Studies On Tht Asymmetric Synthesis Of Some Hydroindole Alkaloids

The hydroindole alkaloids are widespread in nature, and much interest has been shown in them due to their significant biological activities and potential medicinal value. From a synthetic point of view, the effective construction of the chiral all-carbon quaternary carbon centers in the hydroindole cores constitutes one critical element in the asymmetric synthesis of these alkaloids. Despite substantial progress in the total syntheses of hydroindole alkaloids over the last four decades, the asymmetric establishment of such key chiral quaternary stereocenters was mainly based on the employment of chiral substrates or chiral auxiliaries. Therefore, the development of alternative strategies for the stereocontrolled access to such chiral quaternary stereogenic centers, especially using achiral substrates in asymmetric catalytic fashion, is highly appealing. Aiming at this topic, the following three parts in this dissertation are organized as follows:Part I:Focusing on the asymmetric total synthesis of natural hydroindole alkaloids, a retrosynthetic analysis of three representative Amaryllidaceae hydroindole alkaloids, namely (+)-vittatine,(+)-epi-vittatine and (+)-buphanisine, was demonstrated, in which a novel organocatalytic asymmetric intermolecular Michael addition was designed to stereoselectively assemble the unique chiral all-carbon quaternary center.Part II:According to the above retrosynthetic analysis, a target-oriented model for the key Michael addition was then formulated, in which the optimization of enantioselectivity by the extensive catalyst screening constitutes an important issue for the enantioselective construction of all-carbon quaternary center. As was known, cinchona alkaloids and derivatives, which are classified as one of the most privileged chiral backbones, could promote various types of conjugate addition reactions with excellent performances. Based on the chemical modification of cinchona alkaloids, seven types of organocatalysts including forty five cinchona derivatives were prepared. Presently, the optimal enantioselectivity of85%ee for the key Michael addition could be achieved by the various catalyst screening. Combined with the unusual heterochiral crystallization, the optical purity of the Michael adduct with the crucial quaternary carbon could be further enriched to99%ee after one recrystallization, paving a way to asymmetric total synthesis of hydroindole alkaloids.Part III:Commenced with a-cyanoketone1, a key common building block with the cis-arylhydroindole core was readily accessed through13steps in an overall yield of23%, in which the novel asymmetric Michael addition as a key reaction was involved strategically. Based on this method-driven strategy, the asymmetric total synthesis of Amaryllidaceae hydroindole alkaloids (+)-vittatine,(+)-epi-vittatine and (+)-buphanisine were accomplished, in which the asymmetric synthesis of (+)-epi-vittatine and (+)-buphanisine was reported for the first time. The current synthetic route with efficient and effective manner provides an alternative opportunity for the enantioselective synthesis of the structurally related hydroindole alkaloids.