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. 

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). 

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... 

The Monsanto L-dopa process The other L-dopa process... 

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

This idea clearly was inspired by the successful L-dopa process of Monsanto [4]. At that time, little was known about the effects of the substituents at the C=C bond and the amide nitrogen. A selective synthesis of one of the three possible enamide isomers depicted in Fig. 3 looked difficult. 

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... 

Monsanto (2) A catalytic process for synthesizing the drag L-DOPA. The catalyst is a chiral diphosphine-rhodium complex. Invented in the early 1970s. 

According to Knowles [28], Monsanto has been producing L-dopa, a drug to relieve Parkinson s disease, on the scale of ca. 1 ty-1 for many years. A few years after Monsanto, the East-German company VEB Isis-Chemie also carried out this process on a similar scale but terminated the production after a few years [29]. The key step in the synthesis is the enantioselective hydrogenation of an enamide intermediate (Fig. 37.3). 

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. 

L-Dopa was produced industrially by Hoffrnann-LaRoche, using a modification of the Erlenmeyer synthesis for amino acids. In the 1960s, research at Monsanto focused on increasing the L-Dopa form rather than producing the racemic mixture. A team led by William S. Knowles (1917—) was successful in producing a rhodium-diphosphine catalyst called DiPamp that resulted in a 97.5% yield of L-Dopa when used in the Hoffrnann-LaRoche process. Knowles s work produced the first industrial asymmetric synthesis of a compound. Knowles was awarded the 2001 Nobel Prize in chemistry for his work. Work in the last decade has led to green chemistry synthesis processes of L-Dopa using benzene and catechol. 

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),... 

H,H)-D PAMP-Rh complex, 95% ee Figure 3.27 a Chemical structure and 3D representation of l-DOPA b of the chiral ligands tested by Monsanto with their corresponding ee values cthe Rh complex used in the large-scale commercial process. 

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