Unfunctionalised ketones

A range of different functional groups has been introduced into the V-position of the C3 side chain, as shown in Table 6.10. A number of different functionalities were shown to be tolerated in this position, with lipophilic groups such as methyl and dithiolane being preferred over polar groups such as ketones and alcohols. Ketone (118) had similar CBi receptor affinity to the unfunctionalised -heptyl compound (84), while alcohol (120) had lower affinity. The phenyl ketone (119) had lower CBi receptor affinity than the simple benzyl-substituted compound (116), but higher CB2 affinity, with about 12-fold selectivity for CB2 over CBi. 

The reduction of the carbonyl group (and related functionalities) by catalytic methods has been successfully achieved by a number of methods. Rhodium and ruthenium complexes are the most popular catalysts used in the hydrogenation of ketones. While most catalyst systems of this type require the presence of additional chelating functionality on the substrate the recent development of highly active ruthenium(diamine) complexes allows the reduction of simple unfunctionalised ketones. Ruthenium catalysts have also been applied, with much success, to the catalytic asymmetric transfer hydrogenation of ketones in the presence of alcohols or formate. 

The hydrogenation of unfunctionalised ketones has, in the past, proved challenging. However, Noyori and coworkers have discovered that the activity of ruthenium-based ketone hydrogenation catalysts can be greatly improved on incorporation of... 

The enantioselectivity in the TH of prochiral aryl ketones catalysed by (arene)Ru(II) complexes depends not only on the chiral nature of the amine ligand but also on the edge-face C-H/tc interaction which stabilises the electron-rich (usually aromatic) ring of a substrate in a specific orientation as presented with TSl (Fig. 5) [43]. This interaction may explain why aryl ketones usually give better ee values than simple unfunctionalised alkyl-alkyl ketones. 

Subsequent to this, other catalyst systems have been shown to give high enantioselectivities for unfunctionalised ketones, such as Ru-(phosphine-oxazoline) systems and a Rh-PennPhos catalyst in combination with KBr and 2,6-lutidine. ... 

Figure 14.4 Ru-catalysed asymmetric hydrogenation of unfunctionalised ketones.

---