Oxazolinone, amino acid

Treatment of an a-amino acid with an anhydride in the presence of pyridine, known as the Dakin-West reaction,[1431 gives access to a racemic a-amido ketone.1 44 1451 The mechanism involves formation of an oxazolinone (98)J146 In the modified Dakin-West reaction, the oxazolinone is reacted with an acid chloride (Scheme 33)J136 139] Due to the rapid epimer-ization of the oxazolinones, a diastereomeric mixture of product 99 is obtained. No detailed protocol has been published so far for the modified Dakin-West synthesis applied to (oxomethyleneamino) peptides, but the procedure is adapted from that already reported for (oxomethylene) peptides containing the tp[CO-CH2] link.1147 ... 

Substituted oxazolinones (see Scheme 4.23, p. 78) were synthesized directly by heating amino acids with TFA anhydride at 150°C for 10 min or by the action of dicyclo-hexylcarbodiimide on N-acylated amino acids [266]. Oxazolinones of eleven amino acids were chromatographed on 0.325% EGA on Chromosorb G at 40—140°C. 2-H-, 2-methyl-and 2-phenyloxazolinones of Leu were analysed on OV-17 together with 2-trifluoro-methyloxazolinone, which has the shortest retention time and is very volatile. 

Acylaminocarboxylic acids 288 are converted into 5(4//)-oxazolinones 289 by acid anhydrides (Scheme 140). In an extension of this reaction, A-acyl derivatives of glycine 290 react with aldehydes with concomitant cyclization to give azlactones 291 (Scheme 141) this is the basis of the Erlenmeyer synthesis of amino acids. Treatment of amino acid derivatives 292 with PBr3 affords the thiazolidine-2,5-dione 293 (Scheme 142) <1971CB3146>. 

An alternative approach to the DKR of phenyl oxazolinones is represented by alcoholysis in organic solvents. The Hpase from Pseudomonas cepacia was used for this purpose. In organic solvent with low water activity non-enzymatic hydrolysis proceeds very slowly but the rate of enoHzation of the C-4 proton is sufficiently rapid so that 100% of the substrate is converted into product By using methanol as the nucleophile, methanolysis of oxazolones proceeded at a useful rate to furnish methyl esters of N-benzoyl-t-a-amino acids. The optical purity of the products ranged from 66 to 98% e.e. [41]. 

The other major class of cyclic amino acid derivative used in dynamic resolution reactions is the hydantoin group. Like oxazolinones, hydantoins readily undergo racemisation under mild conditions. Systems involving a two step procedure using D-hydantoinase and a carbamoylase were reported to provide a route to D-amino acids[S2, 53). Dynamic resolution of a p-hydroxyphenyl substituted hydantoin was reported in 1987[541. Using the intact cells of Pseudomonas sp. AJ-11220, the amino acid was prepared in over 90% yield, as shown in Fig. 9-24. This hydrolytic procedure leads directly to the amino acid, and the same enantiomer of product, the D-amino acid, was obtained independently of the stereochemistry of the substrate. 

The oxazolinones (279), readily available from a-amino-acids and hexa-fluoroacetone, are excellent equivalents of a-keto-acids in that they give very good yields of quinoxalinones (280) upon reaction with o-phenylenediamine (Scheme 111). ... 

Unsaturated a-Amino-acids. - Oxazolinones (515), readily derived from N-benzoylglycine and ethyl chloroformate, condense smoothly with aromatic aldehydes, N-phenylaldimines, or cyclohexanone to... 

Merrifield s original idea was based on the general scheme of stepwise condensation of N-protected amino acids to the first one, which is linked with its carboxyl function by an ester bond to the insoluble polymer support. This way of solid phase peptide synthesis resulted from the well-known risk of racemization during activation of peptidic carboxyl components, which is minimized in activated amino acid derivatives, N-acylated by urethane-type protecting groups [40] (Fig. 7). Depending on the chosen method, the C-terminal activation of N-protected peptides tends to racemize a certain amount of the material because of the possible formation of an oxazolinone intermediate [41] (Fig. 8). 

Most of the activation methods known from conventional peptide synthesis in solution were explored on polymer concerning their desired reactivity in relation to side reactions, which are particularly unfavorable if the by-products are also bound to the support. Though urethane-masked amino acids generally are shielded from racemization under controlled conditions, this problem limits the use of peptidic building blocks C-terminally activated, since they tend to form the redoubtable oxazolinone intermediate from which the abstraction of a -proton is facilitated (Fig. 40). Recent results indicated a chance to overcome this problem and will be mentioned in the proper section of this chapter. 

