Visible-Light-Driven Germyl Radical Generation via EDA-Catalyzed ET-HAT Process.

We have established a facile and efficient protocol for the generation of germyl radicals by employing photo-excited electron transfer (ET) in an electron donor-acceptor (EDA) complex to drive hydrogen-atom transfer (HAT) from germyl hydride (R3GeH). Using a catalytic amount of EDA complex of commercially available thiol and benzophenone derivatives, the ET-HAT cycle smoothly proceeds simply upon blue-light irradiation without any transition metal or photocatalyst. This protocol also affords silyl radical from silyl hydride.

Dearomative Construction of 2D/3D Frameworks from Quinolines via Nucleophilic Addition/Borate-Mediated Photocycloaddition.

Dearomative construction of multiply-fused 2D/3D frameworks, composed of aromatic two-dimensional (2D) rings and saturated three-dimensional (3D) rings, from readily available quinolines has greatly contributed to drug discovery. However, dearomative cycloadditions of quinolines in the presence of photocatalysts usually afford 5,6,7,8-tetrahydroquinoline (THQ)-based polycycles, and dearomative access to 1,2,3,4-THQ-based structures remains limited. Herein, we present a chemo-, regio-, diastereo-, and enantioselective dearomative transformation of quinolines into 1,2,3,4-THQ-based 6-6-4-membered rings without any catalyst, through a combination of nucleophilic addition and borate-mediated [2+2] photocycloaddition. Detailed mechanistic studies revealed that the photoexcited borate complex, generated from quinoline, organolithium, and HB(pin), accelerates the cycloaddition and suppresses the rearomatization that usually occurs in conventional photocycloaddition. Based on our mechanistic analysis, we also developed further photoinduced cycloadditions affording other types of 2D/3D frameworks from isoquinoline and phenanthrene.

Metalla-Carbaporphyrinoids Consisting of an Acyclic N-Confused Tetrapyrrole Analogue Served as Stable Near-Infrared-II Dyes.

We present herein the synthesis of novel pseudo-metalla-carbaporphyrinoid species (1M: M=Pd and Pt) achieved through the inner coordination of palladium(II) and platinum(II) with an acyclic N-confused tetrapyrrin analogue. Despite their tetrapyrrole frameworks being small, akin to well-known porphyrins, these species exhibit an unusually narrow HOMO-LUMO gap, resulting in an unprecedentedly low-energy absorption in the second near-infrared (NIR-II) region. Density functional theory (DFT) calculations revealed unique dπ-pπ-conjugated electronic structures involving the metal dπ-ligand pπ hybridized molecular orbitals of 1M. Magnetic circular dichroism (MCD) spectroscopy confirmed distinct electronic structures. Remarkably, the complexes feature an open-metal coordination site in the peripheral NN dipyrrin site, forming hetero-metal complexes (1Pd-BF2 and 1Pt-BF2) through boron difluoride complexation. The resulting hetero metalla-carbaporphyrinoid species displayed further redshifted NIR-II absorption, highly efficient photothermal conversion efficiencies (η; 62-65 %), and exceptional photostability. Despite the challenges associated with the theoretical and experimental assessment of dπ-pπ-conjugated metalla-aromaticity in relatively larger (more than 18π electrons) polycyclic ring systems, these organometallic planar tetrapyrrole systems could serve as potential molecular platforms for aromaticity-relevant NIR-II dyes.

20π-Electron Antiaromatic Benziphthalocyanines with Absorption Reaching the Near-Infrared-II Region.

Although second near-infrared (NIR-II, 1000-1500 nm) light has attracted considerable attention, especially for life sciences applications, the development of organic dyes with NIR-II absorption remains a formidable challenge. Herein we report the design, synthesis, and electronic properties of 20π-electron antiaromatic benziphthalocyanines (BPcs) that exhibit intense absorption bands in the NIR region. The strong, low-energy absorption of the antiaromatic BPcs is attributed to electric-dipole-allowed HOMO-LUMO transitions with narrow band gaps, enabled by the reduced structural symmetry of BPc compared with regular porphyrins and phthalocyanines. The combination of peripheral substituents and a central metal decreases the HOMO-LUMO energy gaps, leading to the extension of the absorption bands into the NIR-II region (reaching 1100 nm) under reductive conditions.

