Again, it’s been a while since I blogged, and this time the excuses are two-fold. First of all, I moved home recently to the leafy London suburb of Surbiton (saaf-wess, for natives…), and have been without my computer, interweb access and beer, all three of which are required for blogging. However, more critically, there’s been a real dearth of total synthesis in the ASAPs, so much so that this paper isn’t even a formal synthesis (not in the title at least).
What we have here is a Corey Org. Lett. examining an interesting array of asymmetric catalysis. Primarily, the paper discusses ‘highly enantioselective Diels-Alder reaction with an acetylene equivalent to produce chiral-bridged dienes‘. However, it turns-out that these bridged dienes are also active ligands in a second asymmetric process, ‘enantioselective addition of vinyl or aryl groups to unsaturated ketones‘. It’s this second reaction that is the centre-piece of this post, as it leads to an intermediate found towards the back of the Corey filling cabinet room, early in a 1979 synthesis of the title compound. So this is really just an excuse to look at that paper, but it’s always good to read prime-time Corey.
So first up is this new-fangled asymmetric addition chemistry, using a ligand (12) produced earlier in the paper. This bad-boy coordinates to the rhodium catalyst, allowing delivery of the aryl (or vinyl) boronic acid as a net reduction. Interesting points are the vanishingly low catalyst (and ligand) loading, as well as the opportunity to produce the ligand in-situ, developing a rather special cascade-type reaction.
Moving to the total synthesis, a reaction I’d virtually forgotten was used to transform the methyl ketone into the corresponding carboxylic acid. It’s rather mild, requiring only room-temperature and six hours, and produces a product several steps faster than than might otherwise be construed. The free acid was then chlorinated to the acid chloride, and a bit of Lewis-acid allowed ring-closure onto the proximal aryl position. A bit of alkylation with TOSMIC (hydrolysing the nitrile and methylating) and methyl iodide provided enough carbon to get on with things. A key reaction was de-methylation of the phenol, as this promted gamma-lactone formation. Exhaustive hydrogenation using Nishimura’s catalyst did for the benzene ring, establishing three stereocenters with control presumably arising from the lactone bridge.
Job done, the lactone was opened, reduced and tosylated, providing a nice leaving group. Treatment of the cyclohexanone with base can then, of course, deliver two enolates, with thermodynamically more stable preferred, as internal alkylation with this gives the carbon skeleton of the target. However, using LDA over-turns this preference, and results in cyclobutane formation.
A few more steps were required to install the isonitrile, but with no problems. Neat work from a prof at the top of his game.