The specific aim of this investigation is to explore and develop the chemistry of Alpha-oxoketene dithioacetals. Two procedures are being developed for the efficient exploitation of this functional group for selective (i.e. chemoselective, regioselective and stereoselective) carbon-carbon bond constructions and functional group manipulations. The first method involves the chemoselective and stereoselective conjugate addition of organocuprates to Alpha-oxoketene dithioacetals and to the resultant vinylogous thioesters. The second method involves 1,2-nucleophilic additions to the ketone carbonyl followed by acid catalyzed rearrangement and constitutes a versatile 1,3-carbonyl transposition methodology that permits regioselective sequential carbon-carbon bond constructions. The specific goals are two-fold. First, the scope, limitations, and reaction parameters of these two procedures will be examined in very careful detail. Second, the synthetic application of this chemistry to the synthesis of Alpha-alkylidene ketones, Alpha-pyrones, and simple and annulated benzene derivatives will be examined. Development of these methodologies will provide general routes to several classes of compounds and will provide versatility for the construction of specific substitution patterns. Each of the synthetic applications will require studies to optimize reaction conditions and determine the scope and limitations of the synthetic routes. The development of methods for the sequential regio-, stereo-, and chemoselective construction of new carbon-carbon bonds utilizing the Alpha-oxoketene dithioacetal cascade will provide versatile synthetic opportunities. In preliminary work the power of these synethetic methods has been illustrated by a total synthesis of Myodesmone. The direct entry into the rich chemistry of regio- and stereospecifically substituted allylic alcohols provides another example. The development of methods for the synthesis of heterocycles (e.g. Alpha-pyrones) and benzenoid aromatic compounds will contribute to the search for active medicinal compounds. The methodologies are applicable to the synthesis of biologically active natural products and synthetic medicinals.
