Enamides reductive

Scheme 9.15 Proposed asymmetric enamide reduction to generate taranabant.

The cost of the ligand and catalyst preparation can be critical in the decision to pursue technical transfer to manufacturing stage. Fortunately, the high reactivity of [Rh(COD)(/ ,/ -DIPAMP)]+BF4-(13) in most enamide reductions can offset the high price, low yield synthesis of DIPAMP. 

Other methods were therefore investigated for enamide reduction. 

Although this route did allow access to reasonable quantities of the required protected kainoid analogues 112 to 115, a more stereoselective route was thought to be more desirable, and hence, two further enamide reduction methods were explored. 

The intention was to produce the pyridone moieties toward the end of the synthetic scheme, hence the catechol protecting groups chosen were benzyl with the intention of removing them during the hydroxyl-directed enamide reduction step. 

The first step required was the stereoselective reduction of enamide 184 to give the necessary C-3/C-4 cis stereochemistry. To enable the use of the hydroxyl group directed hydrogenation described in the section on Hydroxyl-Group-Directed Enamide Reduction, enamide 184 was... 

Fig. 5 Mechanism of enamide reductions with Knowles catalyst.

Zhang Catalytic Enantioselective N-acyl-a-Aryl-Enamide Reductions... 

The MonoPhos family of ligands for the reduction of C-C double bonds, including enamides, is based on the 2,2-bisnaphthol (BINOL) backbone. These phosphoramidite ligands are comparatively inexpensive to prepare compared to bisphosphine ligands. For enamide reductions with MonoPhos (20) as ligand, it was found that the reaction is strongly solvent dependent. Very good enantioselectivities were obtained in nonprotic solvents. - ... 

The reduction of a-(aryloxy)acrylates has been reported with the Rh/DUPHOS (2.05) catalyst. Interestingly, the substrate (2.48) was used as a 3 1 ( )/(Z) mixture, but the enantioselectivity is still very high in the product (2.49). When this reaction was attempted using benzene as solvent, no product was formed, even though benzene is a suitable solvent for enamide reduction. This was attributed to coordination of the benzene to the cationic rhodium complex. The enol ester is not able to displace the benzene, whilst an enamide can do so. 

Nugent, T. C. El-Shazly, M. Chiral amine synthesis—Recent developments and trends for enamide reduction, reductive amination, and imine reduction. Adv. Synth. Catal. 2010,352, 753-819. 

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