CHIRAL CATALYSTS FOR ENANTIOSELECTIVE SYNTHESES

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DESCRIPTION: In this renewal proposal, the principal investigator states that the long-term objective of this project is the efficient construction of enantiomerically pure biomedically important compounds, and its focus is on the use of chiral catalysts to achieve this goal. He reports that dirhodium(II)compounds with chiral carboxamide ligands (from pyrrolidone, oxazolidinone-, and imidazolidinone-carboxylates) have proven to be remarkably effective catalysts for highly enantioselective (greater than 90 percent ee) reactions of selected diazoacetate esters that result in intramolecular cyclopropanation or carbon-hydrogen insertion as well as in intermolecular cyclopropenation and that further advances in design and development will improve selectivities with existing transformations, and that they promise significant breakthroughs in new applications. It is indicated that intramolecular carbon-hydrogen insertion reactions will be employed for the syntheses of chiral prostaglandin precursors, of (-)-enterolactone, the parent of a family of endogenous mammalian lignan lactones, and of unique deoxysugar derivatives, including 2-deoxyxylolactone, 2- deoxyribonolactone, and their methyl and heteroatom derivatives. The deoxysugars are to be converted to their adenine and/or thymidine 5'- triphosphate derivatives and then subjected to in vitro evaluation of HIV reverse transcriptase and human DNA polymerase activity. The principal investigator reports that intramolecular cyclopropanation reactions afford highly structured cyclopropane derivatives whose applications have already included presqualene alcohol and renin inhibitors, and whose future promises to deliver optically active cyclopropane analogs of gamma-aminobutyric acid (GABA), among others. He notes that the catalytic methodology being developed provides the opportunity to control diastereoselectivity, chemoselectivity, and regioselectvity, together with enantioselectivity, and thereby achieve the synthesis of single products that are enantiomerically pure. It is indicated that diazoesters, diazoamides, diazoketones, and diazophosphonates are suitable reactants and that ylide generation/rearrangement, N-H and O-H insertion, C-H insertion, and cyclopropanation are targeted transformations. The influence on selectivity of methyl in diazopropanoate esters relative to hydrogen in diazoacetate esters is to be examined. It is noted that accurate predictions of absolute stereochemistry are made possible by evaluations made of the transition state for C-H insertion, cyclopropanation, and cyclopropenation, and computational modeling is in agreement. The principal investigator indicates that although an array of examples exist in which enantiocontrol 94 percent or better ee has been achieved, there are many more for which low to modest enantiocontrol was reported from uses of first generation chiral dirhodium(II) catalysts and that the second generation catalysts that are becoming available will make possible significant enhancement in enantiocontrol. He states that furthermore, the breadth of potential applications that will be evaluated during the proposed grant period is intended to establish the overall synthetic advantages/feasibility of this catalytic methodology.