Pyroglutamic acids

L-Glutamic acid does not racemize in neutral solution, even at 100°C. Deviation of pH from neutral to greater than 8.5 results in thermal racemization with loss of taste characteristics. Racemization in neutral solution occurs at 190 °C after formation of the lactam, 5-oxo-L-proline, pyroglutamic acid [98-79-3]. 

Figure 15.8 Multidimensional GC-MS separation of urinary acids after derivatization with methyl chloroformate (a) pre-column cliromatogram after splitless injection (h) Main-column selected ion monitoring cliromatogram (mass 84) of pyroglutamic acid methyl ester. Adapted from Journal of Chromatography, B 714, M. Heil et ai, Enantioselective multidimensional gas chromatography-mass spectrometry in the analysis of urinary organic acids , pp. 119-126, copyright 1998, with permission from Elsevier Science.

When mercaptoethanol was used, the pyrroHdinone 97 (formally a derivative of pyroglutamic acid) was obtained through the intramoleciflar cyclization of the pyrroline formed under standard conditions. The spiroderiva-tive 96 is hydrolyzed in situ to give the alkylated pyroglutamic derivative 97 (Scheme 34). The diversity and the yields of the products obtained with this method were high, especially if compared with results obtained under conventional heating. 

Nva) nucleoamino adds Fmoc-Nva -OH (15) and Fmoc-Nva -OH (18). Both of these nucleoamino acids have now been synthesized regioselectively in good overall yields starting from the known pyroglutamic acid derivative 10 via the sequences shown in Scheme 5.2 [44]. Preliminary experiments have shown that these two nudeoamino acid derivatives can be incorporated into our SPPS without the need for protection of the exocyclic NH2 groups [45]. 

The heterocyclic scaffolds are prepared from pyroglutamic acid [154, 155]. 1-aminoalkyl boronic acid pinanediol esters are readily available through a diastereoselective homologation with dichloromethyllithium, providing (5)-a-chloroboronic esters. Aminolysis of the chloride yielded... 

Entry 6 uses a chiral auxiliary derived from pyroglutamic acid. Entry 7 is an example of the use of pantolactone as a chiral auxiliary to form a prostaglandin precursor. 

Several chiral ligands have been developed for use with the rhodium catalysts, among them are pyrrolidinones and imidazolidinones.207 For example, the lactamate of pyroglutamic acid gives enantioselective cyclopropanation reactions. 

Pyroglutamic acid is a useful starting material for the synthesis of several natural products, such as pyrrolidine alkaloids, kainoids, and other unnatural amino acids. Interesting chemose-lective Michael additions of anions derived from pyroglutamates have been reported (see Eqs. 4.54 and 4.55).69... 

Hydroxamic acids constitute an important class of siderophores, which play a major role in iron solubilization and transport. Some of them are important as therapeutic agents. The Michael addition of nitroacetyl proline esters to allyl acrylate followed by Pd(0)-catalyzed intramolecular allyl transfer and subsequent reduction of the nitro group yields a novel class of cyclic hydroxamic acids related to pyroglutamic acid (Scheme 5.9).85... 

A rich family of diazaphospholes 260-262 having hcxahydro- l//-pyrrolo [l,2-c][l, 3, 2]diazaphosphole backbone was readily prepared by the reaction of phenylphosphorodichloridite or another P(III) precursor with anilides of (iS )-proline, (S)-pyroglutamic acid, and (S)-indoline carboxylic acid in high yields diastereoselectively [95],... 

Enantiospecific syntheses of amino derivatives of benzo[ ]quinolizidine and indolo[2,3- ]quinolizidine compounds have also been achieved via A-acyliminium ion cyclization reactions, as an alternative to the more traditional Bischler-Napieralski chemistry (see Section 12.01.9.2.2). One interesting example involves the use of L-pyroglutamic acid as a chiral starting material to construct intermediates 240 via reaction with arylethylamine derivatives. Diisobutylaluminium hydride (DIBAL-H) reduction of the amide function in 240 and subsequent cyclization and further reduction afforded piperidine derivatives 241, which stereoselectively cyclized to benzo[ ]quinolizidine 242 upon treatment with boron trifluoride (Scheme 47) <1999JOC9729>. 

Patients have metabolic acidosis caused by excessive formation of 5-oxoproline (pyroglutamic acid Fig. 40-6, reaction 2). This occurs because the diminution of intracellular glutathione relieves the feedback inhibition on the y-glutamylcysteine synthetase pathway (reaction 1), thereby augmenting the concentration of y-glutamylcys-teine and the subsequent conversion of this dipeptide to cysteine and 5-oxoproline in the cyclotransferase pathway (reaction 4). 

A diastereoselective synthesis of 3,5-disubstituted indolizidines based on an intermol. addition of an allylsilane on an acyliminium ion derived from (d )-pyroglutamic acid, is described <2006TA1253>. 

The pyrrolo[l,2-4][l,2,4]triazinone skeleton 76 was also accessible in quantitative yield through a triflic acid-catalyzed heterocyclization of trisilylated diacylhydrazines 75 derived from pyroglutamic acid (Equation 10) <1996JHC1073>. 

Pfaltz and co-workers (45) reported neutral variants of the semicorrins as ligands in this reaction. These ligands, termed 5-azasemicorrins, may be readily assembled from pyroglutamic acid in high overall yields. Azasemicorrin (68) complexed to CuOTf forms an effective catalyst for this reaction exhibiting selectivities intermediate between the semicorrins and neutral bis(oxazolines) (45). 

HE Klieger. On peptide synthesis I. Synthesis of glutamic acid peptides using car-bobenzoxy-L-pyroglutamic acid. Justus Liebig s Ann Chem 640, 145, 1961. 

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