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Catalytic asymmetric transformations by dearomatization have developed into a widely applicable synthetic strategy, but heavily relied on the use of arenes bearing a heteroatom. In this case, the dearomatization is facilitated by the involvement of a p‐orbital electron of the heteroatom. Different from the conventional substrate‐dependent model, here we demonstrate that the activation by a d‐orbital electron of the transition‐metal center can serve as a driving force for dearomatization, and is applied to the development of a novel asymmetric alkynyl copper facilitated remote substitution reaction. A newly modified PyBox chiral ligand enables the construction of valuable diarylmethyl and triarylmethyl skeletons in high enantioselectivities. An unexpected tandem process involving sequential remote substitution/cyclization/1,5‐H shift leads to the formation of the enantioenriched C−N axis. A gram‐scale reaction and various downstream transformations highlight the robustness of this method and the potential transformations of the products. Preliminary mechanistic studies reveal a mononuclear Cu‐catalyzed remote substitution process. [ABSTRACT FROM AUTHOR]

Parahydrogen‐induced polarization (PHIP) followed by polarization transfer to 13C is a rapidly developing technique for the generation of 13C‐hyperpolarized substrates. Chirality plays an essential role in living systems and differential metabolism of enantiomeric pairs of metabolic substrates is well documented. Inspired by asymmetric hydrogenation, here we report stereoPHIP, which involves the addition of parahydrogen to a prochiral substrate with a chiral catalyst followed by polarization transfer to 13C spins. We demonstrate that parahydrogen could be rapidly added to the prochiral precursor to both enantiomers of lactic acid (D and L), with both the (R,R) and (S,S) enantiomers of a chiral rhodium(I) catalyst to afford highly 13C‐hyperpolarized (over 20 %) L‐ and D‐lactate ester derivatives, respectively, with excellent stereoselectivity. We also show that the hyperpolarized 1H signal decays obtained with the (R,R) and (S,S) catalysts were markedly different. StereoPHIP expands the scope of conventional PHIP to the production of 13C hyperpolarized chiral substrates with high stereoselectivity. [ABSTRACT FROM AUTHOR]

Regio‐ and stereoselective formation of the 1,2‐cis‐furanosidic linkage has been in great demand for efficient synthesis of biologically active natural glycosides. In this study, we developed a regioselective and β‐stereospecific d‐/l‐arabinofuranosylation promoted by a boronic acid catalyst under mild conditions. The glycosylations proceeded smoothly for a variety of diols, triols, and unprotected sugar acceptors to give the corresponding β‐arabinofuranosides (β‐Arbf) in high yields with complete β‐stereoselectivity and high regioselectivity. The regioselectivity was completely reversed depending on the optical isomerism of the donor used and was predictable a priori using predictive models. Mechanistic studies based on DFT calculations revealed that the present glycosylation occurs through a highly dissociative concerted SNi mechanism. The usefulness of the glycosylation method was demonstrated by the chemical synthesis of trisaccharide structures of arabinogalactan fragments. [ABSTRACT FROM AUTHOR]

The involvement of nitroalkenes instead of minimal one alkyne motif for (E)‐1,3‐enynes synthesis through a palladium catalyzed stereoselective bond forming pathway at room temperature is presented. Implication of nitro group as a sacrificial directing group, formation of magical alkyne on a newly developed Csp3‐Csp3 bond with initial palladium‐MBH adduct make this methodology distinctive. This protocol features an unprecedented sequential acetate addition, carbon‐carbon bond formation, isomerization of double bond and nitromethane degradation in a tandem catalytic walk via dancing hybridization. Mechanistic understanding through identification of intermediates and computational calculations furnishes complete insight into the tandem catalytic pathway. Broad substrates scope and functional groups tolerance make this synthetic methodology magnificent and dynamic. This represents the first example of stereoselective 1,3‐enyne synthesis exclusively from alkene substrates by introducing the concept of sacrificial directing group. [ABSTRACT FROM AUTHOR]

The Diels Alder (D-A) reaction represents a crucial component of fundamental organic chemistry education and serves as a quintessential example of structural chemistry analyzed via basic principles of chemical sciences. This study explores the Diels-Alder reaction involving 1-methoxy-1,3-butadiene and acrolein, utilizing tools such as the Hückel molecular orbital (HMO) method, frontier molecular orbital (FMO) theory, and quantum chemical calculations. This approach provides detailed quantitative data and intuitive visual illustrations to elucidate the stereospecificity, regioselectivity, and stereoselectivity inherent to this reaction. The findings from this study serve as valuable resources for students, not only enhancing their understanding of D-A reaction properties and principles, but also developing their interest in computational chemistry and augmenting their problem-solving acumen. [ABSTRACT FROM AUTHOR]

Scaffold diversity is a key feature of a compound library and plays a pivotal role in its success in biological screening. Therefore, it is highly desirable to develop efficient strategies to rapidly construct structurally distinct and diverse "privileged" molecular scaffolds, thereby giving rise to compound libraries with selective and differing biological activities. This review covers recent efforts in this emerging field of Ni-catalyzed divergent and selective synthesis, and will focus on reactions using the same substrate to generate structurally diverse molecular scaffolds by varying the ligand backbone under otherwise almost identical reaction conditions. We hope that the field will be encouraged by the progress achieved, drawing attention to the design and development of new selective catalytic systems, and revealing new modes of catalytic transformation for broader synthetic applications. [ABSTRACT FROM AUTHOR]

A stereoselective synthesis of isolycoricidine, a natural product belonging to the Amaryllidaceae alkaloids family was produced. In addition, a synthetic study on the main core of lycoricidine led to the formation of analogues and a diastereomer of dihydrolycoricidine. Our strategy was based on an oxidative phenol dearomatization, a stereoselective Heck process, a selective dihydroxylation on a dienone system, several stereoselective reductions, and an oxidative retro‐Michael procedure as an amine‐deprotecting group strategy. Furthermore, two steps highlight the usefulness of hypervalent iodines in total synthesis of natural products. [ABSTRACT FROM AUTHOR]

