Stereospecific Synthesis Research Articles

One-Pot Stereospecific Synthesis of 1,4-Oligosaccharides by Glycal-Derived Vinyl Epoxides Assembly.

Recently, naturally occurring linear 1,4-glycans have attracted remarkable attention for their activity in cancer and neurodegenerative disease treatment. Classical chemical synthetic strategies for linear 1,4-oligosaccharides are considerably time-consuming due to orthogonal protection/deprotection, the introduction of leaving groups, and various forms of activation of the glycosylation reaction. Herein, we present a new one-pot microwave-activated reiterative assembly of glycal-derived vinyl epoxides in an uncatalyzed substrate-dependent stereospecific process for the preparation of both β-1,4-d-Gulo and α-1,4-d-Manno oligosaccharides.

PPh3 promoted stereospecific synthesis of ethyl α-chloroacrylates from ethyl trichloroacetate and arylaldehydes

A coupling reaction between arylaldehydes and ethyl trichloroacetate is facilitated by PPh3 under mild conditions to stereospecifically produce (Z)-ethyl α-chloroacrylates. This stereospecific coupling reaction only occurs when the arylaldehyde derivative has an electron-withdrawing substituent. On the other hand, when an electron-donating group is present in the aromatic ring, the aryldichloromethyl derivative is formed as the only product, even at low temperature. The stereospecificity in the coupling reaction was established based on the coupling constants 2JCH and 3JCH in the 13C NMR and crystal-X-ray analysis. From this data we propose that the formation of these compounds occurs through two intermediates initially formed by the reaction between the PPh3 and ethyl trichloroacetate.

Convergent and Stereospecific Synthesis of Highly Substituted Azepines.

This study reported a convergent pattern to stereospecifically synthesize 4,5-dihydrogen azepine from simple and readily available starting materials, addressing synthetic and stereoselective issues. Several synthetically important transformations, such as Simmon-Smith cyclopropanation, halogenation, and hydrogenation, demonstrated the utilities of this strategy. Particularly, the final azepine products could effectively contract into highly substituted pyridine derivatives through an intramolecular oxidation rearrangement.

Effective stereospecific synthesis of anomers of nucleoside molecules having hydroxyl group on C2 (antiviral drugs): Cytidine, molnupiravir, and azacitidine

Molnupiravir serves as the prodrug for beta-D-N4-hydroxycytidine, employed as an antiviral agent. The present work describes a new and commercially viable synthesis of anomers of molnupiravir (4), azacitidine (5), and cytidine (6) through an in situ approach, eliminating the requirement for isolating intermediates.. KEYWORDS :Molnupiravir, Azacitidine, Cytidine, Anomer.

Concise and Stereospecific Total Synthesis of Arenastatin A and Its Segment B Analogs.

A novel and concise synthetic method for arenastatin A, a cytotoxic cyclic depsipeptide of marine origin, was developed in this study. The convergent assembly of the four segments, including the cross-metathesis reaction, gave a cyclization precursor, and Fmoc deprotection caused simultaneous macrocyclization. The Corey-Chaykovsky reaction using a chiral sulfur ylide afforded arenastatin A with complete stereoselectivity in the longest linear sequence of seven reaction steps from the known compound. Using this synthetic method, some analogs of segment B were prepared through a late-stage diversification strategy. The simple SN2 reaction of the thiolate toward the tosylate precursor, prepared using almost the same synthetic method as described above, provided the desired sulfide analogs.

Ambient-Light-Promoted Stereospecific Synthesis of (Z)-Vinyl Thioesters under Solvent- and Catalyst-Free Conditions.

An ambient-light-promoted stereospecific olefinic C(sp2)-S bond construction of thioacids and 1,1-diarylethenes has been demonstrated, affording various (Z)-vinyl thioesters in 51-85% yields under solvent- and catalyst-free conditions. Mechanistic studies indicated that the formation of thioacid-olefin complexes is responsible for generating a carbonyl thiyl radical and dioxygen in the air participates in the reaction and functions as a traceless reagent. Moreover, synthetic applications have been demonstrated by the gram scale synthesis and aggregation-induced emission property of representative compound 3i.

