Barrett, Soorukram and Qu. Org. Lett, 2008, ASAP. DOI: 10.1021/ol8015435.
This is the second example of Barrett’s benzyne centred three-component-coupling I’ve featured on the blog, and it’s still looking like a damned smart way of constructing heavily substituted aromatic systems.Â The first was ent-clavilactone B, back in 2006, which shares a further couple feature with todays target – lack of an established absolute stereochemistry, and bacteria-bashing activity.Â For those that didn’t cover benzynes in their schooling, there’s one key feature of their reactivity that is key to this strategy – an electrophilic nature.Â The 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.Â That’s the meat and veg of this approach, so let’s see it in action:
Okay, so what’s going on here is the initial deprotonation of either of the protons betwixt the fluorine and methoxy groups.Â The fluorine then eliminates, generating the intermediate benzyne.Â We’ve then got a regio-controlled addition of the alkyl-Grignard into the benzyne, generating an aryl Grignard.Â This is then treated with carbon-dioxide, leading to a magnesium benzoate salt.Â A bit of iodine then forms an iodonium ion, which iodolactonates to complete the lactone and give the iodide product as a single diastereoisomer.Â Considering how much has happened, that’s an absolutely cracking yield.
To get to the target, they needed to do quite a bit of work on the cyclohexane.Â 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.Â Barrett states that this reaction was far better than the more common enolate formation and trapping with selanide and oxidation/elimination.Â 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 acheived with final reduction using Stryker’s reagent; Barrett ascribes this purely to the relaxed sterics on that olefin.Â The last oxgenation was a stereocontrolled enolate trapping of Davies Davis oxaziridine, attributing the control to preffered cyclohexenone geometry (pseudo-chair over twist-boat).Â Nice work, and a good application of this strategy.
Soorukram, D., Qu, T., Barrett, A.G. (2008). Four-Component Benzyne Coupling Reactions: A Concise Total Synthesis of Dehydroaltenuene B. Organic Letters DOI: 10.1021/ol8015435