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Artochamins F, H, I, and J   

8 September 2007 11,356 views 47 Comments


Nicolaou, Lister, Denton and Gelin. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200702695.

Recently isolated in an attempt to find the bioactive ingredients in some folk-medicines, the artochamins haven’t actually got that much biological activity. They’re described as being weakly cytotoxic, so let’s focus on the interesting ring system as our reason for synthesis. However, before leaping head-long into the chemistry, an interesting note is that the natural product is isolated as a racemic mixture, which suggests a non-enzymatic biosynthesis. Hmm…


The key substrate for this reaction is actually a symmetrical molecule, created very quickly from two small subunits. The ether bonds were put in using an interesting copper(II) chloride and a propargyl carbonate. The terminal acetylene moieties were then reduced to the olefins using Lindlar conditions. The stillbene moiety was then created using an olefination, in this case a Julia Kocienski. However, it’s important to point out at this stage that a Wittig coupling was also attempted…

With the precurosor complete, it was time to get Woodward-Hoffman on it’s arse! (Don’t forget that the thermal decomposition of Boc groups is also a sigmatropic rearrangement…)

Nice!! Straight through to a precursor for the natural product family! However, I’ll bet I’m not the only one who wondered about what the triphenyl phosphine oxide was doing… I quote from the paper:

The effect of Ph3PO was recognized when stilbene 5a derived from the Julia–Kocienski olefination failed to perform well in this process, whilst the same substrate 5a derived from a Wittig reaction (and therefore assumed to contain trace amounts of Ph3PO) went through the cascade sequence smoothly; further investigations into the precise role of the Ph3PO are currently underway and full details will be reported in due course.

shtopp.jpg *

Interesting. Further, those of you up on your Woodward-Hoffman Corey rules will also remember that thermal [2+2] cycloadditions are required to go through a suprafacial-antarafacial sense. An example of this is the addition of ketene, in which the orthogonal set of p orbitals allows the reaction to proceed via a crossed transition state. However, unless I’m mistaken, this isn’t possible in this case. In other words, this is more likely to involve a diradical or ionic mechanism. The authors postulate as much:

We must also consider two further mechanistic alternatives for the microwave-promoted reactions. The first, and least probable, involves a [Ï€2s+Ï€2a] cycloaddition. The second involves a stepwise diradical mechanism in which formation of the five membered ring precedes diradical recombination. Preliminary experiments with (E)- and (Z)-5a indicate that the formal cycloaddition reaction is not stereospecific with respect to the alkene geometry. On the basis of this observation a stepwise radical mechanism, in which bond rotation occurs to some extent before recombination of the diradical, or the redox mechanism shown in Scheme 6 are currently favored. These possibilities are under investigation and full details will be disclosed in due course.

So, again we must wait for another paper. However, given that this is a reasonably short paper, couldn’t we have waited a little longer? They postulate a mechanism, involving auto-oxidation of the catechol moiety to give a ketone, to which the olefin adds in a conjugate manner, but nothing is proven.
[*] Apologies to the non-UKian’s for a Brit-centered gag…

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  • excimer says:

    That picture made me laugh, despite my lack of British citizenship. Yet another example of “publish first, think later?” This really does exemplify Nicolaou’s philosophy of it being more important to get out tot. syn papers quickly as opposed to doing meticulous studies on what appear to be really interesting transformations. Sigh.

  • TWYI says:

    This never happens to me. Impurities in my compounds never makes them work better in key reactions.

  • European Chemist says:

    Interesting synthesis. Can’t get the document as am on vacation till the end of the month, but apart from the funny 2+2 cycloaddition (most probably a radical process) can’t really see what’s new in this. Am I missing some fabulous point?

    I should also say in reply to Excimer that Nicolaou’s philosophy wasn’t at all the same in the 80’s and early 90’s. Who can forget the Endiandric Acid saga for example? As opposed to good wines, it seems that KCN didn’t get that more refined as the years went by… sigh for me too.

