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Helicterin B, Helisorin, and Helisterculin A   

25 January 2009 14,103 views 37 Comments

Snyder and Kontes. JACS, 2009, ASAP. DOI: 10.1021/ja806865u. Article PDF Supporting Information Group Website

It’s amazing how ideas arrive in pairs. Think: Deep Impact and Armageddon, or The Prestige and The Illusionist. Or bloody Peter Mandelson and Ken Clarke… And in as many weeks, we have Porco’s synthesis of chamaecypanone C and Synder’s synthesis of helicterin B, united through the key use of a retro-Diels-Alder/Diels-Alder cascade. The ‘why?’ in this case seems to be a shared love of dimeric (and tetrameric) natural products, where this kind of chemistry is a great way to build such systems. And both PIs cite an apparently inspirational paper by Bedekar back in 1992.

So what’s new with this beast, other than its size (1510 g mol-1 in case you were wondering)? Not much, to be fair – Snyder mentions ‘mild inhibitory activity against the avian myeloblastosis virus’, but when the authors describe the activity as mild, you can be fairly sure it’s almost inactive. So biology done, it’s clearly the structure that’s our raison d’etre. Deciding that going straight for the daddy, so to speak, Synder starts with the synthesis of the slightly simpler helisorin.

So what’s going on here? First up is a dimerisation of derivative of rosmarinic acid, which was produced in five steps, selectively protecting with para-trifluromethylbenzyl groups. This exotic protecting group was used after quite a bit of experimentation, with Snyder trying to find exactly the right group to remove on the final step. Because of the functionality of the target, this meant removal without recourse to acid, base or oxidative deprotections – limiting their choices. So they settled upon using an ether, removable using moderately powerful Lewis acids, but stable to milder – and eventually upon this ‘OTfBn ether’.

The rosmarinic acid derivative was then oxidatively dimerised using a bit of hypervalent iodine. This intermediate was then heated with a dienophile (also produced from rosmarinic acid), bring about the retro-Diels-Alder/Diels-Alder cascade and generating the core of Helisorin. However, one further carbon-carbon bond was still to be formed, and their protecting-group pickiness becomes clear – using a mild Lewis-Acid caused the proximal protected catechol to cyclise onto the bicyclooctane, whilst a stronger LA removed the protection groups to complete this target. I bet you’re thinking ‘why not use the more pokey one to do both steps?’ – well, apparently that doesn’t work so well, and causes rupture of the dimethyl-ketal instead.

With that success, the group were ready to move on to bigger targets, but they had a problem in that the bicyclic cores of the helicterins have subtly different stereochemistry. Converting the penultimate intermediate in the helisorin synthesis was the key, but require reduction of the ketone from the less favourable approach. Doing this reaction directly with hydride-based routes was ineffective, but they were able to use the undesired product by performing an ‘equilibrative ketol shift’. The product of this reaction, a second ketone, was more receptive to reduction, presumably by coordination of the Me4NBH(OAc)3 from the desired face. A little lucky, but well done.

A few steps further on, and they had the bicyclooctane sterochemisty just right. A little bit of weaker LA caused dimerisation of this intermediate, completing the bulk of the natural product. However, the final deprotection of the p-CF3-benzyl ethers was less successful as before, as a methyl group was also lost in reaction. This meant that they hadn’t completed helicterin A, as desired, but were lucky to find that they had isolated helicterin B; good times!

It wasn’t quite time to go to the pub, yet, though. Time for a quick synthetic victory lap, using the same common intermediate, and completion of helisterculin A… too easy, apparently! This is great work, and it’s always pleasing to read about it in a proper full paper.

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37 Comments

  • The Next Phil Baran says:

    just a preemptive ZZZZZZZZ before ZZZZZZ does it

  • earth23 says:

    Synthesis of the sake of synthesis is still good enough to get an article in JACS these days……

  • The Next RB Woodward says:

    Yawn.

