Hydantoin, resolution

Hydantoinases belong to the E.C.3.5.2 group of cyclic amidases, which catalyze the hydrolysis of hydantoins [4,54]. As synthetic hydantoins are readily accessible by a variety of chemical syntheses, including Strecker reactions, enantioselective hydantoinase-catalyzed hydrolysis offers an attractive and general route to chiral amino acid derivatives. Moreover, hydantoins are easily racemized chemically or enzymatically by appropriate racemases, so that dynamic kinetic resolution with potential 100% conversion and complete enantioselectivity is theoretically possible. Indeed, a number of such cases using WT hydantoinases have been reported [54]. However, if asymmetric induction is poor or ifinversion ofenantioselectivity is desired, directed evolution can come to the rescue. Such a case has been reported, specifically in the production of i-methionine in a whole-cell system ( . coli) (Figure 2.13) [55]. 

Figure 6.43 Dynamic kinetic resolution of (rac)-hydantoins by a D-hydantoinase.

For successful DKR two reactions an in situ racemization (krac) and kinetic resolution [k(R) k(S)] must be carefully chosen. The detailed description of all parameters can be found in the literature [26], but in all cases, the racemization reaction must be much faster than the kinetic resolution. It is also important to note that both reactions must proceed under identical conditions. This methodology is highly attractive because the enantiomeric excess of the product is often higher than in the original kinetic resolution. Moreover, the work-up of the reaction is simpler since in an ideal case only the desired enantiomeric product is present in the reaction mixture. This concept is used for preparation of many important classes of organic compounds like natural and nonnatural a-amino acids, a-substituted nitriles and esters, cyanohydrins, 5-alkyl hydantoins, and thiazoUn-5-ones. 

The multipolymer enzymatic resolution of soluble polymer-supported alcohols 42 and 43 was achieved using an immobilised lipase from Candida Antarctica (Novozym 435). The R-alcohol was obtained in enantiomerically pure form (>99% ee) after its cleavage from the poly(ethylene) glycol (PEG) scaffold . The achiral hydantoin- and isoxazoline-substituted dispirocyclobutanoids 47 were produced using both solution and solid-phase synthesis <00JOC3520, OOCC1835>. 

The application of antibiotics as chiral selectors has resulted in the successful resolution of almost all types of neutral, acidic, and basic racemic molecule. These antibiotics have been used for the enantiomeric resolution of amino acids, their derivatives, peptides, alcohols, and other pharmaceuticals. The selectivities of the most commonly used antibiotic-based (vancomycin, teicoplanin, and ristocetin A) CSPs varied from one racemate to another and are given in Table 1. Vancomycin was used for the chiral resolution of amino acids, amines, amides, imides, cyclic amines, amino alcohols, hydantoins, barbiturates, oxazolidinones, acids, profens, and other pharmaceuticals. Teicoplanin was found to be excellent chiral selector for the enantiomeric resolution of amino acids, amino alcohols, imides, peptides, hydantoins, a-hydroxy and halo acids, and oxazolidinones, whereas ristocetin A is capable of chiral resolution of amino acids, imides, amino... 

The applications of re-acidic chiral stationary phases include the resolution of a-blockers and /1-blockers, amines, arylacetamine, alkylcarbinols, hydantoins, barbiturates, naphthols, benzodiazapines, carboxylic acids, lactams, lactones, phthaldehydes selenoids, and phosphorus compounds. Hyun et al. [16] achieved a chiral resolution of a homologous series of iV-acyl-x-(l-naphthyl )cthylaminc on AA(3,5-dinitrobenzoyl-(i )-phenylglycine and N-(3,5 - dini tr o ben zoy I)-(,S ) -1 c u c ine CSPs. The authors used hexane-2-propanol (80 20, v/v) as the mobile phase. Similarly, the scope of re-basic CSPs comprises the chiral resolution of / -blockers, amino acids, amines, diamines, amino phosphonates, naphthols, benza-diazapines, carboxylic acids, hydroxy acids, dipeptides, tripeptides, diols,... 

Cholic acid and 3-phenylcarbamoyl cholic acid allyl esters were grafted to hydride-activated silica gel and the developed CSPs were used for the chiral resolution of derivatized amino acids, amines, alcohols, hydantoins, and 2,2 -... 

Maguire, J.H., Some structural requirements for resolution of hydantoin enantiomers with a-cyclo-dextrin liquid chromatography column, J. Chromatogr., 387, 453, 1987. 

Amoxicillin (21) is a semi-synthetic penicillin antibiotic. The penicillin portion is derived from fermentation of either penicillin-V or penicillin-G, and then the sidechain is removed to afford 6-APA. This transformation can be done chemically.69 207 The alternative, which is growing in importance, is to perform an enzymatic cleavage under mild conditions.208 The D-p-hydroxyphenylglycine is then attached as the new sidechain chemical and enzymatic methods are available to achieve this (Scheme 31.16).209 215 The phenylglycine amino acid is obtained by a resolution (Chapters 2, 7, and 25) or by enzymatic hydrolysis of a hydantoin (Chapter 2, 6, and 19).216-220... 

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]. 

In elegant work the enantioselectivity of a hydantoinase from Arthrobader species for the production of l-methionine in Escherichia coli has been inverted [87]. The approach is similar to the one used in the evolution of (S)- and ( -selective lipases (see above). All known hydantoinases are selective for D-5-(2-methylthioethyl)hydantoin (d-18) which leads to the accumulation of N-carbamoyl-D-methionine (d-19), conversion being complete if the conditions of dynamic kinetic resolution are upheld [88], in this case by the use of a racemase or pH >8 (Fig. 11.22). 

This eoncept has been known for a long time in pure enzymatic synthesis, e.g. amino acid synthesis via hydantoins [1] or oxazolidinones [2]. Cyanohydrins [3] and lactols [4] are prone to in situ racemization as well and may serve as substrates in kinetic resolutions. 

An enantioselective synthesis of TIQ-1-carboxylic acids 91a,b has recently been reported (279). Hydrolysis of the optically active methyl ether enantiomer of hydantoin 103 was accomplished by 20% sodium hydroxide in refluxing methyl cellosolve and led to the dimethyl ether analog of 91a, which was used to establish the absolute configuration of the products. Amino acids 91a,b have also been prepared by chemical resolution of the N,0-benzylated acid 108 with optically active 1-phenylethylamines. Catalytic debenzylation of enantiomer 109a gave... 

Rgure A8.8 Enzymatic processes for the production of opticaiiy active a-amino adds via resolution of the racemic hydantoins. 

The reaction concept with this new hydantoinase-based biocatalyst is economically highly attractive since it represents a dynamic kinetic resolution process converting a racemic hydantoin (theoretically) quantitatively into the enantiomerically pure L-enantiomer [19]. The L-hydantoinase and subsequently the L-carbamoylase hydrolyze the L-hydantoin, l-11, enantioselectively forming the desired L-amino acid, l-2. In addition, the presence of a racemase guarantees a sufficient racemiza-tion of the remaining D-hydantoin, d-11. Thus, a quantitative one-pot conversion of a racemic hydantoin into the desired optically active a-amino acid is achieved. The basic principles of this biocatalytic process in which three enzymes (hydan-toinase, carbamoylase, and racemase) are integrated is shown schematically in Fig. 9. 

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