Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 18 January 2010

Total Synthesis of Hyperforin

Shibasaki, Kanai

Y. Shimizu, S.-L. Shi, H. Usuda, M. Kanai, M. Shibasaki, Angew. Chem. Int. Ed. 2010, 49, 1103-1106.

DOI: 10.1002/anie.200906678

H. Usuda, A. Kuramochi, M. Kanai, M. Shibasaki, Org. Lett. 2004, 6, 4387-4390.

DOI: 10.1021/ol048018s

Hyperforin has been staining the white-boards of many a lab for decades - the isolation 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 paper was published in 2004 in Org. Lett.  where he describes the asymmetric synthesis of the cyclohexanone. Let's 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 β-keto ester, containing a tetrasubstituted alkene, rather easily. Certainly better than the 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, using a Lewis acid and 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 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 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 luck made oxidation of the ‘bridge’ next to impossible. A simple oxidation of the ketone to its 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 lanthanide, some TBHP and sieves didn’t work.

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 strange 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.