Racemization of the substrate and product by serine palmitoyltransferase from Sphingobacterium multivorum yields two enantiomers of the product from d-serine.

Serine palmitoyltransferase (SPT) catalyzes the pyridoxal-5'-phosphate (PLP)-dependent decarboxylative condensation of l-serine and palmitoyl-CoA to form 3-ketodihydrosphingosine (KDS). Although SPT was shown to synthesize corresponding products from amino acids other than l-serine, it is still arguable whether SPT catalyzes the reaction with d-serine, which is a question of biological importance. Using high substrate and enzyme concentrations, KDS was detected after the incubation of SPT from Sphingobacterium multivorum with d-serine and palmitoyl-CoA. Furthermore, the KDS comprised equal amounts of 2S and 2R isomers. 1H-NMR study showed a slow hydrogen-deuterium exchange at Cα of serine mediated by SPT. We further confirmed that SPT catalyzed the racemization of serine. The rate of the KDS formation from d-serine was comparable to those for the α-hydrogen exchange and the racemization reaction. The structure of the d-serine-soaked crystal (1.65 Å resolution) showed a distinct electron density of the PLP-l-serine aldimine, interpreted as the racemized product trapped in the active site. The structure of the α-methyl-d-serine-soaked crystal (1.70 Å resolution) showed the PLP-α-methyl-d-serine aldimine, mimicking the d-serine-SPT complex prior to racemization. Based on these enzymological and structural analyses, the synthesis of KDS from d-serine was explained as the result of the slow racemization to l-serine, followed by the reaction with palmitoyl-CoA, and SPT would not catalyze the direct condensation between d-serine and palmitoyl-CoA. It was also shown that the S. multivorum SPT catalyzed the racemization of the product KDS, which would explain the presence of (2R)-KDS in the reaction products.

Dating the Paleolithic: Trapped charge methods and amino acid geochronology.

Despite the vast array of different geochronological tools available, dating the Paleolithic remains one of the discipline's greatest challenges. This review focuses on two different dating approaches: trapped charge and amino acid geochronology. While differing in their fundamental principles, both exploit time-dependent changes in signals found within crystals to generate a chronology for the material dated and hence, the associated deposits. Within each method, there is a diverse range of signals that can be analyzed, each covering different time ranges, applicable to different materials and suitable for different paleoenvironmental and archaeological contexts. This multiplicity of signals can at first sight appear confusing, but it is a fundamental strength of the techniques, allowing internal checks for consistency and providing more information than simply a chronology. For each technique, we present an overview of the basis for the time-dependent signals and the types of material that can be analyzed, with examples of their archaeological application, as well as their future potential.

Strategies to Design Chemocatalytic Racemization of Tertiary Alcohols: State of the Art & Utilization for Dynamic Kinetic Resolution.

The synthesis of enantiomerically pure tertiary alcohols is an important issue in organic synthesis of a range of pharmaceuticals including molecules such as the anti-HIV drug Efavirenz. A conceptually elegant approach to such enantiomers is the dynamic kinetic resolution of racemic tertiary alcohols, which, however, requires efficient racemization strategies. The racemization of tertiary alcohols is particularly challenging due to various side reactions that can occur because of their high tendency for elimination reactions. In the last few years, several complementary catalytic concepts for racemization of tertiary alcohols have been developed, characterized by efficient racemization and suppression of unwanted side-reactions. Besides resins bearing sulfonic acid moieties and a combination of boronic acid and oxalic acid as heterogeneous and homogeneous Brønsted-acids, respectively, immobilized oxovanadium and piperidine turned out to be useful catalysts. The latter two catalysts, which have already been applied to different types of substrates, also have proven good compatibility with lipase, thus leading to the first two examples of chemoenzymatic dynamic kinetic resolution of tertiary alcohols. In this review, the difficulties in racemizing tertiary alcohols are specifically described, and the recently developed complementary concepts to overcome these hurdles are summarized.

Fortuitous Enantiomeric Self-Rectification of an Unreported Partial Racemisation in the Synthesis of a Chiral Phosphoric Acid: A Warning to Practitioners.

Racemisation without Consequence: MOM deprotection of an ether intermediate during a routine synthesis of phosphoric acid 1 promoted partial racemisation of the product BINOL 5. Surprisingly, however, after phosphorylation of the partially racemised BINOL, enantiopure acid 1 was isolated. Further inspection revealed that during phosphorylation, unhydrolysed racemic phosphorochloridate 6 precipitated, thus restoring homochirality in the product phosphoric acid 1. Moreover, MOM deprotection partial racemisation was avoided by conducting reactions at lower temperatures for no longer than the required deprotection time, and/or by application of other deprotection conditions from the literature.

