Good Yields Research Articles

Rhodium-Catalyzed Asymmetric Reductive Hydroformylation of α-Substituted Enamides.

Chiral γ-amino alcohols are prevalent structural motifs in natural products and bioactive compounds. Nevertheless, efficient and atom-economical synthetic methods toward enantiomerically enriched γ-amino alcohols are still lacking. In this study, a highly enantioselective rhodium-catalyzed reductive hydroformylation of readily available α-substituted enamides is developed, providing a series of pharmaceutically valuable chiral 1,3-amino alcohols in good yields and excellent enantioselectivities in a single step. The development of the 4,4'-bisarylamino-substituted BIBOP ligand is crucial for the success of this transformation. DFT calculations and experimental data have revealed the importance of hydrogen bonding between the N-H group in the structure of TFPNH-BIBOP and the enamide carbonyl group in promoting both high enantioselectivity and reactivity. This method has enabled the concise synthesis of several chiral pharmaceutical intermediates including a single-step synthesis of the key chiral intermediate of maraviroc.

Towards Optimal Automated 68Ga-Radiolabeling Conditions of the DOTA-Bisphosphonate BPAMD Without Pre-Purification of the Generator Eluate.

DOTA-functionalized bisphosphonates can be useful tools for PET imaging of bone metastases when radiolabeled with 68Ga. Moreover, the versatility of DOTA allows the complexation of radiometals with therapeutic applications (e.g., 177Lu), positioning these bisphosphonates as attractive theranostic agents. Among these molecules, BPAMD is a compound whose radiolabeling with 68Ga has already been described, but only through manual methods. Thus, a fully automated protocol for 68Ga radiolabeling of BPAMD on the GAIA® ± LUNA® synthesis module was designed, and a thorough study of the radiolabeling conditions was undertaken. [68Ga]Ga-BPAMD was produced in good radiochemical purity (> 93%) and high radiochemical yield (> 91%) using 0.3 M HEPES buffer. The nature of the reaction vessel showed no significant effect on the radiolabeling outcome. Similarly, addition of an antiradiolysis compound to the reaction medium did not significantly improve the already excellent stability of [68Ga]Ga-BPAMD over time. The radiolabeled product obtained by automated synthesis was evaluated invivo in healthy mice and confirmed high accumulation in the joints and along the backbone.

Organocatalytic Atroposelective C−H Amination of Arenes with Indolines

AbstractAn atroposelective synthesis of axially chiral N‐arylindolines has been established by organocatalytic nucleophilic amination of arenes with 7‐substituted indolines, providing a straightforward way to achieve the expected C−N atropisomers in good yields (up to 95 %) with good to excellent enantioselectivities (up to 97 % ee) from readily available starting materials. Furthermore, axially chiral N‐arylindole derivatives could be prepared upon oxidative aromatization of the corresponding N‐arylindolines.

Nickel‐Catalyzed Atroposelective Carbo‐Carboxylation of Alkynes with CO2: En Route to Axially Chiral Carboxylic Acids

AbstractPrecise synthesis of carboxylic acids via catalytic carboxylation with CO2 is highly appealing. Although considerable advancements have been achieved in difunctionalizing carboxylation of unsaturated hydrocarbons, the asymmetric variants are conspicuously underdeveloped, particularly in addressing axially chiral alkenes. Herein, we report the first catalytic atroposelective carboxylation of alkynes with CO2. A variety of valuable axially chiral carboxylic acids are obtained with good yields and high chemo‐, regio‐, Z/E and enantio‐selectivities. Notably, an unexpected anti‐selective carbo‐carboxylation is observed in the sp2‐hybrid carbo‐electrophile‐initiated reductive carboxylation of alkynes. Mechanistic studies including DFT calculation elucidate the origin of chiral induction and anti‐selectivity in vinyl‐carboxylation of alkynes.

Formally Zerovalent Bis(arene) Germylene Complexes of Zirconium and Hafnium.