We have investigated the stereoselectivity and reactivity of the sodium borohydride reduction of 2‐X‐cyclohexanones (X=H, Cl, Br) using a combined approach of competitive experiments and density functional theory calculations. Our results show that the hydride addition proceeds via a late transition state in which the C–H bond is nearly formed, consistent with the mild reducing power of NaBH4. The reaction barrier decreases from the 2‐halocyclohexanones to the unsubstituted cyclohexanone, in line with relative reactivities observed in the competitive experiments. Furthermore, we provide a protocol to solve the longstanding issue of properly modelling the axial–equatorial facial selectivity of hydride addition to the carbonyl group substituted with a vicinal polar group. The inclusion of implicit solvation in combination with an explicit solvent molecule is crucial to reproduce the stereoselective formation of the cis product observed experimentally. [ABSTRACT FROM AUTHOR]

Herein, we reported an effectual protocol for the stereoselective synthesis of novel C-3 thio/seleno substituted ortho-, meta- and para-(2-benzo[d]oxazolyl)phenyl-β-lactams 7a-i. The reaction was performed by utilizing different S/Se-alkyl/aryl substituted acids 6a-d and isomeric ortho-, meta- and para-(2-benzo[d]oxazolyl)phenyl Schiff's bases 3a-c and afforded exclusive formation of trans-β-lactams. The trans configuration was assigned with respect to coupling constant values of C3-H and C4-H (J = 1.4 to 2.6; C3-H and C4-H). The structure elucidation of all the thio/seleno anchored β-lactams 7a-i was performed using various spectroscopic techniques viz. FT-IR, NMR (1H, 13C, and 13C DEPT–135), 2D-NMR (1H–1H COSY and 1H–13C HSQC), elemental analysis (CHN), and mass spectrometry (ESI-MS). Further, divergent substrate scope accompanied by plausible mechanistic investigation have been also described. Stereoselectivity, good functional group tolerance and excellent yield along with wider synthetic utility bestows advantages to the present protocol. [ABSTRACT FROM AUTHOR]

Flow chemistry offers several advantages for performing chemical reactions and has become an important area of research. It may seem that sufficient knowledge has already been acquired on this topic to understand how to choose the design of microreactor/micromixer and flow rate in order to achieve the desired outcome of a reaction. However, some experimental data are difficult to explain based on commonly accepted concepts of chemical reactivity and performance of microfluidic systems. In this mini review, we attempt to identify such data and offer a rational explanation of unusual results based on the supramer approach. We demonstrate that variation in flow regime (determined by mixer design and flow rate) can either improve or worsen the reactivity and lead to completely different products, including stereoisomers. It is not necessary to mix the reagents with maximum efficiency. The real challenge is to mix reagents the right way since at a too high or too low flow rate (in the particular mixer), the molecules of reagents are incorrectly presented on the surface of supramers, leading to altered stereoselectivity, or form tight supramers, in which most of the molecules are located inside the supramer core and are inaccessible for attack, leading to low yields. [ABSTRACT FROM AUTHOR]

Stereoselective Zweifel olefination using boronate complexes carrying two different reactive π‐systems was achieved to synthesize vinyl heteroarenes and conjugated 1,3‐dienes in good yield and up to 100 % stereoselectivity, which remains unexplored until now. Most importantly, we report the unprecedented formation of E vs. Z‐vinyl heteroarenes for different heteroarenes under identical conditions. Density functional theory (DFT) investigations unveil the mechanistic dichotomy between olefin and heteroarene activation followed by 1,2‐migration, leading to E or Z‐vinyl heteroarenes respectively. We also report a previously unknown reversal of stereoselectivity by using 2,3‐Dichloro‐5,6‐dicyano‐1,4‐benzoquinone (DDQ) as an electrophile. The Zweifel olefination using a boronate complex that carries two different olefins was previously unexplored due to significant challenges associated with the site‐selective activation of olefins. We have solved this problem and reported the site‐selective activation of olefins for the stereoselective synthesis of 1,3‐dienes. [ABSTRACT FROM AUTHOR]

[Display omitted] Quantum chemical modeling of the mechanism of asymmetric induction in the course of alkene (propene, hex-1-ene) coordination with Cp 2 ZrMe(Cl)–methyl-alumoxane stereoisomeric complexes, which could act as catalytically active centers of the alkene oligomerization and polymerization, was carried out. A significant influence of the relative configuration of the chiral centers at the Al atoms of the activator on the parameters of the alkene insertion into Zr–C bond of the complexes was shown. [ABSTRACT FROM AUTHOR]

Protein O-glycosylation, particularly mucin-type glycosylation, plays important biological roles. However, the limited access to homogeneously glycosylated protein isoforms (glycoforms) has impeded the establishment of correlations between diverse glycan structures and protein properties, restricting therapeutic and diagnostic applications. Chemical synthesis of glycopeptides utilizing properly protected glycoamino acids as building blocks has emerged as a valuable approach to address the gap in glycoform acquisition. This review focuses on past efforts for the chemical synthesis of two fundamental glycoamino acid building blocks, Fmoc-Ser[GalNAc(Ac)3-α-D]-OH and Fmoc-Thr[GalNAc(Ac)3-α-D]-OH, by categorizing various methods based on glycosylation donors. The emphasis is on stereoselectivity, synthetic route length, and overall yield, with the goal of inspiring and guiding future research to further improve their synthetic efficiency and promote advancements in protein glycosylation studies and applications. [ABSTRACT FROM AUTHOR]

