Recent Progress in Cyclic Aryliodonium Chemistry: Syntheses and Applications.

Hypervalent aryliodoumiums are intensively investigated as arylating agents. They are excellent surrogates to aryl halides, and moreover they exhibit better reactivity, which allows the corresponding arylation reactions to be performed under mild conditions. In the past decades, acyclic aryliodoniums are widely explored as arylation agents. However, the unmet need for acyclic aryliodoniums is the improvement of their notoriously low reaction economy because the coproduced aryl iodides during the arylation are often wasted. Cyclic aryliodoniums have their intrinsic advantage in terms of reaction economy, and they have started to receive considerable attention due to their valuable synthetic applications to initiate cascade reactions, which can enable the construction of complex structures, including polycycles with potential pharmaceutical and functional properties. Here, we are summarizing the recent advances made in the research field of cyclic aryliodoniums, including the nascent design of aryliodonium species and their synthetic applications. First, the general preparation of typical diphenyl iodoniums is described, followed by the construction of heterocyclic iodoniums and monoaryl iodoniums. Then, the initiated arylations coupled with subsequent domino reactions are summarized to construct polycycles. Meanwhile, the advances in cyclic aryliodoniums for building biaryls including axial atropisomers are discussed in a systematic manner. Finally, a very recent advance of cyclic aryliodoniums employed as halogen-bonding organocatalysts is described.

Symmetric Anion Mediated Dynamic Kinetic Asymmetric Knoevenagel Reaction for N-C and N-N Atropisomers Synthesis.

A symmetric anion mediated dynamic kinetic asymmetric Knoevenagel reaction was established as a general and efficient method for accessing both N-C and N-N atropisomers. The resulting highly enantio-pure pyridine-2,6(1H,3H)-diones exhibit diverse structures and functional groups. The key to excellent regio- and remote enantiocontrol could be owed to the hydrogen bond between the enolate anion and triflamide block of the organocatalyst. This connected the enolate anion and iminium cation by a chiral backbone. The mechanism investigation via control experiments, correlation analysis, and density functional theory calculations further revealed how the stereochemical information was transferred from the catalyst into the axially chiral pyridine-2,6(1H,3H)-diones. The synthetic applications also demonstrated the reaction's potential.

Regio- and Atroposelective Ring-Opening of 1H-Benzo[4,5]oxazolopyridinones.

The development of new methods for regio- and stereoselective activation of C-O bonds in ethers holds significant promise for synthetic chemistry, offering advantages in terms of environmental sustainability and economic efficiency. Moreover, the C-N atropisomers represent a fascinating and crucial chiral system, extensively found in natural products, pharmaceutical leads, and the frameworks of advanced materials. In this work, we have introduced a nickel-catalyzed regio- and enantioselective carbon-oxygen arylation reaction for atroposelective synthesis of N-arylisoquinoline-1,3(2H,4H)-diones. The high regioselectivity of C-O cleavage benefits from the high stability of the in situ formed (amido)ethenolate via oxidative addition. Additionally, the self-activation of the aryl C-O bond facilitates the reaction under mild conditions, leading to outstanding enantioselectivities. The diverse post-functionalizations of the axially chiral isoquinoline-1,3(2H,4H)-diones further highlighted the utility of this protocol in preparing valuable C-N atropisomers, including the chiral phosphine ligands.

Transition Metal-Catalyzed Biaryl Atropisomer Synthesis via a Torsional Strain Promoted Ring-Opening Reaction.

