This project will continue work on the development of methods for the development of solid-phase motifs (disks, monoliths) for reusable and regenerable main-group and transition-metal reagents/catalysts as well as the development of practical asymmetric routes to optically active targets using resin-bound asymmetric pyrrolidine catalysts in enamine-mediated reactions. Adaptation of organometallic mediated processes to the solid state can provide physical segregation of products from reagents, regeneration and reuse of reagents, and the development of flow-through methodologies. Development of resin-bound asymmetric pyrrolidine catalysts which facilitate recoverability and reusability as well as expedite syntheses through microwave-assisted reactions will address a growing need for effective and versatile applications of organocatalysis. These specific aims fit squarely into and are united by the monikers 'reactive polymer' and 'green chemistry'.
With this award, the Organic and Macromolecular Chemistry Program is supporting the research of Professors Mark J. Kurth and Neil E. Schore of the Department of Chemistry at University of California-Davis. Professors Kurth and Schore's research efforts revolve around the investigation of reactive polymers in organic synthesis. Their research could expand the scope of solid-phase strategies in multi-step organic synthesis and solve problems that cannot be readily solved in other ways. Multi-step organic synthesis is required in the manufacture of many prescription drugs.
Awardee: University of California-Davis With NSF support, the M. J. Kurth and N. E. Schore labs at the University of California/Davis developed new tools and new chemistry for combinatorial chemistry (the generation of libraries of structurally complex and diverse small molecules for high-throughput screening) application, which is a vitally important, integral part in the drug discovery process. Two powerful methods for generating structural complexity are cycloaddition reactions and one-pot–multistep methods. We have developed a one-pot–three-step transformation exploiting propargyl bromide-initiated ring opening and a subsequent intramolecular azide-alkyne 1,3-dipolar cyclo-addition, which converts oxazolino-2H-indazoles into novel triazolotriazepinoindazolone heterocycles wherein a 1,2,5-triazepine is fused to both an indazolone and a triazole. We have also shown that oxazolino-2H-indazoles, available via the Davis-Beirut reaction (also discovered with NSF support), can be converted into N2-substituted indazolones by treatment with various nucleophiles or N1,N2-disubstituted indazolones by treatment with various electrophiles. The chemistry we developed combines this electrophilic indazole ® indazolone reaction with an intermolecular "click" reaction to provide an efficient route to triazolotriazepinoindazolones. An interesting aspect of these novel molecules is their fusion of two heterocycles, each with well-established biological activities. The indazolone scaffold is found in molecules possessing analgesic, antiangiogenic, anticancer, antihypertensive, anti-inflammatory, and antitumor activities and the 1,2,3-triazole scaffold is known to express anti-allergic, anticonvulsant, antifungal, anti-HIV, antimicrobial, and antiviral activities. Triazepines, while less fully evaluated, are reported to have antibacterial, antifungal, antioxidant, and immunosuppressive activities. Our chemistry consists of a one-pot–three-step method for the conversion of oxazolino-2H-indazoles into triazolotriazepinoindazolones with three points of diversity. Step one of this process involves a propargyl bromide-initiated ring opening of the oxazolino-2H-indazole (available by the Davis-Beirut reaction) to give an N1-(propargyl)-N2-(2-bromoethyl)-disubstituted indazolone, which then undergoes –CH2Br ® –CH2N3 displacement (step two) followed by an uncatalyzed intramolecular azide-alkyne 1,3-dipolar cycloaddition (step three) to form the target heterocycle. Employing 7-bromooxazolino-2H-indazole allows for further diversification through, for example, palladium-catalyzed coupling chemistry. Furthermore, we have developed a number of methods for catalytic control of the three-dimensional stereochemical outcome of synthetically important chemical reactions. These methods use polymer-bound chiral auxiliaries derived from substances like the naturally-occurring amino acid proline and the useful synthetic trans-1,2-cyclohexanediamine. These allow the preparation of alkenes, ketones, and a variety of other basic systems in good enantiomeric purity. Participating in these studies have been both make and female graduate students from a variety of backgrounds, including several African Americans, Asian Americans and Hispanic Americans. Finally, we have published 121 papers 2000-present that acknowledge NSF support, 31 of which are from our current 3-year NSF project; another 7 papers are in various stages of preparation.
