Of hydantoins

In 1873, almost simultaneously, Maly (24), Volhard (38), and Nencki (42) studied the action of thiourea on chloroacetic acid. As mentioned previously, they believed the product to be the thioanalog of hydantoin and called it thiohydantoin with formula 34. 

Solvent variation can gready affect the acidity of hydantoins. Although two different standard states are employed for the piC scale and therefore care must be exercised when comparing absolute acidity constants measured in water and other solvents like dimethyl sulfoxide (DMSO), the huge difference in piC values, eg, 9.0 in water and 15.0 in DMSO (12) in the case of hydantoin itself, indicates that water provides a better stabilization for the hydantoin anion and hence an increased acidity when compared to DMSO. 

C-nmr data have been recorded and assigned for a great number of hydantoin derivatives (24). As in the case of H-nmr, useful correlations between chemical shifts and electronic parameters have been found. For example, Hammett constants of substituents in the aromatic portion of the molecule correlate weU to chemical shifts of C-5 and C-a in 5-arylmethylenehydantoins (23). Comparison between C-nmr spectra of hydantoins and those of their conjugate bases has been used for the calculation of their piC values (12,25). N-nmr spectra of hydantoins and their thio analogues have been studied (26). The N -nmr chemical shifts show a linear correlation with the frequencies of the N—H stretching vibrations in the infrared spectra. 

Luminescence spectra of hydantoin have been compared (27) with those of related heterocycles, represented by the following stmcture. The spectra are more sensitive to variation in the exocycHc heteroatoms (Y) rather than the endocycHc ones (Z). 

Reactions at G-5. The C-5 atom of hydantoins can be considered as an active methylene group, and therefore is a suitable position for base-cataly2ed condensation reactions with aldehydes (44). 2-Thiohydantoins give the reaction more readily than their oxygen counterparts ... 

Synthesis from OC-Amino Acids and Related Compounds. Addition of cyanates, isocyanates, and uiea derivatives to a-amino acids yields hydantoin piecuisois. This method is called the Read synthesis (2), and can be considered as the reverse of hydantoin hydrolysis. Thus the reaction of a-amino acids with alkaline cyanates affords hydantoic acids, which cyclize to hydantoins in an acidic medium. 

Adding amines to coating compounds containing other polymers of hydantoin derivatives permits thermal curing of the coating compounds, which are useful as electrical insulators of wires under a broad range of conditions without loss of coating flexibiUty (101). 

Hydantocidin. Hydantocidin (182), C2H2QN2O3, is elaborated by S. hygroscopicus (278). It is unique in that the anomeric carbon of the ribosyl moiety forms the spHo bond of hydantoin (279). The ribofuranose moiety which has been reported to be in a Q -endo conformation (279) has been synthesized (280,281). Hydantocidin is a herbicidal nucleoside with activity against monocotyledenous and dicotyledenous plants. 

The formation of hydantoin (2) from carbonyl compound 1 with potassium cyanide and ammonium carbonate or from cyanohydrin 3 and ammonium carbonate is referred to as... 

The other most important synthetic utility of the Bucherer-Bergs reaction is the preparation of amino acids from the hydrolysis of hydantoins. When carbonyl 1 was symmetrical, the Henze modification gave hydantoin 2, which was then hydrolyzed to the... 

A. 5-(p-Hydroxybenzal)hydantoin. An intimate mixture of 6.11 g. (0.050 mole) of />-hydroxybenzaldehyde (Note 1) and 5.5 g. (0.055 mole) of hydantoin (Note 2) is placed in a 250-ml. round-bottomed flask. Dry piperidine (10 ml.) is added, a reflux condenser protected by a calcium chloride tube is fitted to the flask, and the flask is immersed in an oil bath so that the level of the reaction mixture is the same as the oil level of the bath. The oil bath is heated slowly to 130° and is held at this temperature for 30 minutes foaming and gentle boiling occur. The reaction mixture is cooled, and 200 ml. of water at about 60° is added. The contents of the flask are stirred by means of a glass rod until a clear red solution is obtained (Note 3). Any traces of tarry material are removed by filtration. The solution is cooled to room temperature, transferred to an Erlenmeyer flask, and acidified by dropwise addition of 20 ml. of 12N hydrochloric acid. The mixture stands at room temperature a few hours, and then the yellow... 

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]. 

Another approach for the synthesis of enantiopure amino acids or amino alcohols is the enantioselective enzyme-catalyzed hydrolysis of hydantoins. As discussed above, hydantoins are very easily racemized in weak alkaline solutions via keto enol tautomerism. Sugai et al. have reported the DKR of the hydantoin prepared from DL-phenylalanine. DKR took place smoothly by the use of D-hydantoinase at a pH of 9 employing a borate buffer (Figure 4.17) [42]. 

Racemic hydantoins result from the reaction of carbonyl compounds with potassium cyanide and ammonium carbonate or the reaction of the corresponding cyanohydrins with ammonium carbonate (Bucherer-Bergs reaction). Hydantoins racemize readily under basic conditions or in the presence of hydantoin racemase, thus allowing DKR (Figure 6.43). Hydantoinases (EC 3.5.2.2), either isolated enzymes or whole microorganisms, catalyze the hydrolysis of five-substituted... 

