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Communesin F   

25 February 2010 16,977 views 30 Comments

Weinreb, Liu, Seo. ACIEE, 2010, EarlyView. DOI: 10.1002/anie.200906818. Article PDF Supporting Information Group Website

Quite a congested little beast, eh?  I felt that a 3D representation might help show the almost cage-like structure.  Also, having been at a Med-Chem conference for the last few days, I’ve been seeing everything in 3D.  I haven’t seen many molecules with this skeleton before, so I was surprised to see that it was isolated in Penicillium mold; however, this was found growing on a marine algae, so I guess that makes for some pretty special biosynthetic machinery.  This makes for a target with an appealing biological activity – microfilament disruption leading to cytotoxicity, so it’s clear why there’s been quite a bit of synthetic action here.

The synthesis starts with a pretty large fragment, but it was easily made using a Suzuki coupling to produce the styrene (o-nitro phenyl boronic acid), and an acid chloride amide formation to couple the LHS.  However, that aryl iodide looks like it’s there for a reason – a rather tasty Heck coupling.  Treatment of the SM with a fairly standard catalyst brew results in a 5-exo closure to give the quaternary center, and provide the tetra-hydro pyridine as a neat functional handle.

A couple of steps later, and it’s time to close a second intramolecular system to form a further ring, using alane-amine comple to do a rather neat reductive amination.  The diastereoselectivity here is fairly impressive – no numbers quoted, so I assume it’s complete.  It’s then time to do something with the enamine, and it’s a [3+2] cyclisation with an azide.  In this case, the azide is cyanogen azide; not a molecule I’d have thought to be particularly stable!  It turns out that this is a pretty nasty compound, having featured in Derek Lowe’s famous Things I Won’t Work With list… To quote Derek:

Cyanogen azide is trouble right from its empirical formula: CN4, not one hydrogen atom to its name. A molecular weight of 68 means that you’re dealing with a small, lively compound, but when the stuff is 82 per cent nitrogen, you can be sure that it’s yearning to be smaller and livelier still.

To be fair to it, though, it reacts really nicely here to give an intermediate product from the [3+2], and then expel nitrogen (surprise!) to give the amidine – a neat handle for installing a carbonyl, or amide in this case. However, I’d like to know if more routine methods were tried, such as a Wacker oxidation…

A few steps further on, and quite a bit has happened.  Alkylation of the benzylic position was done by simply forming the enolate and trapping the allyl iodide, and a few functional group transformations delivered the pendant azide.  I’m surprised how resilient the primary azide is, as it shrugged-off all their attempts to olefinate the benzaldehyde. Mind you, the aldehyde did too, requiring a different strategy to install the enone.  It turns out that the world’s simplest aldol system was required – a bit of caustic and some acetone. Bosh.

The last bit of chemistry I really liked was the formation of the soon-to-be-bridging piperidene system.  This was done by stirring up the amine in the presence of an allylic alcohol and a bit of PPTS, allowing a conjugate addition/elimination to complete the ring, and engender some diastereoselectivity.

It didn’t take much more to complete this elegant synthesis – a complex and effective route.

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  • Spoon says:

    Correction: This was in Angew. Chem.

    You seem to have failed to mention that Qin (JACS 129, 13794) set the precedent for the end game.

    • Tot. Syn. says:

      Thanks for the correction.
      Qin did take care of much of the end game – from the last scheme I’ve drawn to completion. I’d planned to mention that in the last paragraph but forgot before I hit the publish button. However, if you search TS for Qin, you’ll see I’ve covered a lot of his alkaloid work here, if not his synthesis of Communisen F.

  • antiaromatic says:

    I’d bet the Wacker system would be polarized in the wrong way if it worked at all.

  • MChem says:

    Nice work, gotta say I’m quite surprised about the alkylation with allyl iodide to form a quaternary center adjacent to another quaternary carbon!

  • Radical says:

    My apologies for hijacking the thread, but what do you guys think of these two papers? Same starting materials leading to the same product using vastly different reaction conditions.

    Moses et al. Chem. Commun., 2010, 46, 1272 – 1274, DOI: 10.1039/b922489k
    Larock et al. Org. Lett., 2010, ASAP, DOI: 10.1021/ol902921s

    • Ian says:

      Ok if Larock had references Moses’ work…they are so close in pub times

      But yes a bit naughty

      • Decarboxylation says:

        Why do you say are vastly different conditions? Both of them have F anions. The only difference would be the solvent. THF and CH3CN.

        What do you reckon guys?

