Cysteine racemization

Fig. 25 a Homochiral pairs are observed in STM after adsorption of racemic cysteine. L-cysteine pairs are tilted CW away from the [110] substrate direction as clearly observed via STM (inset). Reprinted with permission of the authors, b Superposition of the most stable structure obtained from DFT calculations and a STM image acquired after annealing of a D-cysteine layer at 380 K. By removing the top-most atomic row underneath the cysteine double row structure the (1 x 1) Au(110) surface is restored. Reprinted with permission from [78]. Copyright (2004) American Physical Society... 

The committee first designed a peptide susceptible to racemization at two residues. His and Cys Arg-Asp-Arg-His-Glu-Cys. Glu was placed after the Cys in order to facilitate determination of the influence of a racemized cysteine on the action of CPA. Arg was placed after the histidine in order to permit examination of whether the presence of a D-His would stop the action of trypsin. 

The synthesis begins with imino ethers, produced fiom nitriles, that ate condensed with racemic cysteine methyl ester hydrochloride to give a set of substituted thiazolines (Scheme )(11,12). 

Original Synthesis. The first attempted synthesis of i7-biotin in 1945 afforded racemic biotin (Fig. I). In this synthetic pathway, L-cysteine [52-90-4] (2) was converted to the methyl ester [5472-74-2] (3). An intramolecular Dieckmaim condensation, during which stereochemical integrity was lost, was followed by decarboxylation to afford the thiophanone [57752-72-4] (4). Aldol condensation of the thiophanone with the aldehyde ester [6026-86-4]... 

The mixture of free amino acids is reacted with OPA (Fig. 7-8) and a thiol compound. When an achiral thiol compound is used, a racemic isoindole derivative results. These derivatives from different amino acids can be used to enhance the sensitivity of fluorescence detection. Figure 7-9 shows the separation of 15 amino acids after derivatization with OPA and mercaptothiol the racemic amino acids may be separated on a reversed-phase column. If the thiol compound is unichiral, the amino acid enantiomers may be separated as the resultant diastereomeric isoindole compound in the same system. Figure 7-10 shows the separation of the same set of amino acids after derivatization with the unichiral thiol compound Wisobutyryl-L-cysteine (IBLC). 

The reaction mechanism for glutamate racemase has been studied extensively. It has been proposed that the key for the racemization activity is that the two cysteine residues of the enzyme are located on both sides of the substrate bound to the active site. Thus, one cysteine residue abstracts the a-proton from the substrate, while the other detivers a proton from the opposite side of the intermediate enolate of the amino acid. In this way, the racemase catalyzes the racemization of glutamic acid via a so-called two-base mechanism (Fig. 15). 

The first reductive kinetic resolution of racemic sulphoxides was reported by Balenovic and Bregant. They found that L-cysteine reacted with racemic sulphoxides to produce a mixture of L-cystine, sulphide and non-reduced optically active starting sulphoxide (equation 147). Mikojajczyk and Para reported that the reaction of optically active phosphonothioic acid 268 with racemic sulphoxides used in a 1 2 ratio gave the non-reduced optically active sulphoxides, however, with a low optical purity (equation 148). It is interesting to note that a clear relationship was found between the chirality of the reducing P-thioacid 268 and the recovered sulphoxide. Partial asymmetric reduction of racemic sulphoxides also occurs when a complex of LiAlH with chiral alcohols , as well as a mixture of formamidine sulphinic acid with chiral amines, are used as chiral reducing systems. ... 

Almqvist and coworkers have developed a two-step synthesis of optically active 2-pyridones via thiazolines (Scheme 6.216) [388]. Thus, heating a suspension of (R)-cysteine methyl ester hydrochloride with 2 equivalents of an imino ether and 2 equivalents of triethylamine base in 1,2-dichloroethane at 140 °C for 3 min furnished the desired thiazolines in near quantitative yield with limited racemization. Purification by filtration through a short silica gel column and concentration of the filtrate gave a crude product, which was used directly in the next step. Thus, after... 

J Kovac, GL Mayers, RH Johnson, RE Cover, UR Ghatak. Racemization of amino acid derivatives. Rate of racemization and peptide bond formation of cysteine active esters. J Org Chem 35, 1810, 1970. 

E Atherton, PM Hardy, DE Harris, H Matthews. Racemization of C-terminal cysteine during peptide assembly, in E Giralt, D Andreu, eds. Peptides 1990. Proceedings of the 21st European Peptide Symposium. Escom, Leiden, 1991, pp 243-244. 

Y Fujiwara, K Akaji, Y Kiso. Racemization-free synthesis of C-terminal cysteine-peptide using 2-chlorotrityl resin. Chem Pharm Bull (Jpn) 42, 724, 1994. 

Y Han, F Albericio, G Barany. Occurrence and minimization of cysteine racemization during stepwise solid-phase synthesis. J Org Chem 62, 4307, 1997. 

Optically active sulfoxides can also be obtained when a racemic sulfoxide is reduced with an insufficient amount of a chiral reagent. Balenovic and Bregant (65) found that L-cysteine reacted with racemic sulfoxides to produce a mixture of sulfide, L-cystine, and nonreduced optically active starting sulfoxide. Mikoikjczyk and Para... 

Alkaline hydrolysis (with NaOH, KOH or more seldom with Ba(OH)2) is almost exclusively applied for the determination of tryptophan and phosphoamino acids. Serine, threonine, arginine, and cysteine are completely destroyed by alkaline hydrolysis, while other amino acids are racemized [190]. Since racemization also occurs during acid hydrolysis, when it is important to... 

If instead of enantiomeric heptahelicene a racemic mixture is sublimated onto the surface, the molecules self-organize in enantiomorphous mirror domains. Thus, as in the case of cysteine on Au(l 10), the surface is stereoselective. 

Scheme 6 Protected Partially Racemic Lanthionine Formation via Michael Addition of L-Cysteine to Dehydroalanine Derivatives133 ...

Under these reducing conditions of hydrolysis of tryptophan peptides, cystine is reduced to cysteine and its coelution with proline using standard buffer gradients, makes quantitation difficult. Thus, cysteine and cystine are generally derivatized prior to acid hydrolysis by oxidation to cysteic acid with performic acid 21 or alkylation, upon reduction in the case of cystine, with iodoacetic acid 21 or, more appropriately, with 4-vmylpyridine)22 23 50 Conversion of cysteine into 5- 3-(4-pyridylethyl)cysteine bears the additional advantage of suppressing epimerization via the thiazoline intermediate, thus allowing for standardization of the acid-hydrolysis dependent racemization of cysteine in synthetic peptides)24 ... 

A chiral recognition was observed in aminolysis of 3-acyl-4(R)-methoxycarbonyl-l,3-thiazolidine-2-thione, a derivative of (R)-cysteine, by racemic amines to give an optically active amide [(S)-excess] and amine [(R)-excess]264). In the reaction of cyclic meso-1,3-diols with chiral N-protected phenylalanyl chlorides, Yamada et al.26S) observed the preferential formation of one of the two possible diastereomeric monoesters, which has been used for the synthesis of optically active steroids 266) and prostaglandins 267). 

---