  • GYA says:

    Remember though that the endiandric acid idea was Black’s and not KC’s, also the case with some of his other syntheses. Facts he doesn’t care to make a point of most of the time. Sad.

  • European Chemist says:

    Good point, GYA. Maybe that’s one of the reasons why despite numerous efforts there won’t probably be any Nobel prizes headed KCN’s way…

    Anyway, back to the synthesis, it seems reeaaaaally funny to see a bromine apparently blocking the ortho-position of the aromatic. Is this how sophisticated we’ve got in manipulation of aromatics and Claisen rearrangements, or have I missed something again?
    Also, I suppose that the 2+2 was originally intended to be carried out photochemically? And is this “biomimetic” strategy KCN’s idea or was this actually proposed by someone else beforehand? Maybe Tot. Syn. can enlighten us on this one?

  • Spiro says:

    #5 “Maybe that’s one of the reasons why despite numerous efforts there won’t probably be any Nobel prizes headed KCN’s way…”

    What would he get a Nobel prize for??? Ultra-fast publication of wobbly syntheses of recently-isolated natural products?

  • jimbo says:

    Some serious self-righteousness going on in here…

    I see nothing wrong with getting a synthesis out the door as soon as it’s done to get your work published in a decent journal. It’s why we have the communication format. Many groups have been scooped because they sat on a synthesis too long while following up all sorts of minutia that could have been saved for a full paper. It looks like this 2+2 is pretty strange, and by publishing, KC has put it out there for other groups to follow up on if they want. His group is much better situated for total synthesis work anyway, and not mechanistic physical organic chemistry.

    Nobody complains when someone reports preliminary data at a scientific meeting, so why is it a big deal when it happens in a paper format? Especially in today’s climate when disclosing something at a meeting could allow a competitor to push their own paper out the door, scooping you in the process.

  • TWYI says:

    No3, what is this Endiandric acid saga you speak of?

  • European Chemist says:

    Absolutely right, jimbo, I don’t have a problem with disclosing important preliminary results. As you rightly point out, that’s what communications are for. And hey, if ACIE thinks that this is worthy of publication, then fine with me.

    However, in present days I don’t think that “getting scooped” is such a big issue. OK, some people like KCN clearly take pride in being “the first” to do some total synthesis. But if getting your paper published in a top journal is the main concern, then I don’t think that being second or third (particularly if your communication closely follows the first one in terms of timing) tarnishes your chances in any manner. Just my opinion. Furthermore, even a communication has a bigger and longer-lasting impact if the results are well “padded”.

    On the other hand, student-wise it’s waaaay better to fragment your work, publish a communication with the minimum possible so as to assure that the Full Paper is a “big one”. It’s all a question of strategy.

    TWYI, these syntheses are a beautiful illustration of the biomimetic approach and actually a great way to practice the Woodward-Hoffman (ooops, I meant Corey lollll) rules. I found this while quickly browsing the net


    One of my all-time favorites. :-)

  • TheEdge says:

    EC, why do you have a problem with using the bromine as a blocking group? You’re going to get mixtures if you don’t have something there, and the Br is really easy to remove at the end via lithium-halogen exchange.

    I think he needed to rush this out because everybody is going to try this route first, and only the first one is worth publishing in an impact journal, no matter how nice the mechanistic investigation is. It’s a really nice route, too, despite the bagging that’s going on above.

  • milkshake says:

    I think the mechanism of the cyclization is a good old Meerwein carbocation-based. Triphenyl phosphine oxide works as a proton transfer catalyst. To get the benzylic cation from p-hydroxy substituted benzyl alcohol is extremely easy (heating with SO2 in water produces p-hydroxybenzylsulfonic acid) so I suppose p-hydroxy stilbene should produce carbocation also. Especially since protonated Ph3PO should be reasonable acidic.

    If I were KC, I would try a catalytic amount of DMAc or NMP instead of the phosphine oxide.

  • Tot. Syn. says:

    Good call, Milkshake…

  • European Chemist says:

    Huuh, just a naive question, but usually cationic cyclisations are terminated by either a nucleophilic species or a proton loss . I can’t see any of those here. Am I missing something again?

