Alkenes are found in a great number of naturally occurring molecules and are employed in some of the most widely used transformations. Processes that allow access to Z or E isomeric forms of olefins efficiently, reliably, with high selectivity and cost- effectively are therefore of great importance to chemistry, biology and medicine. Especially valuable are the catalytic procedures that form alkenes stereoselectively. The proposed studies focus on the design, synthesis and development of molybdenum- and tungsten-based catalysts that can be utilized to facilitate one of the most powerful methods in chemical synthesis: olefin metathesis. A variety of concepts, originally conceived in these laboratories, will be used to introduce the needed new catalysts. The goal is to achieve furnish reactivity and/or selectivity levels that remain entirely out of reach and will have a lasting impat on drug discovery and development. Catalytic methods will be put forth that allow access to a wide range of linear Z- a,b-unsaturated esters and amides, as well as various dienoates. Such entities reside in a myriad of biologically active molecules, and are among the most versatile functional units in chemical synthesis. One of the most critical objectives of the proposed investigations will be the development of efficient catalytic processes that will generate Z-alkeny chloride, bromide, and iodide compounds. These are, again, among the most important and widely used entities in chemistry (e.g., substrates for catalytic cross- coupling); moreover, the ability to incorporate F atoms within organic molecules site- and stereoselectively will be crucial to future drug development. The first examples of catalytically E-selective olefin metathesis reactions will be designed; these processes will deliver valuable E-alkenyl halides. Finally, the first cases of stereoslective catalytic cross-metathesis reactions that generate high-energy trisubstituted alkenes will be introduced. The special utility of the new concepts, catalysts and protocols will be underscored through applications to concise syntheses of biologically significant molecules such as anti-inflammatory agent coriolic acid methyl ester, antiproliferative agent hexachlorosulfolipid as well as alkenyl halide derivatives of dopamine receptor antagonist cabergoline, caspase 3 activator PAC-1, and HMG-C0A reductase swertiamarin.
Our ability to prepare various medicinally active agents in a cost-effective, reliable, efficient and selective manner is critical to advances in human health care. The proposed research will lead to unique, inexpensive and highly selective catalytic reactions that promote efficient formation of alkenes, one of the most common units found in a countless medicinally significant molecules, but which cannot be accessed easily by any other methods.
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