Our objective is to develop new, effcient organic synthetic methods using transition metal reagents and to apply these new methods to the synthesis of biologically active compounds. Three classes of compounds will be synthesized: Beta-lactams, ergot alkaloids, and pyrroloindoloquinones related to the mitomycins.
The specific aims of the proposed Beta-lactam research are: (1) to extend the recently developed synthesis of Beta-lactams from imines and (methoxy)(methyl)chromium carbene complexes to the synthesis of methoxymethyl analogs of oxacephams and penams, carbacephams and-penams, monobactams, and norcardicin; (2) to synthesize (methoxy)-(amino)- and (amino)(hydrido)chromium carbene complexes, and to use these to synthesize biologically active Beta-lactams including oganomycins, cephamycins, moxalactam, norcardicin itself, as well as the classes of Beta-lactams listed in item (1); (3) to study the corresponding Mo and W carbene complexes to develop complementary approaches to recalcitrant systems; (4) to develop the reactions of chromium carbene complexes with azo compound to give 1,2-and 1,3-diazetidinones, and to learn how to control this reaction to give one or the other product, as desired, exclusively; (5) to determine if chromium 'nitrene' complexes are intermediate in this reaction with azobenzenes and, if so, use this to convert olefins to Beta-lactams.
The specific aims of the ergot alkaloid research are (1) to complete a systematic study of palladium catalyzed reactions to introduce functionality in the 3 and 4 positions of indoles, (2) to use this chemistry to develop a general approach to the ergot alkaloids, (3) to demonstrate to utility of this approach by using it to synthesize clavicipitic acid and ergoline.
The specific aims of the quinone research are (1) to further develop the newly discovered oxidative cyclization of allyl-amino quinones to quinolinoquinones to make it a general synthetic approach to the class of compounds, and to use it to synthesize lavendamycin, (2) to prepare pyrroloindoloquinones related to the mitomycins by palladium(II) and palladium(0) catalyzed route, (3) to develop an approach to these compounds using recently developed dienyliron complex chemistry. The proposed research will permit the extremely efficient synthesis of a wide variety of complex molecules having a diversity of biological activities, including antibiotics and antitumor agents. As such it should prove valuable in the development of new compounds for use in the treatment of disease and other physiological disorders.
