Hoveyda's Asymmetric Mo-Catalyzed Metathesis

I recently had the pleasure of listening to an excellent talk by Amir Hoveyda about his chiral-at-metal Mo catalysts for asymmetric metathesis. This kind of catalyst is based on the Schrock-type molybdenum catalysts. Most asymmetric catalysts nowadays employ bidentate ligands such as BINOL-type ligands that carry the stereochemical information. By chelating the metal centre, the fluxionality¹ is reduced, therefore ensuring a well-defined geometrical arrangement of the catalyst-substrate complex and good stereoselectivity. In addition, the loss of stereochemical integrity of the catalyst is suppressed. Hoveyda has used such complexes to achieve the formation of P-stereogenic phosphinates and phosphinoxides (where the phosphorus is a chiral centre) by desymmetrizing RCM of achiral precursors (ACIE: 10.1002/anie.200805066).

There is, however, a downside to reduced fluxionality. As Hoveyda points out, the Mo complex has to undergo a series of geometrical rearrangements during a catalytic cycle. If the complex is too rigid, these rearrangements are hindered. In other words, you may get high e.e.'s, but the catalytic activity will be low. This is where chiral-at-metal catalysts have a clear advantage: they only require monodentate ligands, which makes the complex more able to rearrange, and the reaction will be much faster.

The excellent stereocontrol is due to electronic effects rather than pure sterics. One of the ligands has to be an acceptor (the BINOL-type ligand) that ensures sufficient Lewis acidity of the metal centre. A donor ligand (the pyrrole) is also required because it distorts the complex geometrically in a way that facilitates the coordination of the alkene substrate. The use of this kind of asymmetric RCM is demonstrated in a total synthesis of (+)-quebrachamine, where they get a yield of 84% and an excellent 96% e.e. (Nature: 10.1038/nature07594).

I have only touched some of the most important points made in these papers. They are definitely worth reading!

¹ I wasn't familiar with the term "fluxionality". Apparently, it is often used in organometallic chemistry to indicate the possibility of interchanging between equivalent conformational arrangements. As a simple example, Wikipedia mentions the interchange of the two Me groups in dimethylformamide. A monodentate ligand in a metal complex is fluxional in the sense that it can rotate around the metal-ligand bond.

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