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Totally Synthetic by Paul H. Docherty, 19 March 2008

Total Synthesis of Rhazinocine


E. M. Beck, R. Hatley, M. J. Gaunt, Angew. Chem. Int. Ed. 2008, 47, 3004-3007.

DOI: 10.1002/anie.200705005

Matt Gaunt's work culminates in a smart and concise total synthesis of Rhazinocine described in a paper in Angewandte. The proprties or biological activities of the natural product are not mentioned in detail, just “[it] mimic[s] the cellular effects of pacitaxel“, so Rhazinocine is presumably also a mitotic inhibitor. A retroanalysis:

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 PdII catalysed cyclisation reaction of simple amides. 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…

Ir catalysed in situ borylation 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. A nice synthetic step!

For the synthesis of the carboxylic acidic partner for the amide coupling below, a rather smart sequence of reactions had been used, in which the symmetry of the unit plays a role. Effectively, an eight-member ring anhydride is opened by the TSE protecting group followed by desymmetrisation of the intermediate to yield the free acid. This amide then formed is ready to participate in the further steps.

In the following reaction, C-H activation can 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 using t-BuOOBz as the stoichiometric oxidant and Pd(OAc)2 as catalyst.

Completion of the target was relatively simple: hydrogenation of the nitro group and the alkene, removal of the silyl groups with aluminium trichloride and using Mukaiyama’s reagent to close the lactam.