Method Development for the Stereoselective Synthesis of Heterocycles.

[摘要] Efforts made to improve the scope of palladium-catalyzed carboetherification and carboamination reactions are illustrated herein, and strategies for overcoming various limitations to the method are discussed. As described in this thesis, the synthesis of bis-, fused- and poly-substituted tetrahydrofurans, 1,3-oxazolidines, benzopyrans and benzoxepines was achieved through the palladium-catalyzing coupling of γ-hydroxy alkenes, O-vinyl-1, 2-amino-alcohols, homoallylphenols and 2-(pent-4-en-1-yl)phenols with aryl and alkenyl halides. The synthesis of the aforementioned heterocycles represents a significant advancement in the methodology toward the synthesis of natural products, especially the annonaceous acetogenins. In Chapter 2, a novel strategy for the synthesis of bis- and fused-tetrahydrofurans is described. Sequential Pd-catalyzed carboetherification reactions were performed to yield bis- and fused-THFs, which enabled access into biologically active compounds such as the annonaceous acetogenins. As described in Chapter 3, the diastereoselectivity of Pd-catalyzed carboetherification reactions of substrates bearing internal alkenes was improved by employing S-Phos, an electron-rich, bulky monodentate biaryl ligand, which promoted reductive elimination and suppressed β-hydride elimination. As a result, poly-substituted tetrahydrofurans were produced in excellent diastereoselectivity, and biologically active compounds possessing this motif, such as Simplakidine A, a cytotoxic marine natural product, may be synthesized using the proposed methodology. In Chapter 4, the synthesis of 1,3-oxazolidines using a catalyst system based on S-Phos is described. The use of S-Phos promoted reductive elimination, which was disfavored due to the presence of electron withdrawing substituents on the substrate. Through the work described in this thesis, 1,3-oxazolidines, an important structural motif in organic synthesis, can be obtained using Pd-catalyzed carboamination reactions. A catalyst system composed of Pd2(dba)3/S-Phos also proved to be useful for the production of benzopyrans, which are common in antioxidants and were previously inaccessible through our methodology. As outlined in Chapter 5, the scope of the methodology was expanded to include homoallylphenols, highlighting the ability of the catalyst to overcome entropic effects and the low nucleophilicity of phenols. Heterocycles containing 6-membered rings were produced in a convergent manner, allowing access into motifs common in biologically active materials. In Chapter 6, the methodology was extended towards benzoxepines, enabling the synthesis of biologically relevant materials.

[发布机构] University of Michigan

[效力级别] Chemistry

[关键词] Carboetherification;Chemistry;Science;Chemistry