Oggi , 14, Aratani in Comprehensive Asymmetric Catalysis E. Jacobsen, H. Yamamoto, A. Pfaltz, Eds. Aratani, Pure Appl. Schmid, M. Scalone in Comprehensive Asymmetric Catalysis E. Schmid, E. Schmid, unpublished results. Brown, H. Broger, W. Burkart, M. Cereghetti, Y. Crameri, J. Foricher, M. Henning, F. Kienzle, F. Montavon, G.
Schoettel, D. Tesauro, S.
Wang, R. Zell, U. Foricher, U. Hengartner, C. Jenni, F. Kienzle, H. Ramuz, M. Scalone, M. Schlageter, R. Schmid, S. Wang, Chimia , 51, Hiebl, H. Kollmann, F. Rovenszky, K. Winkler, J. Knowles Abstract The development of catalysts for asymmetric hydrogenation began with the concept of replacing the triphenylphosphane ligand of the Wilkinson catalyst with a chiral ligand.
With these new catalysts, it should be possible to hydrogenate prochiral olefins. Knowles and his co-workers were convinced that the phosphorus atom played a central role in this selectivity, as only chiral phosphorus ligands such as R,R -DIPAMP, the stereogenic center of which lies directly on the phosphorus atom, lead to high enantiomeric excesses when used as catalysts in asymmetric hydrogenation reactions. This hypothesis was shown to be wrong by the development of ligands with chiral carbon backbones. Although the exact mechanism of action of the phosphane ligands has not been incontrovertibly determined to this day, they provide an easy point of access to a large number of chiral compounds.
The inventive process is not clearly understood, but one factor that seems to be important is the necessity for a high degree of naivety. That is why, so frequently, it is not the experts that do the inventing, but they are the ones who, once a lead has been established, come in and exploit the area. Our work is an excellent illustration of this phenomenon. In the study of any of the life sciences, chiral compounds are important. In the past when chiral compounds were required, chemists had to use biochemical processes or prepare racemic mixtures followed by laborious resolutions.
In industry the problem is particularly severe, since resolution, with its numerous recycling loops and fractional crystallizations, is an inherently expensive process. Thus, large-volume products such as monosodium l-glutamate, l-lysine, and lmenthol have traditionally been prepared through biochemical routes, even though efficient procedures are available to produce their racemic forms. The racemic mixture was easy to obtain, but by the time resolution had been implemented, the projected costs had doubled, even though we racemized and recycled the unwanted d-isomer.
It looked as though, if one wanted to beat the bug, it would be necessary to have a catalyst that would direct the reaction in order to give a predominance of the desired isomer, when an asymmetric center was formed. At this point in time I was aware of the extensive studies by Akabori, which began in the mids, in which heterogeneous catalysts such as Raney nickel and palladium were modified with a chiral agent. The asymmetric bias was always too small to be of preparative interest. However, all these thoughts remained dormant for several years. In the interim, I became part of a program for carrying out exploratory research.
I was given a new Ph. Industrial labs always wrestle with the problem of how much undirected research they should do, but this is just one of many ways to achieve a goal. I had been working with several new employees on a number of projects, when I became aware of Professor Wilkinson's discovery of chlorotris triphenylphosphane rhodium, [RhCl PPh3 3], and its amazing properties as a soluble hydrogenation catalyst for unhindered olefins.
Homogeneous catalysts had been reported before, but this was the first one where the rates were comparable with the well-known heterogeneous counterparts.
Asymmetric Catalysis on Industrial Scale : Challenges, Approaches and Solutions
A second development in the mids was in the area of methods for making chiral phosphanes, by Mislow and also by Horner. Phosphorus, like carbon, is tetrahedral and, when four different substituents are attached, can exist in d- and lforms. In the case of phosphanes, the lone pair of electrons counts as a substituent.
