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Englerin A   

6 June 2010 19,663 views 42 Comments

Nicolaou, Chen, Kang, Ng, JACS, 2010, ASAP DOI: 10.1021/ja102927n. Article PDF Supporting Information Group Website

Another popular target today; a last month I wrote a piece in Chemistry World about the first two syntheses of this target, and only a month later, up-pops Nicolau and Chen’s effort.  If nothing else, that’s a whole-lotta funding gone into this target, so it’s no surprise that it’s a pretty biologically active beastie. To quote KCN, ‘…potent and selective growth inhibitory (GI) activities against renal cancer cells‘ is the order of the day, so it’s worth all this effort.  The first two syntheses, published by Ma and Echavarren respectively, use similar gold-mediated cyclisations to build the stereochemically busy 5,7,5- system, using quite different routes to get there. However, Nicolaou and Chen do something rather different.

The paper is divided into two routes; an initial racemic synthesis, and then a later enantioselective formal synthesis.  However, I’m starting with the crux of the synthesis, and their introduction of asymmetry.  The chemistry works by forming a reactive oxopyrilium species from the cyclohexenone, cunningly flattening the molecule, removing those racemic stereocenters.  This exotic beastie then does a [5+2] cycloaddition with the acrylate – in this case bearing a chiral auxiliary.  Creating three new stereocenters in one reaction is quite a challenge, and the paper discusses the development of the chemistry in some detail.  Ultimately, the group couldn’t convince the reaction to give them any more than about a 40% yield, and in the case of the enantioselective chemistry, they were limited to 30% as a 2:1 mixture of diastereomers.

Separation of the diastereomeric mixture was possible, though, leaving two separate pots of enantiomers after removal of the auxiliary.  However, the stereocenter at C-8 looked fairly acidic, and therefore fragile, so the group had to use a rather convoluted reduction/oxidation approach over four steps to achieve what was effectively a transesterification.

A few steps later and the group had introduced a further stereocenter by reduction, and introduced a pendant olefin via elimination.  They then did a palladium-mediated reaction I don’t see very often – a Wacker oxidation.  This provided the desired methyl ketone in excellent yield, and set them up for a nice Robinson Annulation with the cycloheptanone.  Given that there are a couple of modes of reaction for this compound, a yield in the high 70s is pretty respectable, and completes the carbon skeleton of the 5,7,5- ring system.

The next few reaction are what makes this synthesis particularly neat in my opinion.  The enone moiety was reduced in a pair of reaction, firstly tackling the ketone using sodium borohydride and the only Lanthanide I’m ever going to handle.  Then goes the alkene using Crabtree’s catalyst (at a slightly pricey loading…).  Bang – three stereocenters using substrate control and a bit of hydrogen.

The last reaction is yet another that I had to look at for a little while before it clicked (and I felt like an idiot).  After forming the Weinreb amide from the ethyl ester, treatment with methyl lithium gave the group a methyl ketone.  A little peracid then did a Baeyer-Villigar oxidation, forming an ester such that the group were left with an acetate protected hydroxyl.  Neat stuff…

…but is it better than the two preceding syntheses?

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  • ac says:

    there is another “first” synthesis

  • Ben says:

    Great Job! I wanted to say thanks for reviewing the synthesis. I do not mean to be a pain, but I think Crabtree’s catalyst introduces a proton not a methyl group. Did I miss read your structure?


  • chemist_in_the_making says:

    In my opinion, the preceding two syntheses are better than Nicolaou’s synthesis in novelty and efficiency. The key step in this synthesis – “intermolecular version of oxidopyrylium 1,3-dipolar cycloaddition” is an extension of its “intramolecular version” reported by Paul Wender for a very similar substrate en route to more complex diterpenes “Resiniferatoxin and Phorbol” (lathyrane skeleton with 5-7-6 ring system). No reference for this cycloaddition cascade step has been cited and the yield and diastereoselection is modest.
    Ma’s synthesis is the best so far – elegant and concise (16 steps, Nicolaou’s synthesis – 28 steps).

    • Highlander says:

      Too long, inefficient, no novelty, no elegance…still in JACS…

      • Nemesis says:

        Novelty and elegancy? You are not supposed to look for that in KC’s work in the very first place. His top priority is to get “First total synthesis” in the title.

        • GuruMS says:

          “First total synthesis” in the title???….Lolzzzzzzz….Is it a kind of rat race?? :-D.