Mammalian D-cysteine: A novel regulator of neural progenitor cell proliferation Mammalian D-cysteine: A novel regulator of neural progenitor cell proliferation Endogenous D-cysteine, the stereoisomer with rapid spontaneous in vitro racemization rate, has major neural roles

D-amino acids are being recognized as functionally important molecules in mammals. We recently identified endogenous D-cysteine in mammalian brain. D-cysteine is present in neonatal brain in substantial amounts (mM) and decreases with postnatal development. D-cysteine binds to MARCKS and a host of proteins implicated in cell division and neurodevelopmental disorders. D-cysteine decreases phosphorylation of MARCKS in neural progenitor cells (NPCs) affecting its translocation. D-cysteine controls NPC proliferation by inhibiting AKT signaling. Exogenous D-cysteine inhibits AKT phosphorylation at Thr 308 and Ser 473 in NPCs. D-cysteine treatment of NPCs led to 50% reduction in phosphorylation of Foxo1 at Ser 256 and Foxo3a at Ser 253. We hypothesize that in the developing brain endogenous D-cysteine is as a physiologic regulator of NPC proliferation by inhibiting AKT signaling mediated by Foxo1 and Foxo3a. Endogenous D-cysteine may regulate mammalian neurodevelopment with roles in schizophrenia and Alzheimer's disease (AD).

Atroposelective Formal [2 + 5] Macrocyclization Synthesis for a Novel All-Hydrocarbon Cyclo[7] Meta-Benzene Macrocycle.

A novel axially chiral all-hydrocarbon cyclo[7] (1,3-(4,6-dimethyl)benzene (CDMB-7) was designed and synthesized using atroposelective[2 + 5] cyclization through Suzuki-Miyaura coupling. CDMB-7 adopts an irregular bowl-like shape with C2 symmetry and exhibits two diastereoisomers in its crystallographic structure. The conformational isomers of CDMB-7 racemates remain stable at high temperatures (393 K). High-performance liquid chromatography (HPLC) confirmed that a single chiral isomer will spontaneously undergo racemization within 30 min at room temperature. This finding opens up possibilities for achieving adaptive chirality in all-hydrocarbon cyclo[7] m-benzene macrocycles.

Inversion of Diaza[5]Helicenes Through an N-N Bond Breaking Pathway.

1,1',10,10'-Biphenothiazine and its S,S,S',S'-tetroxide are diaza[5]helicenes with N-N linkages. Kinetic experiments on racemization together with DFT calculations revealed that they undergo inversion through the N-N bond breaking pathway rather than the general conformational pathway. In these diaza[5]helicenes with this inversion mechanism, the reduction of electronic repulsion in the N-N bond by modification of S to SO2 at the outer position of the helix led to a significantly higher inversion barrier, 35.3 kcal/mol, compared to [5]helicene. 1,1',10,10'-Biphenothiazine S,S,S',S'-tetroxide was highly resistant to acid-mediated N-N bond breaking and racemization under acidic conditions.

Mammalian D-Cysteine: A new addition to the growing family of biologically relevant D-amino acids.

Mammalian D-Cysteine is racemized from L-cysteine by serine racemase, a pyridoxal phosphate (PLP)-dependent enzyme. Endogenous D-Cysteine plays a role in neural development by inhibiting proliferation of neural progenitor cells (NPCs) via protein kinase B (AKT) signaling mediated by the FoxO family of transcription factors. D-Cysteine binds to Myristoylated Alanine Rich C Kinase Substrate (MARCKS) and alters phosphorylation at Ser 159/163 and its translocation from the membrane. By racemizing serine and cysteine, mammalian serine racemase may play important roles in neural development highlighting its importance in psychiatric disorders.

Organocatalytic-racemization reaction elucidation of aspartic acid by density functional theory.

Aldehydes and carboxylic acids are widely used as catalysts for efficient racemization process of amino acids. However, the detailed reaction mechanism remains unclear. This work aims to clarify the racemization mechanism of aspartic acid (Asp) catalyzed by salicylaldehyde and acetic acid by using computational approaches. Density functional theory was used to obtain the structures and relative energies of 10 intermediates and five transition states, thus characterizing the main stages of the reaction. The calculated energy diagram shows that the dehydration step has the highest energy barrier, followed by the reaction step to change the chirality of Asp, which is a crucial process for racemization. In the dehydration reaction, water molecules can induce a remarkable decrease in the required energy.

Elucidating the Racemization Mechanism of Aliphatic and Aromatic Amino Acids by In Silico Tools.

