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7 June 2007 10,358 views 34 Comments


Evans, Kværnø, Mulder, Raymer, Dunn, Beauchemin, Olhava, Juhl, Kagechika and Favor. ACIEE, 2007, Early View. DOIs: 10.1002/anie.200701515, 10.1002/anie.200701520.

I promised it, and here it is – one damn impressive synthesis. I guess I should talk about it a bit, rather than just concluding with my introductory statement, so we’ll start with the biochemistry. The activity of the beast in humans is actually quite well known; it’s a potent poison, and there have been quite a few cases of azaspiracid poisoning documented. Of course, this isn’t the first synthesis of the target, and many of you will have read Nicolaou’s brilliant synthesis of last year. KC’s work was also notable for the reassignment of the structure to include the doublely anomerically stabilised spiro-ketal fragment rather than the single stabilisation originally postulated. But lets get on with the retro:

The biggest fragment coupling operations were envisaged to come from a pair of sulfone anion additions (getting rid of the sulfone group after the addition is far easier than binning a hydroxyl, which makes this approach appealing), and a pair of aldols (Mukaiyama and “boron”).

The synthesis began with the AB ring system fragment, but my interest was first piqued by the first example of bisoxazaline chemistry and their glyoxylate-ene reaction in this work. This chemistry was mentioned in the comments of my post on Cossy’s synthesis of Leucascandrolide as a nice alternative to an allylation, and nice it is!

This frament was quickly converted to a THF using an efficient ozonolysis of a methylene to free the ketone and cyclise in acid to the THF. They actually used some Sudan III dye in the ozonolysis, something I’ve also done recently – basically, it’s a (unsurprisingly) red diazo compound which reacts after the desired alkene, prompting a colour change, and allowing the chemist to stop the reaction before clobbering the sensative PMB group. Very handy, but nowhere near as impressive as the reductive cleavage of the methyl ether with retention of stereochemistry.


This is neatly explained using some of Woerpel’s chemistry, which one can read for free here. The crux of the issue is handled by one statement: “examination of the highly stereoselective reactions […] revealed that in all cases the nucleophile adds to the same face as the alkoxy substituent at C-3″


Addition of the A[soon to be B] fragment to this unit with the sulphone anion I mentioned earlier led to the “linear” (I know…) precursor of the ABCD system. Treatment of this with TBAF selectively removed the most labile silyl ether (but also the most hindered…), forming the C ring ketal. Then, addition of acid freed the A ring methyl ketal and allowed formation of the B ring, and completion of that fragment. Nice sequence (but these spiroketalisations always look amazing to my eye)!


The remaining hemisphere began with a bit more BOX chemistry, doing an asymmetric hetero Diels-Alder to form the pyran ring. Some nicely controlled additions to this allowed them to construct four stereocenters on the THP E ring very efficiently.


The FG ring fragment was also made using BOX chemistry, this time with a tin center, and a enantioselective catalytic
Mukaiyama aldol reaction of methyl-substituted siloxyfuran to derive two stereocenters. A third was shortly added by a substrate directed reduction of the unsaturated lactone, creating a complex linear substrate when opened.


Lastly, we’ll look at another lovely spiroketalisation (and spiroaminalisation [!]) to form the FGHI ring system. Again, a deprotection goes a long way (and makes what would otherwise be a rather dull step quite exciting). DDQ removes the PMB groupm and forms the H ring, whilst hydroge reduces the azide “protecting” group to the amine, forming the desired aminal in great control and yield.

All that remained then was to combine the two fragments (note the funky oxidation to sulfone with the molybdenum reagent – used more than once in this synthesis), which unfortunately went with no stereocontrol. However, they were able to separate the isomers, and convert the undesired adduct to the desired in two steps. Completion of the natural product then only required global deprotection and oxidation over two steps to the required acid (permanganate would have done it in one step..!!)

An amazing feat of work and stereocontrol, showcasing much of Evan’s recent methodology.

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  • Tot. Syn. says:

    There are bound to be mistakes. Argh… bed.

  • Liquidcarbon says:

    Wow. One post is not enough!

    >> “reductive cleavage of the methyl ether with retention of stereochemistry.”

    this has some dreadful explanation involving molecular orbitals, it was somewhere in Evans 206 course. Should there be an alkyl group instead of alkoxy, the stereochemistry will be different!

  • kiwi says:

    unless i’m mistaken (not uncommon), you’ve got the double bond in the evans ene starting material in the wrong place. but definitely its an awesome reaction.