Stereospecific Synthesis and Biological Evaluation of KRN7000 Analogues with Thio-modifications at the Acyl Moiety.

α-Galactosylceramide (KRN7000 or α-GalCer) analogues terminated with phenyl (Ph) groups at the acyl moiety possess more potency than KRN7000 to activate invariant natural killer T (iNKT) cells for inducing a T helper 1 (Th1)-biased immune response. However, biological activities of phenyl glycolipids with thio-modifications at the acyl moiety remain unknown, and facile approaches for highly stereoselective synthesis of KRN7000 and its analogues are rather scarce. Herein, we exploited 4,6-di-O-tert-butylsilylene (DTBS)-directed stereospecific galactosylation to efficiently synthesize various α-GalCer analogues bearing thioamide, terminal thiophenyl and dual modifications at the acyl moiety. Biological evaluations suggest that a new analogue S34 featuring a terminal Ph-S-Ph-F group exhibits a more superior Th1-biased immune response in mice. Molecular docking analysis revealed that the introduction of a sulfur atom influences vital hydrogen bonding interactions between glycolipids and the cluster of differentiation 1d (CDld), thus adjusting the stability of the glycolipid-CDld complex.

Carbon Dots: Synthesis, Characterizations, and Recent Advancements in Biomedical, Optoelectronics, Sensing, and Catalysis Applications.

Carbon nanodots (CNDs), a fascinating carbon-based nanomaterial (typical size 2-10 nm) owing to their superior optical properties, high biocompatibility, and cell penetrability, have tremendous applications in different interdisciplinary fields. Here, in this Review, we first explore the superiority of CNDs over other nanomaterials in the biomedical, optoelectronics, analytical sensing, and photocatalysis domains. Beginning with synthesis, characterization, and purification techniques, we even address fundamental questions surrounding CNDs such as emission origin and excitation-dependent behavior. Then we explore recent advancements in their applications, focusing on biological/biomedical uses like specific organelle bioimaging, drug/gene delivery, biosensing, and photothermal therapy. In optoelectronics, we cover CND-based solar cells, perovskite solar cells, and their role in LEDs and WLEDs. Analytical sensing applications include the detection of metals, hazardous chemicals, and proteins. In catalysis, we examine roles in photocatalysis, CO2 reduction, water splitting, stereospecific synthesis, and pollutant degradation. With this Review, we intend to further spark interest in CNDs and CND-based composites by highlighting their many benefits across a wide range of applications.

Chiral zeolite beta used as stationary phase for enantioseparation in miniaturized open tubular capillary electrochromatography with amperometric detection

BackgroundWith the rapid growth of the demand for optically pure compounds in the fields of biology, medicine and stereospecific synthesis, it is of great importance to develop efficient, economical, simple enantioseparation and analysis methods. Open tubular capillary electrochromatography (OT-CEC) has attracted much attention in the field of chiral separation, but its column capacity and the sensitivity of common-used optical detection are relatively low. Zeolite beta nanomaterial is both enantioselective and size-selective, providing suitable chiral microenvironment for chiral recognition, and amperometric detection (AD) avoids the low sensitivity caused by the short optical path in optical detection to some extent. ResultsZeolite beta nanomaterials with different particle sizes (25, 50 and 200 nm) were synthesized, and the morphology and structure were characterized by scanning electron microscopy and X-ray diffraction. Then, a novel chiral OT column was prepared by one-step method using zeolite beta nanomaterial as chiral stationary phase, and its separation performance was characterized by miniaturized CEC with AD (mini-CEC-AD) device. Under the optimum conditions, six groups of chiral drugs achieved baseline separation. Norepinephrine enantiomers were used for evaluating the inter-day, intra-day and inter-column reproducibility of the prepared open-tubular column. The relative standard deviations of migration time, peak area, resolution and selectivity factor were within 8.7 %. The limits of detection for norepinephrine enantiomers were 0.18 μg mL−1 (S/N = 3), and the average recoveries were in range of 96.7–105.0 %. This developed method has been successfully applied to the analysis of impurity enantiomer in potassium dichromate (+)-norepinephrine injection sample. SignificanceZeolite beta nanomaterial was used as the stationary phase to prepare chiral OT columns for the first time, and this one-step preparation method is simple and easy. The introduction of zeolite beta enriches the types of chiral stationary phase materials in electrochromatographic columns, and mini-OT-CEC-AD system provides an alternative for fast enantioseparation of chiral compounds.

