Hyperforin and the papuaforins are members of the polyprenylated polycyclic aclyphloroglutinol series of natural products. They all contain a highly substituted bicyclo[3.3.1]nonane trione frame.

These compounds are renowned for their broad spectrum of biological activities ranging from antidepressant to antimalarial and just about everything in between. Hyperforin is a prime example of this compound class and can be isolated from St. John’s wort. Barriault and Bellavance from the University of Ottawa have described their synthetic route to this class of compounds involving a gold(I) catalysed carbocyclisation of a cyclic enol ether to produce the bicyclo[3.3.1]nonane ring system according to the disconnection below:

This was convenient because “Recently, we reported that selective 5-exo- and 6-endo-dig carbocyclizations of silyl enol ethers to alkynes can be achieved by modulating the steric and electronics properties of the ancillary ligand on the cationic gold complex.“

So compound 2 was synthesised in 10 steps in 18% yield from commercially available ketone 3:

Using 5 mol% [(JohnPhos)Au(NCMe)⁺ SbF₆^–] in acetone at room temperature the cyclisation proceeded in >90% yield and could easily be done on a scale >10g to produce the bicyclic compound 4:

This compound was progressed to hyperforin in a few simple steps including a cross metathesis with Grubs II and isobutylene which installed the prenyl side chains followed by generation of the diketone provided hyperforin.

A nice overview of the biological activities of hyperforin is provided in the Richard’s review, reproduced here with thanks:

I like this synthetic route, the chemistry is simple and amenable to scale-up. Also with this synthesis there are countless possibilities of adding different functionality to address the varied biological activities shown above. So all in all a good piece of synthetic chemistry here with great potential.