5 -Oxazolones hydrolysis

Lipases from porcine pancreas (PPL) and from Aspergillus niger are uniquely suited for oxazolone hydrolysis since they catalyze the ring-opening reaction with a high degree of enantioselectivity. Moreover, these lipases exhibited opposite stereochemical preference, thus providing access to both enantiomers of A -benzoyl... 

The hydrolysis and alcoholysis reactions have been extended to the heterocyclic series. A systematic study has been published of the hydrolysis of unsaturated oxazolones derived from a selection of heterocyclic aldehydes. A detailed study of the synthesis and stereospecific hydrolysis and methanolysis of the (Z) and ( ) isomers of 2-methyl (or phenyl)-4-(thienylmethylene)-5(4F/)-oxazo-lones 435 and 437 has also been described (Scheme 7.144). The synthesis of 2-acylamino-3-(indol-3-yl or carbazol-3-yl)acryhc acid derivatives as potential antifertility agents via oxazolone hydrolysis has also been published. ... 

Oxazol-5(2H)-one, 2-benzylidene-4-methyl-tautomerism, 6, 186 Oxazol-5(2ff)-one, 2-methylene-isomerization, 6, 226 Oxazol-5(2H)-one, 2-trifluoromethyl-acylation, 6, 201 Oxazol-5(4ff)-one, 4-allyl-thermal rearrangements, 6, 199 Oxazol-5(4H)-one, 4(arylmethylene)-Friedel-Crafts reactions, 6, 205 geometrical isomerism, 6, 185 Oxazol-5(4ff)-one, 4-benzylidene-2-phenyl-configuration, 6, 185 photorearrangement, 6, 201 Oxazol-5(4ff)-one, 4-benzyl-2-methyl-Friedel-Crafts reactions, 6, 205 Oxazol-5(4ff)-one, 4-methylene-in amino acid synthesis, 6, 203 Oxazol-5(4ff) -one. 2-trifluoromethyl-hydrolysis, 6, 206 Oxazolones... 

The dlenophlle, 3-acetyl-2(3H)-oxazolane, Is an attractive Intermediate for the synthesis of vicinal aminoalcohols with cIs configurations. It reacts with 1,3-dienes, even under quite mild conditions, to form (4+2) cycloadducts. Its high reactivity with deactivated 1,3-dienes Is noteworthy. This property is present also in 2(3H)-oxa201one which can be obtained easily through solvolysis of 3-acetyl-2(3H)-oxa2olone In methanol. 3-Acetyl-2(3H)-oxazolone, on UV irradiation In the presence of a sensitizer, combines easily with olefins to form (2+2) cycloadducts, the hydrolysis of which leads to the class of cis-2-aminocyclobutanols. 

The azlactones of a-benzoylaminocinnamic acids have traditionally been prepared by the action of hippuric acid (1, Ri = Ph) and acetic anhydride upon aromatic aldehydes, usually in the presence of sodium acetate. The formation of the oxazolone (2) in Erlenmeyer-Plochl synthesis is supported by good evidence. The method is a way to important intermediate products used in the synthesis of a-amino acids, peptides and related compounds. The aldol condensation reaction of azlactones (2) with carbonyl compounds is often followed by hydrolysis to provide unsaturated a-acylamino acid (4). Reduction yields the corresponding amino acid (6), while drastic hydrolysis gives the a-0X0 acid (5). ... 

