Syntheses Of 3, 4-Dihydro-3-oxo-2H-1, 4-benzoxazines And C3-C12 Fragment Of 24-Demethylbafilomycin C₁

Target-oriented organic synthesis (TOS) has played an important role in the advancement of contemporary organic chemistry. Studies on total synthesis of natural products of structural complexity have been the driving force for development of new reactions, new reagents, and novel synthetic tactics. The latter collectively enrich the tools available for multi-step organic synthesis. In contrast to TOS, diversity-oriented organic synthesis (DOS), aiming for creation of molecular structural diversity, is emerging as a frontier research direction in recent years. It closely associates with research in chemical biology or chemical genetics. This thesis covers studies on the synthesis of nitrogen- and oxygen-containing privileged heterocycles according to the strategy and protocol of DOS and the synthesis of the C3-C12 fragment of a 16-membered ring antibiotic, 24-demethylbafilomycin C₁, by applying the strategy and protocol of TOS.Chapter 1 briefly introduces DOS, isocyanide-based multicomponent reactions (IMCRs), and microwave-assisted organic synthesis (MAOS). Substituted 2-aminophenols are a class of cheap and readily available starting materials. Selected applications of 2-aminophenols in the synthesis of nitrogen- and oxygen-containing heterocycles are discussed. The structures of the plecomacrolides are then presented and the known strategies in the literature used for synthesis of bafilomycin A₁ are analyzed.Chapters 2-4 compile the results obtained during this thesis research on synthesis of a series of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines and the conjugates with 2-oxindoles under controlled microwave heating. First, optimization of reaction conditions was performed as given in Chapter 2, leading to regioselective annulation of N-arylmethyl-2-aminophenols with ethylα-bromoalkanoates under microwave heating to produce 4-arylmethyl-3,4-dihydro-3-oxo-2H-1,4-benzoxazines. In Chapter 3, a one-pot synthetic sequence was established by combining Ugi-four-component reaction (U-4CR) with intramolecular S_n2 reaction. It offers an efficient microwave-assisted synthesis of 3,4-dihydro-3-oxo-2H-1,4-benzoxazines appended with a variety of functionalities. The latter allow further annulation to install a 2-oxindole subunit via microwave-assisted Cu-catalyzed intramolecular amidation. The byproduct formed from intramolecular O-arylation of the bulky secondary amides was identified. In order to improve efficiency of the intramolecular amidation, the palladium-catalyzed version was developed in Chapter 4. Under controlled microwave heating, the functionalized 3,4-dihydro-3-oxo-2H-1,4-benzoxazines, prepared by the one-pot U-4CR & intramolecular S_n2 reaction in Chapter 3, underwent a rapid and efficient cyclization to furnish a collection of the conjugates with 2-oxindole linked through a C-N single bond.Chapter 5 briefs the reports in the literature on establishment of the C6-C8 stereotriad used for total synthesis of bafilomycin A₁. In this thesis work, the anti-selective aldol reaction of the (E)-enolate of the Abiko's chiral propionate was used as the key step for stereochemical control. The alkylation of 1,3-dithiane was selected for formation of the methyl ketone intermediate, which was then used to install the (E)-1,3-diene moiety via Horner-Wittig reaction. By following some common transformations, the C3-C12 fragment was synthesized by a 13-step sequence and in 12.3% overall yield.The experimental section compiles the synthetic procedures and full characterization data for all new compounds. Copies of original ¹H and ¹³C NMR spectra, and data of X-ray single crystal structural analysis are found in the Appendix.