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Totally Synthetic by Paul H. Docherty, 16 August 2008

Total Synthesis of Dehydroaltenuene B


D. Soorukram, T. Qu, A. G. M. Barrett, Org. Lett. 2008, 10, 3833-3835.

DOI: 10.1021/ol8015435

This is the second example of Barrett’s benzyne centred three-component-coupling and it’s still a very smart way of constructing heavily substituted aromatic systems. The first was ent-clavilactone B, back in 2006, which shares a couple of features with todays target: lack of an established absolute stereochemistry, and antibiotic activity.

One key feature of benzynes is their electrophilic reactivity. This means that attack of a benzyne with an anion results in the generation of a second adduct anion, which one can trap, building an ortho-substituted system. So let’s see it in action:

After the initial deprotonation of either of the protons between the fluorine and methoxy groups, the fluorine eliminates, generating the intermediate benzyne. We’ve then got a regiocontrolled addition of the alkyl-Grignard into the benzyne, generating an aryl Grignard. This is then treated with carbon dioxide, leading to a magnesium benzoate salt. Iodolactonisation gives the product as a single diastereoisomer. Considering how much has happened, that’s an absolutely astonishing yield.

To get to the target, they needed to peform some reactions with the cyclohexane. However, I really enjoyed their strategy of oxidation and functionalisation, moving unsaturation around the ring, so I’ve drawn an abbreviated route:

Most interesting was the oxidation of the enone to give a dienone using a benzeneseleninic anhydride. Barrett states that this reaction was far better than the more common enolate formation and trapping with selanide and oxidation/elimination. He links to a Barton paper from the early 90s, which is well worth a read (and also an earlier paper I found here). Also noteworthy was the selectivity achieved with final reduction using Stryker’s reagent; Barrett ascribes this purely to the relaxed sterics on that olefin. The last oxgenation was a stereocontrolled enolate trapping of Davis oxaziridine, attributing the control to prefered cyclohexenone geometry (pseudo-chair over twist-boat). Nice work, and a good application of this strategy.