The racemization of biomolecules in the active site can reduce the biological activity of drugs, and the mechanism involved in this process is still not fully comprehended. The present study investigates the impact of aromaticity on racemization using advanced theoretical techniques based on density functional theory. Calculations were performed at the ωb97xd/6-311++g(d,p) level of theory. A compelling explanation for the observed aromatic stabilization via resonance is put forward, involving a carbanion intermediate. The analysis, employing Hammett's parameters, convincingly supports the presence of a negative charge within the transition state of aromatic compounds. Moreover, the combined utilization of natural bond orbital (NBO) analysis and intrinsic reaction coordinate (IRC) calculations confirms the pronounced stabilization of electron distribution within the carbanion intermediate. To enhance our understanding of the racemization process, a thorough examination of the evolution of NBO charges and Wiberg bond indices (WBIs) at all points along the IRC profile is performed. This approach offers valuable insights into the synchronicity parameters governing the racemization reactions.

N-Acetyl-l-phenylalanine Racemization during TBTU Amidation: An In-Depth Study for the Synthesis of Anti-Inflammatory 2-(N-Acetyl)-l-phenylalanylamido-2-deoxy-d-glucose (NAPA).

A thorough study on the amidation conditions of N-acetyl-l-phenylalanine using TBTU and various bases is reported for the synthesis of 2-(N-acetyl)-l-phenylalanylamido-2-deoxy-d-glucose (NAPA), a promising drug for the treatment of joints diseases. TBTU-mediated diastereoselective amidation reaction with 1,3,4,6-tetra-O-acetyl-ß-d-glucosamine always gave racemization of N-acetyl-l-phenylalanine. The stereochemical retention under amidation conditions was studied in detail in the presence of difference bases and via other control experiments, evidencing the possibility to reduce racemization using pyridine as base.

On the Nature of the Rotational Energy Barrier of Atropisomeric Hydrazides.

N-N atropisomers represent a useful class of compounds that has recently received important attention from many research groups. This article presents an in-depth analysis of the energy barrier needed for the racemization process of atropoisomeric hydrazides, combining an experimental and computational approach. The focus is on examining how electronic and steric factors impact the racemization process. The results obtained indicate that the barrier observed during the racemization process mainly arises from an increase in the p-orbital character of the nitrogen atoms.

Solid-Phase Synthesis of 2-Benzothiazolyl and 2-(Aminophenyl)benzothiazolyl Amino Acids and Peptides.

2-benzothiazoles and 2-(aminophenyl)benzothiazoles represent biologically interesting heterocycles with high pharmacological activity. The combination of these heterocycles with amino acids and peptides is of special interest, as such structures combine the advantages of amino acids and peptides with the advantages of the 2-benzothiazolyl and 2-(aminophenyl)benzothiazolyl pharmacophore group. In this work, we developed an easy and efficient method for the solid-phase synthesis of 2-benzothiazolyl (BTH) and 2-(aminophenyl)benzothiazolyl (AP-BTH) C-terminal modified amino acids and peptides with high chiral purity.

Semi-Preparative Separation, Absolute Configuration, Stereochemical Stability and Effects on Human Neuronal Cells of MDPV Enantiomers.

Synthetic cathinones, such as 3,4-methylenedioxypyrovalerone (MDPV), are widely abused due to their psychostimulant effects. As they are chiral molecules, studies of their stereochemical stability (racemization can occur in certain temperatures and acidic/basic environments) and of their biological and/or toxicity effects (enantiomers might display different properties) are of great relevance. In this study, the liquid chromatography (LC) semi-preparative enantioresolution of MDPV was optimized to collect both enantiomers with high recovery rates and enantiomeric ratio (e.r.) values. The absolute configuration of the MDPV enantiomers was determined by electronic circular dichroism (ECD) with the aid of theoretical calculations. The first eluted enantiomer was identified as S-(-)-MDPV and the second eluted enantiomer was identified as R-(+)-MDPV. A racemization study was performed by LC-UV, showing enantiomers' stability up to 48 h at room temperature and 24 h at 37 °C. Racemization was only affected by higher temperatures. The potential enantioselectivity of MDPV in cytotoxicity and in the expression of neuroplasticity-involved proteins-brain-derived neurotrophic factor (BDNF) and cyclin-dependent kinase 5 (Cdk5)-was also evaluated using SH-SY5Y neuroblastoma cells. No enantioselectivity was observed.

Construction of Thioamide Peptides from Chiral Amino Acids.

Thioamide peptides were synthesized in a straightforward one-pot process via the linkage of diverse natural amino acids in the presence of thiolphosphonate and trichlorosilane, wherein carbonyl groups were replaced with thiono compounds with minimal racemization. Experimental and computational mechanistic studies demonstrated that the trichlorosilane enables the activation of carboxylic acids via intense interactions with the Si-O bond, followed by coupling of the carboxylic acids with thiolphosphonate to obtain the key intermediate S-acyl dithiophosphate. Silyl-activated quadrangular metathesis transition states afforded the thioamide peptides. The potential applications of these thioamide peptides were further highlighted via late-stage linkages of diverse natural products and pharmaceutical drugs and the thioamide moiety.

