Asymmetric Hydrogenations - The Monsanto L-Dopa Process

Knowles, W. S. Asymmetric hydrogenations — The Monsanto L-Dopa process. In Blaser, H.-U., Schmidt, E. (Eds.), Asymmetric Catalysis on Industrial Scale. Wiley-VCH, Weinheim, 2004, p. 23. 

Knowles, W.S. (2007) Asymmetric hydrogenations - the Monsanto L-Dopa process, in Asymmetric Catalysis on Industrial Scale Challenges, Approaches and Solutions (eds H.U. Blaser and... 

Asymmetric Hydrogenations - The Monsanto L-Dopa Process COOH NHCOCH3... 

In the late sixties, several research groups in the U.S. (6), Europe (7), and Japan (8) initiated studies of homogeneous catalytic asymmetric syntheses. Of these efforts, the catalytic asymmetric hydrogenation of prochiral olefins reported by Knowles, et al. (6,9) attracted most attention. The importance of this technology was shown by its application in the Monsanto L-DOPA process which had since become an industrial flagship in catalytic asymmetric syntheses (Figure 1). 

An early success story in the field of catalytic asymmetric synthesis is the Monsanto Process for the commercial synthesis of l-DOPA (4) (see Scheme 1), a rare amino acid that is effective in the treatment of Parkinson s disease.57 The Monsanto Process, the first commercialized catalytic asymmetric synthesis employing a chiral transition metal complex, was introduced by W. S. Knowles and coworkers and has been in operation since 1974. This large-scale process for the synthesis of l-DOPA (4) is based on catalytic asymmetric hydrogenation, and its development can be... 

Chapter 2 to 6 have introduced a variety of reactions such as asymmetric C-C bond formations (Chapters 2, 3, and 5), asymmetric oxidation reactions (Chapter 4), and asymmetric reduction reactions (Chapter 6). Such asymmetric reactions have been applied in several industrial processes, such as the asymmetric synthesis of l-DOPA, a drug for the treatment of Parkinson s disease, via Rh(DIPAMP)-catalyzed hydrogenation (Monsanto) the asymmetric synthesis of the cyclopropane component of cilastatin using a copper complex-catalyzed asymmetric cyclopropanation reaction (Sumitomo) and the industrial synthesis of menthol and citronellal through asymmetric isomerization of enamines and asymmetric hydrogenation reactions (Takasago). Now, the side chain of taxol can also be synthesized by several asymmetric approaches. 

Catalytic asymmetric hydrogenation processes have been at the forefront of practical applications. Following the classical Monsanto s L-DOPA production using DiPAMP-Rh catalyst, BINAP-Ru catalysts have been used in the industrial synthesis of a P-lactam key intermediate to caibapenem antibiotics (Takasago Int. Corp.), 1,2-propanediol (50 tons/year),... 

Homogeneous hydrogenation is used in polymer synthesis, the hydrogenation of aldehydes to alcohols (oxo process), in asymmetric hydrogenation (L-dopa, Monsanto), and for the hydrogenation of benzene to cyclohexane (Procatalyse). 

From a historical perspective, the Monsanto process for the preparation of (l.)-DOPA in 1974 laid the foundation stone for industrial enantioselective catalysis. Since then it has been joined by a number of other asymmetric methods, such as enantioselective Sharpless epoxidation (glycidol (ARCO) and disparlure (Baker)), and cyclopropanation (cilastatin (Merck, Sumitomo) and pyre-throids (Sumitomo)). Nevertheless, besides the enantioselective hydrogenation of an imine for the production of (S)-metolachlor(a herbicide from Syngenta), the Takasago process for the production of (-)-menthol remains since 1984 as the largest worldwide industrial application of homogeneous asymmetric catalysis. [124]... 

One of the first asymmetric catalysts to be successfully employed for asymmetric synthesis was the rhodium complex of (12.372a), due to Knowles [12,56], This ligand, which contains two asymmetric P atoms, was used in the Monsanto process for the production of L-amino acids by asymmetric hydrogenation of acylamino-acrylic acids. Only the L isomer, namely L-dopa is effective in the treatment of Parkinson s disease, and the synthesis of this compound by the route (12.374) represents an early commercial success [48]. The synthesis of L-dopa in yields of up to 95% optical purity can also be secured with the rhodium complex of (12.372b), the asymmetry of the catalyst in this case arising from the C atoms. 

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. 

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