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Chiral metabolomics is starting to become a well-defined research field, powered by the recent advances in separation techniques. This review aimed to cover the most relevant advances in indirect enantioseparations of endogenous metabolites that were published over the last 10 years, including improvements and development of new chiral derivatizing agents, along with advances in separation methodologies. Moreover, special emphasis is put on exciting advances in separation techniques combined with mass spectrometry, such as chiral discrimination by ion-mobility mass spectrometry together with untargeted strategies for profiling of chiral metabolites in complex matrices. These advances signify a leap in chiral metabolomics technologies that will surely offer a solid base to better understand the specific roles of enantiomeric metabolites in systems biology.

Black garlic is currently attracting interest as a health food and constituent of commercial supplements; however, no data regarding the d-amino acids within black garlic have been reported. Therefore, the amino acid compositions of methanol extracts from fresh and black garlic were compared herein. We investigated the contents of the d- and l-forms of amino acids in commercial fresh, black, and freeze-dried garlic foodstuffs by liquid chromatography–tandem mass spectrometry (LC–MS/MS) using a pre-column chiral derivatization reagent, succinimidyl 2-(3-((benzyloxy)carbonyl)-1-methyl-5-oxoimidazolidin-4-yl) acetate. Several d-amino acids, namely, the d-forms of Asn, Ala, Ser, Thr, Glu, Asp, Pro, Arg, Phe, Orn, Lys, and Tyr, were observed in the methanol extract of black garlic, whereas only d-Ala was detected in that of fresh garlic foodstuffs. These data suggest that several d-amino acids can be produced during fermentation for preparing black garlic.

The sex pheromone of the azalea mealybug, Crisicoccus azaleae (Tinsley, 1898) (Hemiptera: Pseudococcidae), includes esters of a methyl-branched medium-chain fatty acid, ethyl and isopropyl (E)-7-methyl-4-nonenoate. These compounds are exceptional among mealybug pheromones, which are commonly monoterpenes. Determination of the absolute configuration is challenging, because both chromatographic and spectrometric separations of stereoisomers of fatty acids with a methyl group distant from the carboxyl group are difficult. To solve this problem, we synthesized the enantiomers via the Johnson–Claisen rearrangement to build (E)-4-alkenoic acid by using (R)- and (S)-3-methylpentanal as chiral blocks, which were readily available from the amino acids L-(+)-alloisoleucine and L-(+)-isoleucine, respectively. Each pure enantiomer, as well as the natural pheromone, was subsequently derivatized with a highly potent chiral labeling reagent used in the Ohrui–Akasaka method. Through NMR spectral comparisons of these derivatives, the absolute configuration of the natural pheromone was determined to be S. Field-trap bioassays showed that male mealybugs were attracted more to (S)-enantiomers and preferred the natural stereochemistry. Moreover, the synthetic pheromones attracted Anagyrus wasps, indicating that the azalea mealybug pheromone has kairomonal activity.

In a previous study, we reported the identification and synthesis of a male-specific sex pheromone component of the stink bug, Pellaea stictica, as the alcohol 2,4,8,13-tetramethyltetradecan-1-ol (1). To establish the correlation between the stereochemistry of the pheromone and its bioactivity, it first was necessary to determine its absolute configuration. For this purpose, a series of syntheses were designed to: (a) furnish a mixture of all possible stereoisomers; (b) a narrowed down group of diastereomers, and (c) one specific enantiomer. A crucial step in the syntheses involved a coupling reaction between two key intermediates: a phosphonium salt and an aldehyde, through a Wittig olefination. Nuclear magnetic resonance data of a mixture of the synthetic pheromone diastereomers and further comparison of GC retention times with that of the natural product by gas chromatography suggested that the methyl branches at C2 and C4 were in a syn relationship, reducing the possibilities to only four of the eight possible stereoisomers. Employing GC analysis, chiral derivatization reagents and synthetic (8R)-2,4-syn-1 it was possible to confirm the configuration of the methyl branch at C8 as R, reducing the number of possible stereoisomers to two. After enantioselective synthesis of (2R,4R,8R)-1, the absolute configurations of all methyl branches of the natural compound were confirmed as R, fully identifying the male-produced sex pheromone of P. stictica as (2R,4R,8R)-2,4,8,13-tetramethyltetradecan-1-ol.