Oxazolinone 6.226, which is also a chiral auxiliary for the propanoic acid moiety, was converted to its enolate anion and condensed with N-Boc alanine anhydride, to give 6,227.133 Reduction of the ketone moiety and acid hydrolysis led to 2S,3S,4R-4-amino-3-hydroxy-2-methylpentanoic acid (6.226).133 This amino acid is an acid hydrolysis product of bleomycin A2.134.135 Although bleomycin can be categorized as an antibiotic, it is best known for its anti-cancer activity.134,135... 

N-acyl derivatives of amino acids are transformed into oxazolinones (azlactones) by elimination of water ... 

The C-terminal amino acid is then separated from the amino acid hydrazides, e. g., by a cation exchange resin, and identified. It is possible to mark the C-terminal amino acid through selective titration via oxazolinone ... 

Oxazolinones are five-membered azlactones (in some older publications referred to as oxazolones) that can be obtained from a-amino acids, for example, from a-amino isobutyric acid, and carboxylic acids (Scheme 9). 

Scheme 9 Synthesis of 5-oxazolinone starting from a-amino acid and carboxylic acid.

In later publications, however, the same authors reported that the reaction of bis(5(4H)oxazolinones) derived from naturally occurring a-amino acids, that is, with at least one hydrogen atom at the 4 position, with amine-terminated polyethers and polyamides in the bulk at 175-200 °C is also possible. Scheme 12 shows the synthesis in which the bisox-azolinones derived from alanine, valine, phenylalanine, and methionine were obtained. 

S) Several attempts have been made, especially in recent years, to oxidize saturated to unsaturated oxazolinones. Oxazolinone formation activates the a-carbon atom of the corresponding amino acid, so that it can, for example, by easily brominated 100, 315, 417). Morin and Gordon 267) attempted the selective oxidation of the C-terminal amino acid of a peptide chain by first converting it into an oxazolinone. Treatment of the oxazolinones obtained from N-benzoyl- or N-carbo-benzoxydipeptides with Pb(OAc)4 or Hg(OAc)2 resulted however in... 

Following publication by Weygand and coworkers 432, 433) of their studies of the bromination of 2-trifluoroacetyl-A -oxazolinones at the p-carbon atom of the corresponding amino acid, Breitholle and Stammer (68, 69) described the elimination of HBr from these bromo-derivatives (17) to yield unsaturated A -oxazolinones (18). The latter yielded N-trifluoroacetyldehydroamino acid anilides (19) or peptides on treatment with aniline or amino acid esters respectively. Muller and Steglich (270) used this method independently for the synthesis of N-trifluoroacetyl-dehydrodipeptides (20) containing C-terminal alanine. 

Riordan and Stammer (335, 336) employed o-chloranil to oxidize saturated A -oxazolinones, and obtained dioxinones. Treatment of the latter with nucleophiles such as CH3O", PhNH2 or PhCH2SH afforded a-substituted amino acid derivatives, possibly by addition to the acylimine in equilibrium with the quinone adduct. Use of a non-nucleophilic base coupled with scavenging of the phenolic hydroxy groups by etherification made possible the isolation of acylenamino acid derivatives. 

Shemyakin has made a comprehensive study of nucleophilic reactions of 4-halooxazolinones (53) with a variety of alcohols, amines and mercaptans 100, see also 316). Nucleophilic exchange is frequently accompanied by opening of the oxazolinone ring and formation of substituted a-amino acid esters, amides or thiolesters (54). 

Another approach for the coupled racemization step has been used for compounds having an acidic hydrogen on the stereocenter. Examples of such compounds are chiral acyl donors such as a-substituted esters which are prone to base-catalyzed racemization via an enolate intermediate. This approach has been frequently used and a few examples will be given here to illustrate the utility (Scheme 11). The first examples involve oxa-zolinones where it was found that porcine pancreatic lipase and lipase from Aspergillus sp. exhibited opposite enantiopreferences [106,107]. The remaining oxazolinone was spontaneously racemized via the enolate intermediate and both (l)- and (D)-iV-benzoyl amino acids could be produced this way in high chemical and optical yields. The p Ka values of thio esters are lower than those of oxo esters [108]. This has been used in the lipase-... 

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