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Biyouyanagin A   

26 September 2009 20,047 views 53 Comments


Xie, Du, Li, Li. ACIEE, 2009, ASAP. DOI: 10.1002/anie.200902908. Article PDF Supporting Information

A second showing for this complex little target, Zhixiang Xie’s route uses the same end-game as that developed by Nicolaou two years ago.  However, getting to that point is a very different matter, using some quite powerful chemistry.  The RHS of the molecule is a distinct natural product – hyperolactone C, with the LHS also natural – zingiberene.  The latter was produced as in Nicolaou’s paper, but hyperolactone – the more challenging portion – was produced in a rather different manner.

First up is a synthesis of the actual lactone.  The SM for this chemistry is a rather sensitive-looking tricarbonyl compound, with a suspicious looking diazo-group.  Selective diazotisation of the beta-keto-ester postion was achieved in a simple manner – by working with the benzyl alcohol and oxidising the product with DMP.  Of course, a little rhodium catalyst did the usual trick with diazo groups, extruding nitrogen to form a carbonyl ylide, which cyclised to give a furanone.


It was then time for the center-piece – a Pd-AAA.  For those out-of-the-know, this is an abbreviation for a palladium-catalyzed asymmetric allylic alkylation, pioneered by Barry Trost.  In fact, I’ve written a couple of posts about it – Tamiflu, Terpestacin.  Perhaps a better place to read about this chemistry is in this review.  However, one case left untouched by Trost is the creation of two adjacent stereocenters in this reaction – a case Xie intended to tackle.  In this case, he was using a racemic isoprene monoepoxide along with a bit of Pd catalyst and a that beta-keto-ester to do just that, in a manner reminiscent of a further Trost paper.  However, in that paper, Trost’s beta-keto-ester is unsubstituted, so doesn’t create such a complex system.  Using those conditions, Xie has acheived a respectable yield in awesome enantiomeric excess, with a pretty handy d.r. too.  What more do you want?!  Well, if I’m fair, a bit mroe product would be nice, but the problem is the reaction electronics.  Putting a para-chloro substituent on the phenyl ring changes things quite a bit, bringing the yield up to 68%, and improving the d.r.  However, getting rid of such substituents is a pain, so I hope they have future reagent-based success – perhaps experimenting with Lewis acid / base additives could help…


As is obvious, completion of hyperolactone was now no stretch – a little PTSA was enough to snap that ring shut.  And we’re basically done and dusted, but I will reiterate the synthesis of biyouyanagin A, which as I said uses Nicolaou’s chemistry.  What we need here is a [2+2] cycloaddition, so it’ no surprise that the reaction is done in a tanning-bed, but the interesting thing is that this reaction is biomimetic – I wasn’t aware of [2+2]s in nature.  Neatly done; seven steps in all.


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  • UBChem says:

    I’m surprised the Davies lab has not been trying to make ent-zingiberene using their C-H activation/cope chemistry. It seems pretty setup for it from their previous work.

  • Will says:

    re: [2+2] in nature, I remember way back in undergrad orgo sealing flasks with trans-cinnamic acid and leaving it on the roof the chem building for spring break, and coming back to a cyclobutane demanding to have its stereochemisty deduced…

  • drm says:

    good work

  • earth23 says:

    Vicinal quat centers… that Pd AAA is pretty sweet.

  • Don Henley says:

    I’d like a bit mroe

  • krest17 says:

    Nothing to discuss? Boring indeed.

  • WestCoast85 says:

    Phil Baran is publishing in Org. Lett. now !!! I enjoy the reference 3 in his paper… Li returned to China with ideas and strategies of Baran ?

  • Chairman MaoCrystal says:

    Damn nice approach, could easily be in angewandte. Footnote 3 certainly implies foul-play…..

  • alkylate this! says:

    “could easily be in angewandte. Footnote 3..”

