Synthesis Of Benzofurans By Sequential Ugi And Rap-Stoermer Reactions And Construction Of C14-C21Acid Fragment Of Cytochalasin Z8

Ugi four-component reaction (U-4CR) is one of the powerful tools to generate structural diversity and it has found wide applications in drug discovery and development programs. Moreover, through post-Ugi transformations the linear dipeptide-like U-4CR products can be transferred into various cyclic scaffolds, providing an efficient and attractive strategy for attaining molecular shape diversity and allowing a facile access to a number of medicinally relevant heterocycles. The Rap-Stoermer reaction enables synthesis of benzofurans possessing a carbonyl-based substituent at C2position. Incorporation of U-4CR with the Rap-Stoermer reaction would provide a diversity-oriented synthesis of highly functionalized benzofuran-2-carboxamides. This thesis research deals with studies on synthesis of benzofuran-2-carboxamides and the related nitrogen-containing heterocycles via post-Ugi transformations including the Rap-Stoermer reaction, and the palladium-catalyzed direct arylation and amidation. Synthesis of the C14-C21acid fragment of the macrolide, cytochalasin Z8, is addressed as well.A brief introduction on the background of the thesis research is given in Chapter1, including U-4CR, biological activity and general synthetic methods for benzofuran-2-carboxamides, and the molecular structures of the cytochalasin family.Chapter2describes the prior studies on the Rap-Stoermer reaction and its applications in synthesis of2-substituted benzofurans and summaries the current results on the sequential U-4CR and microwave-assisted Rap-Stoermer reaction. It covers optimization of the reaction conditions, and examination of the substrate scope and the reaction mechanism. Starting from a set of four substituted salicylaldehydes, a number of benzofuran-2-carboxamides are successfully synthesized. It is also found that reactions of the above U-4CR products with the salicylaldehydes having strong electron-withdrawing group(s) afford the1,3,5-trisubstituted hydantoins, another class of bioactive compounds.Chapter3focuses on the transformations according to the palladium-catalyzed direct arylation and amidation. Selected prior examples are illustrated with an emphasis on the ligand effect on these palladium-catalyzed cyclization processes. The highly functionalized benzofuran-2-carboxamides obtained from the sequence of U-4CR and Rap-Stoermer reaction undergo, in a selective manner, intramolecular direct arylation and amidation, respectively, to furnish5,6-dihydrophenanthridines and2-oxindoles. Their structures have been confirmed by X-ray crystal structural analysis.Chapter4details with synthesis of the C14-C21acid fragment of cytochalasin Zg. An introduction is provided for the anti-selective Masamune aldol reaction and the B-alkyl Suzuki-Miyaura cross-coupling reaction. A concise synthesis of is described to furnish the desired C14-C21acid fragment in a14%overall yield via a10-step sequence.The experimental section compiles the synthetic procedures and full characterization data for all new compounds, and the cited references are found at the end of the thesis. Copies of the original1H and13C NMR spectra, and data of X-ray single crystal structural analysis are found in the Appendix.