Arising from the restricted rotation of a single bond caused by steric or electronic effects, atropisomerism is one of the few fundamental categories for molecules to manifest their three-dimensional characters into which axially chiral biaryl compounds fall. Despite the widespread occurrence of axially chiral skeletons in natural products, bioactive molecules, and chiral ligands/organocatalysts, catalytic asymmetric methods for the synthesis of these structures still lag behind demand. Major challenges for the preparation of these chiral biaryls include accessing highly sterically hindered variants while controlling the stereoselectivity. A couple of useful strategies have emerged for the direct asymmetric synthesis of these molecules in the last two decades.Recently, we have engaged in catalytic asymmetric synthesis of biaryl atropisomers via transition metal catalysis, including asymmetric ring-openings of dibenzo cyclic compounds. During these studies, we serendipitously discovered that the two substituents adjacent to the axis cause these dibenzo cyclic molecules to be distorted to minimize steric repulsion. The distorted compounds display higher reactivity in the ring-opening reactions than the non-distorted molecules. In other words, torsional strain can promote a ring-opening reaction. On the basis of this concept, we have successfully realized the catalytic asymmetric ring-opening reaction of cyclic diaryliodoniums, dibenzo silanes, and 9H-fluoren-9-ols, which delivered several differently substituted ortho tetra-substituted biaryl atropisomers in high enantioselectivity. The torsional strain not only activates the substrates toward ring-opening under mild conditions but also changes the chemoselectivity of bond-breaking events. In the palladium-catalyzed carboxylation of S-aryl dibenzothiophenium, the torsional strain inversed the bond selectivity from exocyclic C-S bond cleavage to the ring-opening reaction.In this Account, we summarize our studies on copper-, rhodium-, or palladium-catalyzed asymmetric ring-opening reactions of dibenzo cyclic compounds as a useful collection of methods for the straightforward preparation of ortho tetra-substituted biaryl atropisomers with high enantiopurity on the basis of the above-mentioned torsional strain-promoted ring-opening coupling strategy. In the last part, the torsional strain energies are also discussed with the aid of density functional theory (DFT) calculations.

Engineering Nanointerfaces of Au25 Clusters for Chaperone-Mediated Peptide Amyloidosis.

Synthetic nanomaterials possessing biomolecular-chaperone functions are good candidates for modulating physicochemical interactions in many bioapplications. Despite extensive research, no general principle to engineer nanomaterial surfaces is available to precisely manipulate biomolecular conformations and behaviors, greatly limiting attempts to develop high-performance nanochaperone materials. Here, we demonstrate that, by quantifying the length (-SCxR±, x = 3-11) and charges (R- = -COO-, R+ = -NH3+) of ligands on Au25 gold nanochaperones (AuNCs), simulating binding sites and affinities of amyloid-like peptides with AuNCs, and probing peptide folding and fibrillation in the presence of AuNCs, it is possible to precisely manipulate the peptides' conformations and, thus, their amyloidosis via customizing AuNCs nanointerfaces. We show that intermediate-length liganded AuNCs with a specific charge chaperone peptides' native conformations and thus inhibit their fibrillation, while other types of AuNCs destabilize peptides and promote their fibrillation. We offer a microscopic molecular insight into peptide identity on AuNCs and provide a guideline in customizing nanochaperones via manipulating their nanointerfaces.

A Chiral Relay Race: Stereoselective Synthesis of Axially Chiral Biaryl Diketones through Ring-Opening of Optical Dihydrophenan-threne-9,10-diols.

We report herein a point-to-axial chirality transfer reaction of optical dihydrophenanthrene-9,10-diols for the synthesis of axially chiral diketones. Two sets of conditions, namely a basic tBuOK/air atmosphere and an acidic NaClO/n-Bu4NHSO4, were developed to oxidatively cleave the C-C bond, resulting in the formation of axially chiral biaryl diketones. Finally, brief synthetic applications of the obtained chiral aryl diketones were demonstrated.

Nitrenoid from Oxime: A Practical Synthesis of Planar Chiral Ferrocenyl Phenanthridines via Nitrene-Involved Ring-Expansion Reaction.

Nitrenes and nitrenoids are highly reactive species and the proposed key intermediates in nitrogen-containing heterocyclic compound synthesis. In this work, we developed a practical method for the synthesis of phenanthridines by the reaction of oximes and Grignard reagents (with or without diethylzinc) via ring-expansion of magnesium coordinated nitrenoid complex as the key step. The method has been used to synthesize optically active planar chiral ferrocenyl phenanthridines.

Atroposelective Three-Component Coupling of Cyclic Diaryliodoniums and Sodium Cyanate Enabled by the Dual-Role of Phenol.

A copper-catalyzed atroposelective ring-opening reaction of cyclic diaryliodoniums, sodium cyanate (NaOCN) and phenols is reported. The reaction chemoselectively affords axially chiral carbamates by sequential coupling of cyclic diaryliodonium and NaOCN, followed by phenol. Mechanistic investigations revealed that phenol is not only a reagent to trap highly active intermediate isocyanates, but it also activates the copper catalyst as a standby ligand. The carbamates were readily transformed into highly functionalized urea derivatives within a simple nucleophilic substitution reaction.