Earlier, it was thought that phosphanes might invert pyramidally like their nitrogen analogues, but Mislow and also Horner showed that they were stable at room temperature. They turned out to have a half-life of a couple of hours at 8C. For our contemplated hydrogenations, this stability would be quite adequate. The basic strategy was then to replace the triphenylphosphane of Wilkinson's catalyst with a chiral counterpart and hydrogenate a prochiral olefin. This modest result, of course, was of no preparative value, but it did establish that the hydrogenation technique gave a definite asymmetric bias.
In order to achieve this bias, the hydrogen atom, the ligand, and the substrate all had to be on the metal at the same time. Furthermore, we established that the hydrogenation was accomplished in solution and not from some extraneous rhodium plating out in our reactor.
The inherent generality of the method offered almost unlimited opportunities for matching substrate and catalyst, moving towards the goal of achieving efficient results. We were not alone in having this idea, but were the first to report on it. I believe it was discussed in the question session after Wilkinson's lecture on his soluble hydrogenation catalyst at a Welch Foundation conference.
Horner, shortly after our paper appeared, reported even more modest results with the same methylpropylphenylphosphane on a substituted styrene. Other workers were using other phosphanes with uninteresting results. Seemingly, we may have been the only ones naive enough to pursue this lead to any great depth. In fact, there was definitely nothing in the literature to encourage us to proceed further.
A mechanistic study showed that just two ligands were all that were needed and not the three, as in Wilkinson's structure.
Search Results for Enantioselective catalysis -- Industrial applications -- Case studies
While delving around in this area, another apparently unrelated development appeared, which played an important role in our project. This was the discovery that a fairly massive dose of l-dopa was useful in treating Parkinson's disease, which created a sizable demand for this rare amino acid. Because of Monsanto's position in the production of vanillin, which provided the 3,4-dihydroxyphenyl moiety, we learned that they were custom-manufacturing a racemic intermediate, which Hoffman-LaRoche resolved and deblocked to give l-dopa.
The synthesis, which closely followed the Erlenmeyer azlactone procedure described in typical organic syntheses, went by way of a prochiral enamide that was hydrogenated to give blocked d,l-dopa Fig. This enamide offered a golden opportunity for commercializing this burgeoning technology. We soon found out that these prochiral enamide precursors of a-amino acids hydrogenated much faster than one would expect for such a highly substituted olefin. We had a good test reaction, as shown in Fig.
We also had a good test for efficiency, since all we had to do was run rotation measurements on an appropriately diluted reaction mixture. Our job was to find a phosphane of the appropriate structure. Early on we tried phosphanes with a chiral alkyl side chain, and the asymmetric bias was barely detectable.
We felt strongly that, if one wanted to obtain high ee values, the asymmetry would have to be directly on the phosphorus. That is where the action is. Our first real variation was to introduce the o-anisyl group. This should provide some steric hindrance as well as a possible hydrogen-bonding site. Furthermore, the ether linkage would be stable enough to survive the rigors of a phosphane synthesis. In those days, our small group was in constant contact and what we decided to do was arrived at by informal consensus.
I hate to admit it, but it is much easier to invent when working in a small, underfunded group. Being lean and hungry is conducive to invention. These results are summarized in Fig. It all seemed too easy and simple, but this was the first time ever that anyone had obtained enzyme-like selectivity with a man-made catalyst! Never in our wildest imagination did we think a structure versus activity study would converge so quickly to a product with commercial potential.
CAMP was our sixth candidate. As I look back from this perspective, I do not think that we were actually emotionally equipped to realize what we had done. Here, with this simplest of molecules CAMP , we had solved one of the toughest synthetic problems. For the last hundred years, it had been almost axiomatic among chemists that only nature's enzymes could ever do this job. Our patent department always considered our invention was the use of chiral phosphanes with rhodium but, of course, without finding PAMP and CAMP, we would have only had a new way of doing what had been done before.