Chiral Calix[3]pyrrole Derivatives: Synthesis, Racemization Kinetics, and Ring Expansion to Calix[9]- and Calix[12]pyrrole Analogues.

Chiral pyrrolic macrocycles continue to attract interest. However, their molecular design remains challenging. Here, we report a calixpyrrole-based chiral macrocyclic system, calix[1]furan[1]pyrrole[1]thiophene (1), synthesized from an oligoketone. Macrocycle 1 adopts a partial cone conformation in the solid state, and undergoes racemization via ring inversion. Molecular dynamics simulations revealed that inversion of the thiophene is the rate determining step. Pyrrole N-methylation suppressed racemization and permitted chiral resolution. Enantioselective N-methylation also occurred in the presence of a chiral ammonium salt, although the stereoselectivity is modest. A unique feature of 1 is that it acts as a useful synthetic precursor to yield several calix[n]furan[n]pyrrole[n]thiophene products (n=2-4), including a calix[12]pyrrole analogue that to our knowledge constitutes the largest calix[n]pyrrole-like species to be structurally characterized.

A Pair of Interconverting Cages Formed from Achiral Precursors Spontaneously Resolve into Homochiral Conformers.

Without chiral induction the emergence of homochirality from achiral molecules is rather serendipitous, as the rationale is somewhat ambiguous. We herein provide a plausible solution. From achiral precursors are formed a pair of interconverting cage conformers that exhibit a C3 -axis as the only symmetry element. When their interconversion is impeded with intramolecular H-bonding, each conformer self-sorts into a homochiral crystal, which is driven by a helical network of multivalent intermolecular interactions during the self-assembly of homochiral cage conformers. As no chiral induction is involved throughout, we believe our study could enlighten the rational design for the emergence of homochirality with several criteria: 1) formation of a molecule without inversion center or mirror plane; 2) suppression of the enantiomeric interconversion, and introduction of multivalent interactions along the helical trajectory of screw symmetry within the resulting superstructure.

[Chromatographic analysis of hard tooth tissue to determine the age of personality]. / Khromatograficheskii analiz tverdykh tkanei zuba v tselyakh opredeleniya vozrasta lichnosti.

The biochemical approach for age assessment is most appropriate in forensic medicine, as racemization of aspartic acid in bones and teeth is closely related to human biological age. The aim of the study is to assess the biochemical parameters of aspartic acid in human teeth, which can be implemented into forensic practice in Russia. Samples of dentin in amount of 20, taken from the teeth of subjects aged between 16 and 76, were examined. Chromatographic analysis of the samples was performed on a gas chromatograph using chiral column. Statistical data processing showed that the relative squared peak of D-aspartic acid has a strong correlation with human biological age. Data, obtained from the Russian population study, demonstrate the applicability of chromatography for forensic purposes. It should be noted that the approach to the racemization rate estimation in the hard tooth tissue was performed using standard laboratory equipment, which allows to easily implement this method in forensic medical practice.

Construction of hexabenzocoronene-based chiral nanographenes.

The past decade witnessed remarkable success in synthetic molecular nanographenes. Encouraged by the widespread application of chiral nanomaterials, the design, and construction of chiral nanographenes is a hot topic recently. As a classic nanographene unit, hexa-peri-hexabenzocoronene generally serves as the building block for nanographene synthesis. This review summarizes the representative examples of hexa-peri-hexabenzocoronene-based chiral nanographenes.

Copper-Catalyzed Enantioselective Hydrosilylation of gem-Difluorocyclopropenes Leading to a Stereochemical Study of the Silylated gem-Difluorocyclopropanes.

Optically active cyclopropanes have been widely investigated especially from the views of pharmaceutical and agrochemical industries, and substituting one of the methylenes with the difluoromethylene unit should be promising for developing novel biologically relevant compounds and functional materials. In this paper, the copper-catalyzed enantioselective hydrosilylation of gem-difluorocyclopropenes to provide the corresponding chiral gem-difluorocyclopropanes is presented. The use of copper(I) chloride, chiral ligands including bidentate BINAPs and monodentate phosphoramidites, and silylborane Me2 PhSi-Bpin accompanying sodium tert-butoxide in methanol was appropriate for the enantioselective hydrosilylation of the strained C=C double bond, and the resultant chiral difluorinated three-membered ring was unambiguously characterized. Subsequent activation of the silyl groups in enantio-enriched gem-difluorocyclopropanes showed substantial reduction of the enantiopurity, indicating cleavage of the distal C-C bond leading to the transient acyclic intermediates.