Seeds of root parasitic plants, Striga, Orobanche and Phelipanche spp. are induced to germinate by strigolactones (SLs) exudated from host roots. In Striga -resistant cultivars of Sorghum bicolor , the loss-of-function of the Low Germination Stimulant 1 (LGS1) gene changes the major SL from 5-deoxystrigol (5DS) to orobanchol, which has an opposite C-ring stereochemistry. The biosynthetic pathway of 5DS catalyzed by LGS1 has not been fully elucidated. Since other unknown regulators, in addition to LGS1 encoding a sulfotransferase, appear to be necessary for the stereoselective biosynthesis of 5DS, we examined Sobic.005G213500 (Sb3500), encoding a 2-oxoglutarate-dependent dioxygenase, as a candidate regulator, which is co-expressed with LGS1 and located 5ʹ-upstream of LGS1 in the sorghum genome. When LGS1 was expressed with known SL biosynthetic enzyme genes including the cytochrome P450 SbMAX1a in Nicotiana benthamiana leaves, 5DS and its diastereomer 4-deoxyorobanchol (4DO) were produced in approximately equal amounts, while the production of 5DS was significantly larger than that of 4DO when Sb3500 was also co-expressed. We also confirmed the stereoselective 5DS production in an in vitro feeding experiment using synthetic chemicals with recombinant proteins expressed in Escherichia coli and yeast. This finding demonstrates that Sb3500 is a stereoselective regulator in the conversion of the SL precursor carlactone to 5DS, catalyzed by LGS1 and SbMAX1a, providing a detailed understanding of how different SLs are produced to combat parasitic weed infestations. [ABSTRACT FROM AUTHOR]

The resulting solution was evaporated under reduced pressure to give the crude product, which was further purified by column chromatography on silica gel (20% EtOAc/hexane) to furnish B 30 b (49.5 mg, 0.19 mmol, 58%) as a white solid; mp 107.4-107.7 °C. The resulting solution was evaporated under reduced pressure to give the crude product B 29 b , which was further purified by column chromatography on silica gel (20% EtOAc/hexane) to furnish B 29 b (10.5 mg, 0.04 mmol, 75%) as a clear sticky oil. Keywords: epoxidation; cyclization; carbocation; fused-ring systems; stereoselectivity EN epoxidation cyclization carbocation fused-ring systems stereoselectivity 2757 2772 16 08/17/23 20230901 NES 230901 Graph Various oxacycles are privileged scaffolds in pharmaceutical industries, cosmetics, natural products, and drug discovery, among others. TOF-HRMS: I m i / I z i [M + Na] SP + sp calcd for C SB 19 sb H SB 20 sb O SB 4 sb Na: 335.1254; found: 335.1247. tert -Butyldimethyl((3-phenyl-1,3-dihydroisobenzofuran-1-yl)methoxy)silane (26b') By following the General Procedure G, and purification by column chromatography on silica gel (20% EtOAc/hexane), the product (24.0 mg, 0.71 mmol, 44%) was obtained as a yellow sticky gum. [Extracted from the article]

The performing organic reactions in the presence of solid nano-catalysts have attracted significant research interest in recent years. In this regard, a fast and operationally facile one-step tandem strategy for the diastereoselective synthesis of rel-(2R,3R)-2-benzoyl-2,3-dihydro-3-substitutedphenyl-4H-furo[3,2-c][1]benzopyran-4-one has been developed. This protocol has been applied via solvent-free condensation of aromatic aldehydes, 4-hydroxycoumarin, and in situ generated phenacyl pyridinium bromide over SiO2 nanoparticles as a non-metal oxide catalyst. The protocol is environmentally favorable because the organic solvent is not required in the reaction process. Additionally, the method is rapid, has high yields, low catalyst loading and also does not involve extensive workup procedures or chromatographic separations. The catalyst is inexpensive and very mild and also is recyclable in six runs without losing activity significantly. [ABSTRACT FROM AUTHOR]

After administration of the serotonergic antidepressant citalopram (CIT) to beagle dogs, they may experience severe convulsive attacks in relation with considerably higher plasma concentrations of the metabolite didesmethyl-CIT (DDCIT), when compared to those in humans medicated with CIT. This pilot study aimed at determining the role of cytochrome P-450 (CYP450) isozymes in the in vitro metabolism of CIT to desmethyl-CIT (DCIT), and of DCIT to DDCIT in the liver microsomes of a single beagle dog. The incubations with racemic CIT or DCIT reveal a high affinity enzyme with Km between 0.3 µM and 1.4 µM for S- and R-DCIT and S- and R-DDCIT productions, respectively. In comparison to human enzymes, the intrinsic clearance values of this high affinity enzyme are between 15 µL/(min x mg of protein) and 52 µL/(min x mg of protein), i.e. very high. In vitro experiments with inhibitors suggest that CYP2D15, which shows analogy with human CYP2D6, is by far the main CYP450 isozyme involved in the production of DCIT and DDCIT whereas CYP3A12 and CYP2C21/41 showed a weak implication. These observations partly explain why in humans, plasma concentrations of the toxic DDCIT are considerably lower than those observed in dogs, after administration of CIT.

The widely used term asymmetric synthesis was introduced by Emil Fischer in 1894 by demonstration with examples. An early definition by Marckwald was successful in applications involving enantiomeric reaction products. The term caused difficulties in cases of diastereomeric products, because of a lack of a clear definition of the term diastereoisomers, which in turn affected the introduction of the term diastereoselectivity. Clarity was reached only after Wheland had revived a definition by Victor Meyer of 1907. Today, a definition codified by the International Union of Pure and Applied Chemistry (IUPAC) is in use, which is slightly modified here. [ABSTRACT FROM AUTHOR]

A six‐step, stereoselective synthesis of cyclin‐dependent kinase 2 (CDK2) inhibitor GNE‐140 was developed. The key bonds were assembled through palladium‐catalyzed Negishi cross‐coupling and Buchwald–Hartwig C−N coupling steps. The stereodiad was established through a single‐step, CuH‐catalyzed enone reduction proceeding in >99 : 1 er and 89 : 11 dr. GNE‐140 was obtained in 25 % overall yield with 98.6 A% HPLC purity. [ABSTRACT FROM AUTHOR]

Nano-kaolin-SO3H was prepared and used to synthesis of N-nitrosamines. The products were characterized by their spectral (IR and 1H NMR) data. N-nitrosamines can exist in two mesomeric forms but the reaction is quite regioselective and only one of mesomers is formed as a main product which can exist in two E and Z stereoisomers. In this paper, we have studied the mesomeric effect of N-nitrosamines which explained the diastereotopic nature of corresponding protons in symmetric N-nitrosamines and formation of two isomers in asymmetric N-nitrosamines. [ABSTRACT FROM AUTHOR]

