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Lysergic Acid, and definitely not LSD.   

2 November 2008 15,593 views 16 Comments

Fujii, Ohno, Inuki and Oishi, Org. Lett., 2008, ASAP. DOI: 10.1021/ol8022648. Article PDF Supporting Information Group Website

Fancy making your own LSD?  You could do a lot worse that this prep from Kyoto University.  Of course, they don’t actually make the lysergic acid diethylamide, but I’m sure there’s a way to form that amide… Anyway, we should probably stick to the actual paper, and leave the class-A for another time.  I’m sure we’re all aware of the biological activity of some of the members of the ergot alkaloid family, but did you know about synthetic members with anti-Parkinson’s disease properties?  Certainly gives them a more legitimate reason to work on the synthesis.

For me, it gets interesting with a gold-mediated Claisen rearrangement.  Done on a propargyl alcohol, this generates an allene in cracking yield.  This is quoted over two steps, as they did an in-situ reduction of the initially formed aldehyde.  It took a little effort to find these conditions, as their initial attempts with just a bunsen-burner resulted in both a shoddy yield and d.r.  Switching to microwave irradiation boosted the yield, but left the d.r. unimproved, whist a bit of the oxo-gold complex did the job nicely.

However, separation of the diastereoisomers was ‘difficult’, so the mixture (a few steps on) was dumped into an impressive palladium-mediated domino cyclisation.  A variety of conditions were applied, also varying the protecting group on the pendant amine from nosyl to the more optimal tosyl, finally resolving in the conditions shown.  The yield is pretty decent for what is an impressive transformation, and the d.r. also.

I might have taken those yields and moved on, but the group were considerably more thorough, and did a useful mechanistic study.  For this, they separated the mixture of allenic starting materials, and repeated the reactions with diastereomerically pure starting materials.  Using the purified, desired SM, a worse d.r. (but better yield) was obtained for the cyclisations; the group suggest that this could result from two competing pathways.

They suggest that the preferable pathway (on the right) is such because of the disfavoured, strained palladacycle present in the first step of the minor pathway.

Impressive as this is, I must admit that my attention wavered as the group went on to make the title compound, and a pair of diastereomeric compounds, lysergol and isolysergol. However, I was somewhat taken by the use of thioglycolic acid along with lithium hydroxide to remove the tosyl group.  I knew I’d seen that stuff in a bottle back home, and I was right – my grandmother uses it to ‘perm’ her hair

Oh, and if you’re started ordering reagents to follow the prep, can I dissuade you, and suggest reading (or watching) ‘Fear And Loathing In Las Vegas‘ as an alternative to a life time of freaky flash-backs.

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16 Comments

  • The Next Phil Baran says:

    Very nice work. I wonder if these reactions would work without protection of the indole nitrogen. I guess the problem is the reactivity of the enamine during the palladium catalyzed reaction, or some other place in the sequence (haven’t read the paper yet). Cheap LSD for everyone!

  • Martyn says:

    Interesting alternative mechanism; I see you’ve drawn a positive charge on Pd, which probably shouldn’t be there under those reaction conditions (is that as drawn in the paper?). It certainly would be there if they used the triflate instead of the bromide, or used a silver additive – then, the arylpalladium species should be an electrophilic cation and would definitely favour the right-hand mechanism.

    Not sure I see any strain in the 6-exo-dig carbopalladation route – could it just be that the nucleophile coordinates Pd and then reductively eliminates. Incidentally, the first structure on the right hand side is missing some bits.

    As for the indole NH, it shouldn’t make much difference in theory, as it shouldn’t add to the Pd(0) catalyst, and the Pd(II) intermediates are all out of its reach for any intramolecular shenanigans. It might give problems in the Au-catalysed Claisen step, or they might just like making nice crystalline sulfonamides.

  • vik says:

    Martyn : I wonder why you dont see the crowding in the 6-exo-dig cyclization . If you consider the stereoelectronics (allene) and sterics (amine and TIPS) of the “strained” conformation in the pathway on the left you may see the problem.

    Using a tosyl protection for isolating crystalline products can many a times turn into a nightmare as the tosyl is known as one the most unreliable protecting groups when it comes to its extrusion. In this case having an aromatic substrate must have narrowed the choice (eliminating the more general dissoving metal reducitons).

    And maybe indole “N” protection is helping the positioning (regioselectivity) of the Pd on the now comparitively less electron rich indole.

  • milkshake says:

    These indoles are pretty light-sensitive (professional LSD cooks like to work under red light in the photo-darkroom), oxidize easily and act like outstanding scavangers for electrophiles; putting Ts or Boc on indole N1 saves lots of headache. Ts on indole N is not very stable because indole anion is a decent leaving group, even hydroxyde alone can cleave the indole Ts off.

