Subject asymmetric hydrogenation

Clearly, considering the number of variable parameters, the matching of substrates and catalysts to give high selectivity is at this stage somewhat of an empirical art and perhaps mimics in this respect its twin subject, asymmetric hydrogenation (Section III) they were both born in 1968- 1969. 

One of the success stories of transition metal catalysis is the rhodium-complex-catalyzed hydrogenation reaction. Asymmetric hydrogenation with a rhodium catalyst has been commercialized for the production of L-Dopa, and in 2001 the inventor, Knowles, together with Noyori and Sharpless, was awarded the Nobel Prize in chemistry. After the initial invention, (enantioselective) hydrogenation has been subject to intensive investigations (27). In general, hydrogenation reactions proceed... 

Kissel, Ramsden, and other researchers at Pfizer and Chirotech jointly published a novel chiral synthesis of pregabalin (2) in 2003 based on asymmetric hydrogenation (Burk et al., 2001, 2003). Their synthesis started with the condensation of isobutyralde-hyde with acrylonitrile under Baylis-Hillman conditions to give allylic alcohol 65. This alcohol was activated as the carbonate 66 and subjected to palladium-catalyzed car-bonylation conditions to give cyanoester 67. The ester 67 was hydrolyzed and converted to... 

Several recent reviews on catalytic asymmetric hydrogenation are available. The mechanistic studies have been summarized by Halpern.81,259 The synthesis and use of phosphorus(III) ligands have been reviewed by Horner.270 Ferrocene-based and nitrogen-containing phosphorus ligands have also been covered.271 General reviews of the subject have appeared.272"275... 

Despite fruitful results of asymmetric hydrogenation of functionalized ketones, only limited examples have been reported for reaction of ketonic substrates with no functionality near the carbonyl group [1,162,254]. Transition-metal catalysts with a bidentate chiral phosphine, successfully used for functionalized ketones, are often ineffective for reduction of simple ketones in terms of reactivity and enantioselectivity [162b,c]. However, a breakthrough in this subject has been provided by the invention of a new chiral Ru catalyst system. 

The scientific interest in the L-DOPA process was further enhanced by the clear, detailed elucidation of the mechanism of the catalytic reaction (10). To this date, thousands of papers and patents have been published on the subject of catalytic asymmetric hydrogenation. 

There is no doubt that catalytic asymmetric synthesis has a significant advantage over the traditional diastereomeric resolution technology. However, it is important to note that for the asymmetric hydrogenation technology to be commercially useful, a low-cost route to the precursor olefins is just as crucial. The electrocarboxylation of methyl aryl ketone and the dehydration of the substituted lactic acids in Figures 5 and 6 are highly efficient. Excellent yields of the desired products can be achieved in each reaction. These processes are currently under active development. However, since the subjects of electrochemistry and catalytic dehydration are beyond the scope of this article, these reactions will be published later in a separate paper. 

Asymmetric hydrogenation of bromo-substituted aromatic a-enamides 14 affords the corresponding bromo-amino acid derivatives 15, which subsequently is subjected to Pd-catalyzed cross-coupling with aryl and vinyl boronic acids. In addition to diverse phenylalanine derivatives 16, a broad array of other novel aromatic and heterocyclic amino acids have been produced rapidly from a small number of bromo-functionalized intermediates [24], This same two-step process may be applied to the production of many other classes of aromatic and heterocyclic chiral building blocks, such as arylalkylamines, amino alcohols, diamines, and directly on peptides as well. 

More recently, we have found that virtually all substrate types highlighted in this chapter may be subjected to asymmetric hydrogenation in SC-CO2 [36]. Enantioselectivites achieved in SC-CO2 are very high and are comparable to those observed in conventional solvents. The only limiting feature unveiled thus far appears to be substrate solubility in the supercritical fluid (CO2 is a very nonpolar solvent). 

Pinacolatoborylalkenes are subject to asymmetric hydrogenation using (nbd)2RhBF4 and... 

Alkylrhodiums form from the reaction of Rh hydrides and alkenes. This reaction is important in hydrogenation, asymmetric hydrogenation, alkene isomerization and hydroformylation and other catalytic processes. The regiochemistry seen in this reaction is the subject of theoretical study that rationalizes the formation of the less substituted (T-alkyrhodium intermediate on electronic grounds Several Rh complexes form stable ff-alkylrhodiums on reaction of Rh hydrides with fluorinated alkenes (see Table 8) . 

Asymmetric hydrogenation of (3-keto esters has been very successful using chiral Ru catalysts and a detailed review on this subject is available.1 The BINAP-Ru catalyst gives high enantioselectivity on a variety of (3-keto esters.228 Furthermore, a Josiphos-Rh complex is found to be effective for hydrogenation of ethyl 3-oxobutanoate 76 to afford p-hydroxy ketone 77 with good enantioselectivity.34... 

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