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Chartelline C   

12 October 2006 8,862 views 22 Comments


Baran and Shenvi. JACS, 2006, ASAP. DOI: 10.1021/ja0659673.

As a comment on the previous synthesis pointed out, it’s interesting to see this paper in the same week as Corey’s synthesis of antheliolide, as both structures show interestingly complex fused ring structures. I’ve simplified the structure somewhat by flattening the ten-member ring, but with three cis- alkenes, the structure drawn in the paper is more realistic (and based on X-ray data). Baran’s approach to this complex system betrays some of his earlier schooling with Corey, using a rearrangement on a 5,5-fused system to provide the lactam. But first they need the cyclisation substrate:

I’m not going to discuss the synthesis of the above precursor, as the main elements are shown in the retrosynthesis, but he does it quickly and efficiently, using a nice chemoselective Sonagashira in the first step. Also of note was the ambitious bromination of the alkene, which unfortunately only achieved 36% monobromination. Those bromines are hard work! With the cyclisation substrate in hand, a bit of pot-carb does the trick, with a full mechanistic explanation in the paper. Interestingly, the bromide was exchanged for a chloride simply by using brine – nice work!

Only a few more steps were required to complete the synthesis, including a rather tricky decarboxylation. Cu catalysis failed, so they resorted to heating the hell out of it :) . Top stuff!

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  • Undergrad newbee says:

    Man I am only doing aldol condensations with the heating mantle and the 200mhz NMR to check my product. Half the time singlets I get are actually like triplets on the spectra I obtain. Seeing stuff like these total synths come together is totally awesome.

    Pretty soon I will have my first molecule completeled and maybe then I will understand (alteast) a teeney bit what a completed synthesis is like.

    Even though I understand like 10% of what you guys are talking about I still enjoy reading this stuff… CONTINUE ONE!

  • Disillusioned Hamster says:

    Hey, 3/4 of the papers discussed here this week are ones I picked to read out of the literature! Is this coincidence, a sign the papers are truly of wide interest, or a sign we’re being trained by the academic establishmeent to pick up on certain things and probably ignore equally good work by lesser names?

  • Biotech says:

    Without downplaying the Baran paper, which is fantastic stuff and an example of how synthesis doesn’t always go the way you want it to, I totally agree with Disillusioned Hamster…. try looking out for publications by people not at Scripps or Harvard… (dare I say even Oxbridge!).

  • Tot. Syn. says:

    I’m just picking up on what I like… and sticking to total synthesis. Up next is that Tony Barrett paper – he’s from IC, so does that work for you chaps??!

  • European Chemist says:

    Maybe the thing is that the blog is also dedicated to “big molecules”. I wonder wether Tot.Syn. doesn’t like the smaller targets, where much interesting chemistry lies and people usually say more about what worked and what didn’t…

    Anyway this synthesis is very nice. I’m always puzzled by the Baran syntheses because the targets are extremely complex and there’s usually only one name besides Baran’s. But then you read the acknowledgement section and other guys are thanked for their “technical contributions”…. I wonder about their policies for “who should get their name into the paper”….

    And astonished by the number of steps requiring considerable heating (the rearrangement done at >150ºC; the decarboxylation done at 200ºC!!! These molecules must be so tough that they won’t break unless exposed to a gallon of H2SO4). I guess that in these types of work, when you’re desperate you’ll just heat your compound at a higher temperature until something happens!!!

  • diketene says:

    Nice piece of work. Seem Baran always works molecules out in some non conventional ways. It is sometimes even “uncomfortable” to read. Maybe that is what separates him from the others.

  • jimbo says:

    EC: Maybe it requires contributing steps to the synthesis? At least one of those names is listed is an undergrad, which means they may have just done scale up. Maybe the other is a post-doc who bounced around and did a couple of days worth of work, but didn’t contribute to the published synthesis. Personally, I think actually contributing to a work should be a requirement for being on a paper. I know several examples (myself included) where people who worked a project were left off of a paper because they didn’t contribute anything non-trivial. I’ve actually requested not to be on papers… not because the work was bad, but because I didn’t want to dilute the efforts of the people who actually did the work.

  • European Chemist says:

    Jimbo: I think you’ve got a point. The main problem usually arises with Undergrads. Suppose you’re supervising an undergrad who does work worthy of publication. Of course, most of the stuff he did (if not all) was suggested by you or at least originated from your own ideas (and/or the Boss’), except for some particular cases where the undergrad actually is mature enough to orient his projec all alone.
    So who gets their name into the paper? IMHO, although you did no reactions and no “actual” work, you deserve at least as much credit as the person who actually did it. What about the Undergrad? Well, if he did some of the reactions, even if he just repeated them in a larger scale, could the work have been completed without his assistance? Would another undergrad, who could potentially waste synthetic material 10-steps-worth by doing a mistake, have been as useful as this one? For me, he should also get his name into the paper. What do you think?

    Diketene: Yeap, I feel that Baran deliberately picks out the most exotic targets and then works out extremely inventive syntheses. As you read it, the feeling is “how could THIS ever work??” or further “how did they think of THAT?”. Maybe that’s the reason why he has a nearly 100% Masculin group……. (and they keep changing administrative assistants!)

  • Ochemist says:

    Yeah, undergrads are usually treated as slaves in many labs and are not given the authorship even if they were the generators of ideas… unfortunately i am one of these victims…

  • ddd says:

    why is his name first? Has he done that synthesis by himself? Or he joins the club Trost, Wender, KCN who put their names first for the sake of ego…Does anyone know what are the policies in those groups about the name orders?