  • paulm says:

    At the total synthesis conference in Nottingham last year Gerry Pattenden asked what makes the audience (or their supervisors) pick the molecules they pick for total synthesis. Amos Smith III’s answer was “Architecture!”. Pattenden then asked if that was enough reason to make a molecule. Some at the front agreed that it should be.

    Challenging your intellect and creativity to make something for no reason than your own curiosity is, by any definition I know, art. Which is cool. But funding is hard to come by and there are lots of people struggling to do something actually useful with science.

    Things like this appearing in JACS doesn’t seem fair to me.

  • ,,, says:

    to paulm

    It’s not only art, it’s exploring chemistry, posing new methodological problems… This thing belongs to JACS. Period.

  • paulm says:

    Exploring chemistry is not a difficult thing to do, everybody would be getting funding and JACS papers on that basis. The new methodological problems posed are very specific to a molecule that has little use.

    I wouldn’t argue that this shouldn’t be published, it obviously adds to knowledge. But I would expect chemistry appearing in JACS to be practically useful as well as academically interesting.

  • LW says:

    Yep, I was there too when Smith said that architecture was a motivation for synthesis….please. It makes me pretty damn angry when there’s a lot of ideas that don’t get any funding that it deserves. It’s too easy to just look for a molecule and then go and try and make it. We know now that pretty much any molecule can be made from scratch…..Woodward, Corey etc have provided us with enough evidence of that years back. The point is though how long are people going to carry on doing total synthesis just for the sake of it? True, from some total syntesis projects some methodology may arise from it, but to be honest, how often does that happen? Funding should be given to projects where the benefits of that succesful project are to improve our lives in general, and not because the molecule looks fancy and will provide an ‘stimulating’ challenge.

    Nevertheless, this work is good, and Snyder really is going for it now.

  • Activity? says:

    There is too much concern here over the compounds’ activity. Rosmarinic acid itself has lots of useful properties, and is even sold in health food stores. Chances are high that these things might do something important as well. Remember that isolation chemists might only have one or two assays for what they are interested in. As a case in point, the epothilones were isolated long ago and shown to have only mild antibacterial activity. As such, they were viewed as unimportant. Only later, once it was reisolated and run in a different screen was it determined that they would be an amazing cancer drug, and then every group on the planet tried to make it. The point here is that these molecules have been barely analyzed, so it is too soon to determine if they might be useful or not. In any event, the chemistry described here is really nice and shows how to handle some non-trivial problems.

  • earth23 says:

    @Activity?

    Hypothetical future biological activity is a poor reason to justify a synthesis.

  • snack says:

    I have notices that the very best work that appears on this blog is the ones that make the most angry complaining people.

    this synthesis is a masterpiece and far better than a lot of the nano, dna and medchem that is published in jacs. Or even better than the worthless methods that appear.

  • Activity? says:

    Complaining about the absence of activity is a poor way to question a synthesis. How many molecules with reportedly good activity then prove non-effective in retesting? How many people who make a bioactive molecule actually then do something with it? My point is that this a blog about synthesis and synthesis endeavors; critiquing work based on whether or not the molecule will ultimately do somthing is poor. I mean, really, how many natural products become drugs or provide real new leads for the treatment of disease. The number is not zero, but the percentage is not super high. In the last several posts, how many of those will actually “do” something?

  • Martyn says:

    I was at the Nottingham conference too, and I thought more or less the same as paulm – just making a molecule, using no new methodology and for no greater purpose, isn’t the best use of public science funds.

    I don’t think this work falls into that category though. It’s a demonstration (though admittedly not the first demonstration) that oxidative dearomatisation-diels-alder methodology is a great way to make complex bridged ring systems. It further opens the door for the synthesis of ‘useful’ compounds, whatever they may be. That’s a worthwhile contribution to organic chemistry; whether it merits publication in JACS is for the editors to decide.

  • t says:

    @snack: right!

  • ,,, says:

    I have when total synthesis is viewed as an appendix to biochemistry as a provider of material. That is a load of BS. It’s a petty people squeeze out any kind of biological activity they can find to put it in the introduction section of the synthetic paper.

