) Efficient and selective preparation of organic molecules is critical to the synthesis of therapeutics. Thus development of catalytic and stereoselective addition of alkylmetals to olefins stands as an important objective. Catalytic olefin alkylation offers a practical and inexpensive route for synthesis of C-C bonds; these reactions require readily available substrates and alkylmetals. A catalytic enatioselective version would be most useful especially if it were to afford molecules that are readily amenable to further functionalization. Similar to carbomagnesation, the reactions proposed herein are Zr-catalyzed, but they proceed by an entirely different mechanism and will be significantly more general. In catalytic carbometalations reported to-date, the alkyl group of the alkyl metal is typically incorporated within the final product; here it is the alkyl moiety of an electrophilic reagent that is transferred to the product . Thus, the new Zr-catalyzed reactions are unusual: there is efficient reaction between the alkene substrate and the electrophile, but there is little or no reaction between the alkylmetal and the electrophile. The following specific objectives will be pursued: I. Development of regio- and stereoselective Zr-catalyzed alkylation and carbometalation of olefins with alkyl electrophiles. Mechanistic evidence from our previous studies will be used to develop unique methods for catalytic regio- and diastereoselective synthesis of C-C bonds. These transformations offer a new approach to C-C bond formation, where readily available olefinic substrates, alkylmetals and electrophiles can be used. II. Development of diastereoselective intramolecular Zr-catalyzed electrophilic alkylations and carbometalations. The intramolecular version of the Zr-catalyzed alkylation should allow for an unprecedented and efficient synthesis of various carbo- and heterocycles with high regio- and diastereoselectivity. III.Development of Zr-catalyzed enantioselective electrophilic alkylations and carbometalations. We will develop a catalytic and asymmetric alkylation and carbometalation of olefins with various electrophiles. These transformations offer unique and selective routes to the enantioselective synthesis of easily functionalizable molecules. The utility of the new methods will be demonstrated by synthesis of anticancer LY300502, antispastic baclofen, anti-fungal aflatoxin B2, antidepressant gemfexine and anti-leukemic helianane.
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