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(-) Platensimycin   

25 April 2007 15,775 views 22 Comments

Nicolaou, Edmonds, Li and Tria. ACIEE, 2006, Early View. DOI: 10.1002/anie.200700586.

First of all – an apology for my sluggish writing. I’ve been on holiday in Zurich (the ETH is gorgeous!), and thus have been out of the loop. As much as I appreciate all the work done on this molecule, I’m sure I’m not the only one who would like to see it have a little rest for a while. However, we can’t do that without one last flourish, again from KCN’s labs. Those of you who read his original racemic publication of last year (blogged here) will have noticed that had the cycloisomerisation step been enantioselective, the entire synthesis might follow in that manner.

platensimycin_7.jpg

However, as Nicolaou pointed out in the discussion in this paper, the Trost chemistry used in that synthesis wasn’t amenable for enantioselectivity. However, a publication by Zhang et al showed that a similar species of substrate could be cyclised in this manner using a rhodium catalyst. So they tried it, and with a little modification of the substrate, an excellent result could be achieved:

platensimycin_6.jpg

This product was a little different to that acheived in the prior paper, so they used a different approach for the cyclisation, firstly forming the Barton xanthate ester, looking for a radical decarboxylation. However, the reaction went a little further, isomerising via a 1,3-H shift to the more stable internal olefin. No matter – it still did the Sm mediate cyclisation as before, returning a common intermediate, except in enantiomerically enriched form.

platensimycin_8.jpg

Feeling done with this target yet? KCN wasn’t! They have a second route to the molecule in this paper, this time using a oxidative dearomatising cyclisation as the key step. A lot less needs to be said about this synthesis, which builds the cyclisation precursor through a more routine (though no less reasonable) fashion. The cyclisation with hypervalent iodine then went in appreciable yield to return an intermediate recognisable from his other work.
platensimycin_9.jpg

I prefer the former route to the latter (although I love hypervalent iodine as a reagent), but both are smart ideas. This may seem like over-kill for one small molecule, but as I pointed-out in my first post, it’s a novel antibiotic, and therefore worthy of this attention in my book. However, I think I need to leave it alone for a while!

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22 Comments

  • lumo-homo says:

    didnt milkshake suggest the dearomatization approach on this
    blog? why hasnt nicolaou acknowledged totally synthetic blog for this idea !

  • milkshake says:

    …because KCN was directly reading the milkshake’s mind – or the other way around

  • Dylan says:

    ZZZZZZZZZZZZZZZZZZZZZZZZZZZZ

  • Kutti says:

    @Paul: Yeah, Zürich is really great :-) Did you also take a look at some of the organic chemistry groups at the ETH? I am considering joining one of those groups for my PhD studies but I don´t know how the groups and especially their PIs are. Have you heard something about Carreira or Seeberger?

  • milkshake says:

    there is a famous Carreira letter, to one of his students…

  • Non-chemist says:

    http://www.pnas.org/cgi/content/abstract/0700746104v1
    Chemical & Engineering News, 85(17), 39, April 23, 2007

    keep an eye on the battle on total synthesis of “Platencin”

    I had posted a wrong place. yesterday.

  • Kutti says:

    @Milkshake: And what does this letter say? I´m all ears ;)

  • ZAL says:

    Actually, if I am not wrong, the letter was addressed to a post-doc, which makes it even funnier…

  • Tot. Syn. says:

    I’m not getting any further into this… I’ve seen the letter, and it was quite scary, but I’m not linking to it from here…

    My friend works for Seeberger, and life seems good there. The group appear to be pleasant, and he seems to have a fairly diverse array of projects.

  • ddd says:

    letter said that “he” gets a million post-doc applications a day, and if post-doc will not start working 24/7, he will kick him out and will hire a new post-doc…well thats the bottom line of that letter

  • milkshake says:

    It is the normal self-righteous dick boss dressing-down letter written in the proper withering tone. (You are correct, it was a postdoc.) The letter complains that he did not see the guy in the lab in the evenings on few occasions and spells out that his people must work every evening and every weekend day – unless they specifically ask for a day off.

  • question says:

    On holiday in Zurich or interviewing for a postdoc ?

  • Tot. Syn. says:

    Just a break to see some friends – one is at the ETH, the other working for a fragrance synthesis company. Always nice to see somewhere new!

  • The Canadian Chromatographer says:

    Yeah, I saw the infamous Carreira letter, at my former (Ph. D.) institution. One must take this with a grain of salt. This letter was written by the Eric Carreira of the Caltech days – and God knows how little pressure there can be at Caltech, especially on fresh young promising faculty!

    Not to say that working for him, or any new, talented a productive researcher is a picnic. But his expectations may have mellowed down. Or maybe not……

  • ddd says:

    he was tenured by that time

  • passerby says:

    Here is the famous letter.

    http://biochemater.bokee.com/4801022.html

  • Tricia says:

    I was looking for a source but came across the comments on this site. In case anyone wants a copy of that letter: http://i.imgur.com/a40kI.png

  • Tobe Freeman says:

    Note that Guido Koch doesn’t bother to list his time at Caltech on his LinkedIn CV…

  • Alex says:

    An asshole will always remain an asshole, and unfortunately many professors have such an attitude towards their students, whether they’re young and up for tenure or not…

    • PIs have way too much power over their students, having the ability to make or break their careers. Behind closed doors, professors often get away with stuff like the Carreira letter. I’ve set up a website for students and postdocs to review their PIs, and thus allow prospective researchers to make better informed decisions when picking a lab to join. (http://www.myevilprofessor.com)

      • Tot. Syn. says:

        I really can’t think of a more inappropriate channel for criticism. How do you check the veracity of the ‘students’ claims? How do you even know who they work for? And how can the ‘employer’ reply? There are two sides to every story.