Tetrachlorides of zirconium- and hafnium form adducts (2,3) with an intramolecular germylene phosphine Lewis pair. Two electron reduction treating the adducts with [MesNacnacMg]2 gives the low valent metal complexes (4, 5) featuring η6-Trip coordination at the Zr(II) and Hf(II) metal atom. Reduction of the M(II)-complexes gives the zerovalent metal complexes of zirconium (6) and hafnium (7), which have been structurally characterized. Two arene moieties and the germylene exhibit metal coordination. Puckered coordination of a P-phenyl unit was observed for both derivatives 6 and 7. Four electron reduction of a reaction mixture of metal tetrachloride with the germylene-phosphine Lewis pair also gives the zerovalent complexes in good yield. Carbonyl complexes were synthesized treating the reduced metal complexes with carbon monoxide. Dimethylbutadiene shows a reaction with an arene moiety and the coordinated germylene ligand of the zerovalent complexes. A cyclohexadienyl and a triorganogermate ligand are formed. For zirconium this reaction is reversible at room temperature.

Thiol-linked hyaluronic acid-mediated encapsulation of RCR-stabilized gold nanoclusters for hyaluronidase sensing and cellular imaging

Encapsulating peptide-stabilized gold nanoclusters (AuNCs) with thiolated hyaluronic acid (HA-SH) and selectively adding cysteine to the peptide sequence increased their photoluminescence. We found that peptide compositions with cysteine in the middle emitted the most. RCR-stabilized AuNCs can be purified using size-exclusion chromatography to characterize their optical characteristics, chemical composition, and possible structure. Our findings show that RCR-stabilized AuNCs have a unique chemical structure, microsecond photoluminescence lifetime, good quantum yield, and near-infrared emission peak. Due to Au-S bonding and electrostatic interactions, RCR-stabilized AuNCs were encapsulated with HA-SH to create nanocomposites. HA-SH-AuNCs had a longer emission peak, greater particle size, and better photostability than RCR-stabilized AuNCs. HAase break down HA in HA-SH-AuNCs, changing their structure and size. Thus, centrifugation makes it easier to separate HA-SH-AuNCs from HAase-digested ones. Similar to earlier sensors, HA-SH-AuNCs have great sensitivity and selectivity for HAase, with a linear range of 0.5–6.0 U/mL and a detection limit of 0.39 U/mL. They were useful for urine HAase determination, with spike recovery of 103 % to 107 %. HA-SH-AuNCs further served as a platform for targeted imaging of CD44 receptor-expressing cancer cells, demonstrating bioimaging and clinical diagnostic potential.

Synthesis of Highly Fluorescent Thiazole Fused Benzo[a] Carbazoles by Sunlight Driven Photocyclization of Indolylthiazoles

AbstractHerein we report for the first time a sunlight‐driven, irreversible photocyclization reaction of indole‐linked trisubstituted thiazoles, for the synthesis of highly fluorescent thiazole‐fused benzo[a]carbazoles using a mixture of solvents (CH3CN: DMSO; 3 : 1). Ring opening of indole moiety was observed in the case of thiazole derivatives having 2‐methyl indole substituents. Under similar reaction conditions, photocyclization of trisubstituted thiazoles having cyclic 1,3‐dicarbonyls in place of indole moiety also worked. This reaction provides products having two medicinally important moieties thiazole and benzocarbazoles. We have studied the photophysical properties of all the products and found that most of the synthesized products have very good fluorescence quantum yields.

Divergent Synthesis of Novel 3(5)-Aminoazole-Benzopyrone Hybrids and their Evaluation as α-Glucosidase Inhibitors.

An efficient approach has been developed for the trapping in situ generated benzopyrone-based ortho-quinone methide intermediates by 3- and 5-amino pyrazoles or isoxazoles. In cases of naturally occurring phenolic Mannich bases, hybrid compounds between the azole and flavonoid, namely, coumarin, chromone, isoflavone, and aurone were synthesized in moderate to good yields. It is remarkable that depending on 3- or 5-position of the amino group, the reaction led to the formation of C-4 or 3-NH substituted azole derivatives, respectively. In vitro studies showed that some of the obtained compounds bearing 5-aminoisoxazole part exhibit inhibitory activity towards α-glucosidase with IC50 values in the micromolar range.

Unnatural Cyclopeptide Synthesis via Cu-Catalyzed 1,3-Dipolar Cycloaddition of Azomethine Ylides.

Cyclic peptides are valued synthetic targets in organic and medicinal chemistry. Herein, we report an efficient strategy for the synthesis of unnatural cyclic peptides via the Cu-catalyzed 1,3-dipolar cycloaddition of azomethylene ylides. Linear precursors of different lengths and bearing diverse amino acids (26 examples) are shown to be compatible with this method, affording good yields and complete endo-diastereoselectivities. Density functional theory (DFT) calculations support a stepwise mechanism in which Cu plays a key role in the preorganization of the reactants.

