Chirality industrial applications

Thin layer chromatography. 2. Enantiomers—Separation. 3. Chirality—Industrial applications. I. Kowalska, Teresa. II. Sherma, Joseph. III. Title. IV. Series. 

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. 

The use of an analogous (S)-BINAP-Ru-diacetate catalyst with axial chirality has led to important industrial applications, such as the synthesis developed by Monsanto where the asymmetric hydrogenation is involved in the last step to yield naproxen, a widely prescribed, non-steroidal, anti-inflammatory drug (Equation (9)).96... 

The ability to efficiently synthesize enantiomerically enriched materials is of key importance to the pharmaceutical, flavor and fragrance, animal health, agrochemicals, and functional materials industries [1]. An enantiomeric catalytic approach potentially offers a cost-effective and environmentally responsible solution, and the assessment of chiral technologies applied to date shows enantioselective hydrogenation to be one of the most industrially applicable [2]. This is not least due to the ability to systematically modify chiral ligands, within an appropriate catalyst system, to obtain the desired reactivity and selectivity. With respect to this, phosphorus(III)-based ligands have proven to be the most effective. 

As already mentioned, the most important industrial application of homogeneous hydrogenation catalysts is for the enantioselective synthesis of chiral compounds. Today, not only pharmaceuticals and vitamins [3], agrochemicals [4], flavors and fragrances [5] but also functional materials [6, 7] are increasingly produced as enantiomerically pure compounds. The reason for this development is the often superior performance of the pure enantiomers and/or that regulations demand the evaluation of both enantiomers of a biologically active compound before its approval. This trend has made the economical enantioselective synthesis of chiral performance chemicals a very important topic. 

The hydrogenation of allylic alcohols and a,/>-unsaluraled acids leads to products with a very high synthetic potential, and both transformations were used quite early for industrial applications. In both cases Ru complexes with axially chiral biaryl ligands (binap analogues) are the catalysts of choice. Here, we will dis-... 

The cost of the catalysts represents a major hurdle on the road to the industrial application of homogeneous catalysis, and in particular for the production of fine chemicals [1, 2], This is particularly true for chiral catalysts that are based on expensive metals, such as rhodium, iridium, ruthenium and palladium, and on chiral ligands that are prepared by lengthy total syntheses, which often makes them more expensive than the metals. In spite of this, the number of large-scale applications for these catalysts is growing. Clearly, these can only be economic if the substrate catalyst ratio (SCR) can be very high, often between 103 and 105. 

Since the commercial introduction of the P-CAC in 1999, several industrial applications have been shown to be transferable to the system. Moreover, users in the biopharmaceutical and foodstuff industry have seen their productivity increasing dramatically as a result of using the P-CAC technology. Furthermore, a P-CAC has been shown capable of continuously separating stereoisomers when using chiral stationary phases even when there is more than one chiral center in the desired molecule. Below some of the applications are described in more details. Others are proprietary and hence cannot be disclosed. 

Several important industrial applications of the Heck reactions are known. The world s largest producer of Naproxen is Albemarle and they make Naproxen using two homogeneously catalysed steps, a Heck reaction and a palladium catalysed hydroxycarbonylation. The last step is carried out using palladium without chiral ligand and the enantiomers obtained are separated, see Figure 13.18. 

This screening system has also been applied successfully in the directed evolution of enantioselective EHs acting as catalysts in the kinetic resolution of chiral epoxides 95,96) (Section IV.A.4). Moreover, the firm Diversa has applied the MS-based method in the desymmetrization of a prochiral dinitrile (l,3-dicyano-2-hydroxypropane) catalyzed by mutant nitrilases 46). In this industrial application, one of the nitrile moieties was labeled selectively with as in N-17, which means that the two pseiido-eaaniiovaenc products (S)- N-18 and (J )-18 differ by one mass unit. This is sufficient for the MS system to distinguish between the two products quantitatively 46). 

In a related report, ruthenium-catalyzed enantioselective hydrogenation of 3-keto esters was utilized to prepare the crucial alcohol intermediate 36 (Scheme 14.16). The required (3-keto ester 49 was readily prepared from commercial thiophene carboxylic acid 40. Hydrogenation of 49 then led to the desired (S)-alcohol 50 in quantitative yield and 90% enantiomeric excess, catalyzed by a chiral diphosphine-ruthenium complex generated in situ. Catalyst-substrate ratios used were as low as 1/20,000, rendering this approach amenable to industrial application. Alcohol 50 was then converted to known intermediate 36 in three steps and 60% overall yield. 

Asymmetric reduction of a,/l-unsaturated aldehydes with transition metal catalysts has not yet proven ready for widespread industrial application. One area, namely the chiral reduction of enals to yield chiral alcohols using bakers yeast has been... 

A wide range of metals and ligand combinations have been demonstrated to effect the ATH reaction and in this book we concentrate on the systems that have demonstrated high activities and ees that would be the requirement of an industrial application. The initial breakthrough in this area came in 1995 with the report from Ohkuma et alP on the use of chiral monotosylated diamine complexes for asymmetric transfer hydrogenation. 

The resolution of chiral alcohols through lipase-mediated enantioselective acylation (transesterification) is one of the major industrial applications of lipases [50]. Hence, the effects of ionic liquid reaction media on the resolution of various... 

Arylation, olefins, 187, 190 Arylketimines, iridium hydrogenation, 83 Arylpropanoic acid, Grignard coupling, 190 Aspartame, 8, 27 Asymmetric catalysis characteristics, 11 chiral metal complexes, 122 covalently bound intermediates, 323 electrochemistry, 342 hydrogen-bonded associates, 328 industrial applications, 8, 357 optically active compounds, 2 phase-transfer reactions, 333 photochemistry, 341 polymerization, 174, 332 purely organic compounds, 323 see also specific complexes Asymmetric induction, 71, 155 Attractive interaction, 196, 216 Autoinduction, 330 Axial chirality, 18 Aza-Diels-Alder reaction, 220 Azetidinone, 44, 80 Aziridination, olefins, 207... 

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