Asymmetric hydrogenation applications

The first application involving a catalytic reaction in an ionic liquid and a subsequent extraction step with SCCO2 was reported by Jessop et al. in 2001 [9]. These authors described two different asymmetric hydrogenation reactions using [Ru(OAc)2(tolBINAP)] as catalyst dissolved in the ionic liquid [BMIM][PFg]. In the asymmetric hydrogenation of tiglic acid (Scheme 5.4-1), the reaction was carried out in a [BMIM][PF6]/water biphasic mixture with excellent yield and selectivity. When the reaction was complete, the product was isolated by SCCO2 extraction without contamination either by catalyst or by ionic liquid. 

In recent years, the catalytic asymmetric hydrogenation of a-acylamino acrylic or cinnamic acid derivatives has been widely investigated as a method for preparing chiral a-amino acids, and considerable efforts have been devoted for developing new chiral ligands and complexes to this end. In this context, simple chiral phosphinous amides as well as chiral bis(aminophosphanes) have found notorious applications as ligands in Rh(I) complexes, which have been used in the asymmetric hydrogenation of a-acylamino acrylic acid derivatives (Scheme 43). 

I. M. Thommen, Homogeneous asymmetric hydrogenation Mature and fit for early stage drug development. Specialty Chemicals Magazine, May (2005). Hans-Ulrich Blaser, Felix Spindler and Marc Thommen, Industrial Applications m Handbook of Homogeneous Hydrogenation, (ed. J.G. de Vries and C. J. Elsevier), Wiley, (2007). 

This chapter discusses the development of scaleable and robust manufacturing processes for rhodium and rathenium containing precatalysts that are used for the asymmetric hydrogenation of a diverse range of olefins, ketones and imines. The application of these precatalysts to the preparation of a variety of pharmacentical intermediates, many of which have been operated on commercial scale, is also discussed. 

The use of an analogous (S)-BINAP-Ru-diacetate catalyst with axial chirality has led to important industrial applications, such as the synthesis developed by Monsanto where the asymmetric hydrogenation is involved in the last step to yield naproxen, a widely prescribed, non-steroidal, anti-inflammatory drug (Equation (9)).96... 

Oheme and co-workers investigated335 in an aqueous micellar system the asymmetric hydrogenation of a-amino acid precursors using optically active rhodium-phosphine complexes. Surfactants of different types significantly enhance both activity and enantioselectivity provided that the concentration of the surfactants is above the critical micelle concentration. The application of amphiphilized polymers and polymerized micelles as surfactants facilitates the phase separation after the reaction. Table 2 shows selected hydrogenation results with and without amphiphiles and with amphiphilized polymers for the reaction in Scheme 61.335... 

Enantiomencally pure (+)- and (-)-diphenylethylenediamines have recently been used for highly stereoselective Dlels-Alder, aldol,8 allylation,9 osmylation,10 and epoxidafion11 reactions. Other synthetic applications involve enantioselective Michael addition12 and asymmetric hydrogenation.13... 

A series of non-f, -symmetrical ferrocene-based 1,5-diphosphane ligands (TaniaPhos) has been developed by Knochel.88,88a,88b The ligands have been effectively used in Rh- or Ru-catalyzed asymmetric hydrogenations. The ligand 39, which has an MeO group at the chiral carbon center, has shown excellent applications in the hydrogenation of several olefin and ketone substrates.89 Weissensteiner and Spindler have reported a series of structurally different... 

Applications of Chiral Phosphorus Ligands in Asymmetric Hydrogenation... 

Gridnev et al. showed in their study of the asymmetric hydrogenation of en-amides by Rh-catalysts another useful application of coupling constant patterns. By selectively labeling certain atoms, for example with 13C or 2D, additional couplings appear (as compared to the non-labeled product) and this will provide information about the exact structure [22]. 

In general, applications of AMPP have concentrated on the asymmetric hydrogenation of functionalized olefins, especially dehydroamino acids. Among... 

Since monodentate phosphoramidites are so successful in asymmetric hydrogenation - both because of their performance and their ease of preparation - a logical extension is their application in recyclable systems. Doherty et al. were the first to prepare polymer-supported phosphoramidites by using the monomers 40 and 41 (Scheme 28.12) these led to high ee-values which fell somewhat upon polymerization [78]. The catalyst was shown to be capable of being recycled at least four times. 

Nevertheless, there remains a plethora of substrates that have not yet been studied using the monodentate ligand approach. In the application of asymmetric hydrogenation, it is very important to go beyond the benchmark substrates, and several studies have already shown that the scope of enantioselective hydrogenation might be much broader than was originally assumed. 

In chiral ligand 24, the two cyclopentane rings restrict the conformational flexibility of the nine-membered ring, and the four stereogenic centers in the backbone dictate the orientation of the four R-phenyl groups. Scheme 6 15 shows the application of Rh-24 in the asymmetric hydrogenation of dehy-droacylamino acids. 

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