Comparison of Retrograde Intrarenal Surgery and Micro-Percutaneous Nephrolithotomy for Kidney Stones: A Meta-Analysis.

BACKGROUND: Advances in micro-percutaneous nephrolithotomy (PCNL) for kidney stones have made it an alternative approach to the retrograde intrarenal surgery (RIRS) approach. Nevertheless, the superiority of micro-PCNL over RIRS is still under debate. The results are controversial. OBJECTIVES: The purpose of this study was to systematically evaluate the clinical results in patients presenting with kidney stones treated with micro-PCNL or RIRS. METHODS: A literature search was done for electronic databases to identify researches that compared micro-PCNL and RIRS till December 2019. The clinical outcome included complications, stone-free rates (SFRs), hemoglobin reduction, length of hospital stay, and operative time. RESULTS: Five articles were included in our study. The pooled results revealed no statistical difference in the rate of complications (OR = 0.99, 95% CI = 0.57-1.74, p = 0.99), length of hospital stay (MD = -0.29, 95% CI = -0.82 to 0.24, p = 0.28), and operative time (MD = -6.63, 95% CI = -27.34 to 14.08, p = 0.53) between the 2 groups. However, significant difference was present in hemoglobin reduction (MD = -0.43, 95% CI = -0.55 to 0.30, p < 0.001) and the SFRs (OR = 0.59, 95% CI = 0.36-0.98, p = 0.04) when comparing RIRS with micro-PCNL. CONCLUSIONS: Compared with micro-PCNL to treat kidney stones, RIRS is associated with better stone clearance and bearing higher hemoglobin loss. As the advantages of both technologies have been shown in some fields, the continuation of well-designed clinical trials may be necessary.

Diols Activation by Cu/Borinic Acids Synergistic Catalysis in Atroposelective Ring-Opening of Cyclic Diaryliodoniums.

A Cu-catalyzed enantioselective ring-opening alkoxygenation reaction of cyclic diaryliodonium salts and diols in the presence of borinic acids was reported. Tuning structure of borinic acids with six or five-membered ring skeleton could selectively activate 1,2-diols or 1,4-diols. A catalytic cycle through a key ion pair model that accounts for the observed enantioselectivity was proposed.

Hypervalent-Iodine-Mediated Carbon-Carbon Bond Cleavage and Dearomatization of 9H-Fluoren-9-ols.

A transition-metal-free synthesis of spiro compounds from 9H-fluoren-9-ols mediated by hypervalent iodine is reported. In this reaction, an unprecedented ß-carbon elimination of tertiary alkoxyliodine(III) to form new diaryliodonium salts is proposed. The obtained phenol intermediates undergo oxidative dearomatization to furnish a class of oxo-spiro compounds. This domino reaction significantly increases the complexity of these molecules and shows excellent regio- and stereoselectivity.

Atroposelective Ring Opening of Cyclic Diaryliodonium Salts with Bulky Anilines Controlled by a Chiral Cobalt(III) Anion.

The present work demonstrates a CuCl and anionic chiral cobalt(III)-catalyzed enantioselective ring-opening reaction. The small-size, ligand-free copper species enabled the cross-coupling of iodonium salts with a series of bulky aromatic amines in high ee values. The chiral cobalt(III) anion causes appreciable chemical shift changes of cyclic diaryliodoniums in 1 H NMR spectra.

Bioanalysis of Targeted Nanoparticles in Monkey Plasma via LC-MS/MS.

This work represents the first reporting of a comprehensive bioanalytical GLP methodology detailing the mass spectrometric quantitation of PF-05212384 dosed as a targeted polymeric encapsulated nanoparticle (PF-07034663) to monkeys. Polymeric nanoparticles are a type of drug formulation that enables the sustained release of an active therapeutic agent (payload) for targeted delivery to specific sites of action such as cancer cells. Through the careful design and engineering of the nanoparticle formulation, it is possible to improve the biodistribution and safety of a given therapeutic payload in circulation. However, the bioanalysis of nanoparticles is challenging due to the complexity of the nanoparticle drug formulation itself and the number of pharmacokinetic end points needed to characterize the in vivo exposure of the nanoparticles. Gedatolisib, also known as PF-05212384, was reformulated as an encapsulated targeted polymeric nanoparticle. The bioanalytical assays were validated to quantitate both total and released PF-05212384 derived from the encapsulated nanoparticle (PF-07034663). Assay performance calculated from quality control samples in three batch runs demonstrated intraday precision and accuracy within 10.3 and 12.2%, respectively, and interday precision and accuracy within 9.1 and 8.5%, respectively. This method leveraged automation to ease the burden of a laborious and complicated sample pretreatment and extraction procedure. The automated method was used to support a preclinical safety study in monkeys in which both released and total PF-05212384 concentrations were determined in over 1600 monkey plasma study samples via LC-MS/MS.