    TheEdge, I just thought it might be possible to either tune your substrate or change conditions in some manner in order to control regiochemistry. People have been doing aromatic Claisen rearrangements for centuries now (literally) and I’m just surprised to see that using a blocking, “useless” halogen is still our best shot at avoiding mixtures.

  • Spiro says:

    Excellent point about the mechanism. I see no way it can be proton-catalyzed.

  • jimbo says:

    I just read the paper… I think the redox mechanism they propose is completely reasonable and right on. They suggest that the catechol gets oxidized to an o-quinone (by air) turning the stilbene into an electron acceptor… a couple of ionic arrow pushes and a transfer of oxidation state to another molecule of catechol gives product.

    They also note in the paper that Ph3PO isn’t required. My guess is that it may have served as a polar additive which helped get the xylenes nice and hot in the microwave.

    Nice bit of work… we should all be so lucky as to work on a molecule that makes itself.

  • Jose says:

    Anyone want to explain the UK joke? Inquiring minds wanna know- it’s prob more interesting than what will more than likely become a chapter in “classics in t.s. vol 3″!

  • HPCC says:

    Actually we have those shhhtupid ads in Canada too… The Grolsch guy speaking English with a badly faked Netherlands accent, adding “ssshhhhsss” everywhere to every word.

    At least, that’s me risking a Commonwealth answer! :)

  • willyoubemine says:

    15. If that redox mech is so reasonable, why didnt they test it? By excluding O2, no oxidation and therefore no cyclization could happen. Or, oxidize it to the quinone then test the cond. Two simple expts that could have unequivocally answered the question. The fact that they present that mech with no expt results is not right.

    No, i dont think it is reasonable at all. That paper is not good. Not the syntetic work itself (which is fine enough) but the whole thing is one big hand wave. Do some experiments before putting forth an easily testable hypothesis.

  • willyoubemine says:

    Furthermore, being that the product you get is not what you would expect from a thermal 2+2, why would you try it? In other words, the idea that their synthetic plan was to do a thermal 2+2 to set those centers is at best, disingenuous.

    And if their redox mech was truly what happens, why do they not see any other products that result from the cation, i.e. the phenol trapping (18), or the six membered ring quinone/phenol trapping it.

    Its just poor scientific method, I think.

  • milkshake says:

    Maybe the benzene ring of the resorscinol participare -Resorscinols tautomerise to diketones quite easily.

    I think one possibility is that the cyclization is actually [4+2] first, and a strained product forms which then re-aromatizes with the allylic C-C migration, so the net outcome is seemingly [2+2].

  • willyoubemine says:

    why would that mechanism be Ph3PO or catechol PG dependent?

  • willyoubemine says:

    anyone look at the SI? there is none. Its just pictures of NMR’s, no experimental details.

  • HPCC says:

    22: Let me play the devil’s advocate, willy… I find that SI miles and miles ahead of many Supporting Info files that you find in Angewandte. When you find one.

    True, the experimental conditions are not delineated, but we’ve come to never expect them to be found in Angew. Chem. communications. However, remember the J. J. LaClair debacle, where a total synthesis had been claimed, and only one 1H NMR spectrum was present – and many people have argued that it was fake… I think this SI is much better, isn’t it?

  • willyoubemine says:

    agreed. I guess I just hate Angew.

    that and vague mechanistic explanations for unexpexted results, when simple experiments can unambiguously determine the validity of the put forth hypothesis.

    and the Yankees.

  • jimbo says:

    From the article: “Subjection of synthetic artochamin F (1) to the microwave heating conditions in the absence if Ph3PO provided the expected tetracyclic skeleton 20 corresponding to artochamins H, I, and J in 82% yield, thereby demonstrating that neither the bromine atom nor Ph3PO are required for thermal formal [2+2] cycloaddition reaction in this sequence.”

    From willy “Furthermore, being that the product you get is not what you would expect from a thermal 2+2, why would you try it? In other words, the idea that their synthetic plan was to do a thermal 2+2 to set those centers is at best, disingenuous.”