Introduction of a Chiral Biphenanthrene-Diol Unit to Achieve Circularly Polarized Thermally Activated Delayed Fluorescence.

Circularly polarized luminescence (CPL) materials are promising candidates for future display technology. However, such highly efficient emitters suffer from the issues of difficult chiral separation and low photoluminescence quantum yield (PLQY). In this work, the chiral 4,4'-biphenanthrene-3,3'-diol (BIPOL) unit was introduced into a thermally activated delayed fluorescence (TADF) framework for the first time. We presented two series of enantiomers, R/S-o-DCzBPNCN and R/S-p-DCzBPNCN, and the synthesis of enantiopure BIPOL can be prepared via normal column chromatography. Notably, o-DCzBPNCN showed narrow singlet-triplet gap of 0.05 eV, efficient TADF, and high PLQYs of 82 % in doped films. In addition, R/S-o-DCzBPNCN exhibited high luminescence dissymmetry factor (gPL ) values of -1.94×10-2 /+1.91×10-2 in doped films. The strategy of BIPOL introduction offers a new approach to organic emitters with stereospecific synthesis, TADF, and chiroptical properties.

Diastereoselective hydride transfer enables a synthesis of chiral 1,5-carboxamido-trifluoromethylcarbinols.

The deployment of fluorinated functional groups has become a widespread tool in medicinal chemistry due to the impact of fluorine on lipophilicity and metabolic stability. Among these compounds, enantiopure secondary trifluoromethylcarbinols are recurrent features in bioactive compounds. Herein, we present a diastereoselective redox-neutral process allowing the stereospecific synthesis of 1,5-carboxamido-trifluoromethylcarbinols through the formal reduction of a trifluoromethylketone into a trifluoromethylcarbinol. A combined experimental and computational investigation unveiled a network of interconnected equilibria leading to a key hydride transfer event.

Synthesis and characterization of four diastereomers of β-lactamase inhibitor drug intermediate

A short and efficient stereo-specific synthesis of three stereoisomers (two diastereomer and one enantiomer) of Oxalate salt of benzyl (2S,5R)-5-(benzyloxyamino)piperidine-2-carboxylate (8) has been described. Compound 8 is a key intermediate in the synthesis of β-lactamase inhibitors, was synthesized in high diastereomeric excess using chirally pure L-pyroglutamic acid. In this report, we also describe a chiral high performance liquid chromatography (CHPLC) method to separate these isomers. The developed CHPLC method was validated for the accurate determination of the diastereomeric purity of compound 8.

Absolute configuration assignment of highly fluorinated carboxylic acids via VCD and MRR spectroscopy

