| Small, polyfunctionalized heterocycles have attracted significant attention in the design of biologically active compounds in the drug discovery enterprise. Research in the area of combinatorial synthesis employing heterocycles as scaffolds for library development has become very prominent. Pyridine-containing heterocycles, such as tetrahydronaphthyridines, have been shown to possess a variety of biologic activities. Previous work in our group developed an inverse-electron-demand Diets-Alder (IEDDA) strategy to prepare the 1,2,3,4-tetrahydro-1,5-naphthyridines, however, the preparation of the other tetrahydronaphthyridine analogues could not be achieved via this IEDDA strategy. Thus, metal-catalyzed [2 + 2 + 2] cyclizations between a nitrite and two alkynes were investigated in both intermolecular and intramolecular reactions, which have the potential to prepare all the tetrahydronaphthyridine isomers. To determine optimal conditions, different transition metals (Co, Zr, Ni, Ir, Ru, and Au), as well as reaction conditions (thermal heating, photochemical activation, and microwave irradiation) were screened. The best results were achieved when CpCo(CO)2 was employed as catalyst, under microwave irradiation in chlorobenzene. Using the optimized microwave-promoted conditions, the intermolecular cyclizations between amino alkynyl nitriles and alkynes gave the desired 5,6,7,8-tetrahydro-1,6-naphthyridines in modest yields, while the intramolecular cyclizations of dialkynyl aminonitrile precursors afforded dihydropyran ring-fused tetrahydronaphthyridines in excellent yields.; The dihydropyran ring-fused tetrahydronaphthyridine skeleton is an ideal scaffold for library synthesis due to its low molecular weight, multiple sites for diversification, and efficient preparation via intramolecular [2 + 2 + 2] cyclization. Therefore, a 101-membered library was synthesized based on these scaffolds, including ureas, amides, sulfonamides, and tertiary amines. Preliminary biological screening results indicated that four members of this library showed inhibitions against tuberculosis.; Finally, a heterocyclic natural product, naringenin, was investigated for its suitability as a library scaffold. Belonging to the flavonone class, naringenin is characterized by the rigid tricyclic benzopyran core with three phenols at C-5, C-7 and C-4' positions. Recent epidemiological studies showed increasing evidence for the anticancer and antiatherogenic properties of this natural product. Its rigid, densely functionalized tricyclic scaffold is an attractive structure for discovering novel bioactive molecules. Thus, suitable chemistries were explored on these scaffolds in an effort to define regioselective transformations of the phenolic groups through palladium catalyzed cross-coupling chemistry which could be applied to library development. |
