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18 January 2010 16,872 views 16 Comments


Shibasaki, Kanai, Shimizu, Shi, Usuda. ACIEE, 2010, EarlyView. DOI: 10.1002/anie.200906678. Article PDF Supporting InformationShibasakiKanai, Kuramochi, Usuda. Org. Lett.2004, 6, 4387. DOI: 10.1021/ol048018sArticle PDF Supporting Information Group Website

Three amazingly tough targets completed in (almost) as many months – you can’t tell me that total synthesis is stifled.  Hyperforin has been staining the white-boards of many a lab for decades – the isolation (reported in Antibiotik…) was way back in ’71, and has resisted synthesis until now.  Shibasaki himself has been working on it for quite a while, as you’ll have seen in the header – a key Org. Lett. was published in 2004 where he describes the asymmetric synthesis of the cyclohexanone.  Lets step in there…

Two papers aren’t actually enough to cover this work – one has to grab the SI to see how Shibasaki made the key diene for the asymmetric Diels-Alder. I think it’s work a brief look, as the synthesis has a particularly neat cuperate addition to an acetylene.  This procedure allowed them to trap the enolate formed from this with acetyl bromide, forming a beta-keto ester, containing a tetrasubstituted alkene, rather easily.  Certainly no-doubt better than the ropey Knovenagel-type condensation I would have attempted…


A few more steps were required to complete the substrate, turning it into something that reminds me of Danishefsky’s diene.  Anyway, tickling this with a bit of Lewis acid (optimised in that Org. Lett.) with a C-2 symmetric  ligand results in a extremely well controlled Diels-Alder reaction, setting two stereocenters, one of which was quaternary.  A really neat solution to the cyclohexanone, allowing an efficient elaboration strategy to finish the ring.  C-1 was set by simple de-silylation, removing both TIPS groups, reforming the ketone.  A few steps later, C-5 was set by kinetic enolate formation (favouring C-5 over the now more congested C-1), and trapping with prenyl bromide to add the second prenyl group.


Working with that cyclohexanone certainly helped much of the stereochemical control, but by the time the group were installing the second quaternary center, things were clearly becoming much more difficult.  A regio/chemo/diastereoselectivity issue seems extremely likely if one were to continue forming enolates, so the group changed tack, and went in for the rearrangement approach.  O-alkylation, installing an allyl group using NaHMDS and allyl bromide nuked the C-1 asymmetry, but that was inconsequential, as the Claisen rearrangement reinstated it as the desired quaternary center, with exceptional efficiency and control.  Look to the paper for a transition-state model – I couldn’t face redrawing it…


The terminal olefin that has just been installed certainly looks conspicuous, so there’s no surpise that is was up for a bit of transformation next.  An extremely selective hydroboration /oxidation sequence turned it into the corresponding aldehyde, using my favourite boron species (doesn’t everyone have a favourite borane? No?  Just me?…), disiamyl borane.  Using just a little ethanolic base, this did the simple aldol to form the remaining quaternary centre with ease.


Things were definately looking up at this point – three bastard-hard stereocenters installed, two prenyl groups in, and only a bit of oxidation / prenylation to do.  And add to this a massive stroke of luck – I quote: ‘Cleavage of the MOM ether under acidic conditions proceeded with concomitant protection of the homoprenyl group at C8 to give 21. This unplanned selective protection was desirable because the reactive homoprenyl group caused side reactions at a later metathesis stage.’ A unexpected as this was, it clearly still took quite a bit of work, as three recycles were required to achieve a two-thirds transformation.

However, at this point Lady-Luck (or whatever you think really controls your reactions – my firm belief is in the phase of the moon) stuck two-fingers up at the group, and made oxidation of the ‘bridge’ next to impossible.  A simple oxidation of the ketone to it’s unsaturated cousin was done by silyl-enol-ether formation and a bit of palladium.  From then, one would hope for a selective epoxidation on this electronically disparate olefin, and a bit of Lewis-acid controlled delivery of the required alkyl (prenyl) group, leaving oxygenation in the right place.  However, a glance at the SI for the Angewandte reveals that they basically tried every possible method to no avail.  Three different basic-peroxide preps, TBHP with Triton B, and even a bizarre prep using BINOL, triphenyl arsene oxide, a lananide, some TBHP and seieves didn’t work.  Google assures me that the Japanese for bollocks is kudara n !, but I have no idea how to pronounce this.  However, I imagine this may have been mentioned…


The route that was eventually triumphed used a rather neat vinylogous Pummerer rearrangement; however, creation of this substrate took twelve steps from my previous structure, so clearly was a method of last recourse.  Still, triumph it did, using the how-to-fuck-up-your-Swern-Oxidation type conditions we’ve all been warned about.  And I think a 65% yield and stunning d.r. are worth the effort!

The last bit of chemistry I’m showing is a final rearrangement, using a bit of palladium to encourage a intramolecular allyl transfer.  This presumably involves a pi-allyl co-ordinated palladium complex which collapse after rearrangement, controlled by a thermodynamic urge for C-allyl over O-allyl.  Very neat, and needing only a (rather low yielding) metathesis to finish that final prenyl group.


Take a deserved bow, folks – I’m officially in awe.

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  • Chris says:

    Do you have the SM in the cuprate addition scheme wrong? Can’t quite see how you introduce the ester functionality there. AcBr quench should give you the methyl ketone, or am I missing something?

  • Jijy says:

    On the SM just before the MOM deprotection: why that regioselectivity during the aldol reaction????

    • Just Another Chemist says:

      In my experience a substituted cyclohexanone forms an enolate much faster than an isopropyl ketone (which doesn’t work well at all).

      • European Chemist says:

        Exactly – and enolisation of the aldehyde is unproductive since attack onto the neighbouring carbonyls would give 4-membered rings.

      • antiaromatic says:

        This is typically the case as one of the protons on the cyclohexanone is essentially always aligned properly for deprotonation (i.e. axial), whereas in the acyclic systems, the free rotation makes this much more difficult and less likely.

  • The Next Phil McGroin says:

    Really impressive work. I have not read the paper yet, so maybe I am wrong, but based on this recap they did this work using primarily disconnections developed before this century.


  • rings'N'things says:

    Porco’s work makes this look just plain silly

  • Needles says:

    Great example of why methods people should focus on methods.

  • European Chemist says:

    This indeed gets very stepy. The overall approach is quite nice, but the way they solved the problems encountered makes it look like the students involved really suffered to get this through. Anyway, let’s not underestimate the target’s complexity and sensitivity.

    PS: Didn’t read the SI, but does 66% over 3 cycles for the tandem MOM deprotection/hydromethoxylation of the double bond probably mean stopping conversion at close to 30% to avoid problems with the other prenyl double bond?… so much for “highly chemoselective” then…

  • stork naked says:

    tough target, danishefsky/garsubellin was more striking

  • Madforit says:


  • RBG says:

    Can someone explain to me what “how-to-fuck-up-your-Swern-Oxidation type conditions” are? Apparently I’m the only person who has never been warned about them.

    On the synthesis, yes, it’s more a tribute to perseverance than elegance, but it’s the first enantioselective synthesis of ANY member of this class. Almost certainly, groups known for their synthetic prowess have tackled hyperforin over the years, but only Shibasaki’s group has crossed the goal line. They definitely deserve their kudos for this one.

  • PowerfulDarkMagic says:

    Could someone please post the link for the SI? Thanks :)

  • InfMP says:

    Full article on this synthesis: