| The y-lactam (pyrrolidin-2-one) core, found in many natural products and medicinally significant compounds, is a very important building block in chemical synthesis. Many y-lactam derivatives exhibit various biological activities, such as antimicrobial, antiviral, antitumor, inhibition of HIV, anti-senile dementia and so on. It is expected that structural modification on the y-lactam core should generate more derivatives of potential biological activities. This thesis work focuses on two topics: the synthesis of5-alkyl-5-aryl-y-lactams by one-pot reductive lactamization of y-nitrobutyrates and5-alkyl-5-aryl-l-pyrroline N-oxides by reductive cyclization of y-nitrobutaldehydes; and the construction of the5/6-fused y-lactam core of the natural products, cytochalasins, by an intramolecular Diels-Alder reaction as the key step.A brief introduction is given for y-lactams and cytochalasins natural products in Chapter1. The structures of the y-lactam-containing compounds and their biological activities are mentioned, followed by compilation of the known synthetic methods reported in recent years. The structures and biologic activities of cytochalasins are illustrated and the published total synthetic strategies towards several cytochalasin congeners by different groups are highlighted.Chapter2describes the results on the synthesis of5-alkyl-5-aryl-y-lactams and5-alkyl-5-aryl-l-pyrroline N-oxides. The reactions and synthetic applications of nitro compounds are first introduced. It is followed by presentation of the full results on the synthesis of5-alkyl-5-aryl-y-lactams and the compound characterization data. The palladium-catalyzed a-arylation of nitroalkanes, the DBU-mediated Michael addition with methyl acrylate, and the one-pot reductive lactamization of y-nitrobutyrates using NaBH4/NiCl2/K2CO3are used to furnish the5-alkyl-5-aryl-y-lactams in good to excellent overall yields. Selected examples of N-alkylation of the y-lactams are also illustrated. In a similar fashion, the same nitro compounds formed from the palladium-catalyzed a-arylation undergo the Et3N-mediated Michael addition with acrolein, followed by reductive cyclization of the y-nitrobutaldehydes using Zn/HOAc to provide the5-alkyl-5-aryl-1-pyrroline N-oxides. Preliminary results on the1,3-dipolar cycloaddition of the synthesized cyclic nitrones are also covered.Chapter3details the key results of this thesis research on the synthesis of the5/6-fused bicyclic hydroisoindol-1-one core of cytochalasins. Two synthetic routes have been attempted. The SmI2-mediated Barbier reaction is explored first as the key step for closure of the core at C8-C9. The requisite α,β-unsaturated y-lactam and the alkenyl iodide are synthesized and a variety of coupling methods for these two fragments has been attempted but with failure. The successful synthetic route centers on an intramolecular Diels-Alder (IMDA) reaction as the key step to build the5/6-fused core. Starting from L-phenylalanine methyl ester, the two key transformations, i.e. Wittig olefination and IMDA reaction, afford the5/6-fused γ-lactam core. It is followed by vinylation, C9hydroxylation, and BF3·Et2O-mediated deprotection of the Boc and TMSCH2CH2groups with inversion of configuration at C7-OH to furnish the desired hydroisoindol-1-one core. The longest linear steps are11in10%overall yield. Finally, a cross-metathesis (CM) approach has been investigated for the total synthesis of cytochalasin Z12but has not been successful.The experimental section compiles the synthetic procedures, the characterization data for all new compounds, and the cited references. Copies of original1H and13C NMR spectra and the data of X-ray single crystal structural analysis are found in the Appendix. |
PDF Full Text Request