  • European Chemist says:

    At our group (somewhere in the heart of Europe…) the Boss always puts his name first IF he wrote the paper himself. Otherwise, we resort to the most common style of listing all the names in order (which can sometimes be the source of numerous disputes…) and placing him at the end. I personally find it much more elegant to have all the students listed and finally the Boss.

  • jimbo says:

    Baran is from the KCN/Corey school… so his name goes first. My advisor always put his name first, and most people know he didn’t do any of the work. His name is his brand. Although I know people disagree with this, and I once did, I think it’s good that the advisor always just comes first. One reason is that when people cite the work in the text of other papers, they’ll say things like “Corey at al” or “Baran et al” instead of “Shenvi et al”. (No offense to Mr. Shenvi). It isn’t about taking credit away from the person who did the work… it’s about identifying the lab in which the work was done. Another reason is that the headers of many journals will have “First_Author et al” at the top of each page of the article, and by having the advisor first, it makes flipping through the journal easier.

    Becuase there isn’t a standard way of doing this, all job recruiters, particularly in industry, are eager to figure out exactly what your contribution to a work is. Everyone who hires in industry once had a PhD advisor, so they are well versed in the politics of name order… one of the most common questions during job interviews is “how much of this was actually done by you?” I’ve heard that UK interviews are particularly tough… if they don’t ask this directly, they’ll figure out what you did during your interrogation.

    EC: without firsthand knowledge of what went on in this work, I can’t say whether or not these people deserved authorship. But I don’t think that someone who scales up, then blows material should be allowed on a paper. I’m in agreement that a scale up slave who contributes to the completion of a synthesis should get authorship, but I really don’t think having run a couple reacions on a paper earns it. Another way to look at it is, what would have been your perception if there were 4 names on this paper? I would think that 3 people were needed to get this molecule done… not that Mr. Shenvi did almost all of the work and that the other two contributed a couple “technical contributions”. I think handing out un-earned publications teaches the wrong lesson…. you can end up with people who simply bounce from project to project contributing as little as possible on each just to get their name on several high profile papers (I’ve seen post-docs do this way too often).

    Ochemist: I’m with you… I was taken advantage of as a 1st year grad student. It’s part of learning to stand up for yourself. My mistake was sharing the idea and not doing it myself.

  • Come back, zinc! says:

    I think it’s usually customary for young professors to put their name first and then switch to last once they’ve become established. Baran has received quite a bit of recognition so far, but he’s only had an independent career for 3 yrs (though he was granted tenure recently). Maybe he’ll switch to last author in once he graduates his first student.

  • TWYI says:

    Superb post jimbo. Is there actually anything worthwhile to being a 6th author on a 7 author Tett. Lett. publication for example other than to bump up your publication count?

  • question says:

    Though i do agree with most of you on the issues of names on publications, I think it would go beyond that during an interview. If they would ask you questions but you come off as a complete dumbass, the rest of the time that you spend in front of them would simply be out of politeness.

    Dumbass moments: “Lets do a substitution on that quaternary carbon!” or they would ask you about a paper from your group and you’re dumbfounded, because you didn’t even know it existed.

  • ddd says:

    reply to jimbo: when you read the journal are you looking for Authors, or you actually looking for chemistry which has been done regardless of the authors? I vote for a second thing.

    When we talking about brand names….gosh I know so many other brand names (in addition to KCN. EJ etc.) which nevertheless stamped as the last author with “*” on it. And guess what, I do remember them and respect them. I know if I see cool alkaloid synth. it is probably Overman. :)))

    Also I would like to mention that people in some groups getting a list of natural products, they have to choose from, then they have to make those molecules…that is it. They design and run 10 reactions a day, go through the stress, so that in the end adviser would put his name “first” claiming he guided the person “on his way to the mountain” :). I just disagree with that. Do you believe that a COACH of the gold winning olympic team actually deserves a gold medal, and team itself deserves silver? Since coach guided them…I don’t..

    Overall this issue I think is just a matter of different policies, which have to be cleared out in scientific community.

  • ddd says:

    Addition: but COACHES are respected even without claiming a gold medal in olympic games. People are WELL aware of coaches who produced olympic winners

  • TWYI says:

    Supervisors like the power trip that comes with putting their names first in my opinion.

  • jimbo says:

    ddd: I’m looking for chemistry, but people do look more into papers and authors when things get competitive. I also hear you regarding what “should” be the case in name order… like I said, I used to protest this point. And I doubt that my rationale is the one that these arogant academics actually use. One more argument for them going first is that these big names often command several million dollars worth of research funds. Without that money, no work gets done.

    I realized a while ago that your time spend in grad school is a happier experience if you avoid conflicts with massive egos. The whole point is moot anyway, because nobody reads any of the other names. We just count them. Who were the other authors on that last Overman synthesis? Or the other Nicolaou ones? Our eyes scan until we see a familiar name and then we stop.

    re: Overman — I actually think the inverse (converse?) of that — “If I see an Overmann synthesis, I know it’s going to be a cool alkaloid” :)

    Re: coaches. Yeah? If you’re in the business… Maybe it’s just me, but I can’t name a single USA track coach. I can probably name 5-6 runners who have won gold… not one coach. In professional team sports, coaches are awarded with championship rings just like everyone else, and in media commentary, they often get much of the credit for success.

    question: having been through the interview process, I know that people have different ways of asking that question. The people who ask it directly tend to be pricks. The ones who just ask questions about your chemistry are the ones you’re more likely to want to work for.

  • ddd says:

    One more argument for them going first is that these big names often command several million dollars worth of research funds.

    for $$ you have a special acknowledgement section :) this is why you thank NIH and so on…

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  • Colonel Gadaffi says:

    You often highlight among the most uninteresting disconnections of a synthesis. Wittig for that double bond — who would have imagined? Nice blog btw!