This project explores the use of intramolecular nitrene insertions for the preparation of amino sugars. Primary carbamates tethered within the sugar framework are the precursors of metal-complexed nitrenes for insertion into proximal carbon-carbon double bonds. Nucleophilic opening of the resulting aziridines provides a means for stereocontrolled glycosylation. This work focuses on how the stereochemical, conformational, and electronic properties of the glycal and pseudoglycal carbamate substrates influence the nitrene insertion event and the subsequent nucleophilic addition. A deeper understanding of these factors will permit application of the methodology to a wide variety of sugar carbamates and glycosyl acceptors.

With the support of this award from the Chemical Synthesis Program, Professor Christian Rojas of the Department of Chemistry at Barnard College will explore synthetic methods for the preparation of amino sugars. Amino sugars play key roles in biological systems and in medicinal chemistry. For example, many cell-surface proteins are linked to amino sugar-containing fragments that serve as recognition elements for processes such as immune response. In addition, certain amino sugars act as potent inhibitors of enzyme action, others play important bio-structural roles, and some are therapeutically valuable antibiotics. Innovative synthetic methods for the preparation of amino sugars have the potential to open new avenues for the study of their biological properties and pharmacology. In addition, these synthetic studies will improve fundamental chemical understanding of routes to incorporate nitrogen atoms within complex organic molecules. Undergraduate students at Barnard, a liberal arts college for women, will be involved in all aspects of the project. They will contribute to the state of the art in organic chemical synthesis while receiving training that will enable them to pursue further study and careers in science, medicine, and technology.

Project Report

Carbohydrates are molecules of great biological and medicinal significance. For example, carbohydrates are components of antibiotic, antiviral, and antitumor drugs as well as promising lead compounds for anticancer vaccine therapy. Chemical synthesis is a crucial approach for creating specifically designed carbohydrate-based molecules as well as diverse collections of structures for further investigations and applications. This project has focused on the discovery and expansion of new methods for the preparation of 2-amino sugars, a class of carbohydrates wherein a nitrogen-containing group is bonded at a specific location within the carbohydrate molecular framework. 2-Amino sugars and their derivatives are prevalent in commonly used antibiotics and anti-influenza drugs as well as within more complex carbohydrate structures that appear on cell surfaces. During the project period, we have developed a chemical reaction that introduces the nitrogen-containing group at the appropriate location of the carbohydrate and in a well defined spatial orientation. This synthetic approach involves catalysis by a metal, and we have found that appropriate choice of catalyst can be used to tune the reactivity of the system to favor the desired 2-amino sugar products over undesired byproducts. In the process of increasing the efficiency and selectivity of our synthetic method, we have also gained a better insight into the detailed mechanism of the key nitrogen–carbon bond-forming chemical reaction, including the nature of the highly reactive intermediate that leads to the necessary nitrogen-atom-transfer step. We have demonstrated that, with proper catalyst choice, a wide range of 2-amino sugar structures are accessible. An exciting application of this new methodology involves the preparation of collections of 2-amino sugar building blocks for attachment to molecules that have biological and medicinal activity. This so-called "glycodiversification" strategy leads to a variety of molecular analogues that are then tested for altered and potentialy enhanced properties. The synthesis tools developed during the NSF-funded project have provided the necessary preparative route for these ongoing studies. The research was completed with undergraduate co-workers at Barnard College, a liberal arts college for women in New York City. Participation in this research has been an essential component in the scientific training of these undergraduate students and has helped them go on to pursue careers in science and science-related fields, including graduate study in the chemical sciences and careers in medicine, dentistry, and nursing.

Agency
National Science Foundation (NSF)
Institute
Division of Chemistry (CHE)
Application #
0957181
Program Officer
Suk-Wah Tam-Chang
Project Start
Project End
Budget Start
2010-04-01
Budget End
2014-03-31
Support Year
Fiscal Year
2009
Total Cost
$215,000
Indirect Cost
Name
Barnard College
Department
Type
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10027