  • kiwi says:

    wow that was dumb. nevermind. i am easily confused on fridays.

  • accurate says:

    Impurity in a drug manufactured by Roche:

  • milkshake says:

    The Cu-Box asym ene is very impressive when you can use it but quite limited in scope. It is best suited for making small pieces, building blocks that do not have acid-labile functionalities or anything too Lewis-basic (amides) to tie up the catalyst.

    Also the glyoxylate has to be used in excess (>3.5 equiv) and other aldehydes that are not as reactive or lack the chelating functional group on alpha do not work too well.

  • jimbo says:

    #6: re-glyoxylate — that’s the reagent of choice for chemists whose big ideas for asymmetric reactions don’t work on aldehydes. I’ve seen a bunch of talks where professors have a big idea regarding trapping some awesome organometallic intermediate with an aldehyde, then ultimately end up trapping with glyoxylate.

    Still, it’s a fantastic way of making chiral alpha-hydroxycarbonyls without having to do something stupid like an alpha-hydroxylation (friends don’t let friends plan alpha-hydroxylation).

    I’ve done an ethylglyoxylate ene with a titanium-binol catalyst (I can’t remember which variant) that was phenomenal… low loading and done neat. You could make grams and grams of chiral material in a 100 mL roundbottom, and the only purification was a silica plug filtration.

  • The Canadian Chromatographer says:

    I’m sure everyone agrees, though, that doing a Grubbs cross-metathesis (with Grubbs II!!!) in one’s very first step is not the most economical way of bring material forwards. Pardon me for being somewhat “old school”, but I’d have used a good ol’ Roush-Masamune-HWE for that, gotten >19:1 E:Z and carried on… I’m sure the halomethyl Weinreb acetate is a known compound…

  • J says:

    What’s so bad about Grubbs II?

  • Tot. Syn. says:

    It’s bloody expensive, patented to the hilt, and even at a low catalyst loading, you’ll need loads for the first step in a synthesis.

  • HR says:

    “and even at a low catalyst loading, you’ll need loads for the first step in a synthesis.”
    especially considering Grubbs II m.w. is close to 850 g/mol

  • Shmetathesis says:

    yeah, if you use up your quota with Aldrich for the year (I think it’s 8 g), you have to beg Materia to allow you to buy more, even if you’re an academic group. You know… just in case you might be making money by synthesizing marine toxins. And the guy you have to call is a pain in the neck.

    I’m not sure if it’s changed, but if you wanted to use their catalysts to synthesize a drug, Materia would ask for a substantial amount on the back end of the sales of the drug. Which is why nobody uses it.

  • The Dude says:

    Correct me if I’m wrong, but I believe that the Hoveyda catalyst gets more use in industry due to higher TON.

  • sufuric says:

    “It’s bloody expensive, patented to the hilt, and even at a low catalyst loading, you’ll need loads for the first step in a synthesis.”

    I’ll definately agree with this. A big part of my current project is to find a way around using Grubb’s catalyst for the third step of the synthesis of a molecule. The cataylst has a mw 3 times of the starting material and to make enough to get to the end need way to much of the catalyst.

  • jimbo says:

    Has anyone tried to micro-encapsulate Grubbs?

    The catalyst, not the person.

  • Smitty says:

    Is there a good way to recover/reuse Grubbs II? It is a catalyst, after all.

  • dtb says:

    Re: Grubbs’ catalysts – why not just make your own? Furstner has described a class of ruthenium complexes with (supposedly) comparable activity that are dead easy to make (no explodey diazo compounds…):


  • PJ says:

    I once heard that the Materia patent missed a certain substitution on the phenyl ring in the catalyst. I think it was nitro. Anyone know anything about this?

  • jimbo says:

    There are companies which provide Grubbs-like catalysts that get around their patent, but my understanding is that they are slightly less active.

    dtb: I couldn’t get your doi to work, but I don’t think the synthesis of any Grubbs-like catalyst is easy… maybe -easier- that previous methods, but not easy. Then again, I hate doing sensitive chemistry… as soon as someone says “degas” or “glovebox” I lose interest.

