Asymmetric Synthesis Towards Homoharringtonine And Harringtonine Side Chains

In 2012,homoharringtonine was approved by the FDA as an adult orphan-drug for the treatment of chronic myeloid leukemia.Harringtonine and homoharringtonine are all clinically efficacious anticancer drugs in China from 1978.Structurally,they have a common pentacyclic diterpenoid skeleton（cephalotaxine）that bears homologousα-tetrasubstituted ester side chains.The side chains are very important for the biological activity of Cephalotaxus alkaloids since cephalotaxine itself does not exhibit any interesting antitumor activity.The thesis consists of the following three chapters.Chapter 1 involes two sections.The first section described the isolation,chemical structrues and the biological activities of Cephalotaxus alkaloids.Synthetic design and retrosynthetic analysis were introduced in the second section.In Chapter 2,we systematically described the synthesis of side chains of homoharringtonine and harringtonine by new routes and the esterification with cephalotaxine.The sytnesis was acompished starting from bismethyl cyclic ketones in seven steps and the side chain molecules of homoharringtonine and harringtonine were obtained with a total yield of 32.01%and 43.18%,respectively.In chapter 3,attempts to construct chiral side chains via catalytic asymmtric allylic alkylation was conducted.After screening catalytic conditions,the best result（32.18%ee）for synthesis of homoharringtonine side chains is obtained using Pd（dba）₂ as the catalyst and ligand 11 as the chiral ligand.The best result（40.22%ee）for synthesis of harringtonine side chains is obtained using Pd（dba）₂ as the catalyst and ligand 7 as the chiral ligand.