Ketones asymmetric homogeneous hydrogenation

The Stereochemistry of Hydrogenation of , -Unsaturated Ketones Robert L. Augustine Asymmetric Homogeneous Hydrogenation J. D. Morrison, W. F. Masler, and M. K. Neuberg... 

The presence of an NH2 group in the diamine is crucial. Mechanistic studies have shown, unlike other asymmetric homogeneous hydrogenation catalysts, that the ketone substrate does not coordinate to the metal but interacts with the NH2 group and the metal hydride, as shown in the transition state (Figure 12.7). The steric environment of the overall catalyst provides excellent facial stereodifferentiation.194... 

FIG. 19. Asymmetric homogeneous hydrogenation of a ketone in the synthesis of prostaglandin Ej. ACMP = o-anisylcyclohexylmethylphosphine. 

Keywords Asymmetric hydrogenation, Asymmetric transfer hydrogenation, BINAP, Chiral alcohols, Chiral amines, Homogeneous catalysts, Simple ketones... 

Asymmetric reduction of ketones by catalytic homogeneous hydrogenation can be carried out with very high selectivity in many cases and is described below. 

Asymmetric Transfer Hydrogenation of Ketones. The first reports on asymmetric transfer hydrogenation (ATH) reactions catalyzed by chiral metallic compounds were published at the end of the seventies. Prochiral ketones were reduced using alcohols as the hydrogen source, and Ru (274,275) or Ir (276) complexes were used as catalysts. Since then, many chiral catalytic systems for homogeneous ATH of ketones, imines, and olefins have been developed (37,38,256,257,277-289). The catalytic systems are usually based on ruthenium, rhodium, or iridium, and the ATH of aryl ketones is by far the most studied. Because of the reversibility of this reaction, at high conversions, a gradual erosion of the ee of the product has been frequently reported. An azeotropic 5 2 mixture of formic acid/triethylamine can be used to overcome this limitation. 

In 1997, chemists from the Process Exploration Labs at Bristol-Myers Squibb Company reported their development of a simple asymmetric synthesis of d-sotalol 105, a Class III antiarrythmia compound, utilising a CBS reduction as the key step (Scheme 14.34). ° Previous efforts towards synthesis of d-sotalol had utilised techniques such as mandelic acid resolution, chiral chromatography and use of chiral homogeneous hydrogenation. The synthesis of d-sotalol via a CBS reduction is of interest as the molecule contains a methanesulfonamide NH proton, which clearly does not interfere with the yield or enantioselectivity of the process despite the acidic nature of this substituent. The authors discuss the various elements of the reduction process that they investigated and conclude that the optimal procedure involves addition of 1 M BH3 THE over a few minutes to a mixture of the (5 )-2-MeCBS catalyst and substrate ketone 102 in MTBE held at room temperature. Under these reaction conditions (on a 1.8 mmol scale), alcohol 103 was obtained in 92% yield with 96% ee. In this instance, the enantiomeric excess was calculated by conversion of the alcohol product to... 

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