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Stereochemical Reassignment of Mehta and Kundu’s Spiculoic Acid A Analogue   

15 November 2006 9,451 views 29 Comments

spiculoic_acid.jpg

Balwin, Kirkham and Lee. Org. Lett., 2006, ASAP. DOI: 10.1021/ol062361a.

Mehta and Kundu. Org. Lett., 2005, 7, 5569 – 5572. DOI: 10.1021/ol0521329.

Now this is a little scary. Both Sir Jack Baldwin’s group at Oxford and Mehta’s group at the Indian Institute of Science were working on the total synthesis of Spiculoic Acid A. Kundu published the Org. Lett. referenced above, last year, showing their progress towards the target, but it’s taken until now for someone to spot the problems with the paper. Baldwin’s group read the paper thoroughly as part of their publication preparation, and found quite a few problems.

Amazingly, Kundu assigned the stereochemistry quite incorrectly, originating from a Sharpless epoxidation where they predicted the wrong outcome… this in turn led to the incorrect configuration at many of the stereocenters. To compound this, stereocenters invert in configuration during the synthetic scheme for no apparent reason, and the nOe-NMR data looks distinctly suspect.

Come on ACS, lets referee papers properly!

Also, loads more on this over at Curly Arrows… and I should thank the person who emailed me about this (I won’t mention names as some people like to remain anonymous).

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29 Comments

  • The piss-poor refereeing has nothing to do with the ACS – they can only go so far. If group leaders and established, tenured faculty can’t be arsed to check stuff properly then things like this will happen.

    What I find hardest to understand is how no-one noticed the benzyloxy stereocenter magically inverting (although it probably has something to do with the appalling quality of the transition state diagram)

  • Ashutosh says:

    I suspect it was the student who assigned the Sharpless product and the advisor (Mehta) probably did not take a good enough look. But it could be something else.

  • HOMO-LUMO says:

    Uday kundu does not have a group, Goverdhan Mehta (the Head of the Indian Institute of science at Bangalore, indian equivalent of Cambridge or MIT) does.

  • Tot. Syn. says:

    Ah. Cheers for that. That actually makes this whole mess even worse…

  • European Chemist says:

    I agree with HOMO-LUMO and Ashutosh. As from the article, I deduce that Uday Kundu was a Post-Doc at Mehta’s group during the time this synthesis was completed. As can occur too often (unfortunately), Mehta probably trusted wholeheartedly his collaborator who seems to have particularly messed this one up.
    How can you miss things as obvious as the outcome of a Sharpless epoxydation? How can you erroneously change the configuration of a benzyloxy center from one reaction to the next one?
    Don’t get me wrong. Errare humanum est. But before publishing data, you should make sure that no gross mistakes remain. Other than that, it’s the referees’ fault.

    Another question is, was this work thoroughly refereed at all? I mean, there is a 2-month time-span between reception and publication (from September to November!), so it should be enough time for correct, careful refereeing.
    Last time I sent something to Org. Lett., one of the referees sent a three-page list (!!) with corrections and changes he thought should be made to the paper and supporting info. I suppose you don’t assign “picky” referees like that to every paper (specially for “renowned, established group leaders”), but I’m pretty sure that at least, that guy would have spotted all this mess way before it got to the point it did…

  • Tex says:

    Part of the problem with manuscript refereeing is the turn around time – with OL you get a week. If it is a long synthesis, then it requires a significant amount of time to go through all of the data carefully. Some reviewers do not take the time to do this – if the paper looks ok, and the chemistry appears to meet the standard (whatever that may be), then it gets recommended for acceptance. I have reviewed several manuscripts from well-known practioners, and they do not get a free-pass from me!

  • sks says:

    The paper by Mehta had pointers that a curious and careful referee could have investigated.
    http://sanjayat.wordpress.com/2006/11/01/self-correcting-science/
    Unfortunate that the new structure could be obtained using the information given in the paper itself, with no additional experiments being conducted.