    They probably didn’t… if you read carefully, it looks like they did the reaction first on crude Wittig material (which gave poor E/Z selectivity) and found product… they switched to adding Ph3PO when the reaction stopped working on Julia-Kocienski derived material.

    If you don’t think the mechanism is sound, it’s on you to propose a better one. I think the experiment with the silyl groups is convincing.

  • ZZZZZ says:

    ZZZZZ…Claisen rearrangements to allylate an aromatic ring and a 2+2 to make a four-membered ring. I dozed off and woke up in 1965…ZZZZZ…

  • Tot. Syn. says:

    Apologies for the lack of blogging – it’s been a hell of a week, and look what just got published: http://dx.doi.org/10.1021/ja074300t
    I need to spend a bit of time with the *full paper*, so I’ll blog it later this weekend.

  • gilgerto says:

    Have you look at the 1H NMR spectrums…Quality and purity is so bad specially bellow 2 ppm, very ugly (Ex p. 23 of SI).I guess they report crude NMRs as proof of structure. Theses guys should learn how to run a decent flash chromatography.

  • HPCC says:

    27: I know, that Sarain “full paper” was so full that I gave up after page 4-5. It’s still sitting on my desk though. I’ll save it for a long and painful column! ;)

  • organic chemist says:

    I do not think they have bad nmr regarding the presence of many methylene groups in the molecule which usually show up below 2 ppm.

  • whatever says:

    I do not think this molecule or the chemistry is up to the standard of scripps or to that of KCN. What is big deal in getting the total synthesis of this molecule getting done if there is no development of novel chemistry?. Any body can hire a postdoc or two to beat a molecule by following the biosynthetic proposal that some body has proposed. I do not trust in that kind of things.

    Any body want to comment?

  • Spiro says:

    #28: I found your comment brutal, but after I checked the supp info, I have to agree! You would at least expect the synthesized natural products to be clean.
    Usually the natural extracts are dirty but here it is the complete opposite!

  • jimbo says:

    whatever: I think it’s a matter of what question you’re answering. Nobody beats up on biologists if they discover a new mechanism/signaling pathway using standard molecular biology techniques. If you’re hoping to address a biosynthesis or biological action type of question, using old chemistry is a fine way to do it. My process group at work would be perfectly happy if I discovered a drug using ancient reliable reactions.

    In practice, I much prefer executing a total synthesis in a “whatever works” way of doing things as opposed to trying to cram a “novel” rhodium or gold mediated reaction into my route. If you can develop something new in the process, particularly when confronted with a problem, then great. If not, well at least you’ve made a natural product. And if you’re guided by biosynthesis, the chemistry may not be that thrilling, but the route is likely to be efficient.

  • whatever says:

    Jimbo is correct, if it were to be from a process chemistry group. It was with due respect to KCN; I wish, the TS people from academics should aim better and high than Jimbo- because one of the mottos of it is to develop novel chemistry and train the future chemists.

  • Smitty says:

    #34 – whose motto is that, exactly?

    His title is “Professor” Nicolaou (plus a bunch of other official sounding names, I’m sure). That means he is an educator, and as such should be educating his students (and even his post-docs). That is one of the goals of total synthesis in academia, in my opinion.

    He made some clever disconnections, such that he could do a total synthesis in very few steps and using reactions that are amenable to scale-up, if it needed to be – how is that a bad thing? He gets criticized for hammering molecules out and sometimes ignoring brevity and elegance, now he gets criticized for the opposite? I understand part of the criticism stems from his apparent “me first” philosophy, but in this case, I think that’s just a product of the retrosynthesis. The point of this paper is the synthesis of artochamins, not mechanistic studies of the formal [2+2].

  • KCN supporter says:

    Most of the people here are extremely jealous of KC and his accomplishments. The fact is that he has accomplished a volume and quality of work that no one in the field has before. This is factual and undeniable.

    That is why he angers so many of you. It is those same people that will so rapidly open a KCN paper and read it that will also rush to put him down and the field in general.