The lawyers 1. We have called these catalysts man-made but this is not strictly true. We have not violated the general principal that, if you want chiral molecules, you will have to get them with the assistance of previously formed natural products. CAMP worked equally well for the l-dopa precursor Fig. 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. Since CAMP was clearly good enough, we stopped exploring phosphanes and concentrated on converting this unique hydrogenation into large-scale production. This process was helped when another fortuitous event occurred. Monsanto decided to get out of manufacturing its first product, saccharin, and an idle plant was now available for this type of fine-chemical manufacture.
These things were then brought together to give our simplified l-dopa process, which started with vanillin Fig. The chiral hydrogenation was the simplest step in the sequence. These catalysts were fast, so that mole ratios of substrate : catalyst were about 20 : 1. Thus, even this super-expensive complex was used at close to throwaway levels. 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.
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 lforms. 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.
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, years ago. At the time of our initial commercialization, we learned of a new, efficient ligand discovered by Kagan et al. This was a chelating bisphosphane ligand prepared from tartaric acid with chirality on the carbon back- 1. We had hypothesized that, to obtain good results, one needed chirality directly on the phosphorus atom.
It made sense, but Kagan showed us to be totally wrong.
It is most appropriate that this invention using tartaric acid should have come from a Frenchman in the land of Louis Pasteur, who, of course, was the one who got it all started. Kagan's discovery was the wave of the future for a whole series of bisphosphane ligands with asymmetry on the chiral backbone Fig. Shortly afterwards, we came up with our own chelating bisphosphane ligand, by dimerizing PAMP through another Mislow procedure. When we started this work we expected these man-made systems to have a highly specific match between substrate and ligand, just like enzymes. Generally, in our experience and that of those that followed us, a good candidate is useful for quite a range of applications.
This feature has substantially enhanced their value in synthesis.
It turned out that these chiral hydrogenations, as applied to enamides, were entirely general, especially with DIPAMP. It should be pointed out here that these prochiral enamides can exist in both E and Z forms. The Z form hydrogenates efficiently whereas the E form hydrogenates less so. Both give the same product. Fortunately for us, the base condensation used in their preparation gives us only the desirable Z form Fig. It is easy to see how our rhodium catalyst could become confused with two carboxy groups so close together. Thus, aspartic acid is best made by an enzymatic process.
However, almost all the known familiar a-amino acids can be prepared in this way since, at least in principle, an enamide precursor is possible. Evidently the polar carboxy and amide groups overwhelm any variation in the R group. Also, the carboxy- and the nitrogen-blocking groups can be varied extensively.
Once again lady luck was with us, since if we had a choice where the catalyst would be useful, we could not have selected a more important area than the a-amino acids, the building blocks of the proteins. A few of the more important ones are listed in Tab. This generality can be extended to a variety of enol esters and itaconic acid derivatives. Evidently what is required is the ability to chelate with the metal. A number of these aryl propionic acids are valuable as nonsteroidal antiarthritics. Here, as is typically the case, only one enantiomer is active and thus a process to prepare one isomer directly was needed.
We tried hard to solve this problem, even using ruthenium-ligand systems, but without success. This is just another example in the history of invention. The one who makes the first discovery seldom makes the second. On a grander stage, this may explain why there are so few double Nobel Laureates.
All of these worked well with the same enamides and on related oxygen analogues. A few of these are shown in Fig. It is interesting that, over the years, we made a lot of chiral phosphanes but never managed to prepare a good one without our beloved o-anisyl group. Others have used it in connection with their bisphosphanes but it gives them no particular advantage.
Thus, the choice of suitable structures is still pretty much guesswork. Once again, the next invention was made by someone else. These high ee values can be important where the racemate is not a conglomerate. The phosphanes are prepared by a multistep route and are quite expensive, but fortunately one mole of catalyst will make many thousands of moles of product.
