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17 August 2007 8,760 views 33 Comments


Pagenkopf and Wang. Org. Lett., 2007, ASAP. DOI: 10.1021/ol701797e.

Just a quick Org. Lett. to get back in the saddle, so to speak. The target is certainly appealing; quite an interesting array of functionality there. It does have some biological activity, as a Na/K ATPase inhibitor, but isn’t particularly potent. The chemistry gets interesting with a desymmeterisation of a diol using an orthoester to provide the acetate. Then they form the first THF using a tasty Mukaiyama cobalt-catalyzed aerobic oxidative cyclisation, a method popular with the group. They state that the hydroperoxide is there to oxidise the cobalt up to Co(III), but I’m pretty sure that the atmospheric oxygen will do that alone…

Either way, a smart result. They repeat this technique shortly, after a bit of protecting group shuffling, generating the fused bis-THF required. The diene is appended by doing an oxidation followed by a pair of Wittig olefinations. On the other end of the molecule, an oxidation and alkylation provided the propargyl alcohol (interestingly using a titanium acetylide, used by Overman in similar work…). Treatment of this with LiCuBr2 gave the allene, with a strong bias towards the desired diastereoisomer (which, in the event, wasn’t the natural product). Nice chemistry!

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  • Aplysiallene says:

    [...] written by sks [...]

  • sufuric says:

    You’re right. Using just an oxygen atmosphere will do the oxidation to Co(III). The reaction is run by a guy in my lab and he only uses an oxygen atmosphere, but he heats it to ~70 degrees IIRC.

  • milkshake says:

    this one is a total sweetness. Too bad the compound has no medicinal application, I think the scheme would be eligible for a rapid scale-up/

  • anon says:

    Why do you persist in linking to closed access journals?

    How was the desymmetrisation effected?

  • anon says:

    “I think the scheme would be eligible for a rapid scale-up”

    Not really. Air as an oxidant is a disaster. I remember the trouble caused by Jacobsen’s chemistry being brought to a plant near me. Using air as an oxidant is such a stupid idea but everyone was too embarrassed to tell him.

  • Klug says:

    Why is air as an oxidant a disaster?

  • milkshake says:

    For Jacobsen kinetic asym hydrolysis of epoxides, the catalyst loadings are pretty low, something like 0.2 to 2% so the ammount of catalyst that need to be oxidized is actually quite small. One molecule O2 is enough to oxidize 4 molecules of the catalyst, just stirring it in toluene with 1 eq,. of the acid in an open vessel for half an hour is enough. I have done it on a rather large scale and there was no problem.

    For all I care you can pre-oxidize the catalyst separately, blow of the excess of toluene by stream of dry air, add the epoxide and water and you are ready to go.

    The catalyst and the chemistry is quite robust for an asymmetrical method, it takes some focused effort to screw it up. I don’t think Rhodia has much problem running it on multikilo scale. Since you have to but the catalyst from them because of patents, you may just as well ask them to run the reaction for you.

  • TWYI says:

    Sorry to crash the thread, but I need some advice. I have been trying Ar-Me to ArCH2Br transformation on a quite complex aromatic for a while now and despite numerous efforts I am still getting 60 percent or so of the product arising from electrophilic bromination ie, direct bromination on the ring and not the radical bromination I desire.

    Any tricks out there? I have recrystallised/dried the NBS, purified the hell out of the carbon tet, run the reaction with barium carbonate present. Changed the initiator from Benzoyl peroxide/AIBN/lamp (and mixtures of the aforementioned). Premixing the NBS with initiator/lamp present before adding the SM and STILL it is brominating the ring. UNBELIEVABLE!

    Elemental bromine is even worse than NBS

  • Tot. Syn. says:


    “Why do you persist in linking to closed access journals?” Where would you like me to link to? That’s where the authors reference, and thus is the most appropriate place to link. This paper was in a “closed access” journal, like most quality work (I know there are exceptions…). Deal with it.

  • TWYI says:

    anon got out of bed the wrong side.

    Perhaps he is having Br dot to Br plus issues.

  • anon says:

    “Why is air as an oxidant a disaster?” It leads to fires. This risk may be acceptable on a small scale ie when a dry powder extinguisher can put it out but not on a large scale. Do a Hazop study and see where it gets you.

    “That’s where the authors reference, … Deal with it.” – so how did they effect the desymmetrization? (That is, I’m dealing with it by asking). I appreciate that the answer is well presented (peer reviewed and all that) on a piece of paper in a locked safe but … not being part of the clique … I don’t have the keys (so, to me, it may as well not have been written). Anyone care to give me a hint?

  • synthon says:

    TWYI…where is the bromide headed next?

  • TWYI says:


    Take the bromide and treat it with the sodium salt of benzenesulfinic acid.

    Failing that (rare) thiophenol then oxidise

  • Ron says:


    The desymmetrization proceeds by first reaction of the diol with triethylorthoformate, swapping out two of the ethoxy groups with the hydroxyl groups of the diol. Treating this new orthoester with dilute aqueous acid regenerates one of the hydroxy groups by solvolysis, and the orthoester falls apart producing the acetate group.