  • Highlander says:

    I don’t care about being the 1st synthesis or not…in this case it is the 4th synthesis actually. So it is expected from the pursuer of the synthesis to come up with something novel (or at least shorter approach) especially if it is going to be the Nth synthesis of the compound where N>3 in this case…

    • Stef says:

      I think one should keep in mind that such a total synthesis approach is nothing to be finished in a few weeks or month. Very often the synthesis is already ongoing research in a group and then there is during that period another paper coming out. That doesn’t necessarily mean that they were the first to start but only the first to publish. So in my opinion you can only expect an “improvement” if there is a v big time gap between the publication dates. Otherwise what would be the alternative – seeing that yor synthesis route can’t beat the just published one and then say to your student – well, I am sorry, I know you worked hard for 4 years and yes you finished the molecule but in the end we can’t publish it because there has been a publication of another synthesis route just a month ago which is 2 steps shorter…
      I think this would be very unfair and the synthetic community would loose a lot of very valuable information on reactions (scope and limitations) because this is the second big thing coming out of a synthesis paper!

  • European Chemist says:

    Well, not wanting to defend KCN, but the approach IS original – and the difficulties they encountered with the 3+2 (I wouldn’t call it 5+2 but that’s just me) showcase the enormous difference in moving from INTRAmolecular to INTERmolecular oxidopyrillium cycloadditions.

    In terms of final efficiency, this is just one of those bummers. The key-step worked much worse than anticipated and the synthesis takes a huge hit from that. Also these sequences where you’re forced to oxidise then reduce just because you can’t twist the molecule’s arm to do what you want are what tarnishes some of KC’s recent work and, in fine, what makes this synthesis longer and less efficient that the preceding ones. Considering that the options would have been (a) abandon the project as soon as it was realised that the key-step was not going to work well or (b) not publish it, I don’t really see much wrong in this publication…

    • Highlander says:

      3rd (and more honest) option would be to publish it in a different journal…Org.Lett. for example:)

      • chemist_in_the_making says:

        Actually, I was wrong. I should have looked around a bit before posting. The precedence for intermolecular version of 3+2 cycloaddition acascade exists in the literature too (OL, 2002, 4, 3091 and references therein, there are few examples of asymmetric version too).
        The whole debate on the synthesis being published in JACS is pointless, because everything KC does gets published in JACS. In this case,however, they could have tried to tweak around a little with substrate and their synthesis to come up with a much better route.

        • The Next Phil McGroin says:

          or published in ACIEE with little or no experimental.

          I agree the debate about where an article is published is pointless…
          so lets debate whether the debate itself is worth having? Any takers?

  • Highlander says:

    I didn’t have any intentions to initiate usual JACS(Angewandte, Science, Nature) worthiness-type discussion at all. But I don’t agree with the above comment that everything made bu a big guy should go to top journals

    • Nemesis says:

      That’s the reality. You have to accept it.

      • bad wolf says:

        The students should ask themselves why they work such long hours optimizing reactions if they will get published in top journals anyway.

        • HPCC says:

          Because they’re the ones pushing the material through (and would rather get max efficiency if possible) and that they take pride in their work?

  • pTsOH says:

    So the key reaction to make this molecule gives 30% times 67% = 20% yield of the desired diastereomer? And better syntheses were already reported? And it was submitted to JACS? This does a disservice to the respectability of the field IMO.

    Look, sometimes your key step doesn’t work, even though you REALLY wanted it too. It happens.

  • hold on says:

    Unfortunately, this publication by KCN makes him look like a simple ‘molecule maker’ and not a synthetic chemist. We already knew he could do it.

  • European Chemist says:


    There are just two things to this point.

    1- It’s NOT KCN’s fault if he submits this to JACS and it gets accepted. If you were in his position, you would have done the same. The students who spent months trying to optimise that 3+2 to get 20% of the desired diastereomer must surely have felt rewarded by their hard work.

    2- There is as much of publication strategy as of big-name in this. Sure, KCN’s name helps getting things accepted because any reviewer knows him (and most likely in person). But the direct submission of this work as a Full Paper must have also helped a lot – there aren’t the claims of “urgency” or of “extreme novelty” usually associated with Communications.

    There’s so much subjectivity in peer-reviewing that this discussion is REALLY pointless. You will never find out what would happen IF this was submitted to JACS by a different group, IF the reviewers chosen had been different, IF this paper had been sent to your advisor for reviewing (and then again, maybe it was!), and even more importantly how many “No”‘s there were among the reviewers, because in the end it’s always the Editor’s call whether to reject or to accept.
    So please, let’s go back to discussing Chemistry…

    • The Next Phil McGroin says:

      Amen european brother!

