Grubbs reaction

It is also not possible to even partially review all the many applications in synthesis that have already been demonstrated for the Grubbs reaction. I have chosen to focus on three papers. For those desiring to deploy the Grubbs catalyst only from time to time, storage and handling become serious issues. We have found (J. Org. Chem. 68 6047,2003) that the commercial catalyst dissolved in paraffin wax can be stored exposed to the laboratory atmosphere for many months and still retain full activity. The example above of 1 + 2 - 3 is taken from that paper. 

We last reviewed organic synthesis applications of the Grubbs reaction on April 19,2004. The (relatively) robust nature of the commercially-available catalyst and its commercial availability have spurred the expanding exploration of the scope of this reaction. Through this month, we will feature some recent highlights. 

The most straightforward application of the Grubbs reaction is to effect homologation of a terminal vinyl group. One concern with the use of the second generation Grubbs catalyst 3 is the cost, about 100/mmol. In conjunction with a total synthesis of the macrolide RK-397, Frank McDonald of Emory reported (J. Am. Chem. Soc. 126 2495, 2004) that the conversion of 1 to 2 required 10 mol % of 3, but that it proceeded efficiently with just 2 mol % of the Hoveyda Ru catalyst 4 (J. Am. Chem. Soc. 122 8168,2002). The alkene so prepared was cleanly trans. An advantage of 4 is that it avoids the use of the expensive PCy,. 

A simple yet powerful application of the Grubbs reaction is specific homologation of a terminal vinyl group. When there is more than one alkene in the molecule, suitably disposed, one would worry about competing cyclizalion. In studies directed toward the cryptophycins, Mark Lautcns of the University of Toronto has reported (Organic Lett. 2004,6, 1883) that the second generation Grubbs catalyst 2 smoothly converts 1 to 3. The alternative cyclization product 4 is produced only in trace amounts. 

As illustrated above, free alcohols are compatible with the Grubbs reaction. In the course of a synthesis of (+)- puraquinonic acid, Derrick Clive of the University of Alberta reported (J. Org. Chern. 2004,69,4116) that the very easily oxidized alcohol 5 maintains its enantiomeric excess as it is cyclized with the catalyst 2 to give 6. 

There are times that it is important to run the Grubbs reaction under equilibrating conditions. In the course of a synthesis of ophirin 12, Michael Crimmins of the University of North Carolina observed (J. Am. Chem. Soc. 2004,126, 10264) that metathesis of 8 under the usual conditions gave mainly the undesired cyclic dimer. At elevated temperature, the dimer re-entered the equilibrium, leading to the desired 9 as the major (15 1) product. The oxonene ring system of 10 then directed the intramolecular Diels-Alder cycloaddition, leading to 12. 

Rimocidinolide synthesis 162 Ring contraction 12 Ru (see Grubbs Reaction)... 

A real concern when attempting the Grubbs reaction with a complex substrate is the stability of other alkenes. J. Alberto Marco of the University of Valencia, Spain has shown (J. Org. Chem. 68 5672, 2003) that 16 is converted to 17 without isomerization of the Z alkene. Less congested alkenes might not be so resistant. 

The Grubbs Reaction in Organic Synthesis Part One of Three... 

Applications of the Grubbs reaction continue to be developed. This is an update, not the final word. 

Olefin Metathesis (Grubbs Reaction) allows the exchange of substituents between different olefins - a transalkyiidenation. 

In our new antithetic plan (Scheme 21), Weinreb s oxazolidinone 77 would remain a key synthetic objective. However, the Hoveyda-Grubbs reaction would now be applied to the diene 88. The new route would also block 0(4) of the vinyl aldehyde precursor with a TES ether to prevent hemiacetal formation from occurring. The crucial Vasella... 

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