Novel Polycyclic Benzannulated Indole Scaffolds via Indole Aryne Cycloaddition, Pd (0)-Catalyzed Cross-coupling and ROM/RCM methodologies: Their Applications to Library Development and Drug Discovery
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Dissertation under the direction of Keith R. Buszek, Ph.D., Professor of Chemistry, University of Missouri-Kansas City. Heterocyclic chemistry is one of the most valuable sources of novel compounds with diverse biological activity. The indole nucleus for instance, is an important element of many natural and synthetic molecules with significant biological activity. Drug discovery and development processes highly value the utility of the ability to synthesize a diverse library based on one core scaffold which can be screened against a variety of different receptors and cell lines, yielding several active compounds. Privileged structures offer an ideal source of lead compounds for drug discovery due to their inherent affinity for diverse biological targets. Indole motifs represent one of the most prominent privileged structures and are ubiquitous in natural products and pharmaceutical compounds. A variety of fused heterocyclic structures will be designed, resulting in novel polycyclic frameworks with virtually no representation in the National Institutes of Health PubChem and Molecular Library of Small Molecule Repository (MLSMR) databases. These molecular frameworks would be predicted to occupy unoccupied or sparsely occupied regions of the chemical property space, which increase their chances of finding applications as new drug leads with different modes of actions. Consequently, efficient methodologies resulting in polycyclic structures from biologically active heterocyclic templates are highly desired in the drug discovery and development programs. The synthesis of such a unique class of polycyclic benzannulated indole scaffolds is described. The 4,6,7-tribromoindole and the 5,6,7-tribromoindole were synthesized via the Bartoli and Leimgruber-Batcho and indole synthesis protocols respectively. Both indoles underwent selective metal-halogen exchange at C-7 and subsequent elimination to give the 6,7-indole aryne which underwent Diels-Alder cycloadditions with cyclopentadiene, furan and 2,5-dimethyl furan. These cycloadducts were N-alkylated and then subjected to Grubb’s catalyst ring opening metathesis/ring closing metathesis to afford 12 unique 6,7- benzannulated with an additional 7 or 8–membered rings fused from the benzenoid ring to the pyrrole ring of the indole nucleus. Library development is facilitated by the extra bromine at the 4 or 5 position of the indole nucleus which serves as a diversity handle which can be subjected to several palladium catalyzed cross-couplings including but not limited to Suzuki-Miyaura, Negishi and Buchwald-Hartwig. Diversity of these scaffolds can be further enhanced via olefin functionalization: cross metathesis, hydroamination and epoxidation among others to afford pharmaceutically useful functional groups like carbamates, ureas, secondary and tertiary amines as well as sulfonamides.
Table of Contents
Introduction -- Therapeutics inspired by natural products -- Benzannulated indole alkaloid natural products discovery, isolation and synthesis -- Biological studies and results of a benzannulated indole scaffolds libraries -- Design and synthesis of novel 4-, 5-, 6,7 benzannulated tribromo scaffolds for cross-coupled libraries -- Experimental section -- Conclusions