Even so, the ligand must be made from cheap starting materials. Some economy of scale is achieved by making a ten year supply in a few plant-sized batches. Unfortunately, the desired isomer was produced in minor amounts and, to correct this situation, it was necessary to reverse the order of addition of the aryl groups.
The sequence starting with trimethylphosphite is outlined in Figs. A large excess of trimethylphosphite was required to achieve good yields of monosubstituted product 4. In the sequence 4? The fact that the acid chloride 7 can be converted into an 80 : 20 mix of S and R isomers means that the menthol preferentially reacts with one form while the other isomer rapidly racemizes.
Another advantage of the sequence in Figs. Thus, the change to an improved ligand could be done with minimum dislocation, both at the synthesis and the utilization end. It is a clear advantage of catalytic processes that it is often easy to shift from the old to the new. CAMP was prepared by a selective hydrogenation reaction of 10 Fig. The R menthyl ester 8 could also have been used in this sequence if the last step was run with pure HSiCl3; this modification results in retention of configuration.
However, only the base-promoted reaction with trichlorosilane to give a double inversion was applicable. In this case, an empirical study showed that use of tributylamine minimized formation of the meso product. In principle, the menthol recovered in Fig. More useful is the recovery by hydrolysis of the phosphinic acid from the R -menthyl ester Fig. The rate was reasonable, if one considers that inversion at either end destroys chirality. For the sake of convenience, particularly on a large scale, a solid complex was made by reacting two equivalents of phosphane with one equivalent of [Rh cod Cl]2 in alcohol.
We have used the resolved menthyl ester 9 to make a variety of phosphane ligands. You will recall that, in the monophosphane series, the exchange of a phenyl group for a cyclohexyl group gave an enormous increase in selectivity. It was, however, our best candidate for preparing the more hindered amino acid, valine, for which the other systems were very poor Fig. This scarcity of good monophosphanes shows how lucky we were to find an efficient one on almost the first try.
We never found a good candidate that did not have the o-anisyl group. This is in contrast to all our colleagues in other labs who never found much benefit from it. This exploratory effort suffices to show that, as one might expect, the catalysis continues to be a very sensitive function of ligand structure and that our ability to predict or proceed in a rational manner is severely limited. Thus, the asymmetric bias may be caused by very subtle effects. Using the ball-and-stick models in Fig. These of course are mirror images and our catalyst must discriminate between them.
The phenyl groups present an edge and the o-anisyl group a face. This is depicted in Fig. In this picture, we are looking along the phosphorus-rhodium-phosphorus plane. One could speculate that an approaching substrate might prefer to lie on the flat face rather than on the hindered edge. We can more easily show this by a quadrant diagram Fig. We speculated that a prochiral olefin might prefer to lie in the unhindered quadrant. You will note that all the other bisphosphanes in Fig. It makes no difference whether one attributes the bias to the edge-face configuration, as I prefer, or to the skewed methylene group.
We felt pretty good about how things were fitting into place. Then along came Halpern's studies . He had been able to isolate a more advanced intermediate, in which the enamide substrate actually formed a complex with the metal-ligand system. He obtained it in crystalline form, and it was with considerable eagerness that we awaited the X-ray crystallographic analysis results. It turned out that the enamide was lying nicely in the hindered quadrant. So much for our theory. As so often happens in science, one comes up with an explanation in which everything seems to be fitting together nicely, and someone else then shows that your whole interpretation may well be wrong.
We were stranded with the argument that, at the square-planar stage, Halpern reported that these steric factors may not be important. However, to get asymmetric bias, we know that the hydrogen atom, the ligand, and the substrate must all be on the metal center at the same time. Such a configuration requires an octahedral structure. Perhaps then these quadrant constraints are important.
So far as I know, there is no evidence either to support or reject this contention. Our theory, though possibly wrong, does predict correctly. All of this thinking does not explain CAMP, unless we argue that, during the hydrogenation step, this monodentate ligand prefers to occupy adjacent sites on the metal center and acts as a bidentate species. Whatever the case, this unique catalysis has enabled chemists to study mechanistic details that could not previously be studied.
