Resiniferatoxin
If you think capsaicin is hot enough for you, you might want to think again. One of the member of a big family of daphnane diterpene is way beyond capsaicin in Scoville scale. This compound scores 16,000,000,000 Scoville Heat Unit (SHU) which is 1000 times than capsaicin itself. This chemical can be found in resin spurge (Euphorbia resinifera) and it is known as resiniferatoxin (RTX).
As mentioned earlier, RTX scores above the Scoville scale and this makes RTX is a very potent compound and can inflict chemical burns. Based on animal experiments, it is suggested that as little as 40 g may be fatal or cause serious damage to human. Despite not structurally related with capsaicin, it does exhibit activity in common with capsaicin. However, it is not a tumor promoter and does not compete on protein kinase C such as in the more closely structurally related phorbol ester.
Interestingly, RTX is the first and only member of daphnane family that has been synthesised until now. It was totally synthesised for the first time by Wender's group from Stanford University, California in 1997. The key reaction in the asymmetric synthesis of RTX is controlling the stereochemistry since the first step of the reaction.
Absolute controlled-stereochemistry by (-)-diisopropyl tatrate [(-)-DIPT] epoxidation followed by benzyl protection gives epoxide 6 around 98% enantiomeric excess which is a good sign for asymmetric synthesis. Then, opening epoxide with EtOCCLi followed by lactone formation and methylation gives lactone 4 as major product. Reaction of 4 with lithiated TBS-protected furfuryl alcohol followed by acetate protection to give ketone 5. Then, ketone reduction followed by furan oxidation with m-CPBA produces 6-membered ring of pyranone and 6 is finally formed with actetate protection. However, this reaction produced an inconsequential mixture of pyranone. After that, pyranone 6 undergoes highly selective cycloaddition using 1,8-diazabicyclo-[5.4.0]-undec-7-ene (DBU) to give cycloadduct 8 with desired oxygen bridge. Until this step, the 6-membered and 7-membered ring are already intact, so the next step would be forming the 5-membered ring to give the daphnane skeleton.
The first step to form the 5-membered ring was transforming 8 to the desired enone 9 in 5 steps. Then, a conjugate addition of 9 with vinyl cuprate give the first fragment in forming the 5-membered ring. The stereochemistry of formed 10 is dictated by the oxygen bridge in the 7-membered ring. The second fragment was attached by lithiation followed TMS protection of formed alkoxide to give 11. The 5-membered ring is formed via Zr-mediated cyclisation followed by oxidation formed alcohol using tetrapropylammonium perruthenate(VII) (TPAP) to give 12 with 89% of yield. Then, addition of isopropenyl magnesium bromide to 12 completed the daphnane framework. This reaction is a big test of stereocontrolled synthesis but in this reaction it only react at one side, which means a pass in this big test.
Ozonolysis of 14 followed by removal of benzyl group and formation of carbonate give 15 which then undergoes selective removal of TBS and 16 is formed via iodo ether elimination aided by activated Zn. Oxidation by selenium oxide gives the desired alcohol on C7 of 17 which then introduced alcohol to C20 with benyzl protecting group to give 18. This alcohol on C20 will be used in esterification to finish off the synthesis. By this step, the main functional groups of RTX can be converted easily. carbonate opening of 18 under basic condition in dioxane followed by esterification using acid anhydride give the ester on C14. In acidic condition of HClO4, the orthoester 20 is formed. Isopropenyl group in 21 is then regenerated using Peterson olefination followed deprotection of benzoyl group. Then, 21 is undergone C20 benzoylation, formation of C3 silyl enol ether, bromination and elimination of bromine to give 22. To finish off the synthesis, TMS is cleaved under acidic condition with TBAF, benzoyl group is deattached under alkaline condition, then esterification to form RTX.
With this synthesis, further studies in activity, mode of action, and receptor characterisation is made possible. Besides that, with this synthesis it is also possible for RTX is used as future analgesic.
Reference
P. A. Wender, C. D. Jesudason, H. Nakahira, N. Tamura, A. L. Tebbe, and Y. Ueno, J. Am. Chem. Soc., 1997, 119, 12976.
As mentioned earlier, RTX scores above the Scoville scale and this makes RTX is a very potent compound and can inflict chemical burns. Based on animal experiments, it is suggested that as little as 40 g may be fatal or cause serious damage to human. Despite not structurally related with capsaicin, it does exhibit activity in common with capsaicin. However, it is not a tumor promoter and does not compete on protein kinase C such as in the more closely structurally related phorbol ester.
Interestingly, RTX is the first and only member of daphnane family that has been synthesised until now. It was totally synthesised for the first time by Wender's group from Stanford University, California in 1997. The key reaction in the asymmetric synthesis of RTX is controlling the stereochemistry since the first step of the reaction.
The first step to form the 5-membered ring was transforming 8 to the desired enone 9 in 5 steps. Then, a conjugate addition of 9 with vinyl cuprate give the first fragment in forming the 5-membered ring. The stereochemistry of formed 10 is dictated by the oxygen bridge in the 7-membered ring. The second fragment was attached by lithiation followed TMS protection of formed alkoxide to give 11. The 5-membered ring is formed via Zr-mediated cyclisation followed by oxidation formed alcohol using tetrapropylammonium perruthenate(VII) (TPAP) to give 12 with 89% of yield. Then, addition of isopropenyl magnesium bromide to 12 completed the daphnane framework. This reaction is a big test of stereocontrolled synthesis but in this reaction it only react at one side, which means a pass in this big test.
With this synthesis, further studies in activity, mode of action, and receptor characterisation is made possible. Besides that, with this synthesis it is also possible for RTX is used as future analgesic.
Reference
P. A. Wender, C. D. Jesudason, H. Nakahira, N. Tamura, A. L. Tebbe, and Y. Ueno, J. Am. Chem. Soc., 1997, 119, 12976.
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