Natural drugs homoharringtonine and harringtonine are minor alkaloids isolated from the leaves and stems of plum yew Cephalotaxus harringtonia, an evergreen tree native of the southern provinces of China. Structurally, two natural drugs are all chiral compounds and have a common skeleton cephalotaxine, and the ester side chains bear chiral tertiary alcohol at α position. Because of the formidable steric bulk of both the keleton cephalotaxine and ester side chain, the esterification of both sections is extremely challenging. A less hindered side chain intermediate is key element to success for this coupling reaction. Consequently, chemists continuously designed and synthesized structurally diverse side chain intermediates such as α-ketoacids, four-membered lactone heterocycles, tetrahydrofuran heterocycles, tetrahydropyran heterocycles, and seven-membered lactone heterocycles, enabling the completion of synthesis of homoharringtonine, harringtonine and other related natural products. Based on our studies toward the synthesis of Cephalotaxus alkaloids, this paper reviews the strategic development towards the synthesis of Cephalotaxus natural drugs and other products by the types of side chain intermediates, including not only recent strategy advances but also synthetic methods developed by respected older generation chemists.
Contents
1 Introduction
2 Synthesis of homoharringtonine
2.1 α-Ketoacids as coupling partners
2.2 Tetrahydropyran intermediate as coupling partner
2.3 Four-membered lactone intermediate as coupling partner
3 Synthesis of harringtonine
3.1 α-Ketoacid as coupling partner
3.2 Dihydrofuran intermediate as coupling partner
3.3 Seven-membered lactone intermediate as coupling partner
4 Synthesis of anhydroharringtonine
4.1 α-Ketoacid as coupling partner
4.2 Tetrahydrofuran intermediate as coupling partner
5 Synthesis of homodeoxyharringtone
5.1 α-Ketoacid as coupling partner
5.2 Four-membered lactone intermediate as coupling partner
6 Synthesis of deoxyharringtone
6.1 α-Ketoacids as coupling partners
6.2 Four-membered lactone intermediate as coupling partner
7 Synthesis of isoharringtonine, nordeoxyharringtonine and homoneoharringtonine
8 Conclusion