When one thinks of it, it is quite remarkable that we are even in a position to debate such subtle features. Since we are now dealing with pure complexes, we can design something to do just the job we want. This catalysis will continue to find many uses in industry, whenever an efficient route to the unsaturated precursor is available. Here, the problems with dilute solutions and difficult isolations are often less than the problems involved in a multistep synthesis.
One area where these catalysts will reign supreme is in the preparation of d-amino acids or other non-natural isomers, where biochemical alternatives will not be available. Perhaps the most important use of these catalysts will be to provide an easy way of making a large number of chiral compounds. In the past, research chemists have been reluctant to run laborious resolutions and have done so only when necessary. Now they can obtain chiral compounds for their life-sciences research with very little effort. We can look on these catalysts as a labor-saving device for the laboratory.
For this, they will have an impact for as long as chemists run reactions. The first of these is axiomatic; you have got to have a good idea. The second is essential; one needs financial support, but I would suggest a proper balance, too much or too little is inhibitory. For the third, you must have patience. Things never move as fast as you would have them. Finally, luck is all-important. I suspect that no invention has ever been made without some fortuitous help. It would not have been possible without my associates, Jerry Sabacky and Billy Vineyard.
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Komarov, A. Koenig in Asymmetric Synthesis, Vol. Morrison, Ed. Noyori, Angew. Kagan in Asymmetric Synthesis, Vol. Burk, J. Feaster, W. Nugent, R. Harlow, J. Burk, M. Gross, J. Martinez, J. Halpern in Asymmetric Synthesis, Vol. 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. In the s Pracejus had previously worked on asymmetric catalysis and published outstanding results on the reaction of nucleophiles with ketenes catalyzed by chiral bases and developed a fundamental understanding of the mechanism of such enantioselective processes controlled by opposed entropic and enthalpic parts of the free activation enthalpy .
Pracejus was fascinated by the idea of functionalizing cellulose as the cheapest chiral material and to use it in this form as a carrier for monovalent rhodium for asymmetric hydrogenation. Rh was shown by Wilkinson to be useful as a catalytically active central metal in phosphane complexes. To improve the accessibility of the catalytic active centers the author was asked by Pracejus to prepare crosslinked polysaccharides, to functionalize them with chlorodiphenylphosphine and to load the resulting polyphosphinite with simple rhodium complexes.
Thus we decided, with the consent of Pracejus, to first find out the steric prerequisites for highly enantioselective derivatives of monomeric carbohydrates substituted by phosphorus. The synthesis of carbohydrate-phosphinites was, however, unexpectedly successful. The preparation was much easier than that of the phosphanes. The products could be obtained in crystalline state and were less sensitive to oxidation by air.
Their thermal stability was high and drying could be done in vacuum up to 8C without decomposition. The hydrogenation activity which was very low for the l-chloro-bridged neutral rhodium I complexes 3 could be enhanced tremendously by reaction with silver tetrafluoroborate according to Fig. This enhancement of the activity was essential for an industrial application . In we tried to establish contacts with an industrial partner, which were realized by talks with Dr. The company was interested in producing l-dopa and we saw a good opportunity for an industrial process using the asymmetric hydrogenation of O-functionalized derivatives of Z -2acetamidocinnamic acid 1 a with our catalysts as shown in Fig.
For this application we chose phenyl 4,6-O- R -benzylidene-2,3-bis O-diphenylphosphino -b-d-glucopyranoside 9 as the chiral ligand, which we abbreviated to Ph-b-glup Fig. It was advantageous that phenyl b-d-glucopyranoside 7 with an aryl group as aglycon could for instance be prepared in large amounts much more easily by the method of Helferich  as a precursor for Ph-b-glup 8, than the analogous methyl b-d-glucopyranoside.