Visible-Light-Induced trans-Hydroboration of Diaryl Alkynes Utilizing Excited State of Borate Complexes.

We have developed visible-light-induced trans-hydroboration of diaryl alkynes via direct photoexcitation of in-situ-generated diboron complexes, affording previously elusive (E)-1,2-diaryl-vinylboronates with high stereoselectivity. Experimental, spectroscopic, and theoretical mechanistic studies revealed that the triplet-state borate complex facilitates B-B bond cleavage and the desired C-B bond formation. This methodology does not require any catalyst and is operationally simple. The highly borylated 1,2-diaryl alkenes [1-(2-borylphenyl)vinyl)boronates] are shown to be useful as building blocks.

BN-Embedded Aromatic Hydrocarbon Synthesis via Nucleophilic Diboration Reactions.

Activation of bis(pinacolato)diboron with aromatic lithium amide promotes diboration of the proximal C-C triple bond, leading to BN-embedded aromatic compounds. In situ treatment of the initially generated spirocyclic borate intermediate with aqueous acid or organometallic reagents enables ligand installation on the endocyclic boron atom.

Mechanistic Analysis of Stereodivergent Nitroalkane Cyclopropanation Catalyzed by Nonheme Iron Enzymes.

BelL and HrmJ are α-ketoglutarate-dependent nonheme iron enzymes that catalyze the oxidative cyclization of 6-nitronorleucine, resulting in the formation of two diastereomeric 3-(2-nitrocyclopropyl)alanine (Ncpa) products containing trans-cyclopropane rings with (1'R,2'R) and (1'S,2'S) configurations, respectively. Herein, we investigate the catalytic mechanism and stereodivergency of the cyclopropanases. The results suggest that the nitroalkane moiety of the substrate is first deprotonated to produce the nitronate form. Spectroscopic analyses and biochemical assays with substrates and analogues indicate that an iron(IV)-oxo species abstracts proS-H from C4 to initiate intramolecular C-C bond formation. A hydroxylation intermediate is unlikely to be involved in the cyclopropanation reaction. Additionally, a genome mining approach is employed to discover new homologues that perform the cyclopropanation of 6-nitronorleucine to generate cis-configured Ncpa products with (1'R,2'S) or (1'S,2'R) stereochemistries. Sequence and structure comparisons of these cyclopropanases enable us to determine the amino acid residues critical for controlling the stereoselectivity of cyclopropanation.

Structural and Mechanistic Insights into the C-C Bond-Forming Rearrangement Reaction Catalyzed by Heterodimeric Hinokiresinol Synthase.

Hinokiresinol synthase (HRS) from Asparagus officinalis consists of two subunits, α and ß, and catalyzes an unusual decarboxylative rearrangement reaction of 4-coumaryl 4-coumarate to generate (Z)-hinokiresinol with complete stereoselectivity. Herein, we describe the mechanism of rearrangement catalysis and the role played by the heterodimeric HRS, through structural and computational analyses. Our results suggest that the HRS reaction is unlikely to proceed via the previously hypothesized Claisen rearrangement mechanism. Instead, we propose that the 4-coumaryl 4-coumarate substrate is first cleaved into coumarate and an extended p-quinone methide, which then recombine to generate a new C-C bond. These processes are facilitated by proton transfers mediated by the basic residues (α-Lys164, α-Arg169, ß-Lys168, and ß-Arg173) in the cavity at the heterodimer interface. The active site residues, α-Asp165, ß-Asp169, ß-Trp17, ß-Met136, and ß-Ala171, play crucial roles in controlling the regioselectivity of the coupling between the fragmented intermediates as well as the stereoselectivity of the decarboxylation step, leading to the formation of the (Z)-hinokiresinol product.

Mechanistic Investigation of the Degradation Pathways of α-ß/α-α Bridged Epipolythiodioxopiperazines (ETPs).

