A
total synthesis of (+)-resiniferatoxin was completed by the
Paul 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. == Toxicity ==