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22 January 2007 6,066 views 14 Comments


Morimoto, Okita, Takaishi and Tanaka. ACIEE, 2006, EarlyView. DOI: 10.1002/anie.200603806.

Somewhat similar in structure to silvaticin, blogged here back in October, intricatetraol is an interesting C2 symmetric bis-THF. This feature lead to a somewhat unsurprising disconnection along the axis of symmetry, to reveal a dimerisation metathesis and reduction strategy. As dull as that might be, the rest of the synthesis was a whole lot more exciting, if based predominately on epoxidation/opening. However, it’s quite the master-class, so lets look at the epoxidation strategy at a whole. As you can see, the SM is trans,trans-farnesyl acetate, which might actually be the biological SM too.

So, how are they planning to make all those epoxides? Quite easily, really:


The “left-most” epoxide isn’t actually made from a Sharpless epoxidation; they actually do a dihydroxylation, and then selectively mesylate and displace to leave the desired epoxide. With the epoxides in place, the next step was THF formation:

Damn impressive use of the Payne rearrangement, and a fairly impressive yield. However, they still had one more epoxide to make, which as I said before, was generated by selective mesylation of the less hindered secondary alcohol, and then treatment with base. With the epoxide in hand, it was time to halogenate like a beast; however, this is way less than trivial. In the end, they used a rather exotic (in my limited experience) source of bromide, and were able to open the epoxide in their favour. However, what happens next to put in the chlorine is a bit special :)

Finishing the synthesis from here was a matter of a couple of steps, and completed a rather nice synthesis and a great paper.

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  • Russ says:

    Cool molecule.
    If I had to guess at the biological starting material, I might suggest squalene (the tail-tail dimerisation product of two farnesyl pyrophoshate units, so in a sense, I don’t completely disagree with your statement…)

  • petr says:

    what is the difference between sharpless and katsuki-sharpless epoxidation? i thought it was the same.

  • Russ says:

    petr: It’s a Sharpless dihydroxylation on the left, and a Katsuki-Sharpless epoxidation on the right.

  • Tot. Syn. says:

    “Sharpless credits Katsuki for making a key contribution to the discovery of titanium-catalyzed AE. Katsuki is now a chemistry professor at Kyushu University, in Japan, where the reaction is called the Katsuki-Sharpless epoxidation, as Sharpless himself always cites it. Sharpless says that after calling his father first about the news of the Nobel Prize, he called Katsuki next.”

    Taken from: http://pubs.acs.org/cen/science/8143/8143jacs125.html

  • L.C. says:

    Yep, looks like soon we’ll know how to do polyepoxide openings in good yields. Do you think one will be able to fold at least brevetoxin from polyepoxide in the future?

  • sheriff says:

    I am trying to make a terminal epoxide stereoselectively in the presence of another epoxide from sharpless allylic alcohol. Can anybody give any idea

  • Tot. Syn. says:

    What features do you have to direct the epoxidation? If there’s no allylic alcohol, and the substrate doesn’t have any propensity to do a substrate controlled epoxidation from one face (eg. with MCPBA or DMDO), then you basically have two choices – Shi epoxidation, or SAD, then mesylate, eliminate and epoxidise as in this paper…

  • .... says:


    The Jacobsen HKR is a standard protocol for generating enantiopure terminal epoxides at an early stage of a synthesis. The “R” stands for resolution so it won’t work too well for you if your material is precious, unless of course you want to make both antipodes of the final product.

  • sherfiff says:

    Tot. Syn,
    Thanks for the ideas. Since the terminal alkene is mono substituted , Shi wont work. We have tried HKR and it didnt work. For SAD we got 2:1 ratio.

  • synthon says:

    Can you clip the olefin to the aldehyde and do asymmetric Corey-Chaykovsky using the chiral sulfur ylides of Aggarwal? Leading reference: DOI: 10.1055/s-1998-1652

  • synthon says:

    Nevermind…you said terminal epoxide

  • milkshake says:

    Try the AD workaround. Make monotosylate (or p-Bromobenzenesulphonate or p-nitro – whatever will crystallize better)of your chiral diol, crystallize your product to perfect purity then cyclize with a base. You should get inversion on the arylsulphonate center.

  • sheriff says:

    thanks. How u will separae the diol first. any referrence for this

  • milkshake says:

    Asymmetric Sharples dihydroxylation of C=C. No separation of diols please.

    Since the the optical purity of the product of Sharpless AD is sometimes underwhelming (depending on the substrate) it is a good idea to make some crystalline stuff out of it and re-crystallize, in hope of enriching it.