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29 May 2009 8,484 views 13 Comments


van Maarseveen, Hiemstra, Wanner, Boots, Eradus and de Gelder. Org. Lett., 2009, ASAP. DOI: 10.1021/ol900888e. Article PDF Supporting Information Group Website Group Website

Okay, jsut a little Org. Lett. to get my hand back into this blogging thing after being on holiday for a week.  The writing conditions have changed a little in Tot Syn towers, too – I’m now typing this on a new keyboard – a lovely aluminium Apple thing.  So I bid my old Microsoft ‘Natural’ keyboard goodbye, after six years of faithful service, and also six years of crud (putting it as delicately as possible) under the keys.  And a thesis too.  So this is the first real test for the new ‘board, so lets see how it does.

This paper from Holland is definitely a methodology paper with a bit of total-synthesis to prove the point… and looking back into the past, the methodology was proved last year.  The key is an organocatalytic asymmetric Pictet?Spengler reaction – a useful approach, and one that has been developed by other groups (see reference two).  Using an elaborated BINOL-phosphoric acid catalyst, in rather low loading, they were able to develop a rather useful yield and enantiomeric excess.  By reducing the planiarity of the naphthalene moieties, the e.e. could be further enhanced, with the price being a more exotic catalyst.  I’m not entirely sure which one they ran with, but I’m fairly sure it was catalyst B, as they were able to run the reaction on a 5 mmol scale.


With the vast majority of the compound complete, they group were left with only one more C-C bond forming reaction to complete.  This vinyl iodide-enolate coupling was lifted from some work by Sole and Bonjoch back in 2004 (it’s in Adv. Synth. Catal. – not a journal I read enough… never enough time!), and works reasonably well in this case.  This is a situation where, whilst the yield was moderate, the result meant that they had their synthesis complete in only five steps (from known precursors).1 With only a deprotection remaining, this is a good job well done – proving the utility of their method nicely.  I look forward to seeing it used by other groups in the near future!


[1] Why am I bothered about this?  Well, one of the tendancies I see more often these days (probably cause I’m looking for it) is for PIs to only publish in JACS or ACIEE (or better), meaning that only the best chemistry gets published.  This means that the (mearly) very good chemistry (you know what I mean – 80ish% yields, or 4:1 d.r., et c.) gets left on the bench, and no-one wins.  Grrr.  Any contrary views?  (Sure, I know it’s nice for PIs to have that lovely list of publications, where it’s only those top-rung journals.  But surely there’s space for other journals in there…)

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  • earth23 says:


    Looks like the keyboard needs a couple more laps before settling in.

  • Grille says:

    Tot syn– re your footnote. That’s what full papers are for. Some of the groups you refer to actually publish those you know.

    • Tot. Syn. says:

      I didn’t actually mention any groups… I’m naming no names. And sure, that is what full papers are for. But sometimes, a PI’s ideas don’t pan-out exactly. Instead of the 90% yields, 10:1 stereoselectivity they were hoping for, the reaction simply won’t go beyond 75%, 2:1 or whatever. Enough to deem it unworthy of JACS or ACIEE. But it could go into a journal with a lower impact factor (such as Chem. Eur. J.), but instead it gets buried in the filing cabinet.

      Now I understand why PIs do this – the biography/publications page on the website looks all the better, and some institutes measure their researchers performance by adding up impact-factors. But it still leaves good chemistry buried.

      Worse still is that we don’t publish failed chemistry. Just ’cause I can’t figure out why the reaction(s) didn’t work doesn’t mean that someone smarter than me can’t. Perhaps they could take a whole load of failed reaction results and piece the data together into a new understanding that could give us either a solution or at least a rational for the failure.

      It’s very easy for me to rant about this, but finding a genuinely workable solution is another task. No one wants to highlight their failures, and the funding systems aren’t about freedom of publication / research. I’m dreaming of a perfect, blue-sky situation that isn’t going to happen. But we could still improve the status-quo.

      • The Next Phil Baran says:

        We need a journal of failed chemical reactions. But does a bigger failure mean a better paper? lol. Negative affirmations are just as helpful as affirmations according to Karl Popper. A million nos will push one closer to a yes, if we know the nos, hence a need for such a paper.
        Another statement of the first law of thermodynamics: there are no perpetual motion machines. Karl Popper

      • LiqC says:

        It’s the place called JYPID – journal of your PI’s desk…

  • stir_bar says:

    I agree tot syn. Some PIs do publish quite a bit in all different settings (Stoltz) but the majority of top names only choose JACS, ACCIE, etc. I sometimes wonder the interesting methodology papers of which our community never sees.

    On the other hand, Baran has been publishing a ton. Do you think he has more chemistry that should be published? This would make him even more of a machine, publishing something almost every week. In a perfect world this would make sense but in the real world this is nearly impossible.

    I hope that I understood your little footnote…

  • The Next Phil Baran says:

    Nice and fast synthesis of this molecule, but why wouldn’t they try to use tryptophan instead of tryptamine? They are looking for an enantioselective synthesis and they only get 78-89% ee on the Pictet-Spengler reaction which may have been increased by using tryptophan along with the catalyst to influence the formation of the stereocenter (the cost of tryptamine and tryptophan are not that much different and tryptophan is more stable.) A simple decarboxylation would have returned the “tryptamine” segment. They may have gotten better selectivity there.
    About the publication of material in JACS, etc: because this is the problem with science in organic chemistry, if its not new its not relevant. PIs get different levels of funding based on the level of journal, not the quality of their science. Even the journal science, which is ostensibly about science, doesn’t include any scientific discussion or philosophy. It simply gives a magazine style synopsis of “hip” stuff and new stuff (though there are exceptions, but they are publication dependent.) We glamorize synthetic chemistry without acknowledging the background work, the methodology, involved to get there, which is the most crucial part. We admire skyscrapers designed by architects but we don’t give a second thought to the metallurgists and building material scientist who make it possible. The problem is we let others dictate what is essential to the development and furthering of science though we are and should be the ones that know it the best and therefore should tell the funding agencies what is necessary. Its up to individual PIs to refuse funding for b**lshit projects that neither help, nor inspire others, that is the only way it will change.

  • ,,, says:

    what’s the problem with 80ish% yields?

  • ,,, says:

    Besides, I think the reason it’s in Org.Lett. is that the compound is not so complex and the chemistry in use is quite developed. 89%ee? Fairly good, people had way worth in JACS etc. I think yields are not so bad too. I think it’s the idea that defines the level of paper; as long as it’s fairly executed it’ll get where it was designed to get.

  • optional says:

    what does it matter, 88% ee because if you will form diastereomers, the minor component is most likely not to be seen in NMR and most likely to be purified. I would even take a 10:1 er and start a total synthesis as long as there are steps that form stereocenters close enough to the one in question

  • Fluorine says:

    This JACS discussion is anoying.

    In my opinion, good work is rather to be rated by citations, not by impact factor of any journal.

    Stereoselective Pictet-Spengler is fancy, checkout cialis ;-), three steps from Tryptophan.