Ruthenium-catalysed hydrogenation

In addition, several S/S ligands were also investigated for the asymmetric hydrogenation of olefins. In 1977, James and McMillan reported the synthesis of various disulfoxide ligands, which were applied to the asymmetric ruthenium-catalysed hydrogenation of prochiral olefinic acid derivatives, such as itaconic acid. These ligands, depicted in Scheme 8.16, were active to provide... 

As an alternative to the use of hydrogen gas, asymmetric ruthenium-catalysed hydrogen transfer reactions have been explored with significant success [381. 

Enantioselective reduction of acetophenone was achieved in a ruthenium-catalysed hydrogen transfer reaction using isopropanol as the hydrogen source in the presence of mono-tosylated (R, R)-diphenylethylenediamine, ephedrine or norephedrine as chiral auxiliary ligands. Under optimised conditions, ( R)-l-phenylethanol was obtained in 90% yield and 82% enantiomeric excess (ee) within 9 min. f-Butylphenylketone was reduced under similar conditions in almost quantitative yield but in moderate ee... 

Fig. 6.32. Asymmetric BINAP-ruthenium catalysed hydrogenation of enamide with cis-phenyl...

The sertraline precursor is a chiral alcohol with the stereogenic centre adjacent to an aromatic ring. An obvious approach is to make the hydroxyl group by asymmetric reduction of the corresponding ketone. CBS reduction is a possibility, as is a ruthenium-catalysed hydrogenation using the ligand TsDPEN (p. 1115 of the textbook). 

If this compound were needed on the tonne scale then auxihary chemistry is no good, however efficient recychng may be. A good alternative for the synthesis of compounds with unfunctionalized chiral centres adjacent to carboxylic acids or alcohols is the use of ruthenium-catalysed hydrogenation. 

Detailed studies into the mechanism of the ruthenium-catalysed hydrogenation of enamides using catalyst (2.67) in methanol reveals that, while there are similarities to the rhodium-catalysed hydrogenation there are also some fundamental differences. The ruthenium-catalysed process involves the initial formation of... 

Reduction of unsaturated carboxylic adds gives products that you might alternatively think of making by auxiliary-controlled alkylation methods. When the NutraSweet company needed this chiral branched carboxylic acid as a single enantiomer, they initially used the auxiliary methods of p. 1110 to make a small amount, but they found that ruthenium-catalysed hydrogenation was greatly to be preferred on a large scale just 22 g of the ruthenium-(5)-BINAP complex is needed to produce SO kg of product with 90% ee. 

In the last 20 years, the variety of ligands available for rhodium and ruthenium-catalysed hydrogenations has increased to the point where the right combination of metal and ligand will reduce almost any unsaturated carboxylic acid derivative in high enantiomeric excess. Details are beyond the scope of this book, but we leave you with four examples, all from industrial drug syntheses, to illustrate how versatile the method can be. 

An especially elegant industrial-scale access to enantiomericaUy enriched methyl dUiydrojasmonate is illustrated by the enantioselective ruthenium-catalysed hydrogenation of the corresponding cyclopentenone. 

A widely-reported method for the DKR of secondary alcohols and a- and p-hydroxy acid esters involves ruthenium catalysed hydrogenation. No additional base is required as a cocatalyst (and consequently base-catalysed transesterification can be avoided) because one of the ligand s oxygen atoms can act as a basic centre. A robust ruthenium complex (named Shvo s catalyst) along with a p-chlorophenylacetate was developed by the BackvaU group. The metal catalyst must be used in combination with thermostable enzymes because it is activated by heat (Scheme 4.26). This system (with CALB) has been successfully used for the DKR of many secondary alcohols and diols (Scheme 4.27) [52, 63, 64]. 

In 2000, Genet s group described an efficient formal synthesis of ( )-balanol, a natural produet showing remarkable inhibitory properties towards protein kinase This synthesis was based on the ruthenium-catalysed hydrogenation... 

The application of dynamic kinetic discrimination to the ruthenium-catalysed hydrogenation of cyclic ketones such as 2-arylated cycloalkanones was reported by Noyori s group in 2004. Hence, the asymmetric hydrogenation of various 2-arylcycloalkanones with tra s -RuCl2(BINAP)(l, 2-diamine) and t-BuOK in ijo-propyl alcohol selectively gave the corresponding cis-2-arylcycloalkanols in excellent enantiomeric purity and quantitative yield, as shown in Scheme 2.25. 

There are numerous examples of the application of rhodium and ruthenium catalysed hydrogenation of functionalised alkenes to the synthesis of pharmaceuticals. One such example is the hydrogenation of itaconate 3 in the synthesis of MMP-3 (Matrix Metallo Protease) inhibitor 5 (Scheme 14.3). Both rhodium and ruthenium catalysts were screened for the reduction of the free acid and carbojgrlate salts. It was found that rhodium catalysts performed well in the reduction of the free acid conversely the ruthenium catalysts were effective for the reduction of salts. Despite... 

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