    • ListenToMe says:

      This paper is coming from Singapore. KC didn’t even want to publish because he thought it was garbage. Too steppy and poor selectivity. This is Chen’s garbage.

  • UBChem says:

    Yeah but that’s not any fun. Down with KCN!!!

  • Barans bald spot says:

    Down with KCN and up with Ideal Synthesis index!

    • Statistics says:

      Yeah. Let’s boil a complex synthesis down to a few numbers. Statistics are known for capturing beauty.

    • Starvinmarvin says:

      Ummm, shame Baran’s coming up with ideal synthesis index, redox economy WHILE MOSTLY PUBLISHING RACEMIC MOLECULES.

  • CRH says:

    Quoting European Chemist:

    “In terms of final efficiency, this is just one of those bummers. The key-step worked much worse than anticipated and the synthesis takes a huge hit from that.”

    Wow, so because the key-step worked “worse than anticipated” is an argument for acceptance? If so, then pretty much every reaction that doesn’t give 100% falls into that category, and hence every total synthesis should go to JACS.

    Just because a student worked “months to get a 20% yield” does not make this JACS worthy.

    It may, in your opinion, be worthless to discuss whether this belongs in JACS; but I would disagree. This discussion absolutely needs to happen because of the fact that many younger chemists read this blog and they need to know what is appropriate for a journal such as JACS. If nobody gives a dissenting opinion then they will take KCN’s reputation as being JACS-worthy. And one more, shame on KCN for submitting to JACS knowing full well it will be accepted. He should know where certain works should be published – and this synthesis should not be JACS.

    • European Chemist says:

      Whooooaa there cowboy. Before you start preaching your gospel, read my comment again (in case you haven’t already) and tell where do I say that the key-step not working well is an argument for acceptance?

      This blog has, to me, been invaluable throughout the years for the chemistry knowledge which is shared openly and freely among students. I don’t really see the point of endless banter from people who find nothing better to do than to criticise others under the blanket of anonimacy. IMO, some of those “Younger chemists” you mention might be better off learning chemistry, reading classic publications and thoroughly knowing the literature before engaging in discussions about what is or isn’t JACS-worthy…

      What I really find odd is that people seem not to understand that peer-review, as we practice it nowadays, is very subjective and way, way far from foolproof. That’s why we will continue to read “JACS-like” material in Org. Lett. and things like the NaH oxidation of alcohols in JACS. And we will write, complain and ramble about it while missing the opportunities that blogs like these give us to actually talk about the science within those papers. Check the NaH live blogging thread – the hate comments from people who just wanted to bash the authors ultimately served no purpose other than to (presumably) make those people feel better. In contrast, the exchange of information about the literature precedents, possible mechanisms and alternative explanations made that quite probably one of the nicest posts in the history of Totally Synthetic. Of course, we all like a good story and a lot of drama – but there’s a limit to everything.

      Just my two cents.

      • The Next Phil McGroin says:

        Once again, I could not agree more. Those European chemists are not that bad after all!

        I promised myself I would not get emotional, but I just started a slow clap in my lab after reading that. Obviously, no one knows what I am clapping about, but the moment spoke for itself.

  • Ian says:

    Are referees scared of rejecting KCN papers then?

    Why does everything he send fly into JACS?

    • 23l33t says:

      not true. obviously you don’t see the papers which are rejected from JACS in JACS…

  • CRH says:

    “Considering that the options would have been (a) abandon the project as soon as it was realised that the key-step was not going to work well or (b) not publish it, I don’t really see much wrong in this publication…”

    Sure sounds like the key step not working well is an argument for publication; or at least you not having a problem with the publication. Hey it’s either abandon or not publish as the only two options? No, the other option is publish in a more appropriate journal. If this was the first synthesis I wouldn’t have a problem with it being in JACS – but it’s not, and it’s not a very efficient synthesis – ie, not JACS-worthy.

    And to an above commenter – I would say the VAST majority of KCN’s work is published in JACS when submitted and for those few that are rejected somehow get into ACIEE.

    That’s not a knock on KCN…but the younger chemists who one day will become reviewers need to hear discussions on why something should or should not be in JACS (or any other journal). Of course the process if not fool-proof; however, if we as chemists and reviewers just take the status quo as the best it can be, it will never change.

    • European Chemist says:

      You’re a persistent one, huh? :)

      Let me put things this way: I do not know of a single PI that, knowing that his group’s latest work has more than a 50% chance of making it into a high-impact journal, would say “ahhhhhhh you know what? this will almost surely get into JACS but I think we should submit to Org. Lett. instead”. When (and if) you have your own group you can try telling that to your students. Deal?