  • ,,, says:

    If you want to make something useful for medical applications, then go make small molecule libraries in a couple of simple steps and screen those. That is going to be way more efficient. No pharma industry would bet on naturally occuring compounds today.

  • earth23 says:

    @ Activity

    I bet you’re a fan of the nano kids paper.

  • milkshake says:

    The main methodology drawback here is that the retro-DA+DA sequence to the advanced intermediate 34 requires a fairly large excess of dienophile (6.5 eq.) and produces 1:1 mix of diastereomers. This lowers the actual yield in this step to 20%Y and necessitates pretty a big column to remove the dienophile excess and the undesired diastereomer. As this happens reasonably close to the finishing line one can likely get few mgs to push through to the end.

    As for the JACS worthiness: This impressive amount of research was mostly done by a single pair of hands, with a limited building block work done by one undergrad. I think this alone qualifies it for a good journal.

  • antiaromatic says:

    I think the more interesting thing to note about this paper is that none of the previous methodologies that exist that give enantioinduction work in this particular case. Even more interesting, the chiral centers in the molecule don’t influence the outcome of the retro/forward DA; you still end up with a 1:1 mixture of diastereomers from enantiopure starting materials.

  • thiosulfate says:

    sorry, this is an off-topic question.

    sometimes when I use sat. aqueous sodium thiosulfate as a workup to quench an oxidant, it gives this yellow residue, that is partially soluble in organic solvents and will run quickly on a silica gel column. I don’t know what this yellow stuff is, although I think it’s some sort of sulfur compound, but it drives me nuts.

    does anyone know how to avoid this yellow substance or a good way to get rid of it? many thanks!

  • milkshake says:

    what you have is elemental sulfur – It has a wonderful NMR and it runs nicely on the column, and changes appearance from yellow-white monoclinic allotrope to regular yellow S.

    Thiosulfate when acidified decomposes to S and SO2, and sulfur extracts into organics fairly well. Either you need to add some bicarbonate to your thiosulfate during the quench or you need to switch to using NaHSO3

  • optional says:

    @ milkshake: elemental sulphur or S8?

  • ZZZZZ says:

    zzzzz…

    Is this really a valid criteria for deciding on publication-worthiness in high-level journals?: “This impressive amount of research was mostly done by a single pair of hands, with a limited building block work done by one undergrad. I think this alone qualifies it for a good journal.”

    By the way, I’ve had that sulfur issue with thiosulfate too. I’ve been able to remove it from my flasks after the workup though (vigorous use of a brush).

    Oh yeah, and I’m not sure what I think of this synthesis yet. I’ll let you know after my nap.

    …zzzzz

  • pasupathy says:

    thiosulfate: You can get answer for you question regarding sulfur contamination on reactions quenched with sodium thiosulfate, Org. Process Res. Dev., 2008, 12 (1), pp 116–119 “Sulfur Contamination Due to Quenching of Halogenation Reactions with Sodium Thiosulfate: Resolution of Process Problems via Improved Quench Protocols”

  • thiosulfate says:

    awesome! thanks for all your great input!

    @milkshake: do you mean the sulfur NMR is beautiful?

  • milkshake says:

    it was a joke. There were very many people who isolated beautiful yellowish crystals, only to be puzzled by the complete absence of signals on NMR

  • inorganic refugee says:

    Another off topic question (don’t shoot!). I’m an inorganic chemist by training planning to do a Corey-Chaykovsky reaction on 2-butanone. The 2,2-disubstituted epoxide that should result has been synthesized by other methods that all look more complicated to me which makes me worried. Is the Corey-Cheykovsky particularly touchy? Why isn’t it more widely used?

  • Jose says:

    I isolated some gorgeous crystals, ran to the NMR- not product, but TEA*HCl. Damn, they were purdy!

  • labmates says:

    Don’t you people have lab-mates or work in a building with other research groups that you can go ask these questions to? Honestly. Can we please discuss the published synthesis paper, not questions that could be asked to a researcher down the hall?