  • dtb says:

    *insert long, expletive-filled rant about Wiley’s DOIs here*

    the paper I meant to reference was:

    Furstner et. al., Chem. Eur. J. 2001, vol. 7, pp. 4811 – 4820

    They claim it’s a three step synthesis, with all steps run under Ar but without degassed solvents/glovebox use…

  • TheEdge says:

    I think Mulder and Juhl tried some other ways to make the C4-C5 olefin before going with metathesis, but I don’t recall what they were offhand. Outside of the cost of the catalyst, metathesis is ideal for scale-up. The reaction is effectively pitch and stir and there’s no stoichiometric phosphorous biproduct to get rid of.

    re:glyoxylate ene. Kværnø optimized the hell out of that reaction. She found you don’t need to crack the glyoxylate beforehand and you can drop the catalyst loading to .1% (assuming you have the patience to wait a week for your product). The hydro-catalyst used for the reaction is really user-friendly, too.

    My favorite step is the boron aldol w/2 equiv of Cy2BCl to “protect” the second ketone. But I’m an aldol geek, so that isn’t particularly surprising. I also think they did a good job of using the spiroketals as protecting groups during the late stages.

    There’s a nice summary of other groups’ routes to this molecule in Travis Dunn’s thesis, if anyone is interested.

  • sufuric says:

    #16 “Is there a good way to recover/reuse Grubbs II? It is a catalyst, after all.”

    Actually what you buy (or make) is technically a “precatalyst”.

  • kiwi says:

    yes, you lose the phosphine during the reaction, forming the active species (and ultimately leaving the catalyst as a bunch of brown gunk, sometimes irretrievably stuck to your product…). The Hoveyda II phosphine-free catalyst however is allegedly recyclable (not so sure about Hoveyda I, never tried). The remaining green catalyst can be separated from the Ru crap on silica at the end of the reaction. And re #18: Grela has recently described some seemingly awesome nitro-substituted variants of the Hoveyda catalyst, do you mean those?

  • synthon says:

    The Hoveyda catalyst is recyclable; both generations! First elute your product then flush with DCM to elute catalyst. The recoveries can be variable depending of the efficiency of the metathesis process, but for simple substrates the catalyst may be used mutliple times: http://dx.doi.org/10.1021/ja001179g

    Last I knew, the Hoveyda catalyst system was being used at the process level (400 kg) by Boehringer Ingelheim for a difficult macrocyclization. It outperformed the Grubbs system: http://pubs.acs.org/cen/coverstory/85/8507cover3.html

    FWIW, they did NOT recycle the catalyst.

  • wisemanleo says:

    Hey, I’d like to inquire more on the use of Sudan Red III diazo dye. Is it used to detect the loss of an alkene, or the formation of one? Can it be applied to reactions involving ketenes, and/or imines?

  • TWYI says:

    How much solvent must these people go through doing RCM on a 400kg scale… dilution factors and all that

  • Tot. Syn. says:


    The deal is that the ozone reacts with the olefin first, then the diazo compound, and then with whatever functionality is left in your molecule. In my case, this was a PMB group (which we think looses hydride to ozone, and then traps ozone to give the benzoyl ester). Having the dye as a “buffer” between these reactions allows the chemist a couple of minutes to stop the ozone flow before the molecule is trashed. Crimmins has used it too.

  • thirsty scholar says:

    another comment on diazo dyes:

    the choice of dye is completely empirical. it has to be determined by ozonolyzing your olefin in the presence of a dye; once the dye is consumed, the reaction is quenched. hopefully the ozonolysis was selective for the desired olefin and nothing else. if not, it’s back to the drawing board with another dye.

    luckily, there is some literature out there about choice of dyes foor a particular type of olefin. it’s a good starting point, rather than screening them all.

  • wisemanleo says:

    Thanks for the response.

  • huxley says:

    Tot. syn. That mechanism you described looks good on paper. Did you actually isolate the p-methoxybenzoyl ester? Paquette recently published a paper (Org. Lett. vol 7, p 4665) where he isolated and characterized products from the DMDO oxidation of some PMB protected compounds. The paper also has vague references PMB ether ozonolysis work.

  • Tot. Syn. says:

    Nope. I got an 80ish% yield of product, and SM as the mass balance, and then distilled the aldehyde out of the product mixture to give an 80% isolated yield. Couldn’t see anything else in the crude NMR, so I guess the dye did it’s job!

  • Organic Chemistry Help says:

    The cyclic ether structure reminds me of the brevatoxins, is this also a neurotoxin? (Sorry, i didn’t read the original nicolau paper)

  • TheEdge says:

    re:32. I don’t believe so. It causes, um, gastronomic distress.

  • AnferTuto says:

    Hola faretaste