Another method for the synthesis of hydantoins is the cyclization of A-(l-benzo-triazolylcarbonyl)phenylalanine butylamide.[147 ... 

Pietzsch, M. and Syldatk, C. (2002) Hydrolysis and formation of hydantoins, in Enzyme Catalysis in Organic Synthesis, 2nd edn (eds K. Drauz and H. Waldmann), Wiley-VCH Verlag GmbH, pp. 761-799. 

Vessieres, A., Kowalski, K., Zakrzewski, J., Stepien, A., Grabowski, M., and Jaouen, G. (1999) Synthesis of CpFe(CO)-(L) complexes of hydantoin anions (Cp) eta5-C5H5 (L) CO (PPh3), and the use of the 5,5-diphenylhydantoin anion complexes as tracers in the nonisotopic immunoassay CMIA of this antiepileptic drug. Bioconjugate Chem. 10, 379-385. 

For this solid-phase approach, conventional iPrOCH2-functionalized polystyrene resin (Merrifield linker) was employed. After attachment of the requisite substrate, the resin was pre-swollen in a solution of barium(II) hydroxide in N,N-dimethyl-formamide within an appropriate sealed microwave vial. The vial was heated in the microwave cavity for 5 x 2 min cycles (overall 10 min) with the reaction mixture being allowed to cool to room temperature in between irradiation cycles (Scheme 7.50), leading to comparatively modest isolated yields of hydantoins. 

Finally, another related study from the Sun laboratory concerned the synthesis of hydantoins utilizing acryloyl chloride to prepare a suitable polymer support [87]. All steps were carried out under reflux conditions in a dedicated microwave instrument utilizing 50-mL round-bottomed flasks. Identical reactions under classical thermal heating did not proceed in the same time period. 

The treatment of hydantoin derivatives (1293) with alkali metal hydroxide in boiling aqueous ethanol for 1 -2 hr gave orotic acid derivatives (1294) in good yields (82EUP52341). 

A phase-transfer catalysed nucleophilic displacement reaction on chloro-acetanilides by cyanate ions, followed by ring-closure (Scheme 5.10), provides a simple and viable synthesis of hydantoins [41], The formation of the hydantoins is inhibited by substituents in the orf/to-position of the aryl ring, but the addition of potassium iodide, or tetra-n-butylammonium iodide, generally increases the overall rate of formation of the cyclic compounds, presumably by facilitating the initial nucleophilic substitution step. 

Methacrylate polymers are as physically strong as polystyrene gels. Their hydrophobicity is weaker than that of polystyrene gel, and the aromatic selectivity is similar to that of octadecyl-bonded silica gel. A chromatogram of hydantoins on a methacrylate polymer is shown in Figure 3.16. The elution order is related to the hydrophobicity of the chemicals. 

Figure 3.16 Chromatogram of hydantoins on polymethacrylate stationary phase. Conditions columns, Shodex RSPak DE613 (methacrylate gel) eluent, 1 1 mixture of 0.033 M disodium hydrogen phosphate and potassium dihydrogen phosphate flow rate, 2.0 ml min-1 detection, UV 210 nm temperature, 50 °C. Compounds 1, R = (CH2)2C02H 2, R = CH2OH 3, R = H 4, R = CH3 and 5, R = C2H5.

The heterocyclic ring of hydantoins, like that of succinimides (see Sect. 4.4.2), is hydrolytically cleaved by dihydropyrimidine aminohydrolase (DHPase, EC 3.5.2.2). Since both hydantoins and succinimides are hydrolyzed by the same enzyme, it is not surprising that structural features, such as absolute configuration, ring-substitution, and TV-substitution, exhibit comparable influence on catalysis. 

Belafdal, 0., M. Bergon, and J.P. Calmon. Mechanism of hydantoin ring opening in iprodione in aqueous media, Pestic. Sci.,... 

Formation of hydantoins from carbonyl compounds with potassium cyanide (KCN) and ammonium carbonate [(NH4)2C03] or from cyanohydrins and ammonium carbonate. It belongs to the category of multiple component reaction (MCR). 

From the chemical point of view, formally, antiepileptic drugs could be classified as derivatives of hydantoins (phenytoin, mephenytoin, ethotoin), barbiturates (phenobarbital, mephobarbital, and primidone), succinimides (ethosuximide, methosuximide, phensux-imide), benzodiazepines (diazepam, chlorodiazepoxide, clonazepam, lorazepam), oxazo-lidines (trimethadione, paramethadione), and also valproic acid, carbamazepine, and acetazolamide. 

The mechanism of action of hydantoins is not yet conclusive. According to one hypothesis, hydantoins prevent high-frequency activation of the epileptogenic center and also facilitate secretion of sodium ions, which reduces excitation of neurons and prevents then-activation upon contact with impulses from the epileptogenic center. 

Pharmacology The primary site of action of hydantoins appears to be the motor cortex, where spread of seizure activity is inhibited. Possibly by promoting sodium efflux from neurons, hydantoins tend to stabilize the threshold against hyperexcitability. 

Hepatic function impairment Biotransformation of hydantoins occurs in the liver elderly patients or those with impaired liver function or severe illness may show early signs of toxicity. 

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