Histidine racemization

Weissbuch, 1. Zbaida, D. Addadi, L. Leiserowitz, L. Lahav, M. Design of polymeric inhibitors for the control of crystal polymorphism - induced enantiomeric resolution of racemic histidine by crystallization at 25 degrees. J. Am. Chem. Soc. 1987,109 (6), 1869-1871. 

A very straightforward approach as compared with the existing one (Fig. 3) would have been the direct enzyme-catalyzed peptide formation (cf. Chen et al. [30]) by enantioselective aminolysis of ester 2 with histidine methylester 4 or even racemic histidine ester, as it would resolve the objectives of resolution and coupling in one step. Orientating experiments in which 20 proteases adsorbed on porous glass beads (SIKUG 041/02/120/A, Schott) were in contact with EtOH solutions of 2 and 4 with various water contents, however, did not reveal any reaction. 

In chiral systems, the racemic compound and the enantiomer usually undergo different degrees of solvation under given conditions. There are many examples of a change of the degree of solvation as a result of a change in the nature of the racemate [13], For example, enantiomeric histidine hydrochloride forms a monohydrate when crystallized from water, whereas racemic histidine hydrochloride forms a dihydrate. The racemic dihydrate transforms to the conglomerate monohydrate above 45°C [34]. 

Weissbuch I Leisorowitz L, Lahav M (1994) Tailor-made and chtiige-transfer auxiliaries for the control of the crystal polymorphism of glycine. Adv Mater 6 952—956 Weissbuch I, Zbaida D, Addadi L, Leiserowitz L, Lahav M (1987) Design of polymeric inhibitors for the control of crystal polymorphism— induced enantiomeric resolution of racemic histidine by crystallization at 25-Degrees-C. 1 Am Chem Soc 109 1869—1871 Yamashita K, Nakate T, Okimoto K, Ohike A, Tokunaga Y, Ibuki R, Higaki K, Kimura T (2003) Estabhshment of new preparation method for soUd dispersion formulation of tacrolimus. Int J Pharm 267 79-91... 

Crystallization Method. Such methods as mechanical separation, preferential crystallisation, and substitution crystallisation procedures are included in this category. The preferential crystallisation method is the most popular. The general procedure is to inoculate a saturated solution of the racemic mixture with a seed of the desired enantiomer. Resolutions by this method have been reported for histidine (43), glutamic acid (44), DOPA (45), threonine (46), A/-acetyl phenylalanine (47), and others. In the case of glutamic acid, the method had been used for industrial manufacture (48). 

The phenacyl group is stable to HBr-AcOH, CF3COOH, and CF3S03H. It is used to protect the Tr-nitrogen in histidine in order to reduce racemization during peptide bond formation. ... 

The Bum derivative has been used to protect the r-nitrogen of histidine to prevent racemization during peptide bond formation. The related 1-adamantyl-oxymethylamine has been used similarly for histidine protection. 

GC Windridge, EC Jorgensen. Racemization in the solid phase synthesis of histidine containing peptides. Intra-Sci Chem Rep 5, 375, 1971. 

SJ Harding, I Heslop, JH Jones, ME Wood. The racemization of histidine in peptide synthesis. Further studies, in HLS Maia, ed. Peptides 1994. Proceedings of the 23rd European Peptide Symposium, Escom, Leiden, 1995, pp 189-190. 

Racemic mixtures of underivatized amino acids Cu (II)-N - -decyl-L-histidine on ODS silica Water-Cu(II) acetate -1- organic modifier (85/15) 228... 

In the heterocyclic series, racemic 3-(fur-2-yl)alanine has been prepared from furfural using this approach. In addition, (3-(pyrid-3-yl)alanine, ° p-(quinol-3-yl)alanine, ° a p-(benzofuranyl)alanine derivative, 2-amino-3-(2,2 -bipyridi-nyl)propanoic acid, and some interesting derivatives of histidines—in particular 1-alkylhistidines with amphiphilic properties have all been synthesized using this methodology. The complete reaction sequence starting from an aldehyde and an A-acylamino acid derivative is shown in Scheme 7.150. 

Additives that specifically interact with an analyte component are also very useful in altering the electrophoretic mobility of that component. For example, the addition of copper(II)-L-histidine (12) or copper(II)-aspartame (54) complexes to the buffer system allows racemic mixtures of derivatized amino acids to resolve into its component enantiomers. Similarly, cyclodextrins have proven to be useful additives for improving selectivity. Cyclodextrins are non-ionic cyclic polysaccharides of glucose with a shape like a hollow truncated torus. The cavity is relatively hydrophobic while the external faces are hydrophilic, with one edge of the torus containing chiral secondary hydroxyl groups (55). These substances form inclusion complexes with guest compounds that fit well into their cavity. The use of cyclodextrins has been successfully applied to the separation of isomeric compounds (56), and to the optical resolution of racemic amino acid derivatives (57). 

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