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Author: Subject: Salvinorin - finally a total synthesis
Panoramix
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smile.gif posted on 3-7-2007 at 12:36
Salvinorin - finally a total synthesis


Asymmetric Synthesis of Salvinorin A, A Potent Opioid Receptor Agonist
Jonathan R. Scheerer, Jonathan F. Lawrence, Grace C. Wang, and David A. Evans
J. Am. Chem. Soc., 2007, 10.1021/ja073590a

Abstract: The stereoselective synthesis of salvinorin A is described. A macrocyclic bis-Michael reaction cascade provides the requisite tricyclic skeleton as a single diastereomer










Supporting information for experimental details and NMR data


[Edited on by Panoramix]

<sub>Edit by Nicodem: Replaced the dead image links with a couple of new ones.</sub>

[Edited on 5/3/2008 by Nicodem]

Attachment: Salvinorin_total_synthesis.pdf (85kB)
This file has been downloaded 1119 times

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tr41414
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[*] posted on 3-7-2007 at 14:01


It is nice to see that done properly :D But it is no play for home chemist :(
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Sandmeyer
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[*] posted on 3-7-2007 at 15:36


Cyclization was neet, otherwise pretty square, yawn...



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Panoramix
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[*] posted on 4-7-2007 at 09:46
Excellent chemist but....


Great synthesis but their pharmacological knowledge is kind of questionable:


Quote:

the only non-alkaloid psychoactive substance


Perhaps they consider THC as a remedy and not as a psychoactive substance.
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Lego
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[*] posted on 4-3-2008 at 23:04
Another 20 step total synthesis of Salvinorin A


Total Synthesis of the Hallucinogenic Neoclerodane Diterpenoid Salvinorin A
Masato Nozawa, Yuhki Suka, Takashi Hoshi, Toshio Suzuki, and Hisahiro Hagiwara
Org. Lett., 2008, http://dx.doi.org/10.1021/ol800101v

Abstract: Total synthesis of salvinorin A (1), a neoclerodane diterpenoid having the most potent hallucinogenic activity and a selective -opioid agonist, was completed in 20 steps starting from enantiomerically pure hydroxy-Wieland-Miescher ketone 5.



Supporting information
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MagicJigPipe
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[*] posted on 5-3-2008 at 00:21


"A potent opioid receptor agonist" may be a bit misleading to some. Most opioid analgesics rely on mu-opioid receptor activity which is responsible for pain relief and euphoria.

Salvinorin A is a kappa-opioid receptor agonist which is usually associated with hallucenogenic, slight analgesic and sometimes DYSPHORIC effects. Salvinorin A will cause extreme dysphoria in some people.
Quote:
Great synthesis but their pharmacological knowledge is kind of questionable:
...
Perhaps they consider THC as a remedy and not as a psychoactive substance.

I think what they meant was it's the only k-opioid agonist that is not an alkaloid.

What's interesting is that naloxone is a slight k-opioid antagonist. I wonder if Salvinorin's effects could be reversed with naloxone.

This is an interesting synthesis. I would like to see more of this type of post in the future! Especially in place of all the amphetamine & co. posts.

[Edited on 5-3-2008 by MagicJigPipe]




"There must be no barriers to freedom of inquiry ... There is no place for dogma in science. The scientist is free, and must be free to ask any question, to doubt any assertion, to seek for any evidence, to correct any errors. ... We know that the only way to avoid error is to detect it and that the only way to detect it is to be free to inquire. And we know that as long as men are free to ask what they must, free to say what they think, free to think what they will, freedom can never be lost, and science can never regress." -J. Robert Oppenheimer
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Sauron
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[*] posted on 5-3-2008 at 03:56


The two GIF files in the post at top of this thread are not working.



Sic gorgeamus a los subjectatus nunc.
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Nicodem
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[*] posted on 5-3-2008 at 04:42


They should work now.

