Oxazolones, racemization

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. 

To minimize racemization, the use of nonpolar solvents, a minimum of base, low reaction temperatures, and carbamate protective groups (R = O-alkyl or O-aryl) is effective. (A carbamate, R = O-r-Bu, has been reported to form an oxazolone that appears not to racemize during base-catalyzed coupling.) ... 

Carbamates can be used as protective groups for amino acids to minimize racem-ization in peptide synthesis. Racemization occurs during the base-catalyzed coupling reaction of an A-protected, carboxyl-activated amino acid and takes place in the intermediate oxazolone that forms readily from an A-acyl-protected amino acid (R = alkyl, aryl) ... 

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. 

Oxazolones (azlactones) are a form of activated lactones, so they are included in this section. CAL-B is an effective catalyst for the DKR of various racemic four-substituted-5 (4H)-oxazolones, in the presence of an alcohol, yielding optically active N-benzoyl amino acid esters as illustrated in Figure 6.24 [40]. Enantioselective biotransformations of lactides [72,73] and thiolactones ]74] have also been reported. 

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. 

M Goodman, L Levine. Peptide synthesis via active esters. IV. Racemization and ring-opening reactions of optically active oxazolones. JAm Chem Soc 86, 2918, 1964. 

The resolution was then based on the enzymatic propanolysis of this derivative in dioxane as solvent. Lip Novozyme 435 selectively cleaves the L-form of the oxazolone producing an L-enriched (81-87% ee) 2-acetamido-3-(heteroaryl)propionic acid propyl ester, the dynamic aspect of the process being based on the continual racemization of the residual oxazolone. The propyl group was then removed with alkali and a second selective enzymatic step to remove the acetyl protecting group with Fluka Acylase 1 produced the L-amino acid at better than 99% ee (Scheme 13). 

Saturated 5(4//)-oxazolones are easily obtained from //-acylamino acids in the presence of a cyclization agent and have been used extensively in coupling reactions as synthetic equivalents of a-amino acids in the synthesis of peptides. In this context, tautomeric equilibrium can be a significant problem due to the racemization associated with the isomerization. For example, trifluoroacetylation of tryptophan in ether affords the 5(4//)-oxazolone 5 without racemization. However, upon dissolution in acetonitrile, 5 completely racemizes. Further, upon heating, an aqueous dioxane solution of 5 cleanly isomerizes to the isomeric 5(2//)-oxazolone 6 (Scheme 7.2). 

The synthesis of 2-(trifluoromethyl) derivatives is more difficult and the compound preferentially obtained depends on the substituents and on the reaction conditions. Thus, the reaction of tryptophan with TFAA gives the 5(47/)-oxazolone without racemization." However, when this optically active product is dissolved in acetonitrile the racemic 5(47/)-oxazolone is obtained. On the other hand, treatment of the optically active compound with hot aqueous dioxane gave the isomeric 5(27/)-oxazolone (see Scheme 7.2). 

The use of mixed anhydrides derived from Al-acyl-a-amino acids has become an interesting strategy for synthesis of saturated 5(4//)-oxazolones 101 (Scheme 7.26). For example, reaction of Al-acyl-a-amino acids with methyl chloroformate in the presence of Al-methylmorpholine affords racemic 5(47/)-oxazolones. 

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. 

Chiral titanium complexes with a, a, a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol (TADDOL) ligands are versatile auxiliaries in the Lewis acid catalyzed alcoholysis of racemic 4-(arylmethyl)-2-phenyl-5(477)-oxazolones 234, providing the corresponding enantiomerically enriched N-protected amino acid esters 235 (Scheme 7.73). The enantioselectivity of the reaction is dependent on the solvent, temperature, and chiral ligand. Selected examples of the alcoholysis of saturated 5(477)-oxazolones are shown in Table 7.21 (Fig. 7.23). 

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). 

Amino acids have been used as nucleophiles to effect the ring opening of saturated 5(477)-oxazolones 253 as a coupling method in an attempt to describe a general procedure for peptide synthesis (Scheme 7.82). However, the problems arising from racemization, that is, when a proton is present at C-4 of the oxazolone, render this procedure of limited synthetic utility. 

Racemization is not encountered when 4-unsubstituted-5(477)-oxazolones or 4,4-disubstituted-5(477)-oxazolones are used as reagents. Indeed, 4-unsubstituted-5(47/)-oxazolones function as glycine synthons in the synthesis of A-acylglycyl-a-amino acids. For example, aminolysis of 2-(trifluoromethyl)-5(47/)-oxazolone with a-methylphenylalanine affords A-(trifluoroacetyl)glycyl-a-methylphenylalanine. 4,4-Disubstituted-5(4//)-oxazolones, readily available by alkylation of the monosubstituted derivatives, are very useful intermediates in the synthesis of peptides that incorporate ot,ot-disubstituted amino acids. As an example, 4-(aryl-methyl)-2-phenyl-4-(trifluoromethyl)-5(4//)-oxazolones 260 are key intermediates... 

