5- Substituted hydantoins

Uses, cx-Aminonitriles may be hydrolyzed to aminoacids, such as is done in producing ethylenediaminetetracetate (EDTA) or nittilotriacetate (NTA). In these cases, formaldehyde is utilized in place of a ketone in the synthesis. The principal use of the ketone-based aminonitriles described above is in the production of azobisnittile radical initiators (see below). AN-64 is also used as an intermediate in the synthesis of the herbicide Bladex. Aminonitriles are also excellent intermediates for the synthesis of substituted hydantoins by reaction with carbon dioxide however, this is not currently commercially practiced. 

H-nmr chemical shifts of N-1—H and N-3—H signals have been used as a criterion for distinguishing between N-l-substituted and N-3-substituted hydantoin derivatives (22). They can often be related to electronic properties, and thus good linear correlations have been found between the shifts of N—H and Hammett parameters of the substituents attached to the aryl group of 5-arylmethylenehydantoins (23). 

Fig. 1. 5-Substituted hydantoins as synthetic intermediates. Equation 1 (45) equation 2 (46).

Substituted Hydantoins. 5-Methylhydantoin [616-03-5] has been selected from several stmctures as a formaldehyde scavenger for color photosensitive materials and water-thinned inks and coatings (102,103). 

The use of an organic isocyanate instead of potassium isocyanate gives a A-substituted hydantoin. 

In a German patent issued in 1929, Bergs described a synthesis of some 5-substituted hydantoins by treatment of aldehydes or ketones (1) with potassium cyanide, ammonium carbonate, and carbon dioxide under several atmospheres of pressure at 80°C. In 1934, Bucherer et al. isolated a hydantoin derivative as a by-product in their preparation of cyanohydrin from cyclohexanone. They subsequently discovered that hydantoins could also be formed from the reaction of cyanohydrins (e.g. 3) and ammonium carbonate at room temperature or 60-70°C either in water or in benzene. The use of carbon dioxide under pressure was not necessary for the reaction to take place. Bucherer and Lieb later found that the reaction proceeded in 50% aqueous ethanol in excellent yields for ketones and good yields for aldehydes. ... 

Finally, this method is of general utility, for alkaline cleavage of analogously substituted hydantoins has given a series of substituted phenylpyruvic acids.12... 

In many cases, the racemization of a substrate required for DKR is difficult As an example, the production of optically pure cc-amino acids, which are used as intermediates for pharmaceuticals, cosmetics, and as chiral synfhons in organic chemistry [31], may be discussed. One of the important methods of the synthesis of amino acids is the hydrolysis of the appropriate hydantoins. Racemic 5-substituted hydantoins 15 are easily available from aldehydes using a commonly known synthetic procedure (Scheme 5.10) [32]. In the next step, they are enantioselectively hydrolyzed by d- or L-specific hydantoinase and the resulting N-carbamoyl amino acids 16 are hydrolyzed to optically pure a-amino acid 17 by other enzymes, namely, L- or D-specific carbamoylase. This process was introduced in the 1970s for the production of L-amino acids 17 [33]. For many substrates, the racemization process is too slow and in order to increase its rate enzymes called racemases are used. In processes the three enzymes, racemase, hydantoinase, and carbamoylase, can be used simultaneously this enables the production of a-amino acids without isolation of intermediates and increases the yield and productivity. Unfortunately, the commercial application of this process is limited because it is based on L-selective hydantoin-hydrolyzing enzymes [34, 35]. For production of D-amino acid the enzymes of opposite stereoselectivity are required. A recent study indicates that the inversion of enantioselectivity of hydantoinase, the key enzyme in the... 

The described fluorous-tag strategy has also been applied to the synthesis of biaryl-substituted hydantoins (Scheme 7.81) [94]. 4-Hydroxybenzaldehyde was converted into the corresponding perfluorinated species, which was then subjected to a reductive amination. The resulting amine was treated with an isocyanate to produce the fluorous-tagged urea, which spontaneously cyclized to form the corresponding hydantoin. Finally, the fluorous tag was detached by a Suzuki-type carbon-carbon bond formation to furnish the desired target structure in good yield. 

The ureidocarbonylation reaction provides access to hydantoins containing diverse substituents in the 1-, 3-, and 5-positions with good selectivities (Table 2) [37]. With monosubstituted ureas, 3-substituted hydantoins are obtained. 

M. Reist, P. A. Carrupt, B. Testa, S. Lehmann, J. J. Hansen, Kinetics and Mechanisms of Racemization 5-Substituted Hydantoins (= Imidazoline-2,4-diones) as Models of Chiral Drugs , Helv. Chim. Acta 1996, 79, 767-778. 

Substituted hydantoins, allan-toin, and phenylacetic acid 50 mM aqueous phosphate buffer, pH 7.0, with and without 30% (v/v) acetonitrile 10 urn Rutisil ODS-2 313 17 = 0.49 596 490-745... 

Phenytoin is a diphenyl-substituted hydantoin with the structure shown. It has much lower sedative properties than compounds with alkyl substituents at the 5 position. A more soluble prodrug of phenytoin, fosphenytoin, is available for parenteral use this phosphate ester compound is rapidly converted to phenytoin in the plasma. 

