A feature common to many biologically relevant molecules is the alpha-hydroxy carbonyl array [RR'C(OH)C(O)Z]. Compounds containing this moiety are also important auxiliaries and synthons for the asymmetric synthesis of many natural products including antitumor agents, antibiotics, pheromones and sugars. Of particular significance in these structures is the stereochemistry of the hydroxyl group attached to stereogenic carbon; biological activity often critically depends upon its orientation. The principal objective of the proposed work continues to be development of practical methodology for the enantioselective hydroxylation of metal enolates in high enantiopurity (>95% ee) with predictable stereochemistry; the ultimate goal is reagent-controlled asymmetric oxidation of prochiral enolate species. A second major objective is understanding and controlling the various factors that define the molecular recognition. These goals will be achieved by exploring the asymmetric oxidation of prochiral acyclic and cyclic enolates derived from esters (including beta-keto esters), lactones and amides as well as azaenolates; little is known about the stereoselectivity of hydroxylation for these compounds. As chiral oxidants we will employ the readily available, enantiopure (camphorylsulfonyl)oxaziridines 3. The influence of the enolate .substitution pattern and solution structure and the structure of the oxaziridine active-site on the ee's will be evaluated, leading to elucidation of the origins of the molecular recognition and the rational design of more effective reagents. In this regard new procedures for altering the structure of 3 will be devised, particularly methods for introducing metal-chelating groups near the active-site oxygen. Kinetic resolution (the diastereoselective oxidation of racemic enolates with substoichiometric amounts of 3), and double asymmetric synthesis, (the asymmetric oxidation of chiral enolates) will be pursued as methods for preparation of enantiopure materials not readily accessible by other means. Concurrent with the above studies, we will apply the asymmetric enolate oxidation protocol to the synthesis of biologically relevant molecules or their chiral nonracemic precursors. Antitumor synthetic targets include the aglycones of the anthracycline antibiotics, adriamycin and daunomycin, the lactone camptothecin, and the C- 13 side chain of taxol. Site-specific fluorination often profoundly affects the physical, chemical and biological properties of a parent molecule. New enantiopure N-fluoro sultams 4 will be prepared and evaluated as enantioselective fluorinating reagents for the synthesis of chiral nonracemic alpha-fluoro carbonyl compounds. This project win extend our studies of asymmetric enolate hydroxylation; the molecular recognition parameters for the two processes are likely to be similar and the precursor of 3 will serve as the precursor to 4.