The authors applied the same synthetic strategy to racemic 4-alkyl -(iodo-methyl)-2-phenyl-5(4/ )-oxazolones 266 and obtained a diastereomeric mixture of oxazolines 267 and 268 (Scheme 7.86). The diastereoisomers were separated chromatographicaUy and then converted into dipeptides incorporating an a-alkyl-serine residue. ... 

A number of systematic structural analyses have been described for families of saturated oxazolones. First, as mentioned previously, detailed smdies of NMR long-range coupling in 2,4-disubstimted-5(47/)-oxazolones and in 5(27/)-oxazo-lones have been reported." Similarly, detailed NMR studies of the kinetics of racemization of 2,4-disubstimted-5(47/)-oxazolones have been performed. A theoretical study of the spectral-luminescence properties of some 4-alkyl-2-phenyl-5(47/)-oxazolones has been reported and an investigation of the infrared (IR) and Raman spectra of 5(4//)-oxazolones, particularly of the carbonyl group vibration, has been reported. Electron impact mass spectra of saturated 5(47/)-oxazolones have been published. More recently this technique has been used to distinguish between the stereoisomers of some spirocyclopropane oxazolones 352 (Fig. 7.36). Finally, several studies of the HPLC behavior of 5(47/)-oxazolones complete a general view for this family of compounds. " " ... 

Several cases warrant special mention. As an example, ring opening, hydrogenation, and subsequent transformations of the 5(47/)-oxazolone 459 derived from 2,3-dihydroxy-4-methoxybenzaldehyde affords a biomimetic synthesis of racemic stizolobinic acid 463 as shown in Scheme 7.151. ... 

It is well known that hydrogenation of dehydroamino acid derivatives derived from ring opening of unsaturated 5(4H)-oxazolones affords new racemic amino acids and, in some cases, enantiomerically pure compounds. On the other hand, a number of attempts have been made to hydrogenate the double bond of the unsaturated oxazolone itself. For example, 4-benzyl-2-methyl-5(4//)-oxazolone was prepared from 4-benzylidene-2-methyl-5(4H)-oxazolone using Raney Ni as a catalyst. This process is reported to be a general procedure to prepare saturated oxazolones directly (Scheme 7.194). 

Since (Z)- and ( )-stereoisomers of unsaturated oxazolones can be obtained using appropriate isomerization procedures, cis and trans isomers of cyclopropane derivatives can be obtained in a stereoselective manner, although special care must be taken with experimental conditions to obtain the best stereoselectivity. Both racemic cis- and fraui-l-amino-2-phenylcyclopropanecarboxylic acid 641 and 644 have been obtained from the corresponding (Z)- or ( )-4-benzylidene-2-phenyl-5(4//)-oxazolone 621 and 642 using diazomethane. Care was taken to affect the... 

Racemic cw-l-amino-2-phenylcyclohexanecarboxylic acid 693 can be prepared by Diels-Alder reaction of (Z)-4-benzyhdene-2-phenyl-5(47/)-oxazolone 621 and butadiene in an analogous manner. Coupling A-tert-butyloxycarbonyl-L-proline with 693 yielded diastereomeric dipeptides that were separated chromatographi-cally. The behavior of the individual dipeptides was studied as a means to effect p-tum modulation by such cyclohexane analogues of phenylalanine. ... 

To extend this methodology, Diels-Alder reactions of several (Z)-4-arylidene (heteroarylidene)-2-phenyl-5(47/)-oxazolones with butadiene, 2,3-dimethylbuta-diene, cyclopentadiene and Danishefsky s diene have been studied. This work demonstrated that the products depended on the nature of the aromatic ring and the diene used. " An interesting application of this methodology is the synthesis of racemic epibatidine 729, a new alkaloid with a 7-azabicyclo[2.2.1]heptane skeleton that has proven to be a very potent analgesic. Preparation of 729 began with the Diels-Alder adduct 726 obtained from (Z)-4-[5 -(2 -chloropyridyhnethylene)]-2-... 

Electrochemical reduction of 4-benzylidene-2-methyl-5(47/)-oxazolone to produce racemic Al-acetylphenylalanine has been accomplished using lead and cadmium cathodes. ... 

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