Ureides, cyclic

Reaction between ureas and malonic esters (cyclic ureides)... 

Murray, J. S., P. Lane, T. Brinck, P. Politzer, and P. Sjoberg. 1991b. Electrostatic Potentials on the Molecular Surface of Some Cyclic Ureides. J. Phys. Chem. 95, 844. 

This subsection examines the hydrolytic stability of cyclic structures containing a ureido link. Schematically, ring closure can be achieved by N-alkylation or by /V-acylation of the second N-atom of the ureido moiety. The former results in the formation of, e.g., hydantoins and dihydropyrimidines. The latter ring closure leads to, e.g., barbituric acids. Taken together, cyclic ureides can also be regarded as ring structures that contain an imido function with an adjacent N-atom. We begin our discussion with the five-membered hydantoins, to continue with six-membered structures, namely dihydropyrimidines, barbituric acids, and xanthines. 

D-p-Hydroxyphenylglycine is an important component of certain semi-synthetic antibiotics such as the semi-synthetic cephalosporins cefadroxil and cefatrizine and the semi-synthetic penicillin amoxicillin, with a combined world market in excess of 3 x 10 /a. Synthesis was possible from DL-5-monosubstituted hydantoins (cyclic ureides of amino acids) provided that a selective D-hydantoinase could be found, which would be competitive with chemical methods. 

Ethosuximide is the last antiseizure drug to be marketed whose origin is in the cyclic ureide structure. The three antiseizure succinimides marketed in the USA are ethosuximide, phensuximide, and methsuximide. Methsuximide and phensuximide have phenyl substituents, whereas ethosuximide is 2-ethyl-2-methylsuccinimide. 

Table 1. Properties of cyclic ureide-hydrolyzing enzymes...

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]. 

Reductive desulfurization in the synthesis of cyclic ureides and lactams 88MI17 90MI13. 

Periodate oxidation studies on N,N -diacetylstreptamine, N,N -di-benzoylstreptamine (III) " and streptidine (VII) showed that each of these substances consumed only two moles of periodate. A 1,2 arrangement of the two amino or guanidino groups was therefore excluded since this would have required three moles of periodate. This conclusion was substantiated by the failure of streptamine to yield a cyclic ureide when treated with phosgene. ... 

Cyclic Ureids.—With chlorides of di-basic acids, or of hydroxy mono-basic acids, the double acyl group unites with the two amino residues of urea forming a cyclic ureid as follows ... 

Several of these cyclic ureids are of especial importance in connection with uric acid which we shall presently discuss. These are as follows ... 

Urea is a diamide, and as such it exhibits the general properties of its functional groups. Its acyl derivatives are called ureides. A number of synthetic drugs are cyclic ureides. Uric acid is a complex cyclic ureide. On oxidation with nitric acid it forms a molecule of urea and alloxan. The latter may be regarded as derived from... 

Murray JS, Lane P, Brinck T, Politzer P, Sjoberg P. Electrostatic potentials on the molecular surfaces of cyclic ureides. J Phys Chem 1991 95 844-848. 

Our results provide a basis for predicting the relative hydrolytic tendencies of the cyclic ureides 25-32. Susceptibility toward hydrolysis is expected to increase roughly as Vs becomes more positive. However, we anticipate that the number of C=0 groups in the molecule is also an important factor in determining its reactivity, since each of them is a potential site for nucleophilic interaction. 

In this section we have reviewed our initial studies exploring the use of the electrostatic potential to interpret relative tendencies toward nucleophilic attack and have demonstrated that the surface V(r) can be used for both qualitative predictions, as in comparing Figures 5 and 6, and also more quantitatively, e.g., in the study of the cyclic ureides. Further investigations using this approach are in progress. 

Barbiturates are cyclic ureides and are formed when a diearboxylic acid reacts with urea. The acids used are generally in the form of ester and are condensed in the presence of sodium ethoxide i.e., C2H5—ONa) e.g.,... 

Parabanic acid is a cyclic ureide containing a five membered ring, which on hydrolysis by alkali may regenerate the corresponding acid and urea. The cyclic ureides are acidic owing to enolization and hence, they may form metallic salts by replacing the H atom of the -OH group as shown below ... 

Many cyclic ureides are derived from malonic acid or malonic esters. They are collectively known as barbiturates because of their relationship of malonyl urea or barbituric acid. Barbituric acid is prepared by the following two methods ... 

The cyclic ureides containing a six membered ring, are also regarded as derivatives of the funda-... 

Example. Phenobarbital [Gardinal ]. The following scheme vividly explains the base hydrolysis of phenobarbital wherein the cyclic ureide ring (in barbiturate) undergoes cessation. Besides, it may also be seen that the aforesaid cessation strategically takes place either between C-l/C-2 and/or C-l/C-6 locations in the structure of barbiturate. However, the cleavage between C-1 and C-6 is considered to be the most preferred pathway prevailing in the ionized barbiturates , such as aqueous solutions of sodium salts. 

Explain how the cyclic ureide barbituric acid may by prepared from ... 

In the mechanism of the Biginelli synthesis [265], the rate-determining step is the acid-catalyzed formation of an acylimine 35 from aldehyde and urea. By N-protonation (or metal-N-coordination), the imine 35 is activated (as an iminium ion) and intercepted by the P-ketoester (as enol or metal enolate) to give rise to an open-chain ureide 36, which subsequently cyclizes (via the cyclic ureide 37 and its dehydration) to afford the dihydropyrimidinone 33. Biginelli compounds of type 33 have been synthesized independently in multistep sequences [266]. 

Barbituric acid, mp 245 °C, is a cyclic ureide with a remarkably high C-H acidity (pK = 4). Barbituric acid is prepared [272] by cyclocondensation (i) of malonic acid... 

Imides (including cyclic ureides and luic acid)... 

Reactions of the cyclic ureide, hydantoin, with fonnaldehyde haA e been studied by iemeyer and Behrend . Monometbylolhydantoin is obtained by heating hydantoin with formaldehyde solution for a short time. Its exact structural formula has not been determined two isomeric possibilities exist ... 

Takahashi et al. [6] revealed that in Pseudomonas putida (= P. striata) BFO 12996 d-hydantoinase is identical with dihydropyrirnidinase (EC 3.5.2.2), which catalyzes the cyclic ureide-hydrolyzing step of the reductive degradation of pyrimidine bases (Fig. 4). The same results were obtained for other hydantoinases from Pseudomonas sp. [22,23], Com-amonas sp. [23], Bacillus sp. [9], Arthrobacter sp. [24], Agrobacterium sp. [22], and rat liver [25]. From these results, it is proposed that D-amino acid production from dl-5-monosubstituted hydantoins involves the action of the series of enzymes involved in the pyrimidine degradation pathway [24,26,27], However, this contenticm has remained moot because of a lack of systematic studies on the enzymes involved in these transformations [28]. 

Dihydroorotase (EC 3.5.2.3) is one of the known cyclic ureide-hydrolyzing enzymes, which catalyzes the reversible cyclization of L-ureidosuccinate to dihydro-Z/-orotate (Fig. 5c), the third step in pyrimidine biosynthesis. Dihydroorotase from P. putida IFO 12996 was purified to homogeneity and characterized [54]. The enzyme only hydrolyzed dihydro-L-orotate and its methyl ester, and the reactions were reversible. Dihydroorotase is specific for the siK-member cyclic ureides and shows the stereospecificity for the L-isomer. 

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