A straightforward synthesis of the hexasaccharide repeating unit of the O-specific polysaccharide of Salmonella arizonae O62 was achieved in very good yield applying sequential glycosylation strategy. Successful regioselective glycosylation of the di-hydroxylated L-rhamnose moiety allowed achieving the desired compound in minimum number of synthetic steps. TEMPO catalyzed and [bis(acetoxy)iodo]benzene (BAIB) mediated late stage regioselective oxidation of a primary hydroxyl group into carboxylic acid was achieved in the hexasaccharide derivative. The glycosylation steps were high yielding with high stereochemical outcome. The desired hexasaccharide was obtained in 7% over all yield in fourteen steps starting from suitably functionalized monosaccharide intermediates. [ABSTRACT FROM AUTHOR]

An enantioselective reduction of simple carbenium ions with cyclohexadienes containing a hydridic C−H bond at an asymmetrically substituted carbon atom is disclosed. The net reaction is a transfer hydrogenation of alkenes (styrenes) only employing chiral cyclohexadienes as dihydrogen surrogates. The trityl cation is used to initiate a Brønsted acid‐promoted process, in which a delicate intermolecular capture of a carbenium‐ion intermediate by the aforementioned chiral hydride source is enantioselectivity determining. Exclusively non‐covalent interactions are rendering one of the transition states energetically more favored, giving the reduction products in good enantiomeric ratios. The computed reaction mechanism supports the present findings as well as previous results obtained from studies on other transfer‐hydrogenation methods involving the cyclohexadiene platform. [ABSTRACT FROM AUTHOR]

This work comprehensively studies the underlying features of a Diels‐Alder (DA) reaction between an electron‐rich diene D‐1 and an electron‐deficient dienophile Dph‐2. The DA reaction studied takes place along the complete C4‐C5 regioselectivity and a high exo‐stereoselectivity. Based on the kinetics analyses, the evaluated regioselectivity, >99.91 ${\char62 {{99.9}\over{1}}}$ , and exo‐stereoselectivity, >27.81 ${\char62 {{27.8}\over{1}}}$ , represent an excellent agreement with the experimental outcomes. This DA reaction also displays a high polarity caused by a strong nucleophilic and a strong electrophilic character of, respectively, D‐1 and Dph‐2. A prediction of the C4‐C5 regioselectivity is made possible by analysis of the Parr functions values estimated at the reactive sites of reactants. The origin of the exo‐stereoselectivity predominance over the endo one was well discussed employing an activation‐strain model and a natural bond orbital analysis. The molecular mechanistic considerations elucidate that formation of both C4‐C5 and C1‐C6 single bonds takes place via C‐to‐C coupling of the corresponding pseudoradical centers. [ABSTRACT FROM AUTHOR]

Pioglitazone, a PPAR-gamma activator used to diagnose hyperglycemia, was studied for its stereoselective deposition and active enantiomers in female albino Wistar rats. In accordance with USFDA recommendations, a bioanalytical technique was employed to assess the segregation of pioglitazone enantiomers in rat plasma with glimepiride as an internal standard. A Phenomenox i-Amylose-3 column (150 mm × 4.6 mm) of 5 µm was used for high-performance liquid chromatography (HPLC) with a mobile phase of 10 mM ammonium acetate buffer in Millipore water and acetonitrile in 60:40 (v/v) admixture with column temperature 35 °C, wavelength 265 nm, and flow rate 0.6 mL/min, respectively. Pioglitazone-S, Pioglitazone-R, and the internal standard had retention times of 3.1, 7.4, and 1.7 min, respectively. The study found that within-run and between-run precision ranged from 0.1606–0.9889% for Pioglitazone-R and from 0.2080–0.7919% for Pioglitazone-S, while the accuracy ranged from 99.86 to 100.36% for Pioglitazone-R and 99.84 to 99.94% for Pioglitazone-S. In addition, a non-radioactive glucose uptake assay was employed to examine the enantiomers in 3T3-L1 cell lines by flow cytometry. Significant differences were demonstrated in Cmax, AUClast (h*μg/mL), AUCINF obs (h*μg/mL), and AUC%Extrap obs (%) of Pioglitazone-R and S in female albino Wistar rats, suggesting enantioselectivity of pioglitazone. [ABSTRACT FROM AUTHOR]

The sulfa‐Michael addition reaction is a crucial subset of the Michael addition reaction, and aroused the interest of numerous synthetic biologists and chemists. In particular, sulfa‐Michael addition triggered cascade reaction has developed quickly in recent years because it offers an efficient method to construct C−S bonds and other bonds in one approach, which is widely applicable for building chiral pharmaceuticals, their intermediates, and natural compounds. This review emphasizes the recent advancements in sulfa‐Michael addition‐triggered cascade reactions for the stereoselective synthesis of sulfur‐containing compounds, including sulfa‐Michael/aldol, sulfa‐Michael/Henry, sulfa‐Michael/Michael, sulfa‐Michael/Mannich and some sulfa‐Michael triggered multi‐step processes. Moreover, some reaction mechanisms and derivatization experiments are introduced appropriately. [ABSTRACT FROM AUTHOR]

Amine transaminases (ATAs) are powerful biocatalysts for the stereoselective synthesis of chiral amines. Machine learning provides a promising approach for protein engineering, but activity prediction models for ATAs remain elusive due to the difficulty of obtaining high‐quality training data. Thus, we first created variants of the ATA from Ruegeria sp. (3FCR) with improved catalytic activity (up to 2000‐fold) as well as reversed stereoselectivity by a structure‐dependent rational design and collected a high‐quality dataset in this process. Subsequently, we designed a modified one‐hot code to describe steric and electronic effects of substrates and residues within ATAs. Finally, we built a gradient boosting regression tree predictor for catalytic activity and stereoselectivity, and applied this for the data‐driven design of optimized variants which then showed improved activity (up to 3‐fold compared to the best variants previously identified). We also demonstrated that the model can predict the catalytic activity for ATA variants of another origin by retraining with a small set of additional data. [ABSTRACT FROM AUTHOR]