Chiral analysis has become a crucial step in studying the stereospecific synthesis of Active Pharmaceutical Ingredients (APIs). Both Vibrational Circular Dichroism (VCD) and Molecular Rotational Resonance (MRR) spectroscopy are capable of determining absolute configurations (ACs) via comparison of experimental and calculated data. In this regard, each technique has its own caveats. In VCD analysis, accurate prediction of the normal modes as well as rigorous conformational searches of both the analyte and potential (self-)aggregation products are required to optimally match experimental spectra. In MRR analysis, chiral species are resolved through complexation with a chiral tag to prepare spectrally distinct diastereomeric complexes. Although individual complex isomers can be distinguished, spectral assignments need to be matched to unique isomer geometries for unambiguous AC assignment. In this work, the ACs of two highly fluorinated carboxylic acids were successfully assigned using VCD and MRR spectroscopy. In the VCD analysis, the M06-2X functional was demonstrated to be superior to B3LYP and B3LYP-GD3 in accurately predicting the C–F normal modes and both monomeric and dimeric spectral contributions were observed. In a similar analysis with broadband MRR, most experimentally identified geometries had more than one possible computational match. Nevertheless, careful consideration of the chiral tag, as well as additional isomer assignments, resulted in successful assignment of the AC. This comparative study demonstrates the power of contemporary VCD analysis and the unique contributions of MRR to the analytical toolbox.

Harnessing the Peterson Reaction for the Stereospecific Synthesis of Z-Vinyl Ethers.

Vinyl ethers are valuable synthetic intermediates which are also found as natural products, including aflatoxins, rifamycins and plasmalogens. The latter are ubiquitous phospholipids in human cells and contain a vinyl ether moiety with specifically Z configuration. Although numerous methods are available for synthesis of vinyl ethers, there is a lack of methods for obtaining Z isomers of molecules of the type RCH=CHOR' that are applicable to plasmalogens. A variant of the Peterson reaction is described that generates such molecules with very high stereoselectivity (Z/E ratio: 99 : 1). (R,R)/(S,S)-1-alkoxy-2-hydroxyalkylsilanes were synthesized from 1-trimethylsilylalkynes by a sequence of reduction with di-isobutylaluminium hydride to a (Z)-1-trimethylsilylalkene, epoxidation of the alkene to a 2-trimethylsilyl-3-substituted epoxide and regioselective, boron-trifluoride catalyzed ring-opening of the epoxide by reaction with an alcohol. Conversion of the (R,R)/(S,S)-1-alkoxy-2-hydroxyalkylsilanes to vinyl ethers (RCH=CHOR') was achieved under basic conditions as in a standard Peterson reaction. However, near exclusive formation of a Z vinyl ether was only achieved when the reaction was performed using potassium hydride in the non-polar solvent α,α,α-trifluorotoluene, more polar solvents giving increasing amounts of the E isomer. The sequence described embraces a variety of substituents and precursors, proceeds in overall high yield and is readily scalable.

Stereospecific and Regioselective Synthesis of E-Allylic Alcohols through Reductive Cross Coupling of Terminal Alkynes.

We have developed a convergent method for the synthesis of allylic alcohols that involves a reductive coupling of terminal alkynes with α-chloro boronic esters. The new method affords allylic alcohols with excellent regioselectivity (anti-Markovnikov) and an E/Z ratio greater than 200:1. The reaction can be performed in the presence of a wide range of functional groups and has a substrate scope that complements the stoichiometric alkenylation of α-chloro boronic esters performed using alkenyl lithium and Grignard reagents. The transformation is stereospecific and allows for the robust and highly selective synthesis of chiral allylic alcohols. Our studies support a mechanism that involves hydrocupration of the alkyne and cross-coupling of the alkenyl copper intermediate with α-chloro boronic esters. Experimental evidence excludes a radical mechanism of the cross-coupling step and is consistent with the formation of a boron-ate intermediate and a 1,2-metalate shift.

Microwave-Induced Catalytic Transfer Hydrogenation in Different Solvents Toward Optically Active Hydroxy β-Lactams: Effects of Penetration Depth

In present work, the stereospecific synthesis of optically active cis hydroxy β-lactams by catalytic transfer hydrogenation under diversemicrowave-induced conditions is invstigated. The effects of the penetration depth of the solvents are found to be more crucial than solvents with high dipole moments and dielectric constants. Despite significant progress of microwave-induced reactions, no reports have examined the penetration depth of the solvents used in these processes

Stereospecific synthesis of silicon-stereogenic optically active silylboranes and general synthesis of chiral silyl Anions

