This proposal describes a study of the synthesis of various substituted 1-acyldihydropyridines and their utility as synthetic intermediates. Methodology for the regiospecific preparation of various halosubstituted 1-acyldihydropyridines will be explored. Once prepared, the halo substituent will be utilized to further elaborate the dihydropyridine ring. Various regiospecific additions of substituents onto the dihydropyridine ring will be investigated. This will include Vilsmeier formylation and acylations, Friedel-Crafts acylations, and Grignard additions to 1-acylpyridinium salts directed by a Beta-tributylstannyl group. The Beta-tributylstannyldihydropyridines will provide access to several other substituted dihydropyridines via regiospecific organotin chemistry. Regiospecific substitution at all positions of the dihydropyridine ring will be studied. This will allow for development of novel syntheses of substituted pyridines through aromatization of the dihydropyridine intermediates. In addition to the regiospecific syntheses of substituted pyridines, the proposed dihydropyridine chemistry will be used to synthesize various indolizidine and quinolizidine alkaloids. The indolizidine and quinolizidine alkaloids have been subjects of numerous biological and chemical studies. Several of these alkaloids are powerful vesicants and can modulate the growth of various normal and abnormal mammalian tissues. The dihydropyridine chemistry proposed should provide a practical entry into the synthesis of these interesting heterocyclic compounds.
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