Important therapeutic agents are prepared by chemists through the use of chemical reactions. The available reaction methods represent invaluable tools that allow us to synthesize agents critical to human health care selectively and efficiently. Selectivity - particularly enantioselectivity - is crucial, because various studies underline the need for the preparation of drugs in the non-racemic form. This proposal will outline experiments that will lead to the development of new enantioselective catalytic processes for C-C bond formation through addition of Grignard reagents to alkenes. These studies should result in the emergence of effective modern methods that can be utilized in the preparation of important organic molecules in the optically pure form. Many of the transformations described herein are unique - they do not have an existing catalytic or non-catalytic counterpart. (1) We will develop new catalysts and protocols for more efficient and less costly asymmetric catalytic reactions. The (EBTHI) Zr system has been shown to be an impressive construct capable of effecting highly enantioselective C-C bond forming and kinetic resolution processes. However, it suffers from several drawbacks. We will search for a more efficient and less costly route to non-racemic chiral zirconocenes. (2) We will develop a general asymmetric addition of alkylmagnesium halides to alkenes. We will extend the utility of enantioselective carbomagnesation reaction to reactions where a large variety of alkyl units can be selectively and efficiently added to unactivated C-C double bonds. (3) We will develop the Zr-catalyzed enantioselective carboalumination of unsaturated heterocycles. This reaction technology will lead to an efficient and highly asymmetric method for the synthesis of a range cyclic and bicyclic compounds in the enantiomerically pure form. The utility of this method will be demonstrated through short and enantioselective total syntheses of highly potent antibacterial agents. (4) We will demonstrate that Zr-catalyzed kinetic resolution provides a variety of functionalized carbo-and heterocycles efficiently and with outstanding enantioselectivity. This research will lead to a concise and asymmetric total synthesis of (+)- Pumiliotoxin C and the potent antihypertensive agent (S.R.R.R.)-Nebivolol.
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