NOVEL REAGENTS AND CATALYSTS FOR CHIRAL PHARMACEUTICALS

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The project goals are to continue to develop new science at the cutting edge of modern synthetic chemistry. The student co-investigators are an integral part of the research process, not only through the execution of the experimental work and in the analytical spectroscopic evaluation and interpretation, but also, in the scientific development process through literature seminars, presentations and publications, procedures which assure the continued growth of knowledge, both now and in the future. The specific research proposed herein takes full advantage of research expertise developed in our laboratories over the past twenty years in the general area of Main Group organometallic reagents and reactions and their applications to the asymmetric synthesis of simple natural products and important pharmaceuticals. The project's focus will be directed toward the development of new chemistry as It relates to important pharmaceutical and potentially important natural and unnatural products. As specific studies: (1) We have prepared an entirely new type of chiral ouzaborolane which will be screened as a borane-based asymmetric reduction catalyst by analogy to Corey's CBS catalysts which have been employed for the asymmetric syntheses of Prozac, D1 antagonists, beta-agonists, prostaglandins thromboxane A2 and other pharmaceuticals. Numerous potential applications in the synthesis of antihypertensive drugs have been identified. (2) Following our recent successful new asymmetric syntheses of the chiral pheromones, frontalin and exo-brevicomin, the Suzuki protocol will be applied to the total synthesis of alpha- methoxylated fatty acid metabolites which have been isolated locally from the marine sponge, Spheciospongia cusudifera. (3) A new NMR protocol will be applied to the assay of organoborane mixtures. Also a new chiral silane which can effectively derivatize alcohols, amines and carboxylic acids is proposed as an effective new tool to assay the enantiomeric excess present in synthetic products and pharmaceuticals. (4) Our new stable isolable alkynylboranes will be examined particularly with respect to the asymmetric synthesis of propargylic alcohols through known CBS-type catalytic processes and with our new catalyst. Moreover, we plan to expand the Suzuki-Miyaura protocol developed in our laboratory to demonstrate that potential DNA-cleaving compounds of the enediyne type can be prepared through this new technology. (5) Our new simple method for carboxylate protection will be applied to the protection of amino acids for applications to peptide synthesis. (6) A number of remarkably stable silylamine derivatives have been prepared whose chemistry will be explored as new chiral lithium bases as a convenient entry to chiral enol ethers.