Enantioselective Hydrogenation of Enamides

Substrate Ligand SCR Reaction conditionsa) TON TOF [h-1] % ee (config.) Refer- ence(s) 

Alkyl enamides, such as N-(1 -tert-bulyl-viriyl)-acelamide 88 and N-(l-adaman-tyl-vinyl)-acetamide 89, can also be hydrogenated in high enantioselectivity ( 99% ee) and activity (TON 5000 TOF 625 h ) with Rh-Me-DuPhos [19]. Remarkably, these bulky alkyl enamides are reduced with the opposite sense of induction, a phenomenon also observed when the bisphospholane Di Square P 63 was applied [87 b]. A computational modeling study by Landis and Feldgus suggested that the reduction of a-alkyl and a-arylenamides involves different coordination pathways [93, 158]. 

In addition to standard cyclic and acyclic enamides, the effective hydrogenation of several more unusual enamides has been reported (Fig. 24.13). A concise method for the synthesis of chiral yS-amino alcohols, amino oximes and chiral 1,2-diamines has been described by Burk et al. via the enantioselective hydroge- 

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Gridnev et al. studied the mechanism of the enantioselective hydrogenation of enamides with Rh-BisP" and Rh-MiniPHOS catalysts [22]. 

Enol esters have a similar structure as enamides. However, in contrast to many highly enantioselective examples on enantioselective hydrogenation of enamides, only a few successful results have been reported for the hydrogenation of... 

Fig. 31.15 Mechanism of the enantioselective hydrogenation of enamides by Ru BINAP, giving the opposite stereochemical course to the corresponding Rh catalyst. Note the heterolytic nature of the addition process with one of the two hydrogens arising from solvent.

Table 41.13 Enantioselective hydrogenation of enamides catalyzed by Rh-Taniaphos in various ionic liquids/water combinations and in conventional solvents [104].

Chiral rhodium-DuPHOS complexes are highly efficient catalyst for the enantioselective hydrogenation of enamides. One drawback of these catalysts is that they are easily oxidised and inert conditions are required for optimal results. The methyl- and ethyl substituted Rh-DuPHOS compounds, 3a and 3b, have been successfully applied in the reduction of a-acetamidocinnamic acids in [C4Ciim][PF6], Scheme 3.7.[7,39] While activities and selectivities are slightly lower compared to the homogeneous reaction in 2-propanol, the ionic liquid-immobilised catalyst is less prone to oxidation and recycling is feasible at least three times. 

Scheme 3 Enantioselective hydrogenation of enamides to give amino acids...

A highly enantioselective hydrogenation of enamides (152) to afford amines (153), catalyzed by a dual chiral-achiral acid system has been developed by Antilla and Liu (Scheme 41). By employing a substoichio-metric amount of the chiral phosphoric acid (154) and acetic acid, the catalyst loading as low as 1 mol %, excellent chemical yields and enan-tioselectivities of the reduction products (153) were obtained. 

Scheme 2.46 Enantioselective hydrogenation of enamides with the use of chiral heterobimetallic potassium(i)-crown ether rhodium(i) catalysts.

The insertions of enamides into rhodium hydrides have also been studied in detail (Equation 9.46). " In this case, oxidative addition of dihydrogen occurs to the olefin complex to generate the intermediate containing ds olefin and hydride ligands. This reaction controls the stereochemical outcome of enantioselective hydrogenations of enamides to form a-amino acids presented in Chapter 15. As noted in this chapter, the oxidative addition forms two diastereomeric complexes, and the less abundant diastereomer reacts much faster and forms the more abimdant enantiomeric amino acid produd. 

Kitamura M, Hsiao Y, Ohta M, Tsukamoto M, Ohta T, Takaya H, Noyori R (1994) General asymmetric synthesis of isoquinoline alkaloids. Enantioselective hydrogenation of enamides catalyzed by BINAP-ruthenium(II) complexes. J Oig Chem 59 297-310... 

Enantioselective hydrogenation of enamides is a well-established transformation. The corresponding reduction of enamines has been elusive. Qi-Lin Zhou of Nankai University designed (J. Am. Chem. Soc. 2009,131, 1366) an Ir catalyst that reduced 2 to the Carpus alkaloid Crispine A 3 in high ee. 

Enantioselective hydrogenation of enamide 113 to corresponding amino acid derivative 114 in the presence of... 

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