Efficient convergent synthesis of 1,3-diazepinone nucleosides by ring-closing metathesis and direct glycosylation.

A new and highly efficient ring-closing metathesis-based strategy was developed for the synthesis of the cyclic urea 1,3-diazepinone, presenting significant improvement upon previous methods. Using a direct glycosylation approach, analogues of the potent cytidine deaminase (CDA) inhibitor diazepinone riboside were then synthesized including 2'-deoxyribo-, 2'-deoxy-2'-fluoroarabino-, and 2'-deoxy-2',2'-difluoro-diazepinone nucleosides, all with moderate to good yield and excellent anomeric selectivity. Crucially, in contrast to the previous multistep linear synthesis of 2'-deoxyribo- and 2'-deoxy-2'-fluoroarabino-diazepinone nucleosides, this is the first report of direct glycosylation to access these nucleosides. Overall, we report efficient convergent routes to multiple 2'-modified-diazepinone nucleosides for further evaluation as CDA and potential APOBEC3 inhibitors.

Cobalt-Catalyzed Intramolecular Enantioselective Reductive Heck Reaction toward the Synthesis of Chiral 3-Trifluoromethylated Oxindoles.

Herein, a cobalt-catalyzed intramolecular enantioselective reductive Heck reaction is disclosed. Starting from N-ortho-iodoaryl-2-(trifluoromethyl)acrylamides, a plethora of chiral oxindoles bearing trifluoromethylated quaternary stereogenic centers at the C3-position are achieved in moderate to good yields (up to 88% yield) and good to excellent enantioselectivities (up to 94% ee) by employing zinc/silane as reducing agent. Other than the trifluoromethyl group, a number of chiral oxindoles bearing alkyl, aryl, and ester groups at C3-position were also obtained albeit in relatively lower enantioselectivities (68-78% ee).

A New Contribution Confirming the Analogy Between NO+ and Related Aryldiazo Ligands

AbstractThe reaction of the cyclometalated five‐coordinate 16 electron iridium(III) complex [IrCl(H){P(tBu)2C6H4–κ2P,C}{P(tBu)2Ph}] (1) with the diazonium salt [p‐BrC6H4N2]BF4 in dichloromethane at room temperature was investigated. By spontaneous reductive elimination the iridium(I) complex salt trans‐[IrCl(N2C6H4Br‐p){(P(tBu)2)Ph}2]BF4 (2) was obtained in good yield. Therefore, this observed reaction behavior exhibits the diazonium unit as a strong π‐acceptor group and confirms furthermore the analogy between nitrosyl and aryldiazonium ligands. The new compound 2 has been characterized by standard spectroscopic methods and the molecular structure of 2 was determined by a single‐crystal X‐ray diffraction analysis (monoclinic, space group Cc, Z=4).

Chemoenzymatic Cyclization by Vanadium Chloroperoxidase for Synthesis of 4-Hydroxyisochroman-1-Ones.

4-Hydroxyisochroman-1-ones belong to the class of the secondary metabolite 3,4-dihydroisocoumarins. They exhibit a wide range of biological activities. These compounds can be synthesized through halocyclization using hypervalent iodine species or N-bromosuccinimide, followed by hydrolysis. Nonetheless, the reactions required specific conditions and generated toxic byproducts. In this study, Curvularia inaequalis vanadium chloroperoxidase (CiVCPO) catalyzed the chemoenzymatic cyclization of 2-vinylbenzoic acids with different electron-donating groups (1 a-1 e) to produce good yields of 4-hydroxyisochroman-1-ones (3 a-3 e) by adding KBr and H2O2 in citrate buffer (pH 5). The reaction mixture contained 30 % DMSO to improve substrate solubility without enzyme activity loss. The condition is more environmentally friendly than chemical methods. Therefore, it offers an alternative approach for synthesizing 4-hydroxyisochroman-1-ones.

