candidate for a rational drug design in fighting tuberculosi), and pseudosaccharides of GPI anchors (play a pivotal role in signal transduction and cancer metastasis). In the second objective, our group successfully developed a general and effective method for preparation of alpha-urea glycoside. Replacing the native anomeric C-O-C and C-N-C linkages of carbohydrates with a more robust urea linkage is appealing, adding in the development of carbohydrate-based therapeutics with enhanced bio-availability and remarkable stability against acid and enzymatic hydrolysis. However, the task of synthesizing alpha-glycosyl ureas is not trivial. We successfully transformed glycosyl trichloroacetimidatse to the corresponding alpha- trichloroacetamides in good yields and with excellent levels of alpha-selectivity. The trichloroacetamide intermediates were then directly converted into glycosyl ureas in the presence of amine nucleophiles. This process benefits from retention of stereochemistry at the anomeric center and is atom-economical. Mechanistic studies have identified coordination of the cationic nickel catalyst with the equatorial C2-ether group of the glycosyl imidates to be paramount for achieving alpha-selectivity. A cross-over experiment has indicated that the reaction does not proceed in an exclusively-intramolecular fashion. Carbohydrates play important roles in a variety of biological processes. Unfortunately, it is not trivial to obtain defined bioactive carbohydrate molecules from natural sources. In many cases, high purity targets can only be obtained by chemical synthesis. Our methods provide the opportunity to gain access to a variety of complex carbohydrate molecules for useto study their functions and properties. Furthermore, the carbohydrate methods that are being developed in our projects could have a broad impact on developing therapeutic agents for use in the treatment of cancers, bacterial infections, and other diseases. Since our research projects are at the interface of organometallic, organic chemistry and carbohydrates, they provide multidisciplinary training for undergraduate and graduate students and postdoctoral associates. I believe that research is an essential extension of classroom learning. First-hand experience with scientific research allows students to translate their knowledge into practice. I assign each undergraduate to work directly with either a graduate student or a postdoctoral fellow. I believe that this type of interactions allows undergraduate students to gain the benefits in experimental as well as theoretical knowledge, which will prepare them for graduate school. Graduate students and postdoctoral fellows will also benefit from this experience as it helps them to gain mentoring skills, which are essential for their future roles as project leaders or mentors in academic, industrial, and governmental setting. The nature of the project depends on the students’ ability, experience, and motivation. I meet with them weekly to go over their progress and provide them with feedback and suggestions. Overall,my students in the group get involved in every aspects of educational training, including conducting research, writing lab reports and manuscripts, and presenting literature and research topics. During this grant period, I also got involved in recruiting underrepresented minority (URM) to enroll in the Department of Chemistry at the University of Iowa. I participated in the campus and traveled ACS Southeast and Northwest regional meetings and other conferences (e.g. NOBCChe, AGEP, and SROP programs) that target URM students. My goal is to recruit URM students and increase the number of B.S. and Ph.D. candidates in Chemistry here at the University of Iowa. In addition, I will work with our departmental recruiting and admissions committee to lengthen the list of chemistry departments in which we present seminars in order to ensure that we are reaching more schools with a significant number of URM students.

National Science Foundation (NSF)
Division of Chemistry (CHE)
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Program Officer
Carol Bessel
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University of Iowa
Iowa City
United States
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