The discussion at the TotalySynthetic forum about the first total synthesis of Salvinorin A (the paper in the first post above): http://totallysynthetic.com/blog/?p=692
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Drunkguy
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[*] posted on 5-3-2008 at 05:03


It's nice to know these people are professional academics because I cant imagine doing such a torturous reaction scheme for the mere fun of it.

Magicjigpipe: Dont be so cynical, extremely selective ligands such as salvia allow us to probe exactly what the effects of the KOR for example are responsible for.

Try searching out info on Herkinorin if you want a MOR agonist that is made from salvia. However, the KOR selectivity of salvia should be seen as a blessing rather than a curse. It's what makes it so important to researchers.

It's actually KOR antagonists that may be useful in a medicinal context. I've heard salvia described as "the scare herb" so while it's got no medicinal properties whatsoever it may still have uses in spiritualistic shamanism.

Nicodem: Thanks for the link to that website, www.totallysynthetic.com

I've never heard of it b4, but it looks quite heavy, "100% unnatural" and definately a serious place not for lighthearted discussions.

[Edited on 5-3-2008 by Drunkguy]




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MagicJigPipe
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[*] posted on 5-3-2008 at 12:28


How was I being cynical? Just merely pointing out that k-agonists can cause extreme dysphoria, I mean, it's true. Also, most opioids/opiates have some k-receptor activity. Apparently, it is part of what causes the nausea and various other "negative" effects related to opioids.

I know naloxone is a kappa antagonist. I wonder if naltrexone is as well.




"There must be no barriers to freedom of inquiry ... There is no place for dogma in science. The scientist is free, and must be free to ask any question, to doubt any assertion, to seek for any evidence, to correct any errors. ... We know that the only way to avoid error is to detect it and that the only way to detect it is to be free to inquire. And we know that as long as men are free to ask what they must, free to say what they think, free to think what they will, freedom can never be lost, and science can never regress." -J. Robert Oppenheimer
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[*] posted on 12-3-2008 at 14:34


Quote:
Total Synthesis of the Hallucinogenic Neoclerodane Diterpenoid Salvinorin A
Masato Nozawa, Yuhki Suka, Takashi Hoshi, Toshio Suzuki, and Hisahiro Hagiwara
Org. Lett., 2008,


Attachment: Total Synthesis of the Hallucinogenic Neoclerodane Diterpenoid Salvinorin A (Org. Lett., 2008).pdf (84kB)
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Drunkguy
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[*] posted on 14-3-2008 at 09:38


Im not sure what you wrote originally since it looks like u went back to edit is later in the day.

I think Herkinorin might not be that good since there are already alot of mu-agonists out there so what place does it have in an overcorwded field where most of the compounds are inferior to morphine anyway.

Im definately interested in trying salvia at some stage because although its reported not to be fun, I would find trying the "scare herb" educational.

Kids at school should not be taking drugs since it will like reck their grades and if you are paying tuition fees then its even more of a reason why its "not worth it."

However, when u get to my age u have alot of free time on ur hands and something like this would doubtless be more interesting than sitting around all day complaining of boredom. I only want to try it, I have no intention of doing it more than a handful of times at most. Although head-shops sell the extract, I have seen extraction guides online and since im not lazy I might attempt to DIY my own solution.

I dont really care that much about the total synthesis to be blunt. I dont really see what purpose it has other than to show it is possible to make in a lab.




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Nicodem
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[*] posted on 14-3-2008 at 10:16


Was that supposed to be a misguided PM? If it is a reply, to whom are you replying?

Herkinorin is of high interests for the pharmaceutical industry as it is the first mu-receptor agonist that does not induce receptor desensitization. In simple words, this would mean a patient could enjoy the analgesia without tolerance build up. Which also means a lot of profit for the first company that manages to optimize the drug and register it.