Chiral sulfones are recurrent motifs in pharmaceuticals and bioactive molecules. Although chemical methods have been developed to afford α‐ or β‐ chiral sulfones, these protocols rely heavily on the pre‐synthesis of structurally complicated starting materials and chiral metal complexes. Herein, we described a photoenzymatic approach for the radical‐mediated stereoselective hydrosulfonylation. Engineered variants of ene reductases provide efficient biocatalysts for this transformation, enabling to achieve a series of β‐chiral sulfonyl compounds with high yields (up to 92 %) and excellent e.r. values (up to 99 : 1). [ABSTRACT FROM AUTHOR]

Products of the catalytic hydrochlorination of deuterated acetylene over palladium chloride complexes supported on activated carbon are a mixture of vinyl chloride stereoisomers resulting from the syn- and anti-addition of a hydrogen chloride molecule to the triple bond. The reaction is accompanied by the isomerization of the primary trans-vinyl chloride into its cis-stereoisomer; however, the characteristic isomerization times exceed significantly the duration of acetylene hydrochlorination. This fact allowed us to estimate the portion of products formed exclusively during the catalytic reaction, the difference in the effective activation energies of the syn- and anti-addition routes (~21 kJ/mol), and to demonstrate a monotonic increase in the part of the syn-addition product with increasing mass loading ω of the active metal, reaching saturation at ω > 2 wt %. [ABSTRACT FROM AUTHOR]

Regio- and stereoselective switchable synthesis of (E)- and (Z)-N-carbonylvinylated pyrazoles is first developed by using the Michael addition reaction of pyrazoles and conjugated carbonyl alkynes. Ag2CO3 plays a key role in the switchable synthesis of (E)- and (Z)-N-carbonylvinylated pyrazoles. Ag2CO3-free reactions lead to thermodynamically stable (E)-N-carbonylvinylated pyrazoles in excellent yields whereas reactions with Ag2CO3 give (Z)-N-carbonylvinylated pyrazoles in good yields. It is noteworthy that (E)- or (Z)-N1-carbonylvinylated pyrazoles are obtained with high regioselectivity when asymmetrically substituted pyrazoles react with conjugated carbonyl alkynes. The method can also extend to the gram scale. A plausible mechanism is proposed on the basis of the detailed studies, wherein Ag+ acts as coordination guidance. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the comparative antiseizure activity of the individual enantiomers of fenfluramine and its major active primary metabolite norfenfluramine in rodent seizure models, and its relationship with the pharmacokinetics of these compounds in plasma and brain. Methods: The antiseizure potency of d,l‐fenfluramine (racemic fenfluramine) was compared with the respective potencies of its individual enantiomers and the individual enantiomers of norfenfluramine using the maximal electroshock (MES) test in rats and mice, and the 6‐Hz 44 mA test in mice. Minimal motor impairment was assessed simultaneously. The time course of seizure protection in rats was compared with the concentration profiles of d‐fenfluramine, l‐fenfluramine, and their primary active metabolites in plasma and brain. Results: All compounds tested were active against MES‐induced seizures in rats and mice after acute (single‐dose) administration, but no activity against 6‐Hz seizures was found even at doses up to 30 mg/kg. Estimates of median effective doses (ED50) in the rat‐MES test were obtained for all compounds except for d‐norfenfluramine, which caused dose‐limiting neurotoxicity. Racemic fenfluramine had approximately the same antiseizure potency as its individual enantiomers. Both d‐ and l‐fenfluramine were absorbed and distributed rapidly to the brain, suggesting that seizure protection at early time points (≤2 h) was related mainly to the parent compound. Concentrations of all enantiomers in brain tissue were >15‐fold higher than those in plasma. Significance: Although there are differences in antiseizure activity and pharmacokinetics among the enantiomers of fenfluramine and norfenfluramine, all compounds tested are effective in protecting against MES‐induced seizures in rodents. In light of the evidence linking the d‐enantiomers to cardiovascular and metabolic adverse effects, these data suggest that l‐fenfluramine and l‐norfenfluramine are potentially attractive candidates for a chiral switch approach leading to development of a novel, enantiomerically‐pure antiseizure medication. [ABSTRACT FROM AUTHOR]

Stereoselective construction of conjugated dienes and polyenes has remained an enduring synthetic problem owing to the central roles these compounds play in natural product synthesis, methodology, and medicine. This review focuses on recent developments in dienylation as an emerging strategy for the direct installation of unsaturated four-carbon units of conjugated π-systems, outlining the regio- and stereoselectivity, as well as the synthetic scope of reactions with various dienylating reagents and the mechanistic implications of the catalytic cross-coupling processes that are used to enable dienylation. 1 Introduction 2 Sulfolenes 3 1,3-Dienes 4 Small-Ring Dienylation Reagents 5 Pyrones, Alkynes, and Homoallenylboronates 6 Conclusion and Outlook [ABSTRACT FROM AUTHOR]

A novel derivatives of tetraazacalix[4]arene[2]triazine-based catalysts for enantioselective Michael addition reactions of nitroolefins and diketones were presented. Chiral moieties were connected to the heteroatom-bridged calix-triazin scaffold by reactions of (S)- or (R)-(+)-1-(1-Naphthyl)ethylamine with tetraazacalix[4]arene[2]triazine. To utilize the catalytic activity of the chiral catalysts, diketones reacted with a wide variety of trans-β-nitrostyrenes in Toluene, respectively, obtaining the Michael products in excellent yields and enantiomeric excesses (up to 96% yield and 99% ee). [ABSTRACT FROM AUTHOR]

