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2 September 2007 10,733 views 41 Comments


Toste, Linghu and Kennedy-Smith. ACIEE, 2007, EarlyView. DOI: 10.1002/anie.200702695.

Not much room for maneuver in this tightly packed little alkaloid, and that makes the synthetic challange all the more attractive. Two previous syntheses: Inubushi and Heathcock, though both are racemic. Toste’s approach somewhat unsurprisingly uses gold catalysis in the key transformation, but there’s lots of other cool chemistry here. As ever with this type of chemistry, the first goal was a successful synthesis of the key substrate:


This is the first reaction that interested me. Toste references this silyl triflate promoted allene addition to Haruta, and it works like a gem, giving a decent yield and impressive control of stereochemistry. A bit of silver nitrate and iodine gave the halo-alkene, completing the synthesis of the cyclisation substrate. The gold does it’s job reasonably well, but over the three steps from the cyclohexenone, the yield is relatively poor.

However, a far more efficient route was found with a terminal olefin on the sidechain. No explanation for this boost in yield is given… The starting material was made using a neat organocatalytic Robinson annulation, which they state was efficient even on a ten-gram scale. Good stuff.


The rest of the synthesis used more routine chemistry – a sp2-sp3 Suzuki coupling on the vinyl iodide gave the required amine-containing chain. The alkene was then hydroborated and the alchol oxidised to the ketone. Conversion of the terminal olefin to an iodide then allowed displacement by the pendant amine to give the nine-member ring. Treatment of this substrate with TFA released the free amine to cyclise onto the desired ketone, giving the natural product in good yield. Nice work!

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  • UBchem says:

    Sorry man, the Robinson annulation product is missing its conjugated olefin. The keto-ester is missing the terminal olefin as well. But I think you’re right about the complexity of the molecule. It is nice little gem and a nice synthesis, even if it does involve gold.

  • Liquidcarbon says:

    Frankly, I rarely get to see the actual paper, so I pretty much rely on your presentation of the synthesis. I liked this one more than several before!

  • Tot. Syn. says:

    Fixed, I think! This doesn’t bode well for my thesis!

  • UBchem says:

    Just post it on Tot. Syn. I’m sure with the number of your readers you have, we’ll get all of the corrections for you.

  • milkshake says:

    One reason why the yield could have been mediocra with a pendant phtalimide/benzylether would be the coordination to Au catalyst. These Lewis-acidic catalysts are quite sensitive to el. donating functional groups in the molecule -the substitution could affect the turnover rate and/or the selectivity.

    (The other possibility is that the first step was affected by the substituent, the TBS-OTf catalysed addition of Bu3Sn-CH=C=CH2 to enone)

  • Joel says:

    #2. If you are interested in an article that isn’t available, then you should ask one of the authors to send you a copy. Paper requests are often an ego boost for graduate students.

  • kiwi says:

    Ok maybe you guys know this and I’m the last person to work this out, but in the .pdf version, if you click on one of the references it sends you (via a DOI link) to that paper. Thats the future of chasing literature right there.

  • Liquidcarbon says:

    It’s not the way I get articles, but I’ll keep the ego boost in mind. ;)

  • .... says:

    Anyone seen the cover of Science today?

  • brandon says:

    I personally appreciated the iodination reaction.

  • Dien Toast says:

    IMO, Dean Toste is a good chemist but highly overrated, especially by bloggers :)

  • pi* says:

    #9 Science comes out on Friday’s

  • Rof5 says:

    Nice work indeed. The reagents and conditions of C) in Scheme 4 is missing(hydroboration/oxidation) in the original paper. You guys don’t need a microscope to see that.

  • Jose says:

    New Sames paper. Who believes it??

    J. Am. Chem. Soc., ASAP Article 10.1021/ja072577n S0002-7863(07)02577-2

  • neo says:

    #14, why is it so unbelievable !

  • neo says:

    That can actually be a cool way of making new proline derived organocatalysts.

  • Jose says:

    The author’s publication record leaves a bit to be desired, eh?

  • willyoubemine says:

    you would hope that they would insist on an extra measure of security, possibly an Org Synth like proof or double check?

