Synthetic and Mechanistic Studies on Preparatively Significant Reactions

PROJECT SUMMARY/ABSTRACT This application describes two programs of research aimed at improving the efficiency and selectivity of chemical synthesis relevant to small molecule drug discovery efforts. The first program seeks to invent ste- reodefined building blocks that can be used to optimize therapeutic properties of small molecules at various stages of drug discovery and development efforts. The second program seeks to invent a new, modular, pro- grammable synthesis of monosaccharide building blocks which are constituents of glycosylated natural prod- ucts of increasing importance as therapeutic agents and probe molecules for studying cell-cell communication. The primary objective of first program is the creation of a small library of stereodefined, functionalized, three-dimensional building blocks that can be introduced as plugins for the optimization and diversification of small molecule candidates in drug discovery programs. One of the major problems facing the research and discovery efforts in the pharmaceutical industry is the mismatch between the chemical characteristics of avail- able screening libraries and the kinds of characteristics needed to intervene by association and interaction with biomolecular targets. This problem arises from the lack of robust methods that reliably and predictably install three-dimensional carbon centers bearing appropriate functionality (oxygen, nitrogen, sulfur) in both manual and automated platforms. By systematic examination of the stereochemical outcome of the coupling of small, stereodefined boron-containing building blocks and a rigorous understanding of the mechanisms of their intro- duction, this program will provide the medicinal chemistry community with reagents that constitute “stereocen- ters in a bottle”; namely off the shelf plugins to accelerate discovery programs. The primary objective of second program is the creation of a modular, programmable synthesis of mono- saccharides that contain a diverse array of substituents and stereochemical relationships not readily accessible by current methods. The ability to access monosaccharide precursors with programmable substitution and ste- reochemistry is paramount to the precise tuning of properties. This program of research will develop a family of allylic boron reagents that will enable stereocontrolled introduction of three-carbon allyl units bearing a wide variety of substituents. These reactions take place in water using only trace amounts of indium metal as the catalyst. A critical secondary objective of this program is the application of this mild modification method in gly- cochemistry and bioconjugation. Carbohydrates are fundamental to a variety of biological processes including cell-cell recognition, protein folding, neurobiology, inflammation, and infection. Modifying carbohydrate struc- tures to enhance their physiological properties has become a key strategy in the development of innovative pharmaceuticals. Further modification of glycans is necessary to introduce functional groups that enhance their separation and detection. Similar manipulations are used in the synthesis of glycoconjugates by introducing bifunctional chemical linkers to facilitate the conjugation reaction.