  • regularchem says:

    Just want to direct everyone to a interesting piece on blog http://fockingscience.blogspot.com/ about “Adjust your gangbang strategies accordingly”.
    Now that is what I call real science in everyday life.

  • alex says:

    Off-topic
    Tot. syn., are you moving to oxford with Dr Burton?

  • Tot. Syn. says:

    I am indeed! I wasn’t through there with the other chaps today, but I’m actually looking forward to it. It’s definitely non-ideal to move labs during ones thirds year, but the experience and facilities will be great.
    I’m just finalising things with colleges just now; I’ll be at Trinity, but I’m still trying to sort out accommodation. We’ll be moving there at the same time as Mike Willis (formally Bath) – the section at Oxford is really looking busy!

  • alex says:

    Wow!!
    A celebrity!

  • TWYI says:

    Ah, the puzzle of which University awards your degree?

  • ddd says:

    So those who run away from Oxford once in 1200s and established cambridge, now are running back to oxford ? ;))))

  • Hey, regularchem, thanks for the mention!

    The actual post is right here, for the scrolling averse among us.

  • TWYI says:

    TotallyMedicinal. I wouldn’t say it has ‘nothing to do with the ACS refereeing’. The mistakes in that are so basic that and as they were missed it makes me wonder what the referees actually do with communications of total synthesis? I am no referee but I would imagine it is common sense to run through each individual step regarding their integrity etc?

  • Mike says:

    Speaking as someone who has refereed papers for Org. Lett. and other ACS journals, I’m not sure how much to blame the refs here. Of course, once you know there’s an error, it’s difficult to assess whether you, as a referee would have spotted it. I’d like to think that I’d have noted the mysterious inversion of stereochemistry in the Diels-Alder reaction, but I’m pretty certain that I wouldn’t have noticed the wrong enantioselectivity in the Sharpless… it’s just one of those things where you assume the authors knew what they were doing.

    As for re-interpreting someone’s NOESY spectrum – well perhaps I’d have looked at it if I’d noticed the anomaly later on, but almost certainly not otherwise.

    One of the problems for referees is that it takes a really long time to do it thoroughly… and for what reward? As one journal editor put it to me once – “It’s like peeing yourself in a pair of dark trousers – it gives you a warm feeling, but no-one else knows about it.”

  • Ashutosh says:

    This issue also raises the question about how referees can actually do a good job. The problem is of course that there is an exponentially rising amount of information out there waiting to be refereed, and most of it is uninteresting and ordinary. Plus, the referees have their own stuff to do. Is it really possible to have foolproof refereeing, even of simple things? There’s got to be some things that referees have to take on faith, even though ideally they should not do it.

  • European Chemist says:

    Mike’s raised a very important point. Thorough refereeing is really an ungrateful job. It will take a lot of time and sometimes you’ll just spend 3 hours carefully checking a paper, Supporting Info and all NMR spectra included, to find out that there’s nothing wrong with it, other than a few mispelled words and a couple of problems in English.
    2006 seems to be a fertile year in this kind of mistakes and fait-divers! We would be discussing the whole issue of refereeing all over again… any plausible alternatives?

  • I would like to point the synthetic orgchem community
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  • PG says:

    Possible alternative: the model proposed by the Public Library of Science (http://www.plosone.org/) sounds exciting, coupling good old peer review system with open-access community-based reviewing/commenting/rating.

    PS: I would like to point the synthetic community towards the collection of unknown compounds at the back of my fumehood. Features lots of goo and vintage black tar. Help yourself.

  • Tot. Syn. says:

    Yeah, I’m not sure about this post by SpresiWeb – Spam or not spam? Seems a bit of arse to advertise on here, but hmmm…

    The compounds at the back of my fumehood are really starting to worry me. One has destroyed the septum entirely… Plus, we’re moving lab next month, which always unearths an interesting array of dubious bottles. Last time it was two litres of phosgene solution, 1 kg of Strynine derivative and 80% H2O2…

  • regularchem says:

    I just thought of a joke about “Adjust your gangbang strategies accordingly”. Instead of doing combinatory chemistry, these people are doing gangbangnatory chemistry.

