Enantioselection enamides

With the basic (albeit unconventional) tools at hand, we will focus in the following on the detection of key intermediates with standard NMR and the application of the PHIP method to mechanistic studies of enantioselective enamide hydrogenations. 

Figure 9.15 Rhodium monohydrides in enantioselective enamide hydrogenation that were characterized by conventional NMR spectroscopy.

A series of chiral binaphthyl ligands in combination with AlMe3 has been used for the cycloaddition reaction of enamide aldehydes with Danishefsky s diene for the enantioselective synthesis of a chiral amino dihydroxy molecule [15]. The cycloaddition reaction, which was found to proceed via a Mukaiyama aldol condensation followed by a cyclization, gives the cycloaddition product in up to 60% yield and 78% ee. 

In 2006, Berens et al. reported the synthesis of novel benzothiophene-based DuPHOS analogues, which gave excellent levels of enantioselectivity when applied as the ligands to the asymmetric rhodium-catalysed hydrogenation of various olefins, such as dehydroamino acid derivatives, enamides and itaco-nates (Scheme 8.10). ... 

Several S/N ligands have also been investigated for the asymmetric hydrogenation of prochiral olefins. Thus, asymmetric enamide hydrogenations have been performed in the presence of S/N ligands and rhodium or ruthenium catalysts by Lemaire et al., giving enantioselectivities of up to 70% ee. Two... 

The results clearly show that these novel ligands are able to form a suitable asymmetric enviromnent around the metal resulting in high asymmetric induction. Their catalytic potential has been demonstrated in the highly enantioselective Rh-catalyzed hydrogenation of itaconates and a-enamides and Ru-catalyzed hydrogenation of p-functionalized ketone. 

In the early 1990s, Burk introduced a new series of efficient chiral bisphospholane ligands BPE and DuPhos.55,55a-55c The invention of these ligands has expanded the scope of substrates in Rh-catalyzed enantioselective hydrogenation. For example, with Rh-DuPhos or Rh-BPE as catalysts, extremely high efficiencies have been observed in the asymmetric hydrogenation of a-(acylamino)acrylic acids, enamides, enol acetates, /3-keto esters, unsaturated carboxylic acids, and itaconic acids. 

A crucial achievement significantly stimulated the development of the investigation in the field of homogeneous enantioselective catalysis. The Knowles group established a method for the industrial synthesis of I-DOPA, a drug used for the treatment of Parkinson s disease. The key step of the process is the enantiomeric hydrogenation of a prochiral enamide, and this reaction is efficiently catalyzed by the air-stable rhodium complex [Rh(COD)((PP)-CAMP)2]BF4 (Scheme 1.12). 

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