    So, Chairman, by applying the transitive property to this hypothetical, what you’re saying is that the paper referenced in footnote 3 also “could easily be” in ACIE? ’cause they’re the same paper. Its not like the peer review process, including the peer review which goes on right here in this discussion board, ever gives things a “pass” based on the author line, or the sell in the introduction, or the originating institution address. Its all about self-evident quality of science, which is a totally objective, quantifiable, value and never based on something so fickle as individual “feeling”, right?

    Come on. These are both OL papers. The editors, reviewers, authors all agree on that, otherwise they wouldn’t have submitted, recommended, or published them. The vast majority of papers are not on the undiscovered oxidizing power of NaH, and belong right where we see them, for whatever reason. So lets leave it at that.

    However, if you still think they’re both ACIE worthy, well then, pass along your contact info and I’ll recommend you as a reviewer on my next ACIE submission!!

    more on topic, and probably more importantly: Xie’s approach to biyouyanagin is elegant and effective. i disagree, krest17 – there may be a lack of comments, but perhaps that’s since the chemistry speaks for itself. I look at this synthesis and think i’d have a tough time coming up with a better route. it’s certainly better than my initial approach – although in my defense, back then I was thinking about the diasteromer proposed in the original isolation, which is a bit tougher since you cannot rely on the 2+2 to control the relative stereochem about the cyclobutane)

    The “rather sensitive-looking tricarbonyl compound” – my understanding is that the more conjugation you have on the diazo, the less sensitive it is. lots of folks use the acetoacetate version. I do wonder if you see enol tautomers in the NMR – tricarbonyls like this without the diazo usually have a high conc. of enol by HNMR. I think I’ll go check the SI.

  • Chairman MaoCrystal says:

    Well it appears to me that “the paper in reference 3″ shouldnt be published in any worthy scientific journal since it is likely the result of plaigarism so I guess I would not apply the transitive property in this case. And I will probably never review your ACIEE paper since Im guessing you are doing more bloggin’ and less researchin’

    • alkylate this! says:

      hindsight is 20/20, Chairman. no peer reviewer or editor could have known plagiarism was involved until the Baran paper appeared at the OL office. thats my point.

      so, if according to you, Baran’s OL should be ACIE, then the Li paper should have been too. Which is why i’m pretty sure you’ve never reviewed a paper.

      It seems likely to me that Baran’s publication was “provoked” by the plagiarism. I think he would have been unlikely to publish this “studies toward” paper otherwise, since thats not really his style. The OL office might have decided to publish these back-to-back. Baran might have given Amos the heads up on this. Maybe thats why the Li paper has been stuck on the ASAP since July, a good two weeks longer than all the others in the ASAP & current issue. Baran’s paper spent a grand total of 7 days from submit to ASAP – even for OL, that is damn fast. Li’s spent a far more typical 3 weeks to get to asap.

      Listen up: Plagiarism is endemic in China. Anyone who’s had to teach Chinese grad students knows this. Many Chinese students just don’t view it as a serious offense, the way Western societies do. This is an example of it making it all the way through peer review. Since in this case the cheater is ripping off a privileged communication, (NIH Proposals) the reviewer or editor has no chance to catch it.

      Here, educate yourself:


      That said, the quality of science from China has greatly improved over the last 10 years. Unfortunately, this isn’t a good example of that, and more shows how far things still have to go.

      “Im guessing you are doing more bloggin’ and less researchin’”

      You guessed wrong. According to my records, i’ve peer reviewed 36 papers and authored/co-authored 17. You’ve got no idea who i am, and thank goodness. But thanks for reminding me why I haven’t entered the morass of the chemistry blog comment sections in the last few months. Unless you’ve got more foolish comments, and hopefully no more bordering on the ad hominem, I’ll go back to work (and lurking).

  • z says:

    Regarding the Baran paper, is there any penalty for blatantly stealing someone’s chemistry like this? (At least the wording in Baran’s paper implies such blatant theft.) Or will Li’s paper go on to be published like normal, with only a snarky footnote and some muttering in the blogosphere? This seems really bad.

