During the past six months we have been successful in developing the first rationally designed, chiral Lewis acid for the asymmetric induction of Diels-Alder reactions. The objectives are to first apply this method to the synthesis of the chiral aglycones of the anticancer agents Adriamycin (doxorubicin, 1) and 4-demethoxydaunomycin (2). Once those syntheses are complete, the basic concept will be applied to synthesis of granaticin. At the same time the underlying rationale for asymmetric induction of Diels-Alder reactions will be extended first to that class of dienophiles which have a second ligating group (in addition to a carbonyl) which simultaneously can coordinate with the chiral Lewis acid, thereby holding it in place. Finally, what we have learned from these experiments will be combined with the basic concept of a chiral bidentate Lewis acid envisioned to function as a chiral template for the asymmetric induction of Diels-Alder reactions in general. Demonstration of the utility of this approach to controlling absolute stereochemistry will be assesed in part by the synthesis of several agents which are useful in the treatment of a variety of diseases.
