Phillips and Henderson. ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200803593.
Look familiar at all?Â If you’ve seen Phillips’ synthesis of cylindramide A (back in 2005), you might have a strong feeling of dÃ©jÃ vu, but I didn’t cover it, so this is a good opportunity to look at Phillips’ work on this intreuguing class of natural products (termed the ‘tetramic acid containing macrolactams’).Â Again, we’re short on biological data; just a quick mention of ‘cytotoxicity, antimicrobial activity, and the inhibition of superoxide
generation’, but not specifically for this molecule.Â However, we’re not short on chemistry.
Although it’s got more than a little conjugation, the macrocycle (at least to my eye) is the least challenging portion of the target, with the 5,5-fused LHS looking far more problematic. If you’ve read the cylindramide A paper, thenÂ you’ve got a pretty good idea as to how Phillips makes the octahydropentalene system, but it’s such a sweet method, I drew it out in full:
So what’s going on?Â A MacMillan-catalyst directed Diels Alder between the enone and cyclopentadiene gives the bicyclic product, generating a 93% e.e., and setting a quartet of stereocentres.Â A bit of base, followed by TMSCl and then (stoichiometric) palladaium acetate oxidises this ketone to the enone (a Saegusa oxidation), which isomerises when treated with Grubbs 1.Â Presumably, the driving-force for the isomerisation (RORCM) is strain-release.Â Either way, it’s a nice way to get that system…
A few steps down the line, and they did a rather tasty Sakurai allylation, using a mild prep developed by Majetich.Â Using fluroide (rather than, say, tickle-four), the silyl group is attacked creating an enhanced leaving group, faster.Â Unfortunately, though, the stereochemistry went in favour of the undesired isomer with a 1:4 ratio.Â This was improved to 2:1 by forming the silyl ketene acetal and hydrolysing it with HCl, but they had to do the next step (an iodolactonisation) before they could separate the isomers.
The last few steps of the synthesis were a really nice sequence of events (which Phillips describes as requiring a few different strategies before succeeding).Â The two main fragments were coupled by heating together in toluene, giving a Î²-ketoamide.Â A Stille coupling then bolted on the acrylate unit, and was followed by a intramolecular (Lacey) Dieckmann cyclisation, giving the five-membered ring product.Â It’s a very useful reaction for this system, and not the first implementation; Ley’s synthesis of physarorubinic acid is another that comes to mind.
Deprotection of both protecting groups in TFA, and amide coupling completed a rather nice synthesis.