Cu-Catalyzed Enantioselective Ring Opening of Cyclic Diaryliodoniums toward the Synthesis of Chiral Diarylmethanes.

A Cu-catalyzed enantioselective desymmetrizing ring-opening reaction of six-membered cyclic diaryliodonium salts with carboxylic acids or thioacids is reported for the facile access to chiral diarylmethanes. A Cu/[cyclopropyl bis(oxazoline)] catalyst well discriminates two C-I bonds of prochiral cyclic diaryliodonium salts. A stereochemical model was proposed to rationalize the stereochemical outcome on the basis of the crystal structure of cyclic diaryliodonium salt.

Cutting-Edge and Time-Honored Strategies for Stereoselective Construction of C-N Bonds in Total Synthesis.

The main objective of this review is to provide a comprehensive survey of methods used for stereoselective construction of carbon-nitrogen bonds during the total synthesis of nitrogen-containing natural products that have appeared in the literature since 2000. The material is organized by specific reaction in order of decreasing number of applications in natural product synthesis. About 800 total syntheses of natural products with stereogenic carbon-nitrogen bonds described since 2000 have been reviewed.

Palladium-Catalyzed Enantioselective Synthesis of 2-Aryl Cyclohex-2-enone Atropisomers: Platform Molecules for the Divergent Synthesis of Axially Chiral Biaryl Compounds.

The palladium-catalyzed asymmetric synthesis of enone-based atropisomers from 2-iodo-3-methylcyclohex-2-enones and aryl boronic acid is reported. BoPhoz-type phosphine-aminophosphine ligands showed superior enantioselectivity over other ligands. These cyclohexenone-based atropisomers are useful compounds for further elaboration. The divergent synthesis of biaryl atropisomers with different ortho substituents was demonstrated.

Cleavage of the C(O)-S Bond of Thioesters by Palladium/Norbornene/Copper Cooperative Catalysis: An Efficient Synthesis of 2-(Arylthio)aryl Ketones.

A Pd/norbornene/Cu cooperative catalysis for the efficient synthesis of 2-(arylthio)aryl ketones from aryl halides and thioesters has been developed. The first example of cooperative catalysis by palladium, norbornene, and copper, wherein the C(O)-S bond of thioesters is cleaved by a Pd(II) palladacycle with the assistance of CuI, has been observed.

Enantioselective Synthesis of Atropisomeric Vinyl Arene Compounds by Palladium Catalysis: A Carbene Strategy.

An efficient palladium-catalyzed asymmetric synthesis of axially chiral vinyl arenes from aryl bromides and hydrazones is reported. The products were easily oxidized to axially chiral biaryl compounds, and the phosphine oxides were readily reduced to phosphine ligands.

BF3·OEt2-Promoted Synthesis of 2,3-Metallocenocyclohexanones: A 1,2-Hydride Shift and Cationic Cyclization Strategy.

A BF3·OEt2-promoted cyclization of metallocenyl enones to form cyclohexanone-fused metallocenes is reported. 2,3-Metallocenocyclohexanones were formed exclusively, and no normal Nazarov-type cyclopentanone analogues were detected. The reaction possibly proceeded via an unusual cationic 1,2-hydride shift followed by Friedel-Crafts alkylative cyclization process. During the studies of the alkylation reaction of these keto esters, an unusual and rare facial selectivity was observed. The electrophiles would be attacked from the same face as the second Cp ring.

Palladium-Catalyzed Heck-type Domino Cyclization and Carboxylation to Synthesize Carboxylic Acids by Utilizing Chloroform as the Carbon Monoxide Source.

A palladium-catalyzed domino cyclization and carboxylation reaction for synthesis of a variety of carboxylic acids was developed, where chloroform was used as "carbon monoxide" source. The in situ generated neopentylpalladium species by Heck cyclization was efficiently trapped by dichlorocarbene to form a series of carboxylic acids. It was found that in this type of domino reaction CHCl3 is a convenient and safe alternation for CO gas.