Silicon-stereogenic optically active silylboranes could potentially allow the formation of chiral silyl nucleophiles as well as the synthesis of various chiral silicon compounds. However, the synthesis of such silicon-stereogenic silylboranes has not been achieved so far. Here, we report the synthesis of silicon-stereogenic optically active silylboranes via a stereospecific Pt(PPh3)4-catalyzed Si–H borylation of chiral hydrosilanes, which are synthesized by stoichiometric and catalytic asymmetric synthesis, in high yield and very high or perfect enantiospecificity (99% es in one case, and >99% es in the others) with retention of the configuration. Furthermore, we report a practical approach to generate silicon-stereogenic silyl nucleophiles with high enantiopurity and configurational stability using MeLi activation. This protocol is suitable for the stereospecific and general synthesis of silicon-stereogenic trialkyl-, dialkylbenzyl-, dialkylaryl-, diarylalkyl-, and alkylary benzyloxy-substituted silylboranes and their corresponding silyl nucleophiles with excellent enantiospecificity (>99% es except one case of 99% es). Transition-metal-catalyzed C–Si bond-forming cross-coupling reactions and conjugate-addition reactions are also demonstrated. The mechanisms underlying the stability and reactivity of such chiral silyl anion were investigated by combining NMR spectroscopy and DFT calculations.

Stereospecific Synthesis of Cyclohexenone Acids by [3,3]-Sigmatropic Rearrangement Route.

Herein we report a modular synthetic method for the preparation of diaryl-substituted cyclohexenone acids starting from phenyl pyruvate and suitable enones. When the reaction is carried out in alkaline tert-butanol or toluene solutions in microwave-assisted conditions mainly anti configuration products are obtained with up to 86% isolated yield. However, when the reaction is carried out in alkaline water, a mixture of products with anti and syn conformations is obtained with up to 98% overall isolated yield. Mechanistically the product with anti conformation forms by a hemiketal-oxy-Cope type [3,3]-sigmatropic rearrangement-intramolecular aldol condensation route and syn product by an intermolecular aldol condensation-electrocyclization (disrotatory type) route.

Stereospecific synthesis of Pd(0)-catalyzed oxazolidinone with tetracyclic structure

The efficient synthesis of a new class of oxazolidinone with strained rings is described. The allylic cis-diol as the key intermediate was first prepared via two steps starting from p-benzoquinone. Formation of the bis-carbamate groups with p-TsNCO of allylic cis-diol followed by a Pd(0) catalyzed ionization/cyclization reaction gave the corresponding oxazolidinone derivative. Oxidation and acetylation of only one alkene moiety in the compound gave a diacetate oxazolidinone compound stereoselectively. The structure of diacetate oxazolidinone compound was resolved by X-ray diffraction and the stereochemistry of the structure was determined. Characterization of all the synthesized compounds was performed by FT-IR, 1H NMR, 13C NMR, and Elemental Analysis techniques.

Multicomponent and Metal‐Free Diels–Alder/Aromatization Approach to the Stereospecific Synthesis of E‐(Hetero)Stilbenes and Diarylacetylenes

AbstractHerein, we present a novel and metal‐free approach to the stereospecific synthesis of E‐stilbenes. Starting from substituted 6‐arylhexa‐3,5‐dien‐2‐ones, a multicomponent enolacetylation/intermolecular Diels–Alder reaction was performed using ethyl acetate as a green solvent. The obtained cycloadducts were then oxidized without purification to produce the stilbenic products in good yields up to 67 % and with complete (E)‐stereospecificity and regioselectivity. Moreover, heterostilbenes were synthetized using this approach, displaying the potential applications of this protocol in pharmaceutical and material sciences. The proposed methodology was further extended to the synthesis of diarylacetylenes, furnishing a new metal‐free synthetic access to this important class of compounds. Furthermore, DFT calculations were performed confirming a concerted [4+2] reaction mechanism of the key ring‐forming step. At last, the energetic analysis of the possible transition states helps to shed some light on the experimentally observed total regio‐ and chemoselectivity.