Comforth has reviewed literature reports and independently studied the special cases of reaction of 1 with salicylaldehyde and with 2-acetoxybenzaldehyde. Coumarins (10) are afforded in the condensation of 1 with salicylaldehyde or its imine, whereas when 2-acetoxybenzaldehyde is used, acetoxy oxazolone 12 is the major product. The initial aldol condensation product between the oxazolone and 2-acetoxybenzaldehyde is the 4-(a-hydroxybenzyl)oxazolone 11, in which base-catalyzed intramolecular transacetylation is envisioned. The product 9 (R = Ac) can either be acetylated on the phenolic hydroxy group, before or after loss of acetic acid, to yield the oxazolone 12, or it can rearrange, by a second intramolecular process catalyzed by base and acid, to the hydrocoumarin, which loses acetic acid to yield 10. When salicylaldehyde is the starting material, aldol intermediate 9 (R = H) can rearrange directly to a hydrocoumarin. Comforth also accessed pure 4-(2 -hydroxyphenylmethylene)-2-phenyloxazol-5(4//)-one (13) through hydrolysis of 12 with 88% sulfuric acid. 

Modification of the Erlenmeyer reaction has been developed using imines of the carbonyl compounds, obtained with aniline," benzylamine or n-butylamine. Ivanova has also shown that an A-methylketimine is an effective reagent in the Erlenmeyer azlactone synthesis. Quantitative yield of 19 is generated by treatment of 3 equivalents of 2-phenyl-5(4ff)-oxazolone (2) (freshly prepared in benzene) with 1 equivalent of iV-methyl-diphenylmethanimine (18) in benzene. Products resulting from aminolysis (20), alkali-catalyzed hydrolysis (21), and alcoholysis (22) were also described. 

A very attractive and efficient method for the synthesis of L-aminoacids via DKR has been reported by Turner et al. [41a,b]. They employed enzyme-catalyzed ring opening of 5(4H)-oxazolones in combination with a catalytic amount of Et3N. The relatively low pKa of the C-4 proton (8.9) of oxazolones facilitates racemization. Hydrolysis of the ester obtained through DKR, followed by debenzoylation, yields L-aminoacids in excellent enantiomeric excess (99.5%) (Figure 4.16). In their initial studies, they employed Rhizomucor miehei lipase (Lipozyme) as the biocatalyst [41]. More recently, they have obtained excellent results employing CALB [41bj. This method has also been employed by Bevinakatti [41c,d] and Sih [41e,fj. 

The main application of the enzymatic hydrolysis of the amide bond is the en-antioselective synthesis of amino acids [4,97]. Acylases (EC 3.5.1.n) catalyze the hydrolysis of the N-acyl groups of a broad range of amino acid derivatives. They accept several acyl groups (acetyl, chloroacetyl, formyl, and carbamoyl) but they require a free a-carboxyl group. In general, acylases are selective for i-amino acids, but d-selective acylase have been reported. The kinetic resolution of amino acids by acylase-catalyzed hydrolysis is a well-established process [4]. The in situ racemization of the substrate in the presence of a racemase converts the process into a DKR. Alternatively, the remaining enantiomer of the N-acyl amino acid can be isolated and racemized via the formation of an oxazolone, as shown in Figure 6.34. 

The anions of CDs may also function as simple basic catalysts towards acidic substrates included in their cavities. Such was observed by Daffe and Fastrez (1983) who studied the deprotonation and hydrolysis of oxazolones in basic media containing CDs. Also, in a paper dealing mainly with catalysis by amylose, it was noted that CDs catalyse the deprotonation of long chain /3-keto esters in basic aqueous DMSO (Cheng et al., 1985) no saturation kinetics were found for CDs, indicating weak substrate binding under the conditions used. 

The enzymatic hydration of lactones is also documented, a variety of hydrolases having demonstrated activity. Very detailed kinetic studies have, for example, been published on the hydrolysis of oxazolones (7.78, R = H or Me, R = Me or aryl, R" = Me or Ph) catalyzed by a-chymotrypsin [163], These compounds are interesting from a chemical point of view, being enolic lac-... 

Base radical cations are also more acidic than their uncharged forms and the N-1 pAa of G + is 3.9 at the nucleoside level (compared to an N-1 pA a of 9.25 for dG ). Thus, neutral pH deprotonation of G + generates the neutral radical G(—H) that can react with O2 to eventually yield 2,5-diamino-imidazolone (Iz) and its hydrolysis oxazolone derivative In a competitive process, 8-oxoG can also be generated from G( H). ... 

