Asymmetric Catalytic Hydrogenation of a-Acetamidocinnamic Acid Esters

Mechanism of Asymmetric Catalytic Hydrogenation of a-Acetamidocinnamic Acid Esters 

As described previously, the first commercial application of asymmetric hydrogenation was the Monsanto process for the manufacture of L-Dopa, developed by Knowles (Equation 10.23). L-Dopa is used to treat Parkinson s disease. For these reasons, Halpem and Brown studied the mechanism of this enantioselective process, and the results of these studies were particularly enlightening about how physical organic principles apply to asymmetric catalysis. This process was used as a case study in Chapter 14 to present how enantioselectivity is controlled. The findings are reiterated briefly here. 

Multinuclear NMR studies revealed the presence of only a single diastereomer (A or A ) for reactions of EAC with the rhodium complex of the chiral ligand (S,S)-CHIRAPHOS. One might assume that the product chirality is determined by this preferred mode of substrate binding. This would be a form of lock-and-key mechanism that has its origins in Fischer s early concepts of enz)unatic stereospecificity. This assumption, however, is incorrect. The predominant enantiomer of the product is actually formed from the minor diastereomer of the catalyst— namely, olefin adduct A. 

Two sets of data showed that the minor diastereomeric olefin complex generated the major enantiomer of the product. First, the structure of the major diastereomer of [Rh(S,S-CHIRAPHOS)(EAC)] was determined by single-crystal X-ray diffraction. The complex in this structure would form N-acetyl-(S)-phenylalanine ethyl ester, but tfie major enantiomer of the product was the (R)-isomer. Second, both diastereomers of the olefin complex were observed during the hydrogenation of MAC by the rhodium complex of (R,R)-DIPAMP. At temperatures low enough that these diastereomers do not interconvert, NMR studies showed that the minor diastereomer reacted much more rapidly with to form the reduced product than the major diastereomer. 

Free-energy diagram for the addition of hydrogen to the two different diastereomeric olefin adducts. 

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