  • [...] The reviewers work hard, and for no financial reward. They do their best – it’s time-consuming (could take a day or more to review some papers). But they don’t always get it right… TotallySynthetic in his blog has regular comments on synthesis papers (ca. 1 per day). There are between 10-20 useful comments on each from the blogosphere. Every month there is a vote on the best synthesis. So unlike the citation index, there is a considered judgement of worth by votes from the blogosphere. In terms of worth which would you choose? Blogosphere or Thomson-ISI? Can the blogosphere spot things the reviewers missed? Here’s a recent TS post and blogosphere discussion of Stereochemical Reassignment of Mehta and Kundu’s Spiculoic Acid A Analogue: Balwin, Kirkham and Lee. Org. Lett., 2006, ASAP. DOI: 10.1021/ol062361a. [...]

  • European Chemist says:

    It must be nice to see that people do read our rambling. Of course, all credit goes to Tot. Syn. for stimulating these discussions and providing a top-notch blog. IMHO, the best read following the shutdown of Dylan’s Tenderblog.
    And after browsing through the linked post, it feels flattering to see that “petermr” considers us to be capable of “quality peer-reviewing”. I would best qualify what we do as “a posteriori, anonymous considerations on published chemistry”. :-) At least the “anonymous” part has something in common with the established peer-reviewing procedures… ;-)

    Although I would fancy an academic career in the future, I should say that should my Boss hand me an article for peer evaluation tomorrow, I would feel a bit daunted by the task. And then spend a couple of hours on SciFinder trying to be as thorough and complete as possible. Would that have made me a better referee for the Mehta-Kundu paper? No idea. Any thoughts someone?

  • Mike says:

    Like many parts of being an academic, peer reviewing is one of those jobs that you receive absolutely no training for… there’s just an assumption that, as someone who has had papers refereed, you know how to be a referee.

    In my case, when I became an academic, I had only published a handful of papers, and on all of those the correspondence had been through a senior author – I don’t think I’d ever even seen any referees’ comments! So certainly, yes, I felt slightly daunted by the task.

    As for spending time on SciFinder, that’s something that I do for almost everything that I referee (primarily to find out whether the “exciting new methodology” touted in the manuscript is really new). But whether it would help in spotting the errors in the Mehta-Kundu paper, I doubt it. As I said previously (#16), I would like to think I would have spotted the inversion of stereochemistry during the Diels-Alder. I would almost certainly not have spotted the problems with the SAE – but then if it were a reaction I used on a regular basis, maybe I’d remember the mnemonic and quickly check these things. No amount of searching on SciFinder is going to help you in the several hours (more than a couple, I suspect) that it would take to re-assign the reported NMRs and re-interpret the NOESY.

    On a different note, I agree with European Chemist – this has become my “must read” blog since Dylan’s demise… but there’s some stiff competition! :-)

  • European Chemist says:

    I can’t tell if there is any connection with these last few posts, but my Boss gave me yesterday a paper to “train me as a referee”!!!… so I’m supposed to give my opinion on wether it should be accepted, refused, etc., the works, and he’ll actually take my opinion into account (or so he says).

    After all that’s been said, you can betcha I’m going to do this thoroughly!!! ;-)

  • unichem says:

    The real kicker is that these guys only got the stereochemistry of the OBn bearing carbon correct because they made TWO seperate errors. The epoxide error at this stereocentre was later reversed (and therefore corrected) by the random change in stereochemistry later on. The only stereocentre they really got correct was the Me bearing carbon!

  • anonym says:

    Please do not use “stereochemistry” when you mean “configuration”

  • European Chemist says:

    News from my “refereeing test”: it was an easy one, got the right references from the literature after a 5-min search through SciFi and recommended refusal of the paper for lack of originality. My Boss had the same opinion so you could say I passed the test. There were no odd stereochemical issues or dodgy Sharpless-epoxidations, though… :-D :-D