Gaunt , Beck and Hatley, ACIEE, 2008, EarlyView. DOI: 10.1002/anie.200705005.

Another paper from Cambridge, this one from Matt Gaunt’s group. I’ve also seen development of the methodology behind this work progressing, and it’s nice to see it culminate in a smart and concise synthesis. Not much is mentioned about the natural product or it’s biological effects, other than “[it] mimic[s] the cellular effects of pacitaxel“, so are presumably also mitotic inhibitors. Retro time:

Perhaps the most obvious of disconnections is to cleave the amide bond in the medium ring, leaving two linked aromatic systems. The larger fragment would be assembled latterly, using the group’s regioselective oxidative Pd^II-cyclisation reaction, for which the SM is a more simple amide. Disconnection of the amide leaves a biaryl system which was constructed via a Suzuki coupling. And what a nice example of a Suzuki it is too…

In situ borylation with a bit of meteorite-catalyst selectively forms the boronic ester on the C-3 position of the pyrrole, on the less-substituted side. Changing to a less exotic catalyst system and adding the aryl iodide resulted in a high-yielding one-pot synthesis of the desired biaryl unit. Nice!

The synthesis of the acidic partner for the amide SM below is through a rather smart sequence of reactions, in which the symmetry of the unit is capitalised apon. Effectively, an eight-member ring anhydride is opened by the TSE protecting group, desymmetrizing the molecule and giving a free acid to couple to the pyrrole. This amide is then ready to participate in the group’s methodology.

In this reaction, it’s possible for the C-H activation to occur at either the C-2 or C-4 position – and on either side of the olefin. Impressively, the reaction gives a decent yield of the desired product (though from a thermodynamics POV, it seems to be the most likely outcome…?), using t-BuOOBz as the stoichiometric oxidant and the slightly-more-pokey-than-Pd(OAc)₂ catalyst.

Completion of the target was relatively simple – hydrodge the nitro and alkene, remove the silyl groups with aluminium trichloride and use Mukaiyama’s reagent to close the lactam.

Beck, E.M., Hatley, R., Gaunt, M.J. (2008). Synthesis of Rhazinocine by a Metal-Catalyzed CH Bond Functionalization Strategy. Angewandte Chemie International Edition DOI: 10.1002/anie.200705005

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