Studies On The Total Synthesis Of Alkaloids Based On Michael Addition Strategy

Alkaloids are important natural products, most of them possess complicate molecular structures and certain bioactivities. The total synthesis towards alkaloids with significant bioactivities are important for organic synthetic chemistry as well as medicinal chemistry. In this thesis, we focus on asymmetric total synthesis of (-)-stenine and (+)-gelsemine. The Stemona plants have been used as traditional Chinese medicine for human respiratory diseases and anthelmintic agents. As one of stemona alkaloids, stenine have attracted the attention of many synthetic chemists for its unique sturctrue:six contiguous steregenic centers on the cyclohexane ring and a characteristic pyrrolo[1,2-α]azepine nucleus. Although there are five total synthesis of stenine reported from different groups, most of these previous strategies utilize Diels-Alder reaction as the key step to construct the cyclohexane ring. Gelsemine is the major alkaloid component isolated from notorious poisonous plant gelsemium elegans. As one of the earliest alkaloids isolated by chemist, gelsemine has also attracted the attention of many synthetic chemists for its unique hexacyclic cage structure, and its total synthesis have been accomplished by seven groups. The enantioselective total synthesis of stenine and gelsemine are less efficient in terms of step economy. In this thesis, we reported studies on the total synthesis of (-)-stenine and (+)-gelsemine based on Michael addition as the key carbon-carbon bonds formation strategy, aiming to develop novel and efficient methods towards the synthesis of natural alkaloids. Five chapters are included in this thesis.In the first chapter, the applications of Michael addition in total synthesis were summarized. Stenine and its toal synthesis, gelsemine and its total synthesis were also described.In the chapter2, the asymmetric total synthesis of (-)-stenine was described. After the synthesis of β-ketoester and nitroolefin, the asymmetric catalytic intramolecular double Michael additon between these two intermediates afforded the B ring together with its four contiguous steregenic centers. The C and D rings were constructed after one pot reductive amino-cyclization and amidation. After confirmation of the absolute configuration for the key intermediate by X-ray crystallography, the following methylation, sulfurization and reductive desulfurization gave (-)-stenine in14steps with5.9%overall yield.Based on Michael addition, new approaches toward the asymmetric total synthesis of (+)-gelsemine is presented in chapter3. We successfully synthesized some important intermediate for the total synthesis of (+)-gelsemine.In chapter5, the detailed experiment procedure, physical data and spectrum data for related compounds described in Chapter2and Chapter3are recorded.