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Totally Synthetic by Paul H. Docherty, 7 October 2008

Total Synthesis of Aburatubolactam A


J. A. Henderson, A. J. Phillips, Angew. Chem. Int. Ed. 2008, 47, 8499-8501.

DOI: 10.1002/anie.200803593

Aburatubolactam A is a member of an intriguing class of natural products (termed the ‘tetramic acid containing macrolactams’). 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 Aburatubolactam A. However, we’re not short on chemistry:

Although it’s heavily conjugated, the macrocycle (at least to my eye) is the least challenging portion of the target, while the 5,5-fused ring system looks far more problematic. Phillips uses an interesting method to make the octahydropentalene system, so I drew it out in full:

So what’s going on? A MacMillan-catalyst directed Diels Alder reaction between the enone and cyclopentadiene gives the bicyclic product in 93% e.e., generating four stereocenters. Use of a base, followed by TMSCl and then (stoichiometric) palladium acetate oxidises this ketone to the enone (a Saegusa oxidation), which isomerises when treated with Grubbs first generation catalyst. Presumably, the driving-force for the isomerisation (a ring opening / ring closing metathesis - RORCM) is strain-release. Either way, it’s a nice way to get that system…

A few steps later, they performed a Sakurai allylation, using a mild method developed by Majetich. Using fluroide, the silyl group is fastly attacked creating an enhanced leaving group. Unfortunately, though, the stereochemistry went in favour of the undesired isomer with a 1:4 ratio. 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 reactions (which Phillips describes as requiring a few different strategies before succeeding). The two main fragments were coupled by heating together in toluene, giving a β-ketoamide. A Stille reaction was then used for the coupling of the acrylate unit, and was followed by a intramolecular (Lacey) Dieckmann cyclisation, giving the five-membered ring product. It’s a very useful reaction for this system, and not the first implementation; Ley’s total 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.