Enantioselective Three‐Component α‐Allylic Alkylation of α‐Amino Esters by Synergistic Photoinduced Pd/Carbonyl Catalysis

Photoinduced excited‐state Pd catalysis has emerged as an intriguing strategy for unlocking new reactivity potential of simple substrates. However, the related transformations are still limited and the enantiocontrol remains challenging. Organocatalysis displays unique capability in substrate activation and stereocontrol. Combination of organocatalysis and photoinduced excited‐state Pd catalysis may provide opportunities to develop new enantioselective reactions from simple substrates. By applying cooperative triple catalysis including excited‐state Pd catalysis, ground‐state Pd catalysis, and carbonyl catalysis, we have successfully realized enantioselective α‐allylic alkylation of α‐amino esters with simple styrene and alkyl halide starting materials. The reaction allows rapid modular assembly of the three reaction partners into a variety of chiral quaternary α‐amino esters in good yields with 90‐99% ee, without protecting group manipulations at the active NH2 group. The cooperation of the chiral pyridoxal catalyst and the chiral phosphine ligand accounts for the excellent chirality induction.

Arylhydrazone‐Thioeter Palladium Pincer Complexes Catalyzed Carbonylative Suzuki–Miyaura Cross‐Coupling Using Fe(CO)5 as CO Surrogate

ABSTRACTA series of Pd(II)‐pincer complexes 3a–d have been synthesized and characterized in good yields, via C–H bond activation on arylhydrazone‐thioether ligands. The investigation of these new Pd(II)‐pincer complexes has proved that the possesses excellent catalytic activity for carbonylative Suzuki–Miyaura cross‐coupling reactions of aryl iodides with arylboronic acids using Fe(CO)5 as carbonyl source. Notably, this strategy offers several advantages such as shorter reaction time, nonrequirement of toxic CO gas, and good to excellent yield of the desired products for wide range of applicable substrate; mainly, carbonylative Suzuki–Miyaura coupling just requires only 0.5 mol% of Pd(II)‐pincer complexes. We have also demonstrated a new efficient route for the synthesis of an antineoplastic agent 4‐(methoxyphenyl)‐(3,4,5‐trimethoxyphenyl)methanone. Additionally, the possible mechanism of this Pd(II)‐pincer complexes process is further supported by the density functional theory (DFT) study.

Microwave-assisted synthesis, characterization and molecular docking of two C2-symmetric Schiff bases as fluorescent dye for silk fibroin

Using non-cytotoxic fluorescent materials for staining Bombyx mori silk fibroin holds great promise for tissue engineering and regenerative medicine, as it could be used as a scaffold and monitor for cell growth. Here, we report the microwave-assisted synthesis of two fluorescent Schiff bases in short reaction time and good yields. Detailed characterization of the synthesized compounds using NMR (1H, 13C NMR, and 2D NMR experiments), HRMS (DART+), UV/Vis, fluorescence spectroscopy, and X-ray diffraction studies. The Schiff base molecular structures showed a non-planar arrangement with the C2 point group. Both compounds showed low cytotoxicity on colon carcinoma cells (Caco2, ATCCHTB-37) at different concentrations (1 to 5 μg/mL). Notably, Schiff bases exhibit good fluorescent staining of Bombyx mori silk fibroin by the immersion method and were analyzed by confocal microscopy. The fluorescent staining ability of the Schiff bases toward the silk fibroin was explored by molecular docking, where two predominant binding sites were identified, and H-bonding and other polar interactions were found to stabilize the binding modes of the compounds. From the remarkable findings and to the best of our knowledge, this is the first report on Schiff bases as a fluorescent dye of this biomaterial.

Peptide-Functionalized Gold Nanoparticles as Organocatalysts for Asymmetric Aldol Reactions

The use of high catalyst loading is required for most of the organocatalyzed asymmetric aldol reactions in organic synthesis, and this often presents challenges during purification and difficulties in catalyst recovery from the reaction mixture. The immobilization of the catalyst onto gold nanoparticles (AuNPs) can change the structural conformations of the catalyst, thereby improving its catalytic activity and reusability. Herein we report on the synthesis of aldolase mimetic peptide coupled to gold nanoparticles (AuNPs) as efficient organocatalysts for asymmetric aldol reaction. AuNPs were synthesized using the Turkevich method. The conjugation of the peptide to AuNPs was characterized using surface plasmon resonance (SPR), Raman and X-ray photoelectron spectroscopy, and transmission electron microscopy (TEM) was used for particle size determination. The produced nanoparticles, whose sizes depended on the reduction method, were quasi-spherical with a relatively narrow size distribution. The peptide–AuNP conjugates were evaluated for aldol reaction catalytic activity between carbonyls p-nitrobenzaldehyde and cyclohexanone. The products were obtained with good yields (up to 85%) and enantioselectivity (up to 94%). The influence of organic solvents, pH and buffer solutions was also investigated. The results showed that the buffer solutions regulated the colloidal stability of AuNPs, resulting in a significant enhancement in the catalytic rate of the peptide–AuNP conjugate.

