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23 June 2009 16,240 views 46 Comments


Jamison, Trenkle. ACIEE, 2009, ASAP. DOI: 10.1002/anie.200902079. Article PDF Supporting Information Group Website

When a target’s been made as many times as gloeosporone, it’s a good idea to come along with something new.  And when the people you’re following have a bit of a rep, it makes it doubly necessary.  How does Seebach (twice), Fürstner, Schreiber, Ley and Holmes make you feel?  Good thing Tim Jamison’s got quite a thing for a macrocycle, and an impressive creativity with them – as demonstrated in his synthesis of acutiphycin, covered here back in 2006.  He’s moved on from the ene-type cyclisation used in that synthesis to do a bit of Ni-catalysed epoxide opening – but lets not get ahead of ourselves.

In the fragment construction phase, a Jacobsen HKR allowed asymmetric construction of an octeneal.  This stereocenter is a bit too remote to direct alkylation of the aldehyde, so Jamison used a bit of diamylzinc and a trans-cyclohexane-1,2-diamine to provide a cracking d.r. in good yield (chemistry nabbed from Yoshioka).  A coupling with an alkynyl acid provided the cyclisation precursor in short order.


The cyclisation chemistry was developed by Jamison initially to do smaller cyclisations, in which he suggests that the initial process is ligation of Ni to the epoxide, then association of the alkyne and exo-dig.  That mechanism is helped along by the short ‘tether’ between the alkyne and epoxide – which is necessarily far longer when closing a macrocycle.  Jamison probed this issue by varying the macrocycle size, and also spent a bit of time moving the ester moiety along the chain.  What boiled out of this was that the ester is key to the reaction, and might initially ligate the Ni, holding it in a position where both the alkyne and epoxide can get it on.  A problem eventuated, however; to get a decent yield, they needed to use a whole equiv of the nickle ‘catalyst’.  Not a massive problem, as it can’t be too expensive, but man does that cyclooctadiene stink.  And whilst we’re at it – tributylphosphine is some nasty stuff too.


There’s a bit of neat chemistry to finish-of the molecule – quite evidently required as we’re missing a THF.  That furan was put in by closing an alcohol onto a 1,2-diketone – so we need to install a further ketone, adjacent to that currently present.  That presents a huge regioselectivity problem, as either side of the ketone looks pretty tempting to my eye – but using Bredereck’s reagent (it’s okay – I’m not familiar with it either…) did the job with fantastic selectivity.  Finding a rationale for this is quite difficult, but have a read of this JOC


I’m not sure why, but rather than the usual ozonolytic cleavage of the freshly installed exocyclic olefin, Jamison used Rose-Bengal to make singlet-oxygen from the regular, triplet kind.  This does a [2+2] with the olefin to give a strained peroxide, which retro-[2+2]-s to give the desired ketone.  Neat, but I wish a bit of explanation was forthcoming.  However, I know the Jamison group are reading this, so get with the comments…

Neat work, and some tasty methodology too.

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  • Fluorine says:


    pretty curious about the [2+2] proportionation, wonder if adding a porphyrin or chlorin might affect the yield…

  • The Next Phil Baran says:

    I only know of using Rose Bengal to prevent over-oxidation, the color of the solution changes once you start oxidizing the Rose Bengal, then you stop the reaction, it’s a fancy indicator. However, i don’t see immediately how this molecule could be over oxidized, unless it is the 1,2-dione system that is susceptible to a further oxidation.

  • Tot. Syn. says:

    I can certainly cite another ‘use’ of rose bengal in a ‘synthesis’, where it was also intended to be used as a singlet oxygen sensitiser. The singlet oxygen is then to do a hetero-Diels-Alder type reaction. However, there is a catch…


    • TWYI says:


    • Fluorine says:

      also works with macrocyclic tetrapyrroles.
      the excitation hv can be shifter to higher wavelength in this case.

      interestingly, porphyrins and chlorins are used in tumor therapy using the same radiationless transition to oxygen…

  • The Next Phil Baran says:

    Haha, definitely a reliable source there! Does anyone know any other uses of Rose Bengal?

  • chemist says:

    It is called Wasserman oxidation (after Harry Wasserman from Yale who developed it)

  • chemist says:

    Singlet oxygen can do a formal 2+2 cycloaddition with enamines

    • jurel says:

      That’s about all I think that Rose Bengal does (synthetically). It was used in Vietnam, i think, to kill mosquitos; they sprayed metric tons of it….as usual it produced singlet oxygen that killed them.

      Anyway, I wanted to mention a Griesbaum (spelling?) Coozonolysis. it’s the ozonolysis of a methyl oxime in the presence of a ketone to produce a Criegee ozonide. That just popped into my head while thinking of perepoxides and carbonyl oxides that are the usual suspects in singlet oxygen reactions.

      • jurel says:

        because i wonder if the mechanism is as easy as just a 2+2…..might be but it would be nice to have a chiral center alpha to the carbonyl to see if it gets racimized after reaction.

      • homsar says:

        that was agent orange, i think.

  • The Next Phil Baran says:


  • krest17 says:

    I like Bredereck’s reagent – something new for me – cool

  • Jim Trenkle says:

    Thanks for the comments. The regioselectivity of the oxidation was understood due to stereoelectronics – you get a single regioisomer under a number of enolization conditions as well (deprotonation, TMSOTf + Et3N). Modeling ground state energies suggested that one proton was more properly disposed geometrically for ready deprotonation.

