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Totally Synthetic by Paul H. Docherty, 17 November 2008

Total Synthesis of Agelastatin A

Tanaka, Yoshimitsu

T. Yoshimitsu, T. Ino, T. Tanaka, Org. Lett. 2008, 10, 5457-5460.

DOI: 10.1021/ol802225g

Looking at this article, the second thought I had (after being generally impressed with the key steps) was that I’d perhaps described this molecule before. I was right - it was one of the first I wrote, back in April of 2006 - by Trost. Trost’s work centred on his manipulation of allylic chemistry using palladium catalysis - quite different to this approach by Tanaka.

Clearly I wasn’t interested in biological profiles back then (how times change…), but there’s some worth noting here - antiproliferation of ‘several human cancer cell lines’, and a bit of (GSK-3β) inhibition. But a 5,6,5,5-ring system is a good incentive too, especially if one can make it easily. The first ring is bought-in, but that’s forgiveable, as it is cyclopentadiene. An oxidative cycloaddition with Boc-protected hydroxylamine resulted in a dihydro-oxazine, which was reduced to the amino-alcohol using molybdenum hexacarbonyl and borohydride. Of course, this chemistry is racemic, so the next few steps included an enymatic resolution of this cyclopentene.

Formation of the pyrrole was quite nice, and a blast-from-the-past - a Paal-Knorr condensation. Inversion of the hydroxyl was done with a typical Mitsunobu, with only a few more steps to get to the next point of discussion - and the centrepiece of the paper. Formation of an azidoformate (a tricky beast for them to complete), and then heating like stupid in a sealed tube gave them an impressive yield of a pretty strained aziridine.

A bit more azide (and do remember exactly how nasty sodium azide is!) opened the three-membered ring, resulting in a net formation of two stereocenters with great control; six more steps and they’d finished the target. Azidetastic.