Resolution, dynamic kinetic industrial scale

Resolution of cheap racemic mixtures with enzymes is a common route to enantiomerically pure chemicals on an industrial scale. However, the yield with a classical resolution is limited to 50%. An in situ racemization of the undesired enantiomer, combined with the enzymatic kinetic resolution, gives rise to a dynamic kinetic resolution (DKR) that should in principle lead to a 100% yield in the desired isomer. In spite of several Ru and Pd homogeneous systems successfully combined with enzymes and successfully applied on industrial scale in DKR [71, 72], few metal-based heterogeneous catalysts active for alcohol racemization have been reported [19, 73, 74]. 

Carbapenem antibiotics (29) can be manufactured from intermediates obtained by Ru(BINAP)-catalyzed reduction of a-substituted P-keto esters by a dynamic kinetic resolution (Scheme 12.8). 4-Acetoxy azetidinone (30) is prepared by a regioselective RuCl3-catalyzed acetoxylation reaction of 31 with peracetic acid 46 This process has been successful in the industrial preparation of the azetidinone 30 in a scale of 120 tons per year.47 The current process has changed ligands to 3,5-Xyl-BINAP (3c), and 31 is obtained in 98% ee and >94% de (substrate-to-catalyst ratio, or S/C ratio = 1,000).23... 

The enzymes of the nucleic acid metabolism are used for several industrial processes. Related to the nucleobase metabolism is the breakdown of hydantoins. The application of these enzymes on a large scale has recently been reviewed [85]. The first step in the breakdown of hydantoins is the hydrolysis of the imide bond. Most of the hydantoinases that catalyse this step are D-selective and they accept many non-natural substrates [78, 86]. The removal of the carbamoyl group can also be catalysed by an enzyme a carbamoylase. The D-selective carbamoylases show wide substrate specificity [85] and their stereoselectivity helps improving the overall enantioselectivity of the process [34, 78, 85]. Genetic modifications have made them industrially applicable [87]. Fortunately hydantoins racemise readily at pH >8 and additionally several racemases are known that can catalyze this process [85, 88]. This means that the hydrolysis of hydantoins is always a dynamic kinetic resolution with yields of up to 100% (Scheme 6.25). Since most hydantoinases are D-selective the industrial application has so far concentrated on D-amino acids. Since 1995 Kaneka Corporation has produced 2000 tons/year of D-p-hydroxyphenylglycine with a D-hydantoinase, a d-carbamoylase [87] and a base-catalysed racemisation [85, 89]. 

Alternatively, enantiopure 2-hydroxycarboxylic acids can be obtained via a dynamic kinetic resolution of the (chemically synthesized) cyanohydrin in the presence of an enantioselective nitrilase (EC 3.5.5.1) (see Figure 16.1, route b). Racemization of the cyanohydrin, via reversible dehydrocyanation, takes place readily at pH 7 or above. The methodology [1] is attractive on account of the mild reaction conditions and is industrially applied in the multiton-scale synthesis of (R)-mandehc acid [2]. 

This chapter presented the current stage of development in the desymmetrization of mt >o-com pounds and (dynamic) kinetic resolution of racemic compounds in which cinchona alkaloids or their derivatives are used as organocatalysts. As shown in many of the examples discussed above, cinchona alkaloids and their derivatives effectively promote these reactions by either a monofunctional base (or nucleophile) catalysis or a bifunctional activation mechanism. Especially, the cinchona-catalyzed alcoholytic desymmetrization of cyclic anhydrides has already reached the level of large-scale synthetic practicability and, thus, has already been successfully applied to the synthesis of key intermediates for a variety of industrially interesting biologically active compounds. However, for other reactions, there is still room for improvement... 

An enantioselective nitrilase has also been shown to be applicable in the dynamic kinetic resolution of mandelonitrile. Using the nitrilase produced by Alcaligenes faecalis ATCC 8750 Yamamoto et al. showed that they could derive (Rj-(-)-mandelic acid from mandelonitrile in 91% yield with an ee of 100%. Under the reaction conditions used non-reacting (S) -mandelonitrile undergoes spontaneous racemiza-tion leading to the high yield (see Scheme 12.1-8)[48]. Currently (R)-mandelic acid and (R)-chloromandelic acid are produced using nitrilases on an industrial scale by the Mitsubishi Rayon Corp. 

A common entry into the DKR manifold involves racemization of stereocenters a to carbonyl groups. The achiral intermediate formed through base-catalyzed enoHzation allows for facile racemization of the substrate. a-Substituted p-dicarbonyl compounds racemize under particularly mild conditions and undergo highly enantioselective dynamic kinetic resolutions by hydrogenation of the ketone unit to form a-substituted (3-hydroxy carbonyl compounds (Figure 14.30). This type of DKR is used to prepare azetidinone, which is a key intermediate in the synthesis of carbapenem antibiotics on an industrial scale (i.e., 120 ton/year). ... 

Biocatalytic resolution plays a major role in the industrial scale synthesis of a wide variety of optically pure amino acids. Tanabe uses an L-spe-cific aminoacylase for the manufacture of several L-amino acids, immobilized on DEAE-Sephadex. Degussa on the other hand, uses the free acylase in a membrane bioreactor. The process is highly efficient in enzyme use, and racemisation of the D-isomer is straightforward, thus providing good economics, and virtually no waste (Scheme 7.4). The process can be further refined by the use of racemase enzymes, which makes dynamic kinetic resolution feasible. 

In polymer chemistry, one of the most challenging tasks is to efficiently synthesize optically active synthetic polymers. The extraordinary enantioselectivity of lipases offers new perspectives towards these materials, and it is therefore not surprising that some research efforts have focused on the use of lipases to synthesize chiral polymers from racemic monomers. Methodologies like kinetic resolution and even chemoenzymatic dynamic kinetic resolution (DKR) have already been exploited on the industrial scale to afford chiral intermediates for the pharmaceutical and agrochemical industry. Recently, these methodologies have been successfully applied in the synthesis of chiral polymers. 

A powerful application of this technology has been demonstrated by the conversion of racemic p-ketoesters to a single stereoisomer via asymmetric reduction combined with dynamic kinetic resolution. Cationic ruthenium complexes were employed in the conversion of 28 to 29, a key intermediate in the synthesis of carbapenem antibiotics (Scheme 14.10). Increased steric bulk on the aryl groups was required to give high diastereoselectivity as well as enantioselectivity, and this process was used for industrial production on a scale of 100 metric tonnes per year. 

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