    As to the choice of Rose Bengal, it was the second conditions I tried for oxidizing the enamine (after ozone). Ozone worked well, too, but the diketone product was rather sensitive to water. Use of the [2+2] avoided work-up which allowed me to dry the product (silica plug) more quickly. The upshot was better yields and a neat reaction. As “chemist stated” Wasserman had reported the Rose Bengal oxidation back in ’75 (Tet Lett, 1975, 21, 1735.).

    • krest17 says:

      If enolate formation is regioselective – would it be possible to use Rubotton oxidation + oxidation to ketone?

      • krest17 says:

        Rubottom :-)

        • Jim Trenkle says:

          Ah, Rubottom. You’ve nailed about a months worth of agony in that question. :) Yes, Rubottom was investigated, and works. But the resulting alpha hydroxy ketone transferred the TES group from the beta-hydroxy. Use of TBS proved too bulky, and enolization was stopped completely.

          What worked best (albeit in 25% yield), and is quite interesting I think, is direct oxidation of the silyl enol ether to the 1,2-diketone with KMnO4 and acetic anydride.

          • krest17 says:

            Thank you very much for answer.
            You know, once I oxidized Li-enol just by bubbling O2 through reaction mixture – no any silicon – but product is the same as after Rubottom.
            Anyway congratulations with cool synthesis.

    • Moody Blue says:

      Thanks for explanations. Pretty nifty work indeed. I’m just curious regarding the modeling work. Were the modeling calculations performed before the chemistry in question was done? I mean, it would be very difficult to predict regioselectivity on this, let alone hope for it.


      • Jim Trenkle says:

        We had originally hoped to bring in a functional handle at the propargylic position (ie a ketal, or protected alcohol), but this didn’t work (due to the decreased reactivity of the alkyne). The modeling was done post result, to help us understand the selectivity.

    • Tot. Syn. says:

      Sorry for taking so long about replying – congrats on such s sweet synthesis. Real nice piece of work. And thanks for replying to my questions; getting feedback from the original authors is one of the best things about this blog :)

      • Jim Trenkle says:

        Thank YOU for the article and the press. The least I can do is discuss my work (besides the fact that it’s a pleasure to do so).

  • The Next Phil Baran says:

    I think this is awesome Trenkle. By authors responding to these posts we can get a behind the scenes look of strategy,etc. Thanks a lot.

  • krest17 says:

    I did not get it from first reading. You have Si already on beta-hydroxy – disregard my comment.

  • European Chemist says:

    Yeap, this is really neat, Trenkle. Thanks for replying to our comments. How cool is it to directly get feedback from the persons who DID the chemistry at the bench??

    I suppose that this is what JACS and the ACS are trying to emulate with their bunch of new web-initiatives – but it will take them a long time to replicate the critical friendliness of this blog. Totally Synthetic rules! :-)

    • Tok says:

      The authors of this paper probably felt more inclined to respond since there wasn’t the usual “ZOMG NOT JACS WORTHY WTF?!?!?!” Commenters may want to keep that in mind for future posts.

      • European Chemist says:

        Well, for my part I would have found this work hard to bash. Precursor is assembled in virtually no-time, macrocyclisation is simply AWESOME and from then on, the little flair of that Bredereck reagent step should shut down even the more critical among us :-)

      • The Next Phil Baran says:

        Because that would just crush the self-esteem of an adult.

      • Org Lett Reader says:

        Well, of course no one said that. This article was published in Angewandte.

  • Liquidcarbon says:

    I love the discriminating warning about the color of Ni(cod)2 :)

  • G1 says:

    The Jamison group is awesome – for both acutiphycin and gloeosporone, the authors answered questions on this site.

  • lgf says:

    Not sure what I am missing in your Baldwin’s rules designation, I see endo tet not exo dig the electrophilic atom is in the epoxide no?

    • Jim Trenkle says:

      Our best understanding of the mechanism involves initial oxidative addition to the epoxide (to an oxanickellacyclobutane), followed by exo-dig cyclization onto the alkyne (see Molinaro, Jamison, JACS, 2003, 125, 8076).

      • lgf says:

        ok, but there seems scant evidence to support a metallaoxetane intermediate. Certainly not the presence of some rearranged ketone. That anti-Bredt olefin, even with Ni in the loop looks dodgy. With the known propensity for Et3B to initiate radical chemistry (even if you just have some dissolved oxygen in solvents) and with the known propensity of boranes to promote reductive ring opening and nucleophilic ring opening of epoxides, and with some free nucleophilic phosphine swimming around, are there not many other possibilities?

  • John Wood says:

    The new Movassaghi paper is impressive.


  • The Next Phil McGroin says:

    that is how synthesis should be done. Movassaghi has put out quite a few really nice papers this year. Clear hypothesis, nice experimental evidence to support their proposed synthetic route (D incorporation, N-Cl intermediate expt) , clever execution (vinyl azetidinone as a ketone surrogate, NCS transformation).

    Well done.

  • Ian says:

    the Movassaghi paper is superb, only two people doing the practical work too

  • stir_bar says:

    Hey John Wood…we met at that stir fry place on the visit where we discussed this blog…is that where you ended up?? I chose the school that I told you about. Hope all is well.

  • John Wood says:

    Hey Stir Bar…..
    I am not at the Stir Fry place at all, I really didn’t like the school and plus it was cold. So I ended up with loverman, but he’s not taking any students.

    When do you start in sunny….?

  • stir_bar says:

    I started last week on a tot syn. Good luck in cali!

  • Stuart says:

    I made pseudo-gloeosporone once. Haven’t ever got over the pseudo bit!