  • inorganic refugee says:

    Ok, ok, so you want to shoot. The truth is, no there are no researchers down the hall who can answer this. I am at a small liberal arts college with 8 total chemistry faculty and only undergraduates as researchers. Most of my graduate colleagues are inorganic types as well, so there’s not a lot of help there. I’m fine with the this being a forum for discussion of current total synthesis literature and never asking about methods again, but don’t think this was just me being to lazy to ask around. There is simply no-one around to ask.

  • Tot. Syn. says:

    @ inorganic refugee:
    Sorry that you’ve not had a more useful response… I withheld comment as I’m not particularly experienced with this reaction. However, I’ll stick my head above the parapet and try to rationalise the problem.
    First, let’s check we’re talking about the right molecule – 2-ethyl-2-methyloxirane. If so, then one of the issues is that it’s chiral, so there are several methods for making the epoxide asymmetrically, generally starting from other SMs.
    Your other problem is that the typical solvent for Corey-Chaykovsky reactions is DMSO. This presents an issue in that your product is almost certainly more volatile than the solvent, so it might be a pain to get rid of.
    Lastly, I think that there’s a greater chance of side reactions in with the CC reaction – strongish bases like sodium hydride could result in aldol-type chemistry, so would best be avoided.

    If I had to make your molecule, I’d simply start from 2-methylbut-1-ene, and treat it with mCPBA, which will epoxidise without much in the way of side-reactions. The purification of product from starting materials should be trivial.

    But then, as I said, I’ve no actual experience with this reaction.

  • Tot. Syn. says:

    @Labmates:
    That attitude problem of yours stinks worse than a tramp’s underwear. I’ve never once complained about off-topic discussions, and frankly find them quite interesting.

  • inorganic refugee says:

    Tot. Syn.:

    Thanks for the input; it is much appreciated. Epoxidation of the olefin was my first thought, but it’s so damn expensive compared to MEK. The plan was to resolve the epoxide using an early version Jacobsen catalyst (I’ve got loads of the chiral ligand available). I have barely worked with DMSO at all, so hadn’t thought of the issue you raised. You don’t think it’d be possible to distill the product away from the solvent, trap-to-trap style?

    • milkshake says:

      these 2,2-disubst epoxides can be very-acid sensitive, if you decide to make it from the (expensive) olefin please make sure that you add some solid NaHCO3 to your DCM/mCPBA and run the epoxidation on ice, so that you don’t get the addition or rearrangement products.

      You will find that Jacobsen Co-salen catalysts for epoxide kinetic resolution with water do not work well for 2,2-disubst epoxides, Co-salenes are infact best for monosubt epoxides. But you can try your hand on Jacobsen chromium salene catalyst with TMS-azide as a nucleophile – they used it successfully with more hindered epoxides if I remember correctly.

      Volatile product in DMSO: I was once doing Wittig with MePPh3Br and NaH/DMSO on ketone that was made by conjugate addition of TMS acetylene to 3-methyl-2-cyclohexene. The product had unfortunately boiling point close to DMSO so I ended up de-sililating the whole damned thing with KHF2 and then I distilled the pure olefin-acetylene from all that DMSO, salts and Wittig crap through a short Vigreaux column – it worked very well, the yield was in 80s and the product had an awesome pine+fruity smell like a mango peal.

      In your case I would look if there is some easy access to things like 2-methyl-2-hydroxybutyric acid (or its ester) in optically pure form – even by resolution if necessary. I would reduce it with borane and then close the epoxide with mesyl anhydride/NEt3

  • antiaromatic says:

    @inorganic refugee:

    I think what you’ve described will almost certainly work. I think with a lot of the Jacobsen catalyst things, that is the preferred method of purification. You can typically add a high boiling solvent and distill your small epoxide away from the mixture as a pure compound.

  • anonymous says:

    I think you’ll find that the prolific proponents of this work on this blog are themselves members of Snyder’s lab. What a coincidence.

    • Tot. Syn. says:

      Well, whatd’ya know? I did a check on all the IP addresses of the comments on this post, and we’ve got three comments from Columbia, one of which is yours. Hmm.