    • fanofkcn says:

      According to the Baran OL paper that Baran that Li “published” Baran’s approach. However, after reading the original Li paper, it seems that the work was carrued out at two laboratories and Li only worked at one of these laboratories. Therefore, although Li is one of two corresponding authors, he can not be the senior corresponding author. To blame Li for plagiarism alone is not fare.

      • RikeB says:

        Li works for yang in the same lab. Not 2 different labs.

      • fanofkcn says:

        These two papers are printed out side-by-side as shown below:

        Synthetic Study toward the Total Synthesis of Maoecrystal V
        Jianxian Gong†, Guang Lin‡, Chuang-chuang Li*† and Zhen Yang*†‡
        Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen 518055, China, and Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for Molecular Science (BNLMS), College of Chemistry, Peking University, Beijing 100871, China
        Org. Lett., 2009, 11 (21), pp 4770–4773
        † Shenzhen Graduate School of Peking University.
        , ‡ Peking University.

        A Synthesis of the Carbon Skeleton of Maoecrystal V
        Paul J. Krawczuk, Niklas Schne and Phil S. Baran*
        Department of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037
        Org. Lett., 2009, 11 (21), pp 4774–4776

        Ref 3. During this period, one of the corresponding authors of the preceding paper was employed as a postdoctoral associate (C.-C. Li) in this laboratory: Gong, J.; Lin, G.; Li, C.-C.; Yang, Z. Org. Lett. 2009, 11 (21), pp 4770–4773. This work was reported in an NIH proposal (received 8/11/2008 and reviewed on 10/9/2008 by the BCMB-B study section) and a final report to the DFG (submitted 7/17/2009).

  • TWYI says:

    Who’d have thought he’d be Chinese?

    Joins Mr ‘crisamicin A’ and Mr ‘NaH is an oxidant’ on the pile

    ..and that’s just the last 12 months on here alone

  • chemist says:

    Speaking of stealing chemistry, see how Keck’s pyran chemistry (10.1021/ol025645d , 10.1021/ol050511w) was stolen and patented by Wender 10.1021/ja8015632 , 10.1021/ol801235h .

    • Cat Herder says:

      Keck put his work in the public domain years before Wender used (and cited) it. In no way is this stealing. It is fair game to patent a route containing chemistry in the public domain. If not, process chemistry would be mighty difficult.

  • UBChem says:

    To TWYI… Whether the coincidence of the author’s ethnicity comes into play or not, that was one freaking blatant racist remark. WOW.

    • TWYI says:

      Not really, considering my mother is Asian

      • milkshake says:

        so was she a good postdoc? (sorry)

        • TWYI says:

          a medical doctor.

          • Tok says:

            You think someone of a certain ethnicity can’t be racist against that same ethnicity? Think again. It’s a powerful racism since it’s easy to deny it to yourself.

            Your mom should spank your bottom.

          • TB says:

            That’s the truth Ruth! You’re a damn Fool TWYI.

          • ian says:

            No. An Asian crititising asians is xenophobia

            It is certainly not racist, honky

          • The Next Phil Baran says:

            I think the point is that he is talking about culture not race. I don’t think he is attacking the way someone looks, nor associating a particular tendency with the genetics of the person involved. Like all persons, there are good and bad, and its not associated with their physical attributes, however, culture is an accepted process, it requires a choice to either go with the flow or to go against it. If someone jumped on here and said: “All Americans are snobby, arrogant, something or others”, most persons, not all, but especially non-Americans, would wholeheartedly agree, and that person would not be called racist. That would be an attack on culture. What he should have said is that there may be a culture of deceit that may be more prevalent in Asia, which requires those who want to get ahead to make decisions that involve plagiarism, or fraud, etc. I am not taking a side in this, but I think people have blown the whole racism out of proportion. Hatred of your own genotype does not mean you are a racist. Racism is when you think you are superior to another race by virtue of some special gift, your genetics. If you are racist against your own race you are, by default, hating yourself. This is something completely different than racism. And Ian, xenophobia is a hatred of outsiders, not similars.

