page_title: Resiniferatoxin
section_title: Total synthesis
hierarchical_section_title: Resiniferatoxin / Total synthesis
caption_attribution_description: English: A partial synthesis of a resiniferatoxin derivative based on the method put forth by the Wender group of Stanford University. This partial synthesis shows how to create the three-ring backbone of RTX
context_page_description: Resiniferatoxin is a naturally occurring chemical found in resin spurge, a cactus-like plant commonly found in Morocco, and in Euphorbia poissonii found in northern Nigeria. It is a potent functional analog of capsaicin, the active ingredient in chili peppers.
context_section_description: A total synthesis of (+)-resiniferatoxin was completed by the Wender group at Stanford University in 1997. The process begins with a starting material of 1,4-pentadien-3-ol and consists of more than 25 significant steps. As of 2007, this represented the only complete total synthesis of any member of the daphnane family of molecules.
  One of the main challenges in synthesizing a molecule such as resiniferatoxin is forming the three-ring backbone of the structure. The Wender group was able to form the first ring of the structure by first synthesizing Structure 1 in Figure 1. By reducing the ketone of Structure 1 followed by oxidizing the furan nucleus with m-CPBA and converting the resulting hydroxy group to an oxyacetate, Structure 2 can be obtained. Structure 2 contains the first ring of the three-ring structure of RTX. It reacts through an oxidopyrylium cycloaddition when heated with DBU in acetonitrile to form Structure 4 by way of Intermediate 3. Several steps of synthesis are required to form Structure 5 from Structure 4, with the main goal of positioning the allylic branch of the seven-membered ring in a trans conformation. Once this conformation is achieved, zirconocene-mediated cyclization of Structure 5 can occur, and oxidizing the resulting hydroxy group with TPAP will yield Structure 6. Structure 6 contains all three rings of the RTX backbone and can then be converted to resiniferatoxin through additional synthesis steps attaching the required functional groups.
  An alternative approach to synthesizing the three-ring backbone makes use of radical reactions to create the first and third rings in a single step, followed by the creation of the remaining ring. It has been proposed by the Inoue group of the University of Tokyo.
caption: Figure 1. A partial synthesis of a resiniferatoxin derivative based on the method put forth by the Wender group of Stanford University. This partial synthesis shows how to create the three-ring backbone of RTX
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