Thiazolidine carboxylic acid esters

The simplest and most satisfactory method of preparing arylidene-enamino acid esters is the P-elimination from 2-aryl-4-thiazolidinecarbo-xylic acid esters (40) on treatment with silver carbonate 287A). Arylidene-enamino acid N-hydroxysuccinimide esters were prepared and combined with amino acid esters to yield Schiff bases of dehydro-dipeptides. This elimination reaction of thiazolidine carboxylic acid esters has been applied to prepare the extremely unstable benzyUdene dehydroalanine ester, although it was impossible to isolate it. Nevertheless its existence could be proved without a doubt when the reaction was carried out at 0° in trideuterioacetonitrile solution and was followed by NMR spectrometry. Within one half hour at room temperature the unstable substance started to decompose. 

With a-amino carboxylic acid esters and formation of thiazolidin-5-... 

In order to obtain cyclization of an N-a-carboxy dithiocarbamic acid (CLXXXI) to the thiazolidin-5-one-2-thione (CLXIII), dehydrating agents are necessary. These same products may, however, be obtained by simply warming the a-amino carboxylic acid esters with carbon disulfide, especially when there is an aromatic ring attached to the -carbon atom (method D). In this way a-(methylamino) phenylacetic acid and carbon disulfide yield 3-methyl-4-phenylthiazolidin-5-one-2-thione [121) (Table 24). 

Upon treatment with Ag2C03 in aprotic solvents thiazolidine-4-carboxylic acid esters afford a,/8-unsaturated imines in excellent yields (Scheme 41)/° ... 

In his cephalosporin synthesis methyl levulinate was condensed with cysteine in acidic medium to give a bicyclic thiazolidine. One may rationalize the regioselective formation of this bicycle with the assumption that in the acidic reaction mixture the tMoI group is the only nucleophile present, which can add to the ketone. Intramolecular amide formation from the methyl ester and acid-catalyzed dehydration would then lead to the thiazolidine and y-lactam rings. The stereochemistry at the carboxylic acid a-... 

In an extensive study into the application of the decarboxylative approach to azomethine ylides, Giigg reported the construction of numerous, complex polycyclic systems via an intramolecular protocol. Thiazolidine-4-carboxylic acid (263) was shown to react with 264 in refluxing toluene to furnish a 2 1 mixture of 265 and 266 in 63% yield (81). The reaction is assumed to occur via condensation of the aldehyde and amino acid to generate the imine 267, followed by cyclization to 268. Subsequent thermal decarboxylation of the ester generates either a syn dipole leading to 265 from an exo transition state, or an anti dipole and endo transition state generating adduct 266 (Scheme 3.90). 

Access to racemic thiazolidine-2-carboxylic acid (3-thiaproline, 12) is obtained by reacting cysteamine (49) with glyoxylic acid ester (Scheme 9), 165>182>1831 whilst the reaction of (R)-cysteine with glyoxylic acid 184 1851 leads to (2/ /S,5/ )-thiazolidine-2-carboxylic acid. 185 The diastereomers of thiazolidine-2-carboxylic add (12) are rapidly interconverting and therefore cannot be separated. 185 In the presence of (2R,3R)- and (2S,3S)-tartaric acid, reaction of cysteamine with glyoxylic acid leads to the enantiomerically pure (2/ )- and (2S)-thia-zolidine-2-carboxylic acid salts. 186 The acids undergo fast racemization in acetic acid. 186 ... 

So far, only a limited use of thiazolidine-2-carboxylic acid (12) in peptide synthesis has been reported. This amino acid has been acylated as the alkyl ester with suitably N-protected amino acids via the HOBt/DCC method. 165 Subsequent saponification of peptidyl-thiazolidine-2-carboxylic acid ethyl ester proceeds smoothly with 1M NaOH in dioxane/water mixtures. 165 ... 