Treatment of the phenacyliminium salt 114, derived from 5,7-dimethyl[l,2,4]-triazolo[l,5-fl]pyrimidine 113 and phenacyl bromide, with 2 equiv of triethylamine gives rise to the 2-iminooxazoline 118 by way of the in situ generated intermediary A -ylides 115. Acidic hydrolysis affords the 3-(2-pyrimidinyl)-2(3//)-oxazolone... 

Hydrolysis of a suitably 4-substituted oxazole has been reported to produce the corresponding oxazolone but the yields are not very high and the isolations can be difficult. For example, alkaline hydrolysis of 5 affords a low yield of mandehc acid presumably via the intermediacy of 6 (Scheme 6.3).As part of a study... 

The cyclization of a-halo carboxylic acid ureides can be complicated with products from different modes of cyclization. For example, bromination of 70 at low pH affords the 2-amino-4(5//)-oxazolone 71 in excellent yield, whereas bromination at pH 5-6 generates a mixture of hydantoins 72 and 73 in poor yield (Scheme 6.19)." Japanese workers" reported that cyclization of a-bromoisovaleryl-urea with 28% aqueous ammonia yields 2-amino-5-isopropyl-4(5H)-oxazolone 74, not 75 or 76. The structure of 74 was established spectroscopically and confirmed by hydrolysis to 77 (Scheme 6.20). 

The double bond of 2,2-bis(trifluoromethyl)-5(2f/)-oxazolone 71 reacts with ynamines and the resulting cycloadduct 81 is converted into the corresponding amino acid after hydrolysis. The procedure constitutes a new route to 3-alkyl-substituted aspartic acid derivatives 83 (Scheme 7.20 Table 7.14, Fig. 7.15). 

Phenyl-5(477)-oxazolone has been obtained during alkaline hydrolysis of p-nitrophenyl A -benzoylglycinate. A detailed study of this process has shown that the leaving group expulsion is the rate-determining step for conversion of the glycinate to the 5(4//)-oxazolone. ... 

The use of 2-(hydroxymethyl)furan or 2-(hydroxymethyl)thiophene as aUyhc alcohols gives rise to a-(trifluoromethyl)-a-(2-heteroaryl)glycine derivatives 125 after hydrolysis of the corresponding oxazolone 124 as shown in Scheme 7.35. ... 

The behavior of 2-substituted- or 2-unsubstituted-5(4//)-oxazolones is completely different. Reaction of electrophiles with 2-substimted-5(47/)-oxazolones usually occurs at C-4, whereas reaction of electrophiles with 2-unsubstituted-5(47/)-oxazolones affords the corresponding 5(2//)-oxazolones. The best example of the behavior of 2-unsubstituted-5(47/)-oxazolones involves 4-isopropyl-5(47/)-oxazolone 143, the anion of which can be considered as a formyl anion equiva-lent. ° ° Thus, reaction of 143 with a catalytic amount of triethylamine gives 144 that reacts with a,p-unsaturated carbonyl compounds to afford Michael adducts or with aldehydes to produce the corresponding aldol adducts. Mild acid hydrolysis of 145 yields the corresponding aldehydes (Scheme 7.42). 

Alkylation of saturated 5(4//)-oxazolones at C-4 is a well-known reaction that can be achieved under a wide variety of conditions. Numerous articles have described this reaction as a means to prepare 4,4-dialkyl-5(477)-oxazolones 147 that are valuable intermediates to prepare ot,ot-disubstituted a-amino acids. For instance,2-phenyl-5(4//)-oxazolone 146 readily obtained from hippuric acid and A,A -dicyclohexylcarbodiimide (DCC), is alkylated at C-4 with allyl, benzyl, or phenacyl halides if the reaction is conducted in dipolar aprotic solvents in the presence of weak bases. Hydrolysis of the resulting 5(477)-oxazolones leads to a,a-dialkylglycines 148 (Scheme 7.43). 