      Hell, I even know of groups that submit ALL their work to Science (first), then ACIE, then JACS (by the way, not to hurt any susceptibilites here, but you do know that ACIE has a higher impact factor, right? and it’s not even because of the mini-reviews), THEN Org. Lett., regardless of the actual work being published!

      Nobody is taking the status quo as the best – I, for one, believe there should be HUGE changes in the way the peer-review process is handled. But as I wrote above – do you even have a clue about who the referees were? Do you know how many referee reports were requested for this paper? Can you even guess at whether they were really all positive (as usually required by JACS)? Can you really expect, of a community where (presumably) 3 referees (who must also have felt pretty dumb after the whole thing) have given green light for publication of the NaH-catalysed (CATALYSED, for heaven’s sake!) oxidation of alcohols in JACS, an exceptionally high level of accuracy and intelectual discussion of every single paper?…

      Just something to think about. My personal opinion about this (if you even care) is that I’ve seen (much much) worse things published in the journal and think that directly going for the Full Paper was smart from the authors. If I had reviewed it? I might also have rejected it, to be honest – but not before carefully checking the literature for the precedents to the key step and a few of the other transformations.

      • Whatever says:

        No offense, but reading what you are talking above, I am pretty sure you are one of the authors of KC’s erglerin paper… :D

        In my opinion that paper is only acceptable…

        • European Chemist says:

          No offense taken but you couldn’t be farther away from the truth.
          I’m well past Post-Doc time and I actually declined a possibility to go to KC’s lab at some point. Can’t say I regret it.

          Just trying to convey the message that spending time bitching about the peer-review system is pointless. Editors make subjective decisions based on subjective opinions of referees. Referees know authors (hell, they’re colleagues!) and Editors also know authors.

          I also wanted to bring along the message that (in my opinion) JACS full papers which were NOT preceded by a communication are often allowed to be considerably less original than expected for the standards of the journal. The catch could be that, since there is no preceding communication, that article will reap all the citations made subsequently to the work in question.

          • European Chemist says:

            One last thing (although probably no one will read this). As a PI I suppose you are faced with the task of getting different pieces of work published, differing in scope, breadth and especially something that people call “quality” (as defined mostly by impact on the community). While most articles can be easily narrowed down to one or two target journals, I can easily imagine a number (quite likely larger than what you think) of pieces of chemistry that are “a bit better than Org Lett but a bit worse than JACS” for example. This can be independent of the actual amount of work gone into the preparation of the manuscript and even the number of co-workers involved.
            If you as a PI were to be faced with such “ambiguous” papers, what would you do? I suppose this depends a lot on your actual career stage, on your persistence vs. desire to “simply get it published no matter where” and very much your intuition. It’s often much easier to simply submit the best possible version to JACS and let the Editor decide.

            I don’t understand why you people seem to imply KCNicolaou should call a press conference or send a letter to say that “this total synthesis was accepted in JACS but it really shouldn’t have”. Once a paper is accepted, the authors’ only responsibility is to ensure that the chemistry is reproducible and faithfully reported. Period.

  • The Next Phil Baran says:

    Maybe, just maybe, KCN should be commended for tackling smaller molecules that might get used as a potential pharmaceutical. Rapamycin was a waste of time, but his last few probably challenged the students enough while not wasting there time. I think KCN does better on the smaller targets, plus they are a more enjoyable and manageable read. Quite refreshing, actually.

    • chemist_in_the_making says:

      Honestly, none of these complex terpene natural products will ever be developed as a potential drug (one needs kilos and not mgs). However, there are definitely some exceptions. The recent one is “semi synthesis of Prostratin”- already in the clinical trials. In my opinion, small molecules needing 28 step is never “small” :). On th contrary, I think KCN does better on molecules which needs an army of students. But what do I know, I am just a graduate student.

      • PotStirrer says:

        I’m sure the fact that KCN and Chen had biological data in their paper also helped get it into JACS. On that note, a dirty little secret with englerin A: my recollection of reading the SI of the isolation paper was that they could pretty easily get grams of the stuff. This is not a precious molecule that requires total synthesis in order to put different ester side chains on. A (to borrow Danishefsky’s term) diverted total synthesis that gave significantly different analogs that would be otherwise unavailable from the natural substance could be a useful project…otherwise it’s just a synthetic exercise. Nothing wrong with that…I’m reading this blog for crisakes…it would just be nice if we could be honest about that. Tough to get money from health-related initiatives for pure synthesis though.

  • Taxol says:

    s,its too long.