Meanwhile Cullen and Sugi  as well as Jackson and Thompson  had also published work in this field and we were in a hurry to develop the process. However, further publication activity was prohibited by our industrial partner. As can be seen from Tab. However, we soon found that the hydrogenation reactions ran particularly well in suspension and with the amount of solvent reduced in such a way that good stirring, essential for the hydrogen uptake, was still possible.
R2 R3OH Fig. Hydrogenation results No. The negative influence of axially oriented hexopyranoside substituents on the enantioselectivity can be seen in Fig. In order to realize an industrial process it was very important that cationic rhodium I -bisphosphinites could be obtained without the use of silver salts. For this purpose neutral rhodium I -bisphosphinite-cyclooctadiene-acetylacetonate was prepared according to Fig. This could also be achieved as a one pot reaction . It should be noted that in addition we improved the existing procedures for the preparation of the precursor complexes [Rh cod Cl]2, Rh cod acac  and [Rh cod 2]BF4.
What was astonishing and really unexpected was the high stability of the P-O bonds, which are normally very sensitive to hydrolysis. Because of the protecting properties of the coordinated rhodium, the cleavage of the P-O bonds is inhibited even under strongly acid conditions. High-grade and even concentrated sulfuric acid are tolerated. However, strong acid leads to a time-dependent solvolysis of the b b Fig. Even though we applied the non-solvolyzed catalyst 15 in the technical hydrogenation runs, we believe that under the action of the sulfuric acid that is always added, large parts of the catalyst act in the form of 16, carrying two hydroxy groups.
From Tab. This was of course encouraging for an industrial application and an indication that oxygen was responsible for catalyst deactivation. Indeed the turnover number could be enhanced by adding an oxygen-consuming additive such as acetaldehyde, however, this is not practicable in an industrial process. It is not clear why the methanol-free, yellow colored samples of the substrate with the otherwise same chemical purity led to a much poorer result and with a TON of only 2 This yellow solvent-free modification can be obtained Dependence of the maximum TON on the reaction scale and on added acetaldehyde for the hydrogenation of 5 e.
This effect cannot be due a contamination with the intermediate azlactone 12, which is also yellow, because addition of some azlactone had no influence on the reactivity despite the fact that azlactones themselves could not be hydrogenated with our catalysts. As yet, we have no explanation for the remarkable effect described above. In contrast, using the a-glucosidic analogues in benzene led for acid substrates to d-amino acid derivatives with the opposite absolute configuration .
The cheap methanol was particularly attractive for the technical process due to its low evaporation enthalpy. Halogen-containing solvents allowed only low TON because they soon deactivated the catalyst. In water the hydrogenation rate and the enantioselectivities were considerably lower. However, the addition of amphiphiles as proposed by G. Oehme mediates the dispersion of the relatively hydrophobic reactants and effects an enormous increase in hydrogenation activity and selectivity [17, 24, 25].
It can be seen that the best selectivities are obtained with all equatorially oriented hexopyranoside substituents in b-d-glucopyranoside, for all solvents investigated. The addition of sodium dodecyl sulfate generally increases the low enantioselectivity observed in pure water and the values rise above the selectivities achievable in methanol. This is generally valid not only for water-soluble substrates such as 1 c but also for a great number of l-dopa precursors 5 [17, 25]. It has now been confirmed that the micelle forming amphiphiles act by incorporation of the catalyst as well as the substrate into the micelles , in which the hydrogenation rate is enhanced by a higher local concentration of the reagents and the enantioselectivity is often higher than in methanol .
For the latter improvement it seems important that catalysts possess sufficient flexibility, as with our sevenmembered rhodium I chelates, to be able to adopt the optimal conformation for the environment of low polarity . When using five- or six-membered ring chelates the effect of the amphiphiles was very small in our experience . For the industrial syn- 2 Fig. Moreover, the working up of methanol solutions is cheaper. However, in solvents of lower polarity, such as for instance benzene, we observed a larger variation of enantioselectivity. Acetalization of glucosides analogous to Fig.
However, the activity of the polymer catalysts was disappointingly low. It seems that the accessibility of the catalytic centers for the substrates was too low. We believe that the high activity of these immobilized catalysts can be explained by the high mobility of the catalytically active cations.
Passar bra ihop
Thus it is mainly the free cations that are probably active in the hydrogenation. Despite this high mobility the leaching per hydrogenation step was less than 0. This high selectivity could be kept up through to the last run when the catalytic activity almost ceased. This must be due to the fact that the rhodium residue of the decomposed catalyst has no further catalytic activity in our case. This is in contrast to similar rhodium I catalysts with the aminophosphine-phosphinite propraphos  which showed a gradually decreasing ee with repeated use .
In the end propraphos was unsuccessful due to the high cost of the separation of the enantiomers of the propranolol, despite the advantage of the availability of both enantiomers. Accounts of this were first published by its staff in , having par- 49 50 2 The Other L-Dopa Process tially used our reports and whom the author is indepted for the good cooperation .
The pressure of 0. The hydrogenation was performed under normal pressure of 0. Medium pressure could presumably be advantageous and might facilitate an increase in the turnover number. The enantioselectivity proved to be independent up to a pressure 10 MPa . Despite of the fact that a large-scale process could be much more economical increase in the hydrogenation rate and turnover number, decrease in the personnel expenditure , one did not dare to use a larger vessel fearing the loss of the valuable substrate if one batch should fail.
The hydrogenation process was carried out at 40 8C with 32 mol of prochiral substrate per batch. Care had to be taken of course for efficient removal of the reaction enthalpy of ca. The application of less catalyst was possible, but this resulted in an unwanted prolongation of the reaction time and a decrease in the enantioselectivity. Under these conditions the crystallization of the product during the hydrogenation could be avoided. Of particular importance was the careful exclusion of traces of oxygen. A flow diagram of the technical hydrogenation plant and the purification of nitrogen and hydrogen was published by Vocke et al.
At the end of the process the hydrogenation product was hydrolyzed with HBr Fig. This mother liquor and the loaded ion exchanger were ashed and the resulting rhodium reacted with chlorine under heating to redness to give rhodium III -chloride. This was used directly for the synthesis of the dimer rhodium I -cyclooctadiene-chloride from which rhodium I -cyclooctadiene-acetylacetonate could easily be obtained. Using the described process, roughly 1 ton per year of l-dopa was produced between and The first tablets were put on sale under the name of Isicom Fig.
The presence of small amounts of carbidopa is very important, allowing a considerable minimization of the amount of l-dopa required for the effective treatment of the symptoms of the Morbus Parkinson. An enlargement of the plant was envisioned because export into other socialistic countries was planned.
However, production of l-dopa ended in , one year after the collapse of the socialist system and one month after the management had actually decided to increase production capacity for l-dopa. Vocke and Dr. For practical assistance I particularly thank Mrs. Discovery and Development of a Catalytic Asymmetric Conjugate. LargeScale Applications of Hydrolases in Biocatalytic.
Asymmetric Hydrogenations on the MultiKilograms Scale. Application of PhaseTransfer Catalysis in the Organocatalytic. Between and he held postdoctoral positions at the University of Chicago J. Halpern , Harvard University J. Osborn , and Monsanto Zurich. Starting off as bench chemist in Astra at the major Swedish site in Sodertalje, he climbed the ranks to occupy positions both as line and project manager. Time-to-market pressure leads to short development times, which in the past could be a large barrier for the implementation of catalytic steps; now there are new ways to minimise this problem.
The potential problems associated with impurities and other methods that can shut down the hydrogenation reactions are highlighted in this critical review references. The article was received on 17 Nov and first published on 08 Feb If you are not the author of this article and you wish to reproduce material from it in a third party non-RSC publication you must formally request permission using Copyright Clearance Center.
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