Epipolythiodioxopiperazines (ETPs) make up a class of biologically active fungal metabolites with a transannular disulfide bridge. In this work, we used DFT calculations to examine in detail the degradation (desulfurization) pathways of α-ß/α-α bridged ETPs. The chemical stability of ETPs is influenced by the type of sulfur bridge, the structural features, and the storage conditions. Our results suggest appropriate protection of the phenolic OH of ETPs would improve various pharmaceutically relevant properties, including bioavailability.

Total Biosynthesis of Melleolides from Basidiomycota Fungi: Mechanistic Analysis of the Multifunctional GMC Oxidase Mld7.

Mushroom terpenoids are biologically and chemically diverse fungal metabolites. Among them, melleolides are representative sesquiterpenoids with a characteristic protoilludane skeleton. In this study, we applied a recently established hot spot knock-in method to elucidate the biosynthetic pathway leading to 1α-hydroxymelleolide. The biosynthesis of the sesquiterpene core involves the cytochrome P450 catalyzing stepwise hydroxylation of the Δ6 -protoilludene framework and a stereochemical inversion process at the C5 position catalyzed by short-chain dehydrogenase/reductase family proteins. The highlight of the biosynthesis is that the flavoprotein Mld7 catalyzes an oxidation-triggered double-bond shift accompanying dehydration and acyl-group-assisted substitution with two different nucleophiles at the C6 position to afford the Δ7 -protoilludene derivatives, such as melleolide and armillarivin. The complex reaction mechanism was proposed by DFT calculations. Of particular importance is that product distribution is regulated by interaction with the cell membrane.

Nucleophile-Triggered π-Topological Transformation: A New Synthetic Approach to Near-Infrared-Emissive Rhodamines.

We describe a π-topological transformation-based synthetic method for the preparation of a new type of near-infrared (NIR)-emissive rhodamine dye called Polymethine-embedded Rhodamine Fluorophore (PeR Fluor). In contrast to conventional NIR-emissive dyes that require tedious synthetic steps and/or a high cost, linear fully π-conjugated PeR Fluor can be regioselectively prepared in one step by mixing different nucleophiles with ABPXs, a family of rhodamines with a cross-conjugated structure. PeR Fluor exhibits bright NIR fluorescence emission and high photostability owing to the cooperative π-electron system of rhodamines and polymethine scaffolds. Large bathochromic shifts of the absorption and fluorescence emission maxima can be achieved by modifying the N-substituted group to obtain NIR-absorbing/emitting PeR Fluor. We also demonstrate the stimulus-responsive functionality of PeR Fluor through the addition of chemicals (acid/base), which shows switchable NIR and visible fluorescence response. Our π-topological transformation-based synthetic method is a promising approach to produce new functionalized rhodamine dyes.

Effectiveness of Palonosetron, 1-Day Dexamethasone, and Aprepitant in Patients Undergoing Carboplatin-Based Chemotherapy.

INTRODUCTION: Dexamethasone (DEX)-sparing strategy with 5-hydroxytryptamine-3 receptor antagonist (5HT3RA) and aprepitant (APR), as triplet antiemetic prophylaxis, is associated with poor control of delayed chemotherapy-induced nausea and vomiting (CINV) in patients receiving carboplatin (CBDCA)-based chemotherapy. This study aimed to evaluate whether using palonosetron (PALO) as a 5HT3RA provides superior control with CINV than first-generation (1st) 5HT3RA in triplet antiemetic prophylaxis with a DEX-sparing strategy. METHODS: Pooled patient-level data from a nationwide, multicenter, and prospective observational study were analyzed to compare the incidence of CINV between patients administered PALO and 1st 5HT3RA in combination with 1-day DEX and APR. RESULTS: No significant differences were observed in the incidence of CINV, pattern of CINV, or severity of nausea by type of 5HT3RA in triplet antiemetic prophylaxis with DEX-sparing strategy. In both groups, the incidence of nausea gradually increased from day 3, peaked on day 4 or 5, and then declined slowly. The visual analog scale scores in the delayed phase remained high throughout the 7-day observation period. CONCLUSION: Careful patient selection and symptom monitoring are needed when implementing the DEX-sparing strategy in triplet antiemetic prophylaxis for patients undergoing CBDCA-based chemotherapy. Furthermore, additional strategies may be needed to achieve better control of delayed CINV.