Scheme 6.30 Reaction of a-aminonitriles with C02 at ambient temperature synthesis of N-(3)-substituted hydantoins.

The C N functionality of a-aminonitriles may also act as a dehydrating/conden-sating center, as it may formally act as water trap and convert to an amide group [126h, i]. As shown in Scheme 6.30, at ambient temperature neat a-aminonitriles react with C02 to afford unsymmetric disubstituted ureas which, in water and at room temperature, can be converted into N-(3)-substituted hydantoins. 

Highly substituted hydantoins (13) can be obtained in similar yield and very mild conditions starting from pyroglutamates (12) (Scheme 3). 

M. Kato, H. Kitagawa, and T. Miyoshi, Microbial racemization of optically active 5-substituted hydantoins, Japanese Patent JP 62122591, 1987. 

The bacterial D-hydantoinase has been isolated as crystals from cells of Pseudomonas putida (= P. striata) (Table 1) [5]. Because the purified enzyme showed the highest activity and affinity toward dihydrouracil, the enzyme was identified as dihydropyrimidinase (EC. 3.5.2.2). Interestingly, the enzyme also attacked a variety of aliphatic and aromatic D-5-mono-substituted hydantoins, yielding the corresponding D-form of N-carbamoyl-a-amino acids. Thus, the enzyme can be used for the preparation of various D-amino acids. Under the conditions used for the enzymatic hydrolysis of hydantoin at pH 8 to 10, the L-isomers of the remaining hydantoins are racemized through base catalysis. Therefore, the racemic hydantoins can be converted quantitatively into N-carbamoyl-D-amino acids through this step. 

Many kinds of enzymes with different substrate specificities are involved in hydantoin hydrolysis. Ogawa et al. [10] found two hydantoin-hydrolyzing enzymes in Blastobacter sp. A17p-4. These enzymes were purified to homogeneity and characterized (Table 1). One hydrolyzed dihydropyrimidines and 5-monosubstituted hydantoins to the corresponding AT-carbamoyl amino acids. Since the hydrolysis of 5-substituted hydantoins by this enzyme was D-stereo-specific, this enzyme was identified as D-hydantoinase, which is identical with dihydropyrimidinase. The other one preferably hydrolyzed cyclic imide compounds such as glutarimide and succinimide more than cyclic ureide compounds such as dihydrouracil and hydantoin. Because there have been no reports on enzymes which show same substrate specificity as this enzyme, it is considered to be a novel enzyme, which should be called imidase [10]. 

BA Kern, RH Reitz. A general method for the preparation of the D- or L-stereoiso-mers of 5-substituted hydantoins. Agric Biol Chem 42 1275-1278, 1978. 

Scheme 16 shows parallel syntheses of cyclic and acyclic amide compounds. Fluorous benzaldehydes were first subjected to reductive amination reactions. The resulting amines were then reacted with isocyanates to form substituted hydantoin rings 14 or with benzoyl chlorides to form amides 15. Purified F-sulfonates were used for palladium-catalyzed cross-coupling reactions to form corresponding biaryl 16 [31] and arylsulfide 17 [32] products, respectively. 

Hydantoinase-Carbamoylase System for t-Amino Acid Synthesis Despite a number of reports of strains with L-selechve hydantoin-hydrolyzing enzymes [38] the commercial application of the hydantoinase process is stiU restricted to the production of D-amino acids. Processes for the production of L-amino acids are Umited by low space-time yields and high biocatalyst costs. Recently, a new generation of an L-hydantoinase process was developed based on a tailor-made recombinant whole cell biocatalyst. Further reduction of biocatalyst cost by use of recombinant Escherichia coli cells overexpressing hydantoinase, carbamoylase, and hydantoin racemase from Arthrohacter sp. DSM 9771 were achieved. To improve the hydan-toin-converting pathway, the level of expression of the different genes was balanced on the basis of their specific activities. The system has been appUed to the preparation of L-methionine the space-time yield is however still Umited [39]. Improvements in the deracemization process from rac-5-substituted hydantoins to L-amino acids still requires a more selective L-hydantoinase. 

A limiting factor in the use of these CSPs is the fact that the formation of the solute/CSP complex is dependent on the existence of complimentary interaction sites on the solute. However, this is not a problem with a wide variety of enantiomeric compounds. Type I CSPs have been used to stereochemically resolve alkyl carbinols, aryl-substituted hydantoins, lactams, succinimides, phthalides, sulfoxides, and sulfides (20). 

Bucherer, H. T., Libe, V. A. Syntheses of hydantoins. II. Formation of substituted hydantoins from aldehydes and ketones. J. Prakt. Chem. 

D-Hydantoinases exist at different levels in many microorganism strains, and many of them have been cloned and overexpressed [103,122,123], This group of enzymes catalyzes enantioselective ring cleavage of 5-substituted hydantoins to give the corresponding D-A-carbamylamino acids that can be further hydrolyzed chemically or enzymatically to the free D-amino acids. The chemical... 

Higher alkyl substituents shielded the hydantoin rings and gave lower glass temperatures. The same shielding effect was observed in the reduced hydrophilicity of higher alkyl-substituted hydantoin epoxy resins cured with triethylenetetramine. 

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