Nicolaou, Chen, Kang, Ng, JACS, 2010, ASAP DOI: 10.1021/ja102927n.
Another popular target today; a last month I wrote a piece in Chemistry World about the first two syntheses of this target, and only a month later, up-pops Nicolau and Chen’s effort. If nothing else, that’s a whole-lotta funding gone into this target, so it’s no surprise that it’s a pretty biologically active beastie. To quote KCN, ‘…potent and selective growth inhibitory (GI) activities against renal cancer cells‘ is the order of the day, so it’s worth all this effort. The first two syntheses, published by Ma and Echavarren respectively, use similar gold-mediated cyclisations to build the stereochemically busy 5,7,5- system, using 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 beastie then does 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 pretty respectable, and completes the carbon skeleton of the 5,7,5- ring system.
The next few reaction are what makes this synthesis particularly neat in my opinion. The enone moiety was reduced in a pair of reaction, firstly tackling the ketone using sodium borohydride and the only Lanthanide I’m ever going to handle. Then goes the alkene 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 little peracid then did a Baeyer-Villigar oxidation, forming an ester such that the group were left with an acetate protected hydroxyl. Neat stuff…
…but is it better than the two preceding syntheses?