  • received date reader says:

    hey alkylate this!
    fyi: baran’s received date is August 24, 2009 – that equals 5 weeks between submission and asaps – a relatively slow review process

    just trying to open up a discussion here: is there even a slim possibility that academic dishonesty was not involved?

    im going with it must have been stolen

    also, where does li get that starting material? scifinder does not know how to make it and its not commercial. looks like the reviewers missed that one. can you believe they both use MOM?

  • regularchem says:

    Have you guys read those two papers carefully or not? The only thing that Li stole form Baran is the straitegy, the IMDA, not the synthetic route. I guessed that is the reason why Li did not consider it stealing. Though I do think that Li has made a foolish mistake, it is that as big as others think.

    • GYA says:

      if you look more closely, the li publication is an early route utilized in the baran lab (apparently its a dead end). what’s not stealing about that?

    • ben says:

      which paper are you guys talking about? can anyone give a link of the two paper? thanks

  • EuNiQuA says:

    I have read the papers carefully. Here is the Baran route: arylation, reduction, esterification, (deprotection), dearomatization, diels-alder, Pd/C, and SmI2. You would say the same thing for the Li route except for the deprotection, which occurs earlier in the sequence. Generally, when we talk about “the synthetic route” in the field of total synthesis, we are referring to the sequence of steps. I suppose they are slightly different. The only thing that Li did not steal was the starting material (maybe he couldn’t figure out how to make it enantiopure) and the exact conditions (I guess he didn’t make copies of the notebooks). Also notice that Danishefsky and Nicolaou’s routes are not the same.

    • TA says:

      Hey where can i find the Nicolaou’s approach?
      I can’t find it on RSC webpage and googling doesn’t find me too

      • Moody Blue says:

        I just wonder how did Baran know that his idea was being scooped. I mean, we usually come to know about this sorta stuff only when we see the patents/pubs after they come out.

    • ben says:

      you must be kidding, that is just a proposal….I have many proposal for pau’la amine too :-)

    • phenol says:

      in the critical late-stage, IMDA in that proposal, the diene is a tautomer of phenol. looks doomed to failure.

  • unlikely says:

    happy birthday Paul

  • Radical says:

    Even more off-topic here, but does anyone else find it difficult to locate older literature in the RSC journals? I usually end up finding the article I am looking for, but how I get there is generally a matter of patience and luck. The RSC journals website must be one of the most complicated and non-intuitive websites out there.

  • John Wood says:

    The Nobel Prize(Chemistry) is gonna be announced this week, any picks?

  • Tot. Syn. says:

    Hey folks – sorry for the lack of blogging-action. I’ve been home (in Scotland) after at a family funeral. However, that was balanced with the happiness of a friend’s wedding. You balance the good with the bad…

    Anyway, I’ll be back at it shortly (on the train south right now), and should have a post out soon.

    And thanks for the happy-birthday comment!

  • unedrgrad says:

    Biologists not use our chemistry, but also steal our noble prizes and our grants. I am shifting my major to biology unless some body remedies the situation, and there by save some agony in the future.

  • unedrgrad says:

    Biologists not only use our chemistry, but also steal our noble prizes and our grants. I am shifting my major to biology unless some body remedies the situation, and there by save some agony in the future.

  • stir_bar says:


    You probably should just give up…c’mon.

  • John Wood says:

    undergrad, with an attitude like that, you won’t be missed.

  • C. Bailey says:

    [2+2]s in nature aren’t that uncommon, actually. I can think of several other examples of cyclobutanes formed from a photochemical [2+2] or ring openings due to retro [2+2]. Check out Dirk Trauner’s review, “Biomimetic and Biosynthetic Electrocyclizations” in Chemical Reviews (published 2005 or something like that I think?)