Intramolecular Alkylations. Intramolecular spiroalkylation of the suitably functionalized 5(477)-oxazolone 188 produced 189 in good to excellent yield. Acid hydrolysis of 189 then gave the cyclic amino acid 190 required in the synthesis of the aldose reductase inhibitor sorbinil (Scheme 7.57). ... 

When carbonyl compounds are used as electrophiles reaction with 4-monosub-stituted-5(4//)-oxazolones affords substituted serines after subsequent hydrolytic ring opening of the initial aldol product. As an example, 4-methyl-2-phenyl-5(4//)-oxazolone 193, prepared from alanine, reacts with benzaldehyde in a base-catalyzed addition to give, after hydrolysis, a 3 1 mixture of threo- and... 

However, important transformations can be made, for example, at C-4 and thus the sequence of cyclization of a typical amino acid to the oxazolone, followed by modification at C-4 and subsequent hydrolysis, has become a useful strategy to prepare new, non-proteinogenic amino acids. 

In addition, the use of an enantioselective or diastereoselective hydrolysis of racemic oxazolones offers another possibility to obtain new synthetic amino acids. Similarly, alcoholysis of 5(4H)-oxazolones gives the corresponding A -acylamino acid esters. 

A number of points should be considered to determine the most appropriate experimental conditions for the desired reaction and, to that end, the kinetics of hydrolysis and ionization of 4-methyl-2-phenyl-, 4-benzyl-2-phenyl-, and 4-benzyl-2-methyl-5(4//)-oxazolones have been investigated. Deprotonation of 5(477)-oxazolones in aqueous media, which leads to racemization of optically active 5(477)-oxazolones, is a fast process that competes with the ring opening. The difference between the rate constant for racemization and the ring opening is greater in solvents with dielectric constants less than water and thus, oxazolones racemize faster than they hydrolyze. 

The use of chiral organometaUic compounds as catalysts in the enantioselective hydrolysis of saturated oxazolones was reported several years ago and the mechanism of the hydrolysis of 4-benzyl-2-methyl-5(4//)-oxazolone catalyzed by the copper(II) complex of (5)-[(A-benzylprolyl)amino]benzaldoxime has been described. ... 

Other compounds smdied as chiral catalysts include a- and p-cyclodextrins that were used in the hydrolysis of oxazolones although the enantioselectivity in the ring-opening reaction was rather low. When a phenyl group is present at C-2 in these systems the enantioselectivity of the reaction is somewhat higher. 

An elegant method to suppress the undesired spontaneous hydrolysis of a 5(47/)-oxazolone in aqueous media uses a lipase-catalyzed alcoholysis reaction. Of particular importance is the synthesis of /crt-leucine, a non-proteinogenic a-amino acid that has found widespread use both as a chiral auxiliary and as a component of potentially therapeutic pseudopeptides. Racemic 4-/ert-butyl-2-phenyl-5(47/)-oxazolone 238 was submitted to Mucor miehei catalyzed alcoholysis using butanol as a nucleophile. Addition of a catalytic amount of triethylamine promoted in situ racemization. In this way, the enantiomericaUy pure butyl ester of (5)-A-benzoyl-/ert-leucine 239 was obtained in excellent yield (Scheme 7.75). 

The preparation of protected derivatives of D-allo- and L-fl//o-threonine by enzymatic hydrolysis of 5(47/)-oxazolones using hog kidney acylase has also been described. This methodology has been extended to a wide variety of amino acids and, at present, constitutes a general procedure to prepare non-quaternary... 

Dimerization of 5(4//)-oxazolones affords two different products depending on the reaction conditions. In one case, 4-benzyl-2-phenyl-5(4F/)-oxazolone 291 was converted to the pyrrolidinedione 292 with potassium carbonate followed by acidic hydrolysis (Scheme 7.96). ... 

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