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. 

There is little doubt that the hydrogenation of dehydro a-amino acids is the best-studied enantioselective catalytic reaction. This was initiated by the successful development of the L-dopa process by Knowles (see below) and for many years, acetylated aminocinnamic acid derivatives were the model substrates to test most newly developed ligands. As can be seen below, this is the transformation most often used for the stereoselective synthesis of a variety of pharma and... 

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). 

The scientific interest in the L-DOPA process was further enhanced by the clear, detailed elucidation of the mechanism of the catalytic reaction (10). To this date, thousands of papers and patents have been published on the subject of catalytic asymmetric hydrogenation. 

It must be noted that the enantioselectivity reached by the catalyst does not have to be absolute for industrial production. In this case 100% enantioselectivity of the product was obtained by crystallization. In the past, Selke in the former GDR independently developed a sugar based bis-phosphinite as a ligand which formed the basis for the L-DOPA process by the company VEB-Isis [69,... 

Enzymatic reduction, oxidation, ligase, or lyase reactions, especially, provide us with numerous examples in which prochiral precursor molecules are stereo-selectively functionalized. Ajinomoto s S-tyrosinase-catalyzed L-dopa process [112], the formation of L-camitine from butyro- or crotonobetaine invented by Lonza [113], and the IBIS naproxen route oxidizing an isopropylnaphthalene to an (S)-2-arylpropionic acid are representative, classic examples for many successful applications of enzymatic asymmetric synthesis on an industrial scale. A selection of recent industrial contributions in this field are summarized below. 

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... 

An analysis of Tab. 9 shows that hydrogenation/reduction and hydrolysis reactions are by far the predominant transformations (31 out of 38) that have successfully been developed to industrial processes. The most important reason for this fact is the broad scope of these reaction types. For the catalytic hydrogenation it could also be attributed to the early success of Knowles with the L-dopa process, because for many years most academic and industrial research was focused on this transformation. Concerning hydrolysis, important points might be the rather good substrate tolerance (low substrate specificity) and the availability of a number of commercial enzymes. 

At this point, we were strongly motivated to develop a commercial L-dopa process. It is a rare thing that the emergence of a substantial demand for a chemical is so closely timed with an invention for a new way of making it. Our management reluctantly increased our manpower but did not really believe we could do it until the hydrogenation was achieved on a 50 gallon scale without incident. 

Even in the best case, some racemic product is produced and must be separated out. This separation is easy or hard, depending on the nature of the racemate. If the racemic modification has a different crystalline form to that of the pure d or l, then separation of the pure excess enantiomer will be inefficient. If one achieves a 90% ee value, then it is quite possible to get out only 75-80% pure enantiomer. With lower ee values, the losses become prohibitive. For such a system, a catalyst of very high efficiency must be used. Unfortunately, most compounds are of this type their racemic modifications do not crystallize as pure d- or l-forms. If, on the other hand, the racemic modification is a conglomerate or an equal mix of d- and L-crystals, then recovery of the excess the L-form can be achieved with no losses. Since the l- and D,L-forms are not independently soluble, a 90% ee value easily gives a 90% recovery of pure isomer. In our L-dopa process, the intermediate is just such a conglomerate and separations are efficient. This lucky break was most welcome. If one thinks back, ours was the same luck that Pasteur encountered in his classical tartaric acid separations, 150 years ago. 

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

In January 1986 Isicom, a prescription drug used to treat the Parkinson syndrome, went on sale in the former German Democratic Republic. Isicom is a combination of L-dopa [L-dopa=(S)-3-(3,4-dihydroxyphenyl)-alanine] and L-carbidopa. For both components, new synthetic procedures were developed independently at the former Academy of Sciences of the GDR and the production of the active substances was realized at the former VEB ISIS-Chemie Zwickau. In this contribution the history and details of the development of the L-dopa process are recounted. For the commercial application of enantioselective catalysis, this is of some importance, since it was the first industrial process utilizing asymmetric complex catalysis to be realized in the former socialistic countries as well as in Europe. 

I would like to express my deeply felt thanks to Prof. H. Pracejus for development of the field of asymmetric catalysis and to the staff of the research department of the former VEB ISIS-Chemie in Zwickau, particularly Dr. W. Vocke and Dr. F.-U. Flother, for the elaboration of the industrial L-dopa process. For practical assistance I particularly thank Mrs. R. Pinske, Mrs. H. Bumeleit, DC H. Foken, Dr. H. Griiner, Dr. R. Hanel and DC G. Konig. I gratefully acknowledge the support of Prof. G. Oehme, Dr. C. Fischer and Dr. H. Dreycr particularly with respect to analytical problems. I am indebted to Prof. H.-W. Krause for useful advice in many instances. 

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. 

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