Synthetic studies towards total syntheses of natural products daphenylline and calyciphylline A & target identification and mechanism study of dihydromotuporamine C (synthetic part)

Abstract

Natural products as a key source of bio-active compounds not only play an important role in discovery of new drugs, but also have been a promoter in developments and applications of organic synthetic methodologies. In addition, chemical synthesis of intriguing natural products with diverse and complicated scaffolds is an art and science defining the frontiers of organic chemistry. Daphniphyllum alkaloids isolated from the flowering plant Daphniphyllum possessing over 330 members have displayed a range of biological activities containing anticancer, antiHIV1, anti-oxidatant, etc. Besides, their charming structures with diverse and polycyclic framework have attracted a variety of attention in natural product synthesis community. Among 14 structural types of Daphniphyllum alkaloids, calyciphylline A-type with 6-6-5-7-5-5 hexacyclic system is the most popular one recently. In this thesis, the synthetic studies toward total syntheses of daphenylline and calyciphylline A are presented. In chapter 1, the general introduction of Daphniphyllum alkaloids including the history of isolation, structural types, biological activities and biogenesis is presented. On basis of current reviews, doctoral thesis, etc. Subsequently, strategies involved in the accomplished total syntheses of Daphniphyllum alkaloids are summarized. In chapter 2, the isolation, biogenesis and our synthetic studies of daphenylline are introduced. [5+2] cycloaddition and Ring-Closing-Metathesis (RCM) cascade are employed in synthetic studies of daphenylline culminating in the construction of 6-5-7-6-5 pentacyclic skeleton of daphenylline. In chapter 3, the isolation, biogenesis, previous synthetic efforts and achievements of calyciphylline A are introduced. [5+2] cycloaddition and Pauson-Khand reaction are employed in synthetic studies of daphenylline culminating in the construction of 6-5-7-5-5 pentacyclic skeleton of calyciphylline A. In chapter 4, the introduction to dihydromotuporamine C, which displays a significant bioactivity about antimigration is described briefly. As a collaborator, my duty is to prepare enough dihydromotuporamine C to support further biological investigations. The routes access to dihydromotuporamine C and its derivatives are presented in this chapter. The synthetic studies about daphenylline and calyciphylline A aim at not only providing an alternative route access to scalable syntheses for further biological investigations, but also allowing syntheses of other calyciphylline A-type alkaloids.