Chemoselective Dehydrogenation and Hetero-Arylation of Amides via Radical Translocation Enabled by Photoexcited Triplet Ketone Catalysis.

We herein report the chemoselective dehydrogenation and heteroarylation of amides through photoexcited triplet ketone catalysis. Under mild reaction conditions, the generated aryl radical through the halogen atom transfer (XAT) process further undergoes an intramolecular 1,5-HAT event to generate an α-amido alkyl radical, which then intercepted with either cobalt or a reduced cyano arene radical leads to dehydrogenated and heteroarylated products, respectively, in good yields.

DFT supported studies of multi-responsive AIE active fluorophores for the sensitive fluorescence recognition of p-nitrophenol and pH: Vapor phase and solution mode sensing

Designing of an aggregation-induced emission (AIE) active multi-responsive fluorophores for the sensitive recognition of targeted analytes has been a hot spot in recent time. In pursuit of this endeavor, two chromene core sensors KG01 and KG02, installed with phenyl rotors, were efficiently designed, synthesized, and characterized through NMR spectroscopy. Proposed fluorophores demonstrated striking features of structure–property relationships, including solvatochromism and J-aggregates-based aggregation induced emission (AIE). Subsequently, well-thought-out developed sensors KG01 and KG02 were subjected to photoinduced electron transfer (PET) operated fluorescence quenching driven optical tracing of p-nitrophenol (p-NP) in the co-existence of competing analytes, with LOD down to 4.7 and 6.6 nM, respectively. Further, diversified theoretical calculations were executed to validate J-aggregates, supreme selectivity of sensors towards p-NP and PET as its primary sensing mechanism. Additionally, Jobs plot experiment, dynamic light scattering (DLS) size distribution, and 1H NMR titration assay also endorsed the selective p-NP sensing. Further, reported sensors were exploited for the fluorescence along with visual recognition of trifluoroacetic acid (TFA) and sodium hydroxide (NaOH). Interestingly, devised sensor KG01 disclosed naked-eye detection of TFA vapors. Furthermore, real water sample analysis, engineering of hand-held thin layer chromatography (TLC) plates-based fluorescent kits, and fabrication of logic devices were carried out to signify the convenient point-of-need applications of the proposed sensors. To the best of our knowledge, sensors KG01 and KG02 are first-ever solvatochromic and AIEgen chromenes with good quantum yield (Φ) and absorption coefficient as potential candidates to establish a range of easy-to-apply platforms for the selective and sensitive distinguishing of different aforementioned analytes. Given the role of p-NP as a priority pollutant from industrial sources with severe ecological and health impacts, these fluorescence sensors offer promising potential for developing cost-effective tools for rapid and precise trace-level detection. Additionally, industrial seepage of TFA and NaOH into water reserves poses serious health risks. These fluorescence sensors could be adapted to create devices capable of detecting these contaminants at nanomolar concentrations.

Re-engineering of a carotenoid-binding protein based on NMR structure.

Recently, a number of message passing neural network (MPNN)-based methods have been introduced that, based on backbone atom coordinates, efficiently recover native amino acid sequences of proteins and predict modifications that result in better expressing, more soluble, and stable variants. However, usually, X-ray structures, or artificial structures generated by algorithms trained on X-ray structures, were employed to define target backbone conformations. Here, we show that commonly used algorithms ProteinMPNN and SolubleMPNN display low sequence recovery on structures determined using NMR. We subsequently propose a computational approach that we successfully apply to re-engineer AstaP, a protein that natively binds a large hydrophobic ligand astaxanthin (C40H52O4), and for which only a structure determined using NMR is currently available. The engineered variants, designated NeuroAstaP, are 51 amino acid shorter than the 22 kDa parent protein, have 38%-42% sequence identity to it, exhibit good yields, are expressed in a soluble, mostly monomeric form, and demonstrate efficient binding of carotenoids in vitro and in cells. Altogether, our work further tests the limits of using machine learning for protein engineering and paves the way for MPNN-based modification of proteins based on NMR-derived structures.