  • mono says:

    Despite the issue with some of Sames’ previous work I don’t think he should be held accountable for the poor decision making of a former co-worker. All supervisors rely on the honesty and integrity of their group members.

    This is a nice paper!

  • GYA says:

    The advisor must be held accountable however. After all, the environment he creates within his lab is what ultimately led to the dishonesty. The advisor also selects his students at some point.

  • mono says:


    I disagree. I have worked in a number of high-pressure research environments where “the next result” is all that matters. I’m in no doubt that Sames expects ‘superhuman” output from his associates, however, you’re implying that this turns all of his group into liars and cheats. I’m almost certain that he has (for the most part) a group of very hard working people who are intent on developing some interesting and useful science.

    With regard to student selection; all potential students are (or should be) carefully interviewed. However, is the student ever asked “are you a dishonest person?” or “will you make up results in order to get papers?”. If so…will the person reply “yes!”?

    The fact that the work in question was published by Sames suggests that there was never any issue with the work ethic of the student and hence any need to investigate their honesty. Short of each supervisor personally repeating every experiment how should these developments be reported? The students must be trusted. In the Sames case he subsequently hung the student responsible out to dry. I think he should be applauded for his honesty and for showing that this sort of behavior will not be tolerated in his laboratory.

    GYA, I have a question for you. How many procedures have you followed that did not work first time and needed “tinkering”? Does this mean that the procedure is rubbish or that something has been missed out in the experimental? In the groups I have worked in, the group leader has written the paper but not the experimental procedures…this is the responsibility of the researcher who carried out the work!

    I look forward to your thoughts

  • GYA says:

    You’ve gone overboard on a number of fronts. The environment isn’t what creates dishonesty, but it can allow for it or encourage it–pressure can push people to do things they normally might not. Also, I don’t think he’s really the one who initiated this inquisition into the validity of the work–ultimately he had no choice, but to separate himself from the student as far the character issue goes (or he doesn’t stand a chance).
    Of course, I’ve followed numerous procedures that don’t work–the first time or ever. This means one of three things–the procedure wasn’t reported correctly, I’ve done something wrong (we’d all like to think that couldn’t possibly be the problem), or the procedure has been fabricated. I strongly disagree–at the end of the day, the professor/group leader has a great degree of responsibility to ensure the integrity of the work he and his group are producing. Its a shame that there will always be dishonesty, but a professor/leader must be diligent in their awareness of ethical issues.

  • Tool says:

    Please, ladies and gentlemen – this is far too much fuss over a very simple idea : If your name has the asterisk beside it, then the burden is on you to ensure that the work that you have put your name to is accurate.

  • GYA says:


  • willyoubemine says:

    In a total synthesis, the proof is in the pudding. The structure either matches the natural, and its done; it doesnt match, and therefore, you’re wrong or the original is wrong (which clearly happens)

    In a methodology where the products are known and the proof is in the reproducibility, a PI should ensure the validity of the work by either: a) doing it himself (unlikely) or b) having another group member repeat their experimental (easy to do). This answers all questions of dishonesty, and more than likely, deters liars and cheats bc of the ease of exposure.

  • willyoubemine says:

    side note poll:
    For how many of you do the words Either and Neither rhyme?

    they do for me…dont for a labmate.

  • Spiro says:

    #25 “In a total synthesis, the proof is in the pudding.”

    In my opinion:
    * the yields of 90% of JACS/Angewandte total syntheses are made up. It is easy to find out which ones in the supporting information (when there is one…).
    * a very small fraction of published total syntheses are syntheses of another diastereoisomer, with matching spectroscopical analysis.
    * a small fraction of published total syntheses are syntheses of the correct natural product, but still with the same wrongly-assigned structure.

  • Harry Bosco says:


    Now that even the man himself, Dean Toste, has succumbed to organocatalysis, Dalibor Sames is our the last man standing. I seriously doubt that he will make new proline organocatalysts ;)

  • neo says:

    I never said that Sames would do an investigation on organocatalysts, all I said was this can help “people”test a new breed of proline derivatives which can be tested for several reactions.

