Ketones asymmetric hydrogenation, molecular

In summary, the asymmetric hydrogenation of olefins or functionalized ketones catalysed by chiral transition metal complexes is one of the most practical methods for preparing optically active organic compounds. Ruthenium and rhodium-diphosphine complexes, using molecular hydrogen or hydrogen transfer, are the most common catalysts in this area. The hydrogenation of simple ketones has proved to be difficult with metallic catalysts. However,... 

The above mechanism is novel in that it does not require the interaction of a carbonyl moiety with the metal center. Neither a ketone/Ru complex nor a Ru alkoxide is involved in the mechanism, and the alcohol forms directly from the ketone. This non-classical mechanism also explains the high functional selectivity for the C=0 group. When the chiral molecular surface of the Ru hydride recognizes the difference of ketone enantiofaces, asymmetric hydrogenation is achieved. This is different from the earlier BINAP Ru chemistry where the enantio-face differentiation is made within the chiral metal template with the assistance of heteroatom/metal coordination. Similar heterolyses of H2 ligands have been shown by Morris and others (92) to be the critical step in the mechanism of reaction processes related to the Noyori systems. 

Asymmetric hydrogen transfer shows promise for use at industrial scale as ruthenium complexes that contain chiral vicinal diamino (64) or amino alcohol (65) ligands allow the reductions of substrates such as aryl ketones and imines to be achieved under mild conditions compared to the high pressures required when molecular hydrogen is used [13,81],... 

Homogeneous catalytic asymmetric hydrogenation has become one of the most efficient methods for the synthesis of chiral alcohols, amines, a and (3-amino acids, and many other important chiral intermediates. Specifically, catalytic asymmetric hydrogenation methods developed by Professor Ryoji Noyori are highly selective and efficient processes for the preparation of a wide variety of chiral alcohols and chiral a-amino acids.3 The transformation utilizes molecular hydrogen, BINAP (2,2 -bis(diphenylphosphino)-l,l -binaphthyl) ligand and ruthenium(II) or rhodium(I) transition metal to reduce prochiral ketones 1 or olefins 2 to their corresponding alcohols 3 or alkanes 4, respectively.4... 

More recently Noyori developed asymmetric hydrogenation of simple ketones with BlNAP/diamine-ruthenium complexes.In this system the catalytic process contrasted with the conventional mechanism of asymmetric hydrogenation of unsaturated bonds which requires metal-substrate 7t-complexation. In fact with BlNAP/diamine-ruthenium neither the ketone substrate nor the alcohol product interacted with the metallic centre during the catalytic cycle. The enantiofaces of the prochiral ketones were differentiated on the molecular surface of the coordinatively saturated RuH intermediate. 

A similar argument about prediction of predominant configuration of products in asymmetric hydrogenation and hydrosilylation has been reported [49]. Inspection of CPK-molecular models for (H-)-DIOP-rhodium(I) system makes the author suggest VII as a model suffering the least steric hindrance in asymmetric addition of a dihydrosilane to a ketone. 

Preparation of enantiopure chiral molecules by transformation of prochiral substrates can offer the most elegant of available approaches, especially when the source of chirality is a man-made chemical catalyst rather than a reagent used in stoichiometric quantitites. Tremendous effort has been devoted to the development of asymmetric synthesis methodology, with notable success in the fields of asymmetric hydrogenation [98], hydride reduction of ketones [99], epoxidation [100] and dihydroxylation [101] of alkenes. In constrast to the enzymes which are used in organic synthesis, man-made chiral catalysts [102] are much simpler molecular entities and are routinely available in both enantiomeric forms. Since reactions employing such catalysts usually follow a predictable course, the correct form can be chosen for the desired product configuration. 

R. Noyori and T. Ohkuma, Asymmetric Catalysis by Architectural and Functional Molecular Engineering Practical Chemo- and Stereoselective Hydrogenation of Ketones , Angew. Chem. Int. Ed. Engl, 2001, 40, 40. 

The catalytic alcohol racemization with diruthenium catalyst 1 is based on the reversible transfer hydrogenation mechanism. Meanwhile, the problem of ketone formation in the DKR of secondary alcohols with 1 was identified due to the liberation of molecular hydrogen. Then, we envisioned a novel asymmetric reductive acetylation of ketones to circumvent the problem of ketone formation (Scheme 6). A key factor of this process was the selection of hydrogen donors compatible with the DKR conditions. 2,6-Dimethyl-4-heptanol, which cannot be acylated by lipases, was chosen as a proper hydrogen donor. Asymmetric reductive acetylation of ketones was also possible under 1 atm hydrogen in ethyl acetate, which acted as acyl donor and solvent. Ethanol formation from ethyl acetate did not cause critical problem, and various ketones were successfully transformed into the corresponding chiral acetates (Table 17). However, reaction time (96 h) was unsatisfactory. 

After succeeding in the asymmetric reductive acylation of ketones, we ventured to see if enol acetates can be used as acyl donors and precursors of ketones at the same time through deacylation and keto-enol tautomerization (Scheme 8). The overall reaction thus corresponds to the asymmetric reduction of enol acetate. For example, 1-phenylvinyl acetate was transformed to (f )-l-phenylethyl acetate by CALB and diruthenium complex 1 in the presence of 2,6-dimethyl-4-heptanol with 89% yield and 98% ee. Molecular hydrogen (1 atm) was almost equally effective for the transformation. A broad range of enol acetates were prepared from ketones and were successfully transformed into their corresponding (7 )-acetates under 1 atm H2 (Table 19). From unsymmetrical aliphatic ketones, enol acetates were obtained as the mixtures of regio- and geometrical isomers. Notably, however, the efficiency of the process was little affected by the isomeric composition of the enol acetates. 

Noyori, R. and Okhuma, T. (2001) Asymmetric catalysis by architectural and functional molecular engineering practical chemo- and stereoselective hydrogenation of ketones. Angewandte Chemie-International Edition, 40 (1), 40-73. 

Application of Molecular Orbital Theory to Catalysis Roger C. Baetzold The Stereochemistry of Hydrogenation of aj3-Unsaturated Ketones Robert L. Augustine Asymmetric Homogeneous Hydrogenation... 

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