Novel triazine-type chiral derivatization reagents, i.e., ( S )-1-(4,6-dimethoxy-1,3,5-triazin-2-yl)pyrrolidin-3-amine (DMT-3( S )-Apy) and ( S )-4,6-dimethoxy- N -(pyrrolidin-3-yl)-1,3,5-triazin-2-amine (DMT-1( S )-Apy), were developed for the highly sensitive and selective detection of chiral carboxylic acids by UPLC-MS/MS analysis. Among the synthesized reagents, DMT-3( S )-Apy was a more efficient chiral reagent for the enantiomeric separation of chiral carboxylic acids in terms of separation efficiency by reversed-phase chromatography and detection sensitivity by ESI-MS/MS. The DMT-3( S )-Apy was used for the determination of 13 carboxylic acids in human saliva of healthy volunteers and diabetic patients. Various biological carboxylic acids including chiral carboxylic acids, and mono- and di-carboxylic acids were clearly identified in the saliva of healthy persons and diabetic patients. The concentrations of carboxylic acids detected in the saliva of diabetic patients were relatively higher than those in the healthy persons. Furthermore, the concentration of d -lactic acid (LA) and the ratio of d / l -LA in the diabetic patients were significantly higher than those in the healthy persons. The low ratio of d/l -LA in healthy persons was also identified to be independent of age and sex. These results suggest that the determination of the d / l -LA ratio in saliva might be applicable for the diagnosis of diabetes. Based on these observations, DMT-3( S )-Apy seems to be a useful chiral derivatization reagent for the determination not only of chiral carboxylic acids but also achiral ones. In conclusion, the proposed method using DMT-3( S )-Apy is useful for the carboxylic acid metabolomics study of various specimens. Graphical Abstract DL-Lactic acids in saliva

Although d,l-amino acids are symmetrical molecules, l-isomers are generally dominant in living organisms. However, it has been found that some d-amino acids also have biological functions. A new method for simultaneously analyzing d,l-amino acids in biological samples is required to allow unknown functions of d-amino acids to be investigated. d-Amino acids in urine are currently receiving increasing amounts of attention, particularly for screening for chronic kidney diseases. However, simultaneously analyzing d,l-amino acids in human urine is challenging because of interfering unknown compounds in urine. In this study, the axially chiral derivatizing agent (R)-4-nitrophenyl-N-[2-(diethylamino)-6,6-dimethyl-[1,1-biphenyl]-2-yl] carbamate hydrochloride was used to allow enantiomers of amino acids in human urine to be simultaneously determined by liquid chromatography electrospray ionization tandem mass spectrometry. The optimized method gave good linearities, precision results, and recoveries for 18 proteinogenic amino acids and their enantiomers and glycine. The chiral-switching method using (S)-4-nitrophenyl-N-[2-(diethylamino)-6, 6-dimethyl-[1,1-biphenyl]-2-yl]carbamate hydrochloride confirmed the expected concentrations of 32 of the 37 analytes. The method was successfully used to determine the concentrations of d-serine, d-alanine, d-asparagine, d-allothreonine, d-lysine, and the d-isomers of 10 other amino acids in five human volunteer urine samples.