  • Spiro says:

    #11: I agree with you. O2 atm is bad unless you use water as a solvent.
    #11(bis): I guess there must be a 1,3-dioxolane intermediate, that is broken during work-up. Otherwise I see no way to desymmetrize with 100% yield.

    #7: Rhodia (Chirex) has actually had a lot of problem scaling up those Jacobsen Salen-metal reactions (especially the Mn epoxidation), from what I heard a few years ago. They would typically use 10 times the amount of catalyst used (or supposed to be used……..) by Jacobsen et al.

    #8: Sci-Finder, 3200 hits:
    ** sodium bisulfite + sodium bromate
    ** CBrCl3
    ** CBr4
    ** etc…
    Not found on Sci-Finder, but I don’t see why it would not work (any idea?): BuLi then quench with Br2

  • TWYI says:

    BuLi (n,s,t) metalates the ring and quenching with a variety of bromine electrophiles gives no CH2Br product.

    Will look into the sodium bromate etc.

  • Tot. Syn. says:

    Sorry Anon; Ron beat me to it. It’s an interesting method, and I’m not entirely sure why it is selective to the mono acetate. I can sort-of see a rationalisation for 1,2 diols, which is the case here.

  • The Next Phil Baran says:

    Maybe try the last possible sequence. NBS plus lamp. I think based on what you said that this is the only combination you didn’t try. It should make it so that only radicals are formed.

  • Spiro says:

    #8: “Any tricks out there? I have recrystallised/dried the NBS, purified the hell out of the carbon tet, run the reaction with barium carbonate present.”
    LOL! Have you actually tried the commercial yellow NBS?
    The trick to get the radicalar bromination preferentially over the electrophilic reaction, is to have a trace of Br2 in the NBS, that will catalyze the reaction!

  • TWYI says:

    Yep, was originally trying the yellow NBS striaght from the jar, then the orange 5 year old stuff from the back of the cupboard. Then the recrystallised stuff.

    All give more or less the same result

  • jimbo says:

    #8: Pb(OAc)4 + hv, then convert the acetate.

    I’d do a solvent scan as well… try things like water or acetic acid.

  • milkshake says:

    Looks like your aromatic core is pretty electron rich – and if that is the case then no amount of trickery will help your radical bromination (except for finding another substrate with a sybstitution that makes the ring more el deficient.

    As an alternative to radical bromination of the methyl, you can try bromomethgylation or chloromethylation (paraformaldehyde, dry HBr in AcOH etc).

  • synthon says:

    TWYI…benzylic oxidation perhaps? I think that is where jimbo is headed.

  • Spiro says:

    OK TWYI, you’ve got serious trouble.
    Since you want to make a phenylsulfone, there is the possibility to append the phenylsulfide via a radical reaction using stuff like Ph2S2, then oxidize the newly formed sulfide.

  • milkshake says:

    Here is your best bet: brominate the ring first, then brominate the methyl. Do your sulfone thing, then get rid of the ring bromine by simple hydrogenation over Pd or Raney Ni.
    A baloon or a PArr saher should do it promptly.

    By the way, you can make sulfones with benzyl bromide directly, without the oxidation, from sulfinate salts. Sulfinates are easy to make by Zn reeduction of sulfonyl chlorides or by quenching aryl lithiums with SO2. Phenyl sulfinic acid Li, Na salts are commercial.

  • TWYI says:

    Milkshake, sulfones don’t like Pd do they? Raney Ni it is i think? Did think of this, a bit unelegant but at least it gets me there.

    I do use the sulfinate salt, cuts out the oxidation step I agree

  • milkshake says:

    Hydrogenation over Raney Ni is OK with sulfones, nothing should happen. You need a strong reducing agent like Na in liquid ammonia or LAH to hurt your sulfone. With Pd/H2 I don’t know because it is a benzylic position, you would have to try and see.

  • anon says:

    Thanks for the answer re: desymmetrisation.

    Hey, Spiro – it wasn’t only Jacobsen chem that gave ChiRex trouble. Compare this patent with what it says in this later patent “Following observations and comparative studies carried out in the taxane series, it was found that, despite a steric bulk which is greater than that for the hydroxyl of the cephalotaxines, the hydroxyl located at position 13 on the taxane skeleton made it possible to receive acylation with a relatively bulky chain such as, for example, an N-benzoylphenylisoserine protected in the 2′ position (although attempts to acylate baccatin with a chain bearing an hydroxyl group protected with a benzoyl group all failed).”

  • ... says:

    Baran’s got a nice review on terpene synthesis in Nature Chemical Biology

  • ArrowPushingMonster says:

    Where I can’t seem to find it?

  • anon says:


  • ArrowPushingMonster says:

    thanks some other good nat prod articles in that issue as well….

  • squirmy says:

    happy to see this post! i had a role in the story…came up with the bicyclic THF as a target. i split off some of the bis-epoxide from the linked acetogenin synthesis and hit it with vinyl Grignard instead of allyl and tried the Mukaiyama oxidation on the product. thought it was a cute substrate and the oxidation product caught boss’ eye. maybe if i’d tracked down this natural product application, i’d be on the paper :(

    i’m still happy about it.