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Salvinorin A   

1 July 2007 8,344 views 64 Comments

salvinorin.jpg

Evans, Scheerer, Lawrence and Wang. JACS, 2007, ASAP. DOI: 10.1021/ja073590a.

The first JACS total synthesis I’ve seen in a while, this is a nice piece of work by the legend that is Dave Evans. The target certainly has a bit of a kick; I quote: “the most potent naturally occurring hallucinogen“. Interesting times for the students in that lab. I can see them now – being chased around the lab by malevolent HPLC machines… It’s apparently also the only non-alkaloidal psychoactive natural product, so certainly of quite some interest.

The start of the synthesis is distinctly Evans terratory, with a catalytic enantioselective ortho-ester alkylation using an interesting nickel complex. A bit of hindered base, LA and ortho-ester then returns the stereocenter in very good e.e. It’s also interesting to see the use of ortho-esters, which are of course just masked aldehydes… The reference for the methodology (it’s Evan’s own work from 2005) is here.

salvinorin_1.jpg

There’s a whole sequence of impressive transformations on this substrate – which I’m not reiterating here, but I’d love to hear your comments. However, there is another fragment to discuss – that of the furan. The stereochemistry on this fragment is derived from a simple CBS reduction, but the acetylene is in the wrong place, so it’s simply “zipped” down the chain using Charles Brown’s isomerisation. This is a reaction that my supervisor is quite enthusiastic about, and I agree – it engenders incredible synthetic utility, and seems so simple!

salvinorin_2.jpg
This terminal acetylene is then carbometalated and coupled to the more elaborate sidechain, with macrolactonisation giving the twelve-member ring. Then it’s time for the piece de resistance – an impressive bis-Michael transannular cyclisation, which they prefer to think of as stepwise. The alternative, an exo-Diels Alder is also possible, however.
salvinorin_3.jpg

The reaction efficiency is amazing, and seems very mild, so was well planned! This sets-up a further three stereocentres from the original three, and completes the carbocyclic skeleton. Elaboration to the natural product was quickly and efficiently completed from here. Excellent stuff.

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64 Comments

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  • TWYI says:

    Disgusting :lol:

    Sure, some molecules are more pleasing to my eye than others, but none are disgusting

  • Dude says:

    I make skatole all the time, and trust me, it’s disgusting.

  • typical organic chemist says:

    my skatole doesn’t stink when i make it. I don’t know what you’re talking about.

  • mevans says:

    You don’t make it in high enough concentrations then!

  • carbazole says:

    I was reading a DEA report that stated that something like 95% of the LSD in this country is produced in the San Francisco bay area. Since it’s so potent, the whole country’s supply is only about a kilogram per year. Pretty neat stuff.

  • Dude says:

    It’s my guess that about 95% of the nation’s LSD flashbacks occur in the SF bay area as well.

  • milkshake says:

    This used to be true – but after the main cook Pickard was busted (and sentenced to life in prison) LSD is not readily availe in CA anymore. The starting ergot alkalods are hard to get and one has to have decent lab and a good procedure.

  • kiwi says:

    wow milkshake, just looked that guy up on wikipedia (link attached to my name above). They reckon their two man operation turned out 1 kg LSD/ five weeks (1 kg = street value ~ US$100 million), and from busting those two guys alone, they saw a 95% reduction in LSD availibility in the entire US. You’ve got to wonder how an operation that size ever stayed under the radar.

  • milkshake says:

    The cops were exaggerating. Pickard had few kilos of ergot precursors and also few hundred grams of epimer of the acid saved for later recycling when they searched his lab – so it is likely that his overal output over a year period must have been in kilo range. But not a kilo every month – 100g-sized batches are more realistic. As any process chemist can tell you kilo scale is hard to handle in normal-sized glassware, the procedure in this case is multistep, you have to crystallize, etc. 100g is still about half a million of doses, though.

  • carbazole says:

    Ah, I must have been reading an old report. It had mentioned that guy, but not by name, as they hadn’t caught him yet. Back to the synthesis, was anyone else a little disappointed that there was no commentary on their key-step at all? If that was the first thing they tried, kudos to them, but a footnote about what didn’t work would have been nice. TBAOH? Did it have to be an ammonium salt because the other metal salts would chelate to the 1,3 dicarbonyl anion? I would have appreciated something…

  • organic chemist says:

    Can anybody tell me why hydroxy-acid (especially in macrolides) is called seco acid ?

  • synthon says:

    The seco acid results from saponification of the marcolide ring. Term can be used for any ring system and is not exclusive to saponification; http://www.iupac.org/goldbook/S05512.pdf

  • Vince Noir says:

    Other non-alkaloidal natural product psychoactives include: THC from marijuana, and the kavalactones from kava root. Salvinorin A is, as far as I know, the first non-nitrogenous (kappa) opioid receptor agonist. However, hallucinations are a not uncommon side-effect of other kappa agonists, and for this reason are rarely used in medicine despite a low abuse potential and excellent antinociceptive activty.

    Oh, and sweet synthesis!

  • HPCC says:

    You, three Wine Bottles, are the spawn of Satan. Die, please!!!