Imidazole dipeptides (IDPs) and taurine (Tau) have several health benefits and are known to be contained in natural seafoods. However, their levels vary widely in different natural seafoods, making their simultaneous determination desirable. Herein, we employ a liquid chromatography–tandem mass spectrometry approach using a novel amino group derivatization reagent, succinimidyl 2-(3-((benzyloxy)carbonyl)-1-methyl-5-oxoimidazolidin-4-yl) acetate ((R)-CIMa-OSu), for the simultaneous quantification of IDPs (carnosine (Car) and anserine (Ans)), their related amino acids, and Tau in natural seafoods. Each seafood sample contained different concentrations of IDPs (Car: ND to 1.48 mmol/100 g-wet, Ans: ND to 4.67 mmol/100 g-wet). The Car levels were considerably higher in eel, while Tau was more abundant in squid, boiled octopus, and scallop. Thus, the derivatization reagent (R)-CIMa-OSu provides a new approach to accurately assess the nutritional composition of seafoods, thereby providing valuable insight into its dietary benefits.

A new chiral derivatizing agent for α-amino acids is described which leads to diastereomers that can be separated by reverse-phase HPLC with direct detection by a diode array detector. The main advantage of the presented procedure is the fact that an excess of the derivatizing reagent can be employed as the product exhibits an absorption maximum at 360 nm, while the reagent has its absorption maximum at 260 nm. Therefore, it is possible to suppress the reagent signal by a detection wavelength of 400 nm leading to an easy and general method for the enantioseparation of a mixture of dl-amino acids and the determination of the enantiomeric purity of α-amino acid as exemplified by 16 different α-amino acids.

A new synthesis strategy for the preparation of cellulose derivative-based chiral selectors and the subsequent mild immobilization onto pre-functionalized silica gel are introduced, utilizing Cu(I)-catalyzed alkyne-azide Huisgen cycloaddition (“click”) chemistry. A cellulose 3,5-dimethylphenyl carbamate derivative carrying propynyl carbamate groups was prepared by a combination of carbonate aminolysis and isocyanate chemistry. For immobilization, 3-azidopropyl-functionalized silica gel as an inert carrier was used, synthesized via a 3-chloropropyl intermediate. The chiral selector, as well as the inorganic/organic hybrid materials (silica gel/chiral selector), were comprehensively characterized by ATR-FTIR, solid-state 13C and 29Si NMR, liquid-state NMR, GPC, TGA, and elemental analysis. The enantioseparation performance of the immobilized-type chiral stationary phase was evaluated by HPLC with a set of representative chiral test analytes and different eluents and compared to a respective coated-type (=non-covalently bound) chiral stationary phase carrying the same selector quality and quantity on the same silica gel matrix. The immobilization did not adversely affect the chiral separation performance; on the contrary, in some chromatographic separations the immobilized-type chiral stationary phase surprisingly even surpassed the coated reference material.

The stability of collagen, the most abundant protein in humans and many animals, is related to the hydroxylation of L-proline, a post-translational modification occurring at carbon 3 and 4 on its pyrrolidine ring. Collagens of different origins have shown different proline hydroxylation levels, making hydroxyprolines useful biomarkers in structure characterizations. The presence of two chiral carbon atoms, 3-hydroxyproline and 4-hydroxyproline, results in eight stereoisomers (four pairs of enantiomers) whose quantitation in collagen hydrolysates requires enantioselective analytical methods. Capillary electrophoresis was applied for the separation and quantitation of the eight stereoisomers of 3- and 4-hydroxyproline and D,L-proline in collagen hydrolysates. The developed method is based on the derivatization with the chiral reagent (R)-(-)-4-(3-Isothiocyanatopyrrolidin-yl)-7-nitro-2,1,3-benzoxadiazole, enabling the use of a light-emitting diode-induced fluorescence detector for high sensitivity. The separation of the considered compounds was accomplished in less than 10 min, using a 500 mM acetate buffer pH 3.5 supplemented with 5 mM of heptakis(2,6-di-O-methyl)-β-cyclodextrin as the chiral selector. The method was fully validated and showed the adequate sensitivity for the application to samples of collagen hydrolysates. The analysis of samples extracted from chicken Pectoralis major muscles affected by growth-related myopathies showed different stereoisomer patterns compared to those from the unaffected control samples.