  • Karl Hungus says:

    “* the yields of 90% of JACS/Angewandte total syntheses are made up. It is easy to find out which ones in the supporting information (when there is one…).” How? Inquisitive readers want to know?

  • Spiro says:


    When I see a 30 step tot syn with an average yield per step of 90%, I frown but I think OK maybe. So this means 4.2% overall yield, but when the peon who did the work did not manage to make more than one mg, he either did the first step on a 0.1 mmol scale, or did not have enough precursor left (though he could have made gram quantities considering his humongous yields), or something is wrong.

    Same thing with authors announcing 98 to 100% yield for a complex product, when simple substrates give less than 90% for the same reaction in the methodology paper. Typical for oxidation and reduction steps.

    Do people fraud intentionally? Stephen Colbert would tell us that people believe in the “truthiness” of their articles.

  • willyoubemine says:

    Yields are not nearly as important in a total synth paper as in a methodology. I mean, its the strategy, and the elegance, and the cleveress (if thats a word), of the approach. The problems found and solved, the use of the molecules inherent chemistry, reactive functional groups, and stereocontrol that (albeit IMO) make up a great synthesis.

    I do agree that low yields and poor regio and stereo selectivities can hurt the appeal of even the most elegant work, but they are not the “thing” itself. Furthermore, yield embellisment does not (again, IMO) constitute ethical impropriety in the same way that fraudulent results do.

  • brandon says:

    ‘what ever happened to good-ole fashinoed bucket chemistry of the fifties and sixties? How is yield inflation not unethical…even though high yield is not the ultimate goal?”
    Cheers, B

  • willyoubemine says:

    i do not mean to suggest that yield inflation is not unethical, merely that it is less of an impropriety than say completely fabricated results.

    I suppose in my mind, it boils down to what is preventable by the PI. Can you weed out yield inflation? Prob not with truth serum. Can you prevent fabricated results? Easily. That is why I consider one more egregious than the other.

  • milkshake says:

    I was not such a situation – but know people who suppesedly were: If your prof tells you “this cyclization yield should be better than 40%” and he keeps telling you it should be better than 40% at least twice a week (and you have tried the cyclization dozen times and it was never better than 42% , and most of time more like 30-35%) you feel less inlined to pump up on your oil overnight on highvac, before weighing the flask. So you weight the flask, calculate the yield and take the NMR next morning. Then you move on to the next step. You need only 2 mg of the material to finish the project and move on. (You also need to get a very good recommendation from the prof, to find a job in US that would sponsor your visa and the green card.)

  • willyoubemine says:

    Also, similar “yield inflations” may happen innocently.

    What do you do when you do a reaction on 5 dif scales (as in a total synthesis) and the best yield (say 92% on 100mg scale) is vastly different from other results (say 82% on 1g, 78% on 2g, 66% on 5 g) which is the honest way to report it, and is that yield inflation?

  • Cat Herder says:


    report the best yield as this is what everyone does, but comment on the fact that the transformation didn’t scale well if it was an important one (i.e. not TBS deprotection or some crap). One can also give a more thorough disclosure of yields in the SI.

  • At ChemSPider we are presently beta testing a structure deposition system so that we can deposit structures there, predict a few properties and link the structures up to websites, blogs and publications

    See: http://www.chemspider.com/blog/?p=122 for an example
    I’m not sure whether you draw the structures you post online yourself or they are clipped from the PDF. BUT, if you draw them can you post the InChI also…it would be easy to convert that back to a structure to Index on ChemSPider. Thanks

  • Jose says:

    I think it should be obvious there is no way to stamp out yield inflation. However, a PI has the option to foster two very different environments. They can either say, “40%?? There’s no way in hell I/we can publish that. Go optimize it!” or “40%, eh? Did you spent a reasonable time optimizing? OK, great. 40% it is.”

  • brandon says:

    39…i agree with your post. you would be amazed that i once heard of someone who could complete a whole reaction without ever leaving his/her desk…procedure, yield, even NMR. There must have been some magic involved.

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