      • Tex says:

        If you check out the date the Chem. Commun. was accepted versus when the OL was received there is no overlap – the Chem. Commun would not have appeared on-line until the proofs had been corrected. So unless Larock refereed the Chem. Commun. paper, and then copied the work, I don’t see the big deal. Also, the Larock group has published previously (OL 2008, 10, 2409 using azides), so it is not surprising that they have investigated this reaction with another 1,3-dipole. It seems to me that this was simply a case of two groups working on the same thing independently. One might argue that there should have been a note to the effect that after the Larock work was submitted a related paper appeared.


    • Martyn says:

      Firstly, there’s nothing wrong or unusual with publishing different conditions for the same reaction – just look at how many conditions for Suzuki couplings have been published. Having a range of literature conditions to choose from is useful when optimising a reaction.

      From what little I understand of the subject, the formation of arynes from these types of precursor is fairly slow and controlled in polar solvents like MeCN, and faster in toluene or THF. Hence, MeCN is used for a lot of the Pd catalysis by Larock, Greaney etc because the concentration of aryne stays low and side-reactions like trimerisation are minimised.

      With that in mind, it makes sense that the reaction takes seconds in THF and hours in MeCN – Larock’s group are probably just transferring the same conditions they use for their Pd work, and didn’t feel the need to use other solvents.

  • optional says:

    Oh Canada! Number 1

  • Duce says:


    Moses et al. Chem. Commun. was fisrt published on the web on the 11th January 2010. Larock’s OL was first recieved on december 18th. I don’t think they had the proof ready by the time Moses’ paper was online given to the fact that the Chirstmas and new year holidays followed soon after the OL was submitted. Atleast they deserved a reference about the work as they were the first to get there lol.

    Check the dates guys!!


    • Tex says:

      I thought that I made that point at the end of my comment – i.e. that Larock should have included a note to the effect “after submission of our manuscript, and while it was in review, a similar study was reported, see Chem. Commun. etc”. It is conceivable that the Larock group was not aware of the initial Chem. Commun. report.

      • ,,, says:

        the reviewers should’ve pointed out

      • Johnny Bravo says:

        Maybe Larock is like most people and only reads ChemComm once every three months. It is conceivable that he just missed it – it happens all the time.

  • Duce says:


    I think you are right! lol I hardly read Chemm Comm but still its a higher ranking journal then OL.


  • GYA says:

    disagree! OL is a stronger journal than Chem Comm.

    • Tot. Syn. says:

      Not an opinion – fact:

      Chem. Comm. is rated 9th, Org. Lett. is 18th…

      • GYA says:

        something about that listing seems off. must not factor in frequency of publication. how can angew. be so low?

        • bad wolf says:

          The second list is total citations, which would favor long-running journals (TL) over parveneau upstarts (OL) if i understand the criteria (and ACIEE #3). The third list is impact factor which favors review journals (ACIEE #8). Both lists are the ‘normal’ rankings i’ve seen before. The first list seems strange but i’m a little uncertain what they mean.

          When you look at impact factor rankings in sub-areas like organic you get OL > TL~Chem Comm, which is what organic chemists probably expect.

  • TWYI says:

    This exact route has cropped up in Tet Lett this week too. LOL

  • Duce says:

    The tetlet came after Larock’s but they still site Moses and not larock’s. May be the tetlet guys read more chem. comm. the OL.

  • ZZZZZ says:


    …about those journal rankings: Tet Lett is #5, so it’s ‘stronger’ than both Chem Comm and Org Lett…


  • Hippy says:

    Why all this comments about rankings??What matters is what you pubblish? Shit work will always remain shit work, regardless the journal in which you pubblish.

  • optional says:

    These freaking chemists cant keep their hands off useless conversations!!! Get a life! You are all stuck in a freaking ego-frantic cycle of what I consider “BULLOCKS”

  • NaClH2O says:

    the first diagram in this write-up: what determines the regioselection of closure at the olefin, the electronics or some other ringstrain type issue?

    • Martyn says:

      It’s just a 5-exo-trig carbopalladation rather than 6-endo-trig – intramolecular Heck reactions pretty much always go exo, even if it makes a really strained ring system. Have a look at Jean Suffert’s work for the craziest examples.

  • chaitanya says:

    Why always the attack of indole 3rd position on carbonyl centre is from upper side? Even in aspidophytin by Corey also the same thing.Is it something that can be understood by model studies?

  • Erik says:

    Damn, you’re actually talking chemistry, I thought this blog was mostly about Corey and Nicolaou’s careers….