  • jimbo says:

    whatever: the ad hominem is unnecessary–you don’t know me. In my PhD work, I did all sorts of old chemistry which required substantial investigation to get it working on my scaffold. It was a fantastically frustrating experience, and as a result I’m came out as pretty decent chemist and scientist.

    If you wanted to access quantities of a natural product, wouldn’t you prefer to have a route that just works? How many routes have we seen where someone crams a nice reaction into a synthesis then spends the next 10-20 steps adjusting oxidation state and functional group handles. (Wender’s Resiniferatoxin synthesis?) Too often I think academics invent problems to justify their research when simple old chemistry works just fine. Sometimes the development of new chemistry works out well and sometimes it doesn’t, but if that were a criterion for publication there would be few published total syntheses.

    You’re right that total synthesis in a vacuum is pointless (besides training), but I’d rather my work answer an interesting biological question than come up with another way of making a bicyclo[3.2.0]heptane system.

  • nido says:

    I think the main problem for the purity may be due to stability, the ortho dihydro quinone ring is very sensitive to oxidation.

  • gilgerto says:

    #38: Natural product seems to be very stable according to the NMR supplied in SI…

  • nido says:

    #32 and #39: Having looked at the SI it seems that synthetic
    3 is quite a bit cleaner than natural 3.

  • nido says:

    also just becuase an isolationist supplies a clean NMR
    spectrum that does not been that a natural product is
    “very stable” it may have been the result of 10+ prep HPLC
    runs starting with 100mg and ending up with a clean 2mg for the spectrum with the rest lost due to decomposition.

  • gilgerto says:

    #41: May be your right regarding products stability, but I don’t believe that if a product is really instable you can get a nmr as clean as solationist report. Time from lyo to NMR should be enough to see some degradation of material. It’s not the first time I see messy NMR’s in ACIEE, and it just seems to me a lack of rigor from ACIEE referees. We can also wonder how someone can report a yield for a transformation if you get something unclean at the end…

  • Jose says:

    KCN supporter writes, “The fact is that he has accomplished a volume and quality of work that no one in the field has before. This is factual and undeniable.”

    eh? Undeniable? No-one? I think it is fair to say KCN has published a boatload of good synthesis, but to put him in a pantheon all by himself is truly absurd.

  • milkshake says:

    I would rather see a quick and efficient tot synth of an interesting molecule, you know kind of case-study type than azadiratchtin kind of moster.

    I think this kind of asignment is also better for the students – it is a lovely thesis story/job interview talk if you finished the molecule by yourself rather then being responsible for a “D-E-F south-eastern fragment” of some spongi-made monster that never got to be used in the actual synthesis because the acetonide deprotection in the final step failed so somebody else is going to re-synthesise the piece with SEM groups on it.

  • willyoubemine says:

    I disagree with you milkshake.

    While I agree that a quick and efficient total synthesis of an int molecule is always impressive, especially for interviews (hopefully), I disagree that this kind of assignment is better for the student. If the student is only interested in a job, and not in the research or science they are doing, then that is a separate issue. Given that a student is enthusiastic and bright and diligent, the more challenging the project, the better they will be. Methinks at least.

  • jimbo says:

    Meh… big molecules are no fun to me. Half your PhD is spent scaling up. Nice and short routes are more intellectually stimulating, and if your compound has activity you get a chance at probing biological activity and doing analog synthesis. Establishing those collaborations (or running the biological assays yourself) is way more educational than learning the ins and outs of selective protections and deprotections of 12 different alcohols.

    Another thing I really like about small natural products is that if a route encounters a dead end, you can very rapidly switch it up, whereas a large compound could require months of re-working and scale up. I just don’t find that type of work intellectually stimulating, though I can appreciate that some do. Running 100g of compound down a column is just not that educational (although it will teach you a lesson).

    IMO, the best total syntheses answer a question bigger than “can I make this?”

  • gilgerto says:

    This is a SI compared to previous KCN synthesis in ACIEE. Very detailed exp for every compound and 1H NMR as clean Mr. Clean cap. Great job.