  • teknoslug says:

    Isn’t Lysergic acid made in one step, by the acid hydrolysis of ergotamine (which is harvested from infected rye)? And then the diethylamide is simply a peptide coupling.
    I think this group should have used this methodology on a more recently discovered molecule.

  • milkshake says:

    Slug: LSD from ergot is not as straightforward hydrolysis – there is epimerisation problem, and isolysergic acid (inactive material) is best separated from the mix and recycled. Also the amide coupling has to be done carefully – the traditional reagent used was (Et2N)2POCl generated in situ from POCl3 and diethylamine, but more modern reagents work also. Then there is a problem of relative sensitivity of the material to light and air – not a straightforward garage cook-amendable chemistry

    These allenes cyclizations are impressive and they can have direct bearing on developing new CNS drugs.

  • ... says:

    teknoslug,

    I disagree that new methods are best applied to new molecules. By using your new reaction to assemble a molecule that has been built several times before, there is a good basis for comparison to other reactions/strategies.

  • RBW says:

    Having dabbled with lysergic acid synthesis myself, I can initiate the young ones into the issues when working with unprotected indoles. If you’ve made such compounds and smell them, you’ll know what I mean (hint: think skatole). Then there’s potential for double bond isomerization from the indole skeleton to a naphthalene..
    While tosyl was a popular indole protecting group in my days, I’d have expected something less robust nowadays e.g nitro-substituted phenylsulfonamides a la Fukuyama, or one of the menagerie of carbamates.
    I agree with the previous comment that teknoslug is overly seduced by being the first to make a molecule rather than create a synthesis of lasting beauty.

  • teknoslug says:

    I wouldn’t call myself a fan of being the ‘first’ to make a molecule camp, by any means. Rather, I’d like to see a ‘best-synthesis’, exemplified by a shorter number of steps than any previous synthesis, or perhaps involving a unique in-house methodology. I think this group’s methodology has promise, but would perhaps have a better impact if it shortened the number of steps of previous syntheses of this target. Think of the DuBois synthesis of tetrodoxin, or many of the polyether marine toxin syntheses since KCN’s brevetoxin as a case in point.

  • vik says:

    I would love to be a fan of the first to make- club if the mlecules are of the Azadirachtin or palau-amine type..

  • reminder says:

    tecknoslug – the dubois tetro synthesis was longer than Kishi’s 1972 synthesis.

  • teknoslug says:

    Reminder – correct, but Kishi’s synthesis is racemic. Isobe’s synthesis is asymmetric (which is usually more challenging), as is DuBois’, but DuBois did it in half the number of steps of Isobe.

  • RBW says:

    Total synthesis has moved on tremendously since my day. It is essentially a solved problem, and there are no natural products that cannot be made given time and resource. Not like those glory days of the fifties, when molecules like erythromycin and vitamin B12 offered challenges that would take generations to solve.
    Now, every year, there are thousands of total syntheses, most so unremarkable that I will forget them the day after. This one, for example is not particularly concise and racemic- good enough for Org Lett and that’s all.
    For a conceptually innovative disconnection to the ergot skeleton, look at Julia’s. The route floundered due to pitiful yields and offers a challenge to the young whippersnappers- surely with current methodology his strategy can be reduced to practice elegantly?

  • Cat Herder says:

    RBW, I’d argue that most human endeavors realistically fall under the catagory of “it will work if enough resources are thrown at it”. While I agree that there are many syntheses published that are not groundbreaking, this was undoubtedly also the case 25 and even 50 years ago. I don’t see this as a reason to stop doing TS, but as a reason to further challenge ourselves with “uncomfortable” disconnections and bond-forming sequences.

    As per your examples of the glory days, did those molecules actually take *generations* to solve (given that a generation is defined as 20 years)? Also, it is disingenuous to pick a couple of targets and say that things were different back in the day. Go read TL, JACS, JOC, etc. and see how many syntheses there are from 1950-1990 that are just ho-hum. On the flip side, how long did(will) it take for people to make azadiractin? How about palauamine? There are several molecules that still test the limits of synthetic technology, just like erythromycin did back then. It is still worth it to make these and see where the rabbit-hole takes you.

  • RBW says:

    Yes, Mr Cat, those molecules really took generations. Vitamin B12 was purified during WWII, the X-ray structure was solved by Hodgkin in 1956, and the total synthesis literally took more than a generation of chemists at Harvard and the ETH. Similarly, the total synthesis of erythromycin was not reported until 1981.
    While I marvel at the total syntheses of azadirachtin and palauamine, I contend that neither has produced a lasting contribution to the science of organic chemistry, besides reaching their target. Vitamin B12, on the other hand, led to the laws of pericyclic reactions and the Eschenmoser sulfide contraction reaction among others while the challenge of erythromycin largely fuelled the growth of acyclic stereocontrol and asymmetric synthesis.

  • lovesorganometallics says:

    So.. whats the end of story here? You can do total synthesis as long as there is novelty in methodology and it’s concise.