Due to the extremely low nucleophilicity of the imino group, 187,188 acylation of thiazolidine-4-carboxylic acid (11) is not a trivial procedure. In fact, N-protected Thz derivatives can be prepared by standard procedures, but strong acylating conditions are required. The related N-Boc derivative is obtained only by prolonged reaction times with Boc-N3 U2,189 or with Boc20. 113 For preparation of the N-Z derivative, silylation of Thz with, for example, chlorotrimethylsilane is recommended prior to the reaction benzyl chloroformate. 200 Due to the stability of thiazolidine-4-carboxylic acid to acids its methyl ester is obtained by HC1 catalyzed reaction with methanol, 190 whereas the amide is formed by reacting Thz N-carboxyanhydride with ammonia.1 89 Derivatives of thiazolidine-4-carboxylic acid are listed in Table 8. 

As mentioned above, thiazolidine-4-carboxylic acid is characterized by an anomalously low basicity and thus difficult acylation in peptide synthesis. 189 Therefore, the incorporation of this amino acid residue into a growing peptide chain is preferentially preformed via dipeptide derivatives. 139 Suitably N-protected amino acids are coupled directly to the thiazolidine-4-carboxylic acid by the acid fluoride 139 or iV-carboxyan hydride 1392111 methods. The resulting dipeptides are used as building blocks without risk of racemization 139 and standard coupling procedures are applied as pentachlorophenyl esters prepared by the mixed anhydride procedure 121 or PyBOP. 171 ... 

Thiazolidin-4-one-2-thiones (CLXXXVIII), compounds which possess strong bacteridical and fungicidal properties, can be very simply prepared by reacting an a-halo carboxylic acid or its ester with dithiocarbamic acids (CLXXXVI) [35, 42, 170, 205, 285, 396). The N-alkyl-S-a-(carboxyalkyl) dithiocarbamic acid or ester (CLXXXVII) is first formed and the cychzation carried on by refluxing with strong acids (method A). 

The ester-amine reaction is slow and requires long reaction times (see Chapter IV). Many active carboxylic acid derivatives such as the azides, p-nitrophenyl esters, and thiazolidine-2-thiones as well as carboxylic acid activators, such as dicyclohexylcarbodimide (DCCI), have been used to improve this reaction (see Chapter IV) (Kimura et al., 1989a, 1989b Krakowiak et al., 1989, 1990a Nagao et al., 1980, 1981 Uoto et al., 1990). These cyclization reactions seldom need high-dilution conditions. Even though ex-... 

Thiazolidine residues have also been introduced into protein in other ways. Treatment of insulin in aqueous solution with the hydroxy-succinimide ester of 3-formyl-2,2-dimethyl-L-thiazolidine-4-carboxylic acid (353) yields three products, separable by chromatography. They are characterized, by end-group analysis, electrophoresis, and amino-acid analysis of the performic acid-oxidized chains, as monosubstituted derivatives (354) formed by interaction at each of the free amino-groups of... 

C17H18N2O5S, 5,5-Dimethy1-2-(2-phenoxymethyl-5-0x0-1,3-oxazolin-4-ylidene)-1,3-thiazolidine-4-carboxylic acid methyl ester, 45B, 434 C17H18N2O5S, 6-Methoxyphenoxymethylanhydropenicillin, 39B, 280 Ci7Hi8NftS2, Methylene blue thiocyanate, 39B, 278 C17H1gClN2OS, 7-Hydroxy-2-chloro-10-(3 -dimethylamino-n-propyl)-phenothiazine, 43B, 490... 

Carbonyl Group Reduction. The flow of new methods for reduction of acid derivatives and aldehydes or ketones to alcohols continues unabated. The Report last year (4,134) featured the sodium borohydride reduction of carboxylic acid derivatives, originally thought to be 2-thiazoline-2-thiol esters (14), to give alcohols in good yields. Full details of the method have now appeared (Scheme 8), and it seems that the acid derivatives are in fact the 3-acyl thiazolidine-2-thiones (IS) dissappearance of their yellow colour is an easy way to monitor the reduction. Carboxylic acids or their chlorides can also be reduced to primary alcohols in good yields at room temperature using a titanium tetrachloride-sodium borohydride combination. ... 

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