Totally Synthetic by Paul H. Docherty, 6 June 2010
Total Synthesis of Englerin A
K. C. Nicolaou, Q. Kang, S. Y. Ng, D. Y.-K. Chen, J. Am. Chem. Soc. 2010, 132, 8219-8222.
Englerin A gets a lot of attention, because it is a biologically very
active compound. To quote KCN, ‘…potent and selective growth inhibitory (GI)
activities against renal cancer cells‘, so it’s worth
all this effort. Two syntheses, published by
respectively, use similar gold-mediated cyclisations to build the
stereochemically crowded 5,7,5- system but quite different routes to get there.
However, Nicolaou and Chen do something rather different.
The paper is divided into two routes; an initial racemic synthesis, and then a later enantioselective formal synthesis. However, I’m starting with the crux of the synthesis, and their introduction of asymmetry. The chemistry works by forming a reactive oxopyrilium species from the cyclohexenone, cunningly flattening the molecule, removing those racemic stereocenters. This exotic compound then undergoes a [5+2] cycloaddition with the acrylate - in this case bearing a chiral auxiliary. Creating three new stereocenters in one reaction is quite a challenge, and the paper discusses the development of the chemistry in some detail. Ultimately, the group couldn’t convince the reaction to give them any more than about a 40% yield, and in the case of the enantioselective chemistry, they were limited to 30% as a 2:1 mixture of diastereomers.
Separation of the diastereomeric mixture was possible, though, leaving two separate pots of enantiomers after removal of the auxiliary. However, the stereocenter at C-8 looked fairly acidic, and therefore fragile, so the group had to use a rather convoluted reduction/oxidation approach over four steps to achieve what was effectively a transesterification.
A few steps later and the group had introduced a further stereocenter by reduction, and introduced a pendant olefin via elimination. They then did a palladium-mediated reaction I don’t see very often - a Wacker oxidation. This provided the desired methyl ketone in excellent yield, and set them up for a nice Robinson Annulation with the cycloheptanone. Given that there are a couple of modes of reaction for this compound, a yield in the high 70s is very respectable, and completes the carbon skeleton of the 5,7,5- ring system.
The next few reactions are what makes this synthesis particularly interesting in my opinion. The enone moiety was reduced in a pair of reactions, firstly tackling the ketone using sodium borohydride and cerium(III) chloride. Then the alkene is reduced using Crabtree’s catalyst (at a slightly pricey loading…). Bang - three stereocenters using substrate control and a bit of hydrogen.
The last reaction is yet another that I had to look at for a little while before it clicked (and I felt like an idiot). After forming the Weinreb amide from the ethyl ester, treatment with methyl lithium gave the group a methyl ketone. A subsequent Baeyer-Villiger oxidation formed an ester such that the group were left with an acetate protected hydroxyl. An interesting total synthesis…
…but is it better than the preceding syntheses?