Asymmetric hydrogenation enol esters

The DKR processes for secondary alcohols and primary amines can be slightly modified for applications in the asymmetric transformations of ketones, enol esters, and ketoximes. The key point here is that racemization catalysts used in the DKR can also catalyze the hydrogenation of ketones, enol esters, and ketoximes. Thus, the DKR procedures need a reducing agent as additional additive to enable asymmetric transformations. 

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. 

The rhodium-catalyzed enantioselective hydrogenation of enol esters is an alternative to the asymmetric reduction of ketones. Although enol esters are accessible both from ketones and alkynes, the number of studies reporting successful asymmettic hydrogenation has been limited. It appears that, compared... 

Reetz and Goossen et al. reported recently the asymmetric hydrogenation of a series of enol esters using monodentate phosphite ligands 17 and 24 based on a combination of BINOL and carbohydrates or simple alcohols the results of these studies are shown in Table 28.6. 

Asymmetric Hydrogenation of Enol Esters. Prochiral ketones represent an important class of substrates. A broadly effective and highly enantioselective method for the asymmetric hydrogenation of ketones can produce many useful chiral alcohols. Alternatively, the asymmetric hydrogenation of enol esters to yield a-hydroxyl compounds provides another route to these important compounds. 

While Rh-DuPhos mediated asymmetric hydrogenation of acyclic enol esters shows high levels of enantioselectivity, it does not provide the same high... 

The asymmetric hydrogenation of enol esters can also be catalyzed by chiral amidophosphine phosphinite catalysts derived from chiral amino acids, but the enantioselectivity of these reactions has thus far been only moderate.35... 

Although enol esters have a similar structure to enamides, they have proven more difficult substrates for asymmetric hydrogenation, which is evident from the significantly fewer number of examples. One possible explanation is the weaker coordinating ability of the enol ester to the metal center, as compared to the corresponding enamide. Some rhodium complexes associated with chiral phosphorous ligands such as DIPAMP [100, 101] and DuPhos [102] are effective for asymmetric hydrogenation of a-(acyloxy)acrylates. 

The asymmetric hydrogenation of enol esters is an alternative to asymmetric ketone hydrogenation. The precursors can be prepared from the ketones but also via ruthenium-catalyzed addition of the carboxylic acids to the 2-postion of terminal alkynes. This latter method allows the study of the effect of the carboxylate on the enantioselectivity of the asymmetric hydrogenation. A remarkable study by Reetz and colleagues established that it is possible to hydrogenate enolate... 

Hydrogenation of Enol Esters. In addition to the high activity and excellent enantioselectivity being obtained in the asymmetric... 

A chiral ligand system based on C2-symmetric chiral bis(phospholanes) (5 and 6) has shown to be a powerful ligand in the asymmetric hydrogenation of various substrates that include enamides, enol acetates, C=N bond reduction, and P-keto esters. Detailed discussions of this class of ligands are included Chapter 18. 

Freskos reported the synthesis of chiral succinate using Pd-catalyzed carbonylation of enol triflate 26 (Scheme 18) followed by asymmetric hydrogenation of resulting a,/3-unsaturated ester 27 using a ruthenium complex. - " In the absence of HCOOH, the yield was low (15-20%). Similarly, when water was substituted for formic acid, low product yields (15-20%) were observed. As one possible pathway to produce 27, reductive elimination from the palladium complex to yield a mixed anhydride derived from the product and triflic acid would be considered. 

In the early 1990 s, Burk at Dupont spearheaded the development of new classes of biphospholane ligands - BPE (130) and DuPHOS (131) - that have significantly expanded the field of enantioselective hydrogenations [96-98]. As illustrated below, both enol esters (132, Equation 37) [96] and enamides (134, Equation 38) [97] were subjected to asymmetric reduction in the presence of Burk s catalysts to give the products in superb optical purities. An additional important feature of these systems is that the reductions can be conducted with mixtures of ( )- and (Z)-olefins, affording the same product in a stereoconvergent manner [96-98]. 

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