Fluostatins, benzofluorene-containing aromatic polyketides in the atypical angucycline family, conjugate into dimeric and even trimeric compounds in the post-biosynthesis. The formation of the C-C bond involves a non-enzymatic stereospecific coupling reaction. In this work, the unusual regio- and enantioselectivities were rationalized by density functional theory calculations with the M06-2X (SMD, water)/6-311 + G(d,p)//6-31G(d) method. These DFT calculations reproduce the lowest energy C1-(R)-C10'-(S) coupling pathway observed in a nonenzymatic reaction. Bonding of the reactive carbon atoms (C1 and C10') of the two reactant molecules maximizes the HOMO-LUMO interactions and Fukui function involving the highest occupied molecular orbital (HOMO) of nucleophile p-QM and lowest unoccupied molecular orbital (LUMO) of electrophile FST2- anion. In particular, the significant π-π stacking interactions of the low-energy pre-reaction state are retained in the lowest energy pathway for C-C coupling. The distortion/interaction-activation strain analysis indicates that the transition state (TScp-I) of the lowest energy pathway involves the highest stabilizing interactions and small distortion among all possible C-C coupling reactions. One of the two chiral centers generated in this step is lost upon aromatization of the phenol ring in the final difluostatin products. Thus, the π-π stacking interactions between the fluostatin 6-5-6 aromatic ring system play a critical role in the stereoselectivity of the nonenzymatic fluostatin conjugation.

The [3+2] cycloaddition reaction of N-aryl-C-carbamoylnitrone (nitrone 1) with N-arylitaconimide (ethylene 2) was computationally studied using the B3LYP/6-31G(d) level of theory. An analysis of the different energetic profiles and the transition states’ optimized structures clearly indicated that this 32CA occurred through a non-polar, asynchronous, one-step mechanism, favoring the formation of the ortho–endo cycloadduct, as observed experimentally. The analysis of the reactivity indices derived from the conceptual DFT explains well the low polarity of this 32CA reaction. Parr functions and a dual reactivity descriptors analysis correctly explained the regioselectivity ortho of this 32CA reaction. Solvent effects did not modify the obtained selectivity but it increased the activation energies and decreased the exothermic character of this 32CA reaction. A thermodynamic parameters analysis indicated that this 32CA wascharacterized by an ortho regioselectivity and endostereoselectivity and exothermic and exergonic characters.

Lipopolysaccharides from Bacteroides vulgatus represent interesting targets for the treatment of inflammatory bowel diseases. However, efficient access to long, branched and complex lipopolysaccharides remains challenging. Herein, we report the modular synthesis of a tridecasaccharide from Bacteroides vulgates through an orthogonal one‐pot glycosylation strategy based on glycosyl ortho‐(1‐phenylvinyl)benzoates, which avoids the issues of thioglycoside‐based one‐pot synthesis. Our approach also features: 1) 5,7‐O‐di‐tert‐butylsilylene‐directed glycosylation for stereoselective construction of the α‐Kdo linkage; 2) hydrogen‐bond‐mediated aglycone delivery for the stereoselective formation of β‐mannosidic bonds; 3) remote anchimeric assistance for stereoselective assembly of the α‐fucosyl linkage; 4) several orthogonal one‐pot synthetic steps and strategic use of orthogonal protecting groups to streamline oligosaccharide assembly; 5) convergent [1+6+6] one‐pot synthesis of the target. [ABSTRACT FROM AUTHOR]

[Display omitted] • QM/MM approach was used to study the mechanism and stereoselectivity of the challenging β-hydrogen (p K a ≈ 40) elimination reaction catalyzed by the [4Fe-4S]-dependent (R)-2-hydroxyisocaproyl-CoA dehydratase. • Different from the iron-sulfur containing radical S-adenosylmethionine (SAM) enzymes, the electron is directly transferred from the [4Fe-4S]1+ cluster to the substrate, and an α-carbonyl radical intermediate is formed with a spin-center shift process. • The calculations show that residues Ser37 and Glu55 play very important in the transfer of the electron from the [4Fe-4S]1+ cluster to the substrate. • By comparing all six possible antiferromagnetically-coupled doublet states, the calculations show that one alpha electron is transferred from the [4Fe-4S]1+ cluster to the substrate to achieve the maximum exchange and super exchange interactions, which can decrease the energy barriers. • The calculations in this work not only explain the current experimental results and can also be helpful for the understanding of the mechanisms and stereoselectivity of other members of the (R)-2-hydroxyacyl-CoA dehydratase enzyme family. The dehydration of proteinogenic amino acids is an essential fermentation process mediated by the (R)-2-hydroxyacyl-CoA dehydratase enzyme family. (R)-2-hydroxyisocaproyl-CoA dehydratase catalyzes the dehydration of (R)-2-hydroxyisocaproyl-CoA to harvest an E - product in the fermentation of L-leucine. In this work, QM/MM calculations were performed to elucidate the mechanism and stereoselectivity of this enzyme. Six possible antiferromagnetically coupled spin states (ααββ, αβαβ, αββα, ββαα, βαβα, βααβ) were considered for the [4Fe-4S] cluster. First, the binding mode of the substrate to the reduced [4Fe-4S]+ cluster switches from carbonyl oxygen coordination to α-hydroxy group coordination. This ligand exchange is coupled with the formation of a hydrogen bond between the substrate carbonyl oxygen and a second-shell serine residue, leading to an electron transfer from the [4Fe-4S]+ cluster to the substrate and the formation of a ketyl radical anion intermediate. This is followed by the heterolytic cleavage of the substrate C-OH bond, which is coupled with a spin-center shift process, generating a Fe-coordinated hydroxide and an α-carbonyl radical intermediate. Subsequently, the Fe-coordinated hydroxide abstracts the β-proton from the substrate, generating the experimentally identified allylic ketyl radical product. The syn -elimination to afford an E -product is kinetically more favorable than the anti -elimination (Z -isomer). The results highlighted the importance of using a redox pathway to activate inert substrates for dehydration, which should be helpful for the mechanistic understanding of related enzymes in the [4Fe-4S] cluster-dependent dehydratase family. [ABSTRACT FROM AUTHOR]