Perfluoroalkoxylation reaction via dual concurrent catalysis.

A catalytic amount of CsI enables dual concurrent activation of poorly reactive perfluoroalkoxide and alkyl halides, especially alkyl chlorides, leading to the formation of diverse perfluoroalkoxylated organic compounds. Installation of perfluoroalkoxy groups by this methodology is cost-effective, circumventing the need for over-stoichiometric cesium or silver salts. This methodology also provides high functional group compatibility and tolerance of sterically hindered substrates.

Revision of the Peniroquesine Biosynthetic Pathway by Retro-Biosynthetic Theoretical Analysis: Ring Strain Controls the Unique Carbocation Rearrangement Cascade.

Peniroquesine, a sesterterpenoid featuring a unique 5/6/5/6/5 fused pentacyclic ring system, has been known for a long time, but its biosynthetic pathway/mechanism remains elusive. Based on isotopic labeling experiments, a plausible biosynthetic pathway to peniroquesines A-C and their derivatives was recently proposed, in which the characteristic peniroquesine-type 5/6/5/6/5 pentacyclic skeleton is synthesized from geranyl-farnesyl pyrophosphate (GFPP) via a complex concerted A/B/C-ring formation, repeated reverse-Wagner-Meerwein alkyl shifts, three successive secondary (2°) carbocation intermediates, and a highly distorted trans-fused bicyclo[4.2.1]nonane intermediate. However, our density functional theory calculations do not support this mechanism. By applying a retro-biosynthetic theoretical analysis strategy, we were able to find a preferred pathway for peniroquesine biosynthesis, involving a multistep carbocation cascade including triple skeletal rearrangements, trans-cis isomerization, and 1,3-H shift. This pathway/mechanism is in good agreement with all of the reported isotope-labeling results.

Near-Infrared Fluorescence Enhancement by Deuteration of Phthalocyanine.

Organic compounds with near-IR (NIR) fluorescence have many potential applications in materials and life sciences, but the much weaker intensity of fluorescence in the NIR region than in the UV-visible region is a major obstacle. Herein we show that deuteration of phthalocyanines, a representative class of organic NIR dyes, increases both the fluorescence quantum yield and the fluorescence lifetime compared with non-deuterated phthalocyanines.

Origin of Large Near-Infrared Solvatochromism of 18π-Electron Aromatic Monohydroxybenziphthalocyanine.

Near-IR (NIR) organic dyes have been widely utilized in life sciences and materials science. Herein we report an unusually large NIR solvatochromism of monohydroxybenziphthalocyanine, an analogue of 18π-electron aromatic phthalocyanine in which a single isoindoline unit is replaced with a phenol ring. The solvatochromism is attributed to deprotonation of the phenol moiety in highly polar solvents, leading to the generation of a strongly NIR-absorptive 18π-electron aromatic quinoidal monoanion.

TEAD1 trapping by the Q353R-Lamin A/C causes dilated cardiomyopathy.

Mutations in the LMNA gene encoding Lamin A and C (Lamin A/C), major components of the nuclear lamina, cause laminopathies including dilated cardiomyopathy (DCM), but the underlying molecular mechanisms have not been fully elucidated. Here, by leveraging single-cell RNA sequencing (RNA-seq), assay for transposase-accessible chromatin using sequencing (ATAC-seq), protein array, and electron microscopy analysis, we show that insufficient structural maturation of cardiomyocytes owing to trapping of transcription factor TEA domain transcription factor 1 (TEAD1) by mutant Lamin A/C at the nuclear membrane underlies the pathogenesis of Q353R-LMNA-related DCM. Inhibition of the Hippo pathway rescued the dysregulation of cardiac developmental genes by TEAD1 in LMNA mutant cardiomyocytes. Single-cell RNA-seq of cardiac tissues from patients with DCM with the LMNA mutation confirmed the dysregulated expression of TEAD1 target genes. Our results propose an intervention for transcriptional dysregulation as a potential treatment of LMNA-related DCM.

Visible-Light-Driven Silyl or Germyl Radical Generation via Si-C or Ge-C Bond Homolysis.

We report a simