The Other L-Dopa Process

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

The DA neurons were initially identified by Sulston and coworkers, who used the catecholamine-specific technique of formaldehyde-induced fluorescence (FIF) (23). DA cell bodies and processes were visualized using fluorescence microscopy, confirmed as DA by aluminaabsorptionandthin-layerchromatography (TLC). The precursor L-DOPA was also identified but not the catecholamines norepinephrine and epinephrine. Based on FIF micrographs and worm DA content as well as the estimated volume of the cell bodies and processes, the concentration of DA in the nerve endings is predicted to be very similar to the concentration within mammalian varicosities (23). We and others [(6) R. Nass, unpublished data] have confirmed via high-perfomance liquid chromatography (HPLC) that DA and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) are present in the animal. 

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. 

While Table 4 describes the situation in 2001 and many additional processes have been reported. The following analysis is still valid. A look at the processes listed in Table 4 shows that hydrogenation of C=C and C=0 is by far the most predominant transformation applied for industrial processes, followed by epoxidation and dihydroxylation reactions. On the one hand, this is due to the broad scope of cataljrtic hydrogenation and on the other hand it could 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. The success with epoxidation and dihydroxylation can essentially be attributed to the efforts of Sharpless, Katsuki, and Jacobsen. If one analyzes the structures of the starting materials, it is quite obvious that many of these compounds are often complex and multifunctional, that is, the successful catalytic systems are not only enantioselective but tolerate many functional groups. 

Table 3.12 surveys current industrial applications of enantioselective homogeneous catalysis in fine chemicals production. Most chiral catalyst in Table 3.12 have chiral phosphine ligands (see Fig. 3.54). The DIP AMP ligand, which is used in the production of L-Dopa, one of the first chiral syntheses, possesses phosphorus chirality, (see also Section 4.5.8.1) A number of commercial processes use the BINAP ligand, which has axial chirality. The PNNP ligand, on the other hand, has its chirality centred on the a-phenethyl groups two atoms removed from the phosphorus atoms, which bind to the rhodium ion. Nevertheless, good enantio.selectivity is obtained with this catalyst in the synthesis of L-phenylalanine. 

A thorough discussion of the mechanisms of absorption is provided in Chapter 4. Water-soluble vitamins (B2, B12, and C) and other nutrients (e.g., monosaccharides, amino acids) are absorbed by specialized mechanisms. With the exception of a number of antimetabolites used in cancer chemotherapy, L-dopa, and certain antibiotics (e.g., aminopenicillins, aminoceph-alosporins), virtually all drugs are absorbed in humans by a passive diffusion mechanism. Passive diffusion indicates that the transfer of a compound from an aqueous phase through a membrane may be described by physicochemical laws and by the properties of the membrane. The membrane itself is passive in that it does not partake in the transfer process but acts as a simple barrier to diffusion. The driving force for diffusion across the membrane is the concentration gradient (more correctly, the activity gradient) of the compound across that membrane. This mechanism of... 

Involvement of several proteolytic enzymes, secretases, is probably crucial for this process but other hypotheses, including, for example, cholinergic transmission or accumulation of metal ions, have also been considered. Future perspectives in this area concern the search for novel pharmaceuticals that cross the blood-brain barrier, without side effects (e.g., the dyskinesias of L-Dopa), or potent and selective inhibitors of improper cleavage of amyloid protein, or even stem cell therapy to restore neuronal cells. 

The rising need for new separation processes for the biotechnology industry and the increasing attention towards development of new industrial eruyme processes demonstrate a potential for the use of liquid membranes (LMs). This technique is particularly appropriate for multiple enzyme / cofactor systems since any number of enzymes as well as other molecules can be coencapsulated. This paper focuses on the application of LMs for enzyme encapsulation. The formulation and properties of LMs are first introduced for those unfamiliar with the technique. Special attention is paid to carrier-facilitated transport of amino acids in LMs, since this is a central feature involved in the operation of many LM encapsulated enzyme bioreactor systems. Current work in this laboratory with a tyrosinase/ ascorbate system for isolation of reactive intermediate oxidation products related to L-DOPA is discussed. A brief review of previous LM enzyme systems and reactor configurations is included for reference. 

Knowles catalyst has been used to prepare a wide range of a-amino acids at scale. L-Dopa is still produced at scale using the original process developed by Monsanto. Other amino acids are produced at a smaller scale for a variety of pharmaceutical applications. 

The development of applications often leads to another round oft hypothesizing and testing in order to refine the applications. There was some initial success with L-dopa. It caused remission of Parkinson s disease in about one-third of the patients treated and improvements in one-third of the others, but there were also problematic side effects, including nausea, gastrointestinal distress, reduced blood pressure, delusions, and mental disturbance. The drug s effects on blood pressure seem to be caused by the conversion of L-dopa to dopamine outside the brain. For this reason, L-dopa is now given with levocarbidopa, which inhibits that process. 

Enantiomers show no difference in their reactions with achiral molecules, e.g., NaOH, HCl, and Brj. The situation is very different for reactions with chiral molecules or for reaetions in which chiral enzymes are involved. The typical biological process involves some chiral molecule undergoing reaction under the influence of a chiral enzyme. One enantiomer reacts rapidly while the other reacts at a much slower rate or does not react at all. The body can use one enantiomer efficiently but not the other. For example, o-glucose is utilized by the body but L-glucose cannot be utilized. L-Dopa is used to treat Parkinson s disease the o-enantiomer has no effect. Taste and odor also involve highly selective biochemical reactions. For example, (-)-carvone has the odor of caraway seeds while (-I- Fcarvone has the odor of spearmint. 

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]... 

Other than the L-DOPA, there have been two other significant processes developed for industrial applications. The first of these uses a Sharpless asymmetric epoxidation, one of the most widely applied asymmetric transition metal catalysed transformations, to convert allyl alcohol (41) into (5)-glycidol (43), a valuable chiral building block, developed by ARCO Chemical Company (Scheme 4.12) [29]. Most of the successful applications of transition metal mediated asymmetric... 

Phenylethylamines and catecholamines are of crucial importance for many physiological processes [2]. l-DOPA (2) serves as precursor for dopamine, which acts as neurotransmitter in the human brain. Dopamine is associated with reward-motivated behavior and cognitive alertness, and the compound is linked to controlling the release of other important hormones. In contrast to dopamine (4), l-DOPA is able to cross the blood-brain barrier, and it is used to increase the concentration of dopamine in the brain in patients suffering from Parkinson s disease [3]. 

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