The effects of Salvinorin A on humans is a very intense dissociation of a specific type and you better think twice about even considering what you said. The experience is so out of this world that it can change how you think about the life and the rest for ever, for the better or worse. It is like when you learned to speak - there is no turning back! The kappa-receptors are pretty much terra incognita of the human brains and god only knows what they are for.
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Drunkguy
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[*] posted on 16-3-2008 at 17:59


Wue yea.

I've suddenly started getting much more interested in ethnobotanicals since I realized I have saved up quite alot of pocket money relative to how I was living before and am not quite so poor as previously.

There are 2 main things stopping me from going out to buy salvia though.

1) I already have a 500g untouched bag of powdered mimosa hostilis which I haven't touched since it only arrived last Thursday.

2) There is currently some cheap Kratom for sale and I might also want to get this.

But, yes baby! Sally is a drug that I definately want to try at some stage, perhaps not imminently though.




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microcosmicus
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[*] posted on 16-3-2008 at 18:18


Quote:

The kappa-receptors are pretty much terra incognita of the human brains
and god only knows what they are for.


According to the following article, it seems that they have something
to do with sensing visceral pain.

The kappa opioid receptor is associated
with the perception of visceral pain

Black D, Trevethick M

Gut 1998 Sep; 43(3):312-3

Abstract available at
http://opioids.com/kappa/visc.html

So, it seems that if you mess them up, you might not be able to properly
sense when your tummy aches or, maybe get fake stomachaches. Ouch!
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Nicodem
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[*] posted on 17-3-2008 at 00:44


Actually I was talking about their role in the CNS.

Drunkguy, please sober up and stop posting off topic! This is not a thread where to discuss your herb collecting habits or pretend you are posting private messages.
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Drunkguy
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[*] posted on 21-3-2008 at 19:50


I dont drink anymore. I havent had a drink in 6 months.

I was never really a problem drinker per se, inasmuch as although I had a drink almost every day, it was normally just a pint or two of best bitter.

I have been homebrewing beer since my 18th birthday. I started out brewing beer from tins and "kits" but gradually got fed-up with the transparency and lack of depth of this way of doing it.

I had more time after graduating from university at 22, and by the age of 23 I had progressed to "all grain" brewing. The incentive is that in the long-run the cost of equipment is an investment that pays for itself many times over based on the money that you save on the cost of the beer that you drink.

However, when you volunteer this on yourself you also need to be prepared for some disaster zone scenarios as a novice.




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[*] posted on 4-4-2008 at 12:52


you guys google herkinorin a derivitave of this 100X the affinity with the mu recetor made by a simple tranesterification reaction of salvinorin a then we'll have a reall good discsuusion hereand f*** all of this theorietical complexity let's get to real chemistry you extract and then chromatogragh the salvinronin-a from the natural herb it ain't hard to get folks.

[Edited on 4-4-2008 by jon]
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Nicodem
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[*] posted on 5-4-2008 at 10:06


Turning salvinorin A into herkinorin? You must be joking (and it's not even 1st April anymore). It would be like turning diamonds into shit. Not to mention it would be kind of sacrilegious as well, taking a nature's evolutionary jewel and turning it into a mu agonist. :o
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[*] posted on 5-4-2008 at 10:27


not to argue with you nicodem you get my respect as being one of the most knowledgable people around, but kappa agonists are no fun.
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Nicodem
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[*] posted on 5-4-2008 at 10:49


Who said anything about fun? I only said it would amount to nonsense to modify one of the most precious gifts nature gave us into something as boring as a mu agonist. As if there was a lack of mu agonists around… even some kids next door even sell one of them (not to mention that several mu agonists are widely available in every pharmacy). The "people" using mu agonists surely don't seem fun either, on the contrary, they constantly remind me that humans are quite possibly an evolutionary dead end. Surely in this global civilization there is no lack of mu agonists!
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[*] posted on 5-4-2008 at 11:57


i'd have to argue with that one, it depends on where you live.
where i live even, people with records and real pain issues get thier scripts but the pharmacies refuse to fill them to keep the diversion task force off thier ass.
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