Glucocorticoid (GC)‐induced osteoporosis (GIO) is a concurrent disease commonly appeared in chronic inflammatory and autoimmune disease patients. Stereoselective recognition between chiral drugs and homochiral biological molecules could directly affect their distribution, adhesion and transport. Herein, trace element selenium (Se) with bone formation‐regulating activity, is employed to construct cysteine‐decorated chiral nanoparticles (Cys@SeNPs) to attenuate GIO. Interestingly, comparing with the racemic (DL‐Cys@SeNPs) and D‐Cys@SeNPs, the L‐Cys@SeNPs displays higher uptake in osteoblast cells and could lessen reactive oxygen species overproduction to block dexamethasone (Dex)‐induced osteoblasts cells apoptosis. Intracellular L‐Cys@SeNPs could be predominantly transformed to selenocystine to upregulate the expression levels of antioxidative selenoproteins to effectively scavenge Dex‐induced excessive ROS accumulation in osteoblasts, and thus reduce the undesirable apoptosis through activating Wnt/β‐catenin pathway. Consistently, L‐Cys@SeNPs significantly alleviates the main osteoporosis symptoms of bone trabeculae destruction and decreased bone density in vivo, and also reduces the weight gain and fatty liver formation in Dex‐exposed mice, thus suppressing the overall side effects of Dex. This study not only demonstrates an effective strategy for treatment of GIO by using chiral Se nanomedicine, but also elucidates the important roles of selenoproteins in alleviating osteoporosis, which could help for future Se‐based drug design through chirality control engineering. [ABSTRACT FROM AUTHOR]

The development of the merger of a Ni(II) catalyst with an appropriate photocatalyst under visible‐light irradiation provides a new strategy for realizing direct functionalization of C(sp3)−H bonds. Mechanistically, whether the reduction of Ni catalyst to form a Ni(0) species is necessary in the dual catalysis still remains under debate. Herein, DFT calculations were carried out to gain a mechanistic insight into the enantioselective acylation of α‐amino C(sp3)−H bonds to furnish α‐amino ketones via photoredox and Ni dual catalysis. A feasible mechanistic pathway for the Ni catalysis via the Ni(I)−Ni(III)−Ni(II)−Ni(III)−Ni(I) cycle is suggested with the sequential elementary steps of oxidative addition, single electron reduction, radical addition, and reductive elimination in leading to the final product, whereas a nickel catalytic cycle, Ni(I)−Ni(0)−Ni(II)−Ni(III)−Ni(I), might not be feasible for the photoredox and Ni dual‐catalyzed acylation of α‐amino C(sp3)−H bonds. The origin of the stereoselectivity for this reaction is also discussed, which could be attributed to the minimization of the steric hindrance between the alkyl moiety of radical part and phenyl group of the chiral ligand. [ABSTRACT FROM AUTHOR]

The application of bifunctional organocatalysts in organic chemistry has advanced remarkably owing to their high stability to moisture and air, relatively low toxicity, ease of handling, and recoverability. Among chiral bifunctional organocatalysts, squaramides have emerged as a privileged catalyst in recent years. This review article presents a comprehensive report on fine-tunable bifunctional chiral squaramide-catalyzed sulfa-Michael addition, which is based upon synchronous interplay of synergistic 'electrophilic–nucleophilic' dual activation strategies via multiple H-bonding interactions for the construction of both common and complex molecular entities bearing multiple stereocenters. Mechanistic discussions are kept brief, but significant understandings have been recorded. The contribution of squaramide catalyst to the construction of C–S bonds via sulfa-Michael addition has been applied in medicinal, natural, and industrial chemistry. Attention is focused on summarizing the progress made in chiral squaramide-catalyzed asymmetric sulfa-Michael addition and subsequent cascade/domino reaction sequences between 2011 and 2022. 1 Introduction 2 Quinine-Squaramide Organocatalysis 3 Iminophosphorane-Squaramide Organocatalysis 4 Chinchona-Squaramide Organocatalysis 5 trans -1,2-Diaminocyclohexane-Squaramide Organocatalysis 6 Conclusion [ABSTRACT FROM AUTHOR]

The strained/frustrated electrostatic interactions between the ion pair of TTBPy+ X– increases the reactivity in both the ions, resulting in the activation of a third molecule like sulfonamides (aromatic/-aliphatic) via hydrogen bonding. This intriguing weak-interactions-based reactivity has been utilized to develop an organocatalytic synthesis of 2-deoxy-sulfonamido-glycosides from glycals. The sulfonamidoglycosylation of glycals using a catalytic amount of 2,4,6-tri- tert -butylpyridinium salts proceeded stereoselectively to provide N -glycosides in good to high yields. This process was demonstrated with l -rhamnal and d -galactal. Besides, IR spectroscopic studies explain that the hindered protonated pyridine cannot behave as a cationic Brønsted acid as is generally perceived. [ABSTRACT FROM AUTHOR]

After administration of the serotonergic antidepressant citalopram (CIT) to Beagle dogs, the dogs may experience severe convulsive attacks in relation to the considerably higher plasma concentrations of the metabolite didesmethyl-CIT (DDCIT), when compared to those in humans medicated with CIT. This pilot study aimed at determining the role of cytochrome P-450 (CYP450) isozymes in the in vitro metabolism of CIT to desmethylCIT (DCIT), and of DCIT to DDCIT in the liver microsomes of a single Beagle dog. Incubations with racemic CIT or DCIT reveal a high-affinity enzyme with Km between 0.3 µM and 1.4 µM for S- and R-DCIT and S- and R-DDCIT productions, respectively. In comparison to human enzymes, the intrinsic clearance values of this highaffinity enzyme are between 15 µl/(min × mg of protein) and 52 µl/(min × mg of protein), i.e., very high. In vitro experiments with inhibitors suggest that CYP2D15, which shows an analogy with human CYP2D6, is by far the main CYP450 isozyme involved in the production of DCIT and DDCIT, whereas CYP3A12 and CYP2C21/41 showed a weak implication. These observations partly explain why, in humans, the plasma concentrations of the toxic DDCIT are considerably lower than those observed in dogs, after administration of CIT. [ABSTRACT FROM AUTHOR]

