Studies On The Transformation Of α-Amino Esters To Heterocycles

The transformation of a-amino acid derivatives is always a research hotspot in chemistry and biology. a-Amino acid derivatives are not only the basic substances for the construction of biomolecules in the biology but also an important class of building blocks for the syntheses of peptide-based natural products and drug molecules. Moreover, in recent years, they have gradually become a good platform for the exploration of organic reactions. Based on the existing developments of a-amino acid derivatives, we have made research on the transformation of a-amino acid esters to heterocycles and have successfully obtained novel methodologies for the syntheses of pyrroles, pyrimidines and a-enamino esters from the readily available a-amino acid esters. This thesis involves three chapters as followed.The first chapter presents Cu/Mn co-oxidized cyclization for the synthesis of highly substituted pyrrole derivatives from a-amino acid esters. With a review of the synthesis of pyrroles mediated by transition metals and the inspiration from the biosynthesis of chromopyrrolic acid from tryptophan, we made research on the synthesis of pyrroles from a-amino acid esters and developed a novel route to polysubstituted pyrroles from a-amino acid esters through the co-oxidation of copper and manganese. This reaction proceeded through multiple dehydrogenations, deaminations, and oxidative cyclization to give pyrroles in reasonable yield. This transformation presented good functional group tolerance and broad substrate scope. With this methodology, several key intermediates of natural products have been obtained and the biomimetic syntheses of lycogarubin C and chromopyrrolic acid have been completed in high efficiency.The second chapter describes Cu(OAc)2/TEMPO-promoted one-pot synthesis of highly substituted pyrimidines from a-amino acid esters. During the study on the preparation of pyrroles from a-amino acid esters, we found that some a-amino acid esters could also be transformed to polysubstitued symmetrical pyrimidines. Therefore, we turned to the investigation of the synthesis of polysubtituted pyrimidines from a-amino acid esters and developed an one-pot synthesis of highly substituted pyrimidines from a-amino acid esters with the promotion of Cu(OAc)2 and TEMPO. In this reaction, the a-amino acid esters act as the only C-N source for the construction of corresponding pyrimidines, which makes this method the first example to prepare pyrimidines form single C-N source. The mechanism of this process includes oxidative dehydrogenation, the generation of an imine radical and a formal [3+3] cycloaddition, which turns this reaction into a high atom-economic and simple straightforward strategy for the synthesis of pyrimidines with various functional groups in moderate to good yield.The third chapter gives Cu(OAc)2-promoted dehydrogenation of a-amino acid esters for the synthesis of a-enamino esters employed to construct polysubstituted pyrroles with alkynes. a-Enamino esters which possess both nucleophilicity and electrophilicity, play an important role in biosynthesis and chemical synthesis. Moreover, the method which provides access to a-enamino esters directly from a-amino acid esters in one step has not been reported so far. The a-enamino esters have been obtained as key intermediates in the transformation from a-amino acid esters to pyrroles and pyrimidines. Therefore, we made research on the synthesis of a-enamino esters from a-amino acid esters in one step, and developed an efficient method to prepare a-enamino esters through the copper-promoted oxidative dehydrogenation of a-amino acid esters. Meanwhile, in the research on the reactivity of a-enamino esters, we have successfully employed the a-enamino esters to construct polysubstituted pyrroles through a Cu(OAc)2-promoted oxidative coupling reaction with alkynes and investigated the mechanism of the transformation.We dedicate to studying the transformation of a-amino acid esters to heterocycles and achieve new methods to prepare pyrroles, pyrimidines and a-enamino esters from a-amino acid esters. We have also undertaken research on the reactivity of a-emino acid esters and achieved new method for the preparation of polysubstituted asymmetric pyrroles. All of these developments powerfully demonstrate that a-amino acid derivatives provide a good platform for the investigation of organic reactions, and we will continue to search for new reactions on the platform.