FR901483

FR901483

fr901483

Cheryl A. Carson and Michael A. Kerr

Link: http://dx.doi.org/10.1021/ol802870c

FR901483 is an interesting synthetic target with regard to the aza-tricyclic core structure and it’s biological activity “as an inhibitor of purine biosynthesis” which “acts with a novel mode action”. That’s all in the paper about biology so far. This is not the first synthesis of FR901483 but the first time that the intriguing ring closure was used in a total synthesis.

Retro:


retro

They decided to close the tricyclic core using their own methodology and combine the two fragments by a substrate controlled Reformatsky reaction.

The key step looks like this:


cyclisation_step

The preformed imine opens the cyclopropane which in turn attacks the iminium-ion in an 5-endo-trig ring closing reaction. They found that the deprotected amine does not affect the ring opening before forming the imine. Building up the intermediate is straightforward:

intermediate

With the two fragments combined and some protecting group manipulations they closed the ring as shown above, and after some decarboxylation, hofmann rearrangement and phosphonate ester formation they got FR901483 in hand:


last_steps

All in all an interesting synthesis especially (or almost exclusively) the ring closure. That’s it so far. A short paper needs only a short review I think. Maybe next time I got more time for writing. And the nice graphics compensate the short text.

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