The application of early-metal-based catalysts featuring natural chiral pool motifs, such as amino acids, terpenes and alkaloids, in hydroamination reactions is discussed and compared to those beyond the chiral pool. In particular, alkaline (Li), alkaline earth (Mg, Ca), rare earth (Y, La, Nd, Sm, Lu), group IV (Ti, Zr, Hf) metal-, and tantalum-based catalytic systems are described, which in recent years improved considerably and have become more practical in their usability. Additional emphasis is directed towards their catalytic performance including yields and regio- as well as stereoselectivity in comparison with the group IV and V transition metals and more widely used rare earth metal-based catalysts. [ABSTRACT FROM AUTHOR]

A molecular electron density theory study of the [3+2] cycloaddition reaction of 5-oxo-2-(phenylmethylidene)pyrazolidin-2-ium-1-ide, a simple azomethine imine, with 3-nitro-2-phenyl-2H-chromene was carried out at the B3LYP/6-311G(d,p) computational level in order to unravel the origin of the stereoselectivity experimentally observed. Electron localization function and natural population analysis showed that the azomethine imine is a zwitterionic three-atom component. Analysis of the conceptual density functional theory reactivity indices indicates that azomethine imine is a strong nucleophile, while 3-nitro-2-phenyl-2H-chromene is a good electrophile, which accounts for a polar process confirmed by the high global electron density transfer values. The Parr function indices explain well the experimentally obtained ortho regioselectivity. Analysis of the energy profiles of the possible reactive pathways in gas phase and in solution of i-PrOH points to high exo stereoselectivity and complete ortho regioselectivity of the reaction in excellent agreement with the experimental findings. Analysis of the transition state structures indicates a very asynchronous molecular mechanism for the favored orthoregioisomeric reaction channels. Analysis using noncovalent interactions, quantum theory of atoms in molecules, and independent gradient model based on Hirshfeld distribution indicates that the presence of several hydrogen bonds and van der Waals intermolecular noncovalent interactions are the factors favoring the ortho-exo selectivity. The bonding evolution theory study of the most favorable pathway reveals a two-stage one-step molecular mechanism. [ABSTRACT FROM AUTHOR]

A one-pot chemo-, regio-, and stereoselective synthesis of 1-[(Z)-acylethenyl)-4-{(E)-[(Z)-acyl-ethenyl]imino}-1,4-dihydroquinolines with high yields (66–98%) via reaction of 4-aminoquinoline with alkynones in the system KOH/H2O/MeCN has been developed. [ABSTRACT FROM AUTHOR]

Glycosylation of primary (3-trifluoroacetamidopropanol) and secondary (methyl 2,3-O-isopropylidene-α-l-rhamnopyranoside) alcohols with phenyl 3,4,6-tri-O-acetyl-2-azido-2-deoxy-1-seleno-α-d-glucopyranoside in the presence of N-iodosuccinimide and trimethylsilyl triflate in diethyl ether afforded the corresponding 2-azido-2-deoxyglu-cosides in rather high yields and with good α-stereoselectivity (α:β = 3−5:1). Similar glycosylation with phenyl 3,4,6-tri-O-acetyl-2-azido-2-deoxy-1-seleno-α-d-manno-pyranoside resulted exclusively in α-linked 2-azido-2-deoxymannosides. [ABSTRACT FROM AUTHOR]

Pesticides and heavy metals commonly coexist in soil. In this study, the influence of Cd and Cu on the toxicity of rac-dinotefuran and the enantioselective behavior of dinotefuran enantiomers in soil-earthworm microcosms were investigated. The acute toxic tests showed that S-dinotefuran has higher toxic than that of R-dinotefuran. The rac-dinotefuran and Cd has an antagonistic effect on earthworms, and the Cu and rac-dinotefuran has a synergistic effect. Earthworms maybe promoted the enantioselective behavior of dinotefuran in soil. Co-exposure to Cd or Cu inhibited the dissipation of dinotefuran enantiomers (S-dinotefuran and R-enantiomers), and slightly reduced the enantioselectivity in soil. The earthworms were found to be preferentially enriched with S-dinotefuran. However, Cd or Cu attenuated the accumulation of dinotefuran enantiomers in earthworms and decreased the enantioselectivity. The effect of Cd and Cu on the environmental behaviors of dinotefuran enantiomers were correlated positively with the dose of Cd/Cu. These results showed that Cd and Cu alter the environmental behaviors and the toxicity of dinotefuran enantiomers in soil-earthworm microcosms. Thus, the influence of coexistent heavy metals on the ecological risk assessment of chiral pesticides should be considered.

We synthesized six new camphor-derived homochiral thioureas 1–6, from commercially available (1R)-(−)-camphorquinone. These new compounds 1–6 were evaluated as asymmetric organocatalysts in the stereoselective formation of glycosidic bonds, with 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl and 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates as donors, and several alcohols as glycosyl acceptors, such as methanol, ethanol, 1-propanol, 1-butanol, 1-octanol, iso-propanol, tert-butanol, cyclohexanol, phenol, 1-naphtol, and 2-naphtol. Optimization of the asymmetric glycosylation reaction was achieved by modifying reaction conditions such as solvent, additive, loading of catalyst, temperature, and time of reaction. The best result was obtained with 2,3,4,6-tetra-O-benzyl-D-galactopyranosyl trichloroacetimidates, using 15 mol% of organocatalyst 1, in the presence of 2 equiv of MeOH in solvent-free conditions at room temperature for 1.5 h, affording the glycosidic compound in a 99% yield and 1:73 α:β stereoselectivity; under the same reaction conditions, without using a catalyst, the obtained stereoselectivity was 1:35 α:β. Computational calculations prior to the formation of the products were modeled, using density functional theory, M06-2X/6-31G(d,p) and M06-2X/6-311++G(2d,2p) methods. We observed that the preference for β glycoside formation, through a stereoselective inverted substitution, relies on steric effects and the formation of hydrogen bonds between thiourea 1 and methanol in the complex formed.