Organic Chemistry Portal
Reactions >> Total Syntheses

Totally Synthetic by Paul H. Docherty, 30 September 2007

Total Synthesis of Paucifloral F, Ampelopsin D, Isoampelopsin D, Quadrangularin A, Isopaucifloral F, Pallidol, Hemsleyanol E


S. A. Snyder, A. L. Zografos, Y. Lin, Angew. Chem. Int. Ed. 2007, 46, 8186-8191.

DOI: 10.1002/anie.200703333

Resveratrol must be the simplest looking natural product I’ve drawn. However, it isn’t actually the goal of this work - rather, the goal is an array of targets based on resveratrol. If you are thinking that you might have read about resveratrol before - congratulate yourselves on reading the labels on red wine bottles thoroughly. Yes, it’s in red wine, and is known to combat inflammation, heart disease, aging, and cancer. Impressive. Snyder also mentions it may be responsible for the ”French paradox“… interesting!

With this impressive biological profile, Snyder proposes that the oligomers of resveratrol may be even more potent, and are therefore worth investigating. Rather than just making one or two, he make a whole load from common precursors. The first of building block is made simply from an addition to give the diaryl alcohol shown below. Treatment of the alcohol with acid (either TFA or TsOH) promotes cation formation, and trapping in a 5-endo-trig manner to give the cyclopentane.

When TFA was used, the trifluroacetate anion trapped the resulting cation to give the trifluoroacetate product. This was saponified in situ and after oxidation and deprotection gave paucilfloral F. However, using an acid with a non-nucleophillic conjugate base (TsOH in this case) allowed intermolecular trapping with p-methoxy-toluenethiol to give the sulfide. This was oxidised to the sulfone, and treated with base to induce a Ramberg-Bäcklund reaction. This rearrangement extruded the SO2 moiety and gave the alkene product, which after deprotection left ampelopsin D.

Not quite done with this skeleton - treatment of ampelopsin D with a touch of acidic methanol promoted rearrangement to isoampelopsin D. A nice synthetic step!

Use of the same approach with a different building-block (which is structurally very similar - I’ve shown the similarity by indicating the previous building-block functionality in grey) worked just as well. TsOH, sulfide trapping and Ramberg-Bäcklund rearrangement led eventually to quadrangularin A (a great name!). TFA, oxidation and deprotection gave isopaucifloral F. If it works…

Next, Snyder looked at the fused bis-cylopentane natural products. Taking permethylated quadrangularin A, they performed a stepwise bromination, terminating with the tribromo intermediate shown below. The oxonium ion then rearranged via a Friedel-Crafts type reaction to give the required 5,5-fused skeleton. Reductive dehalogenation and deprotection then gave pallidol. However, you’re probably wondering why bromination was required? Snyder answers this by suggesting that their bulk controls the stereoselectivity of the cyclisation.

With a further series of resveratrol based natural products to consider, they sucessfully applied the same chemistry to a further substrate, again cyclising with bromination to give a [3.2.1] bicyclic ring system. This time the extraneous halogens were removed with a radical reduction, which after deprotection gave ampelopsin F.

Switching substrate, the same trick gave them a seven member ring. However, this time they didn’t quite make it to a natural product. Treatment of the bromide with silver acetate promoted elimination to give the stabilised cation, which the neigbouring methoxylphenol trapped to give a cyclopropane with the methyl oxonium ion. This then quenched by opening of the cyclopropane to give the actate. This was then saponified and oxidised to the ketone, which they hope to use for future syntheses.

This was cetainly a tour de force, especially for Snyders first paper. However, the end of the paper felt a little ragged, in that we were left with an amazingly intricate and impressive jigsaw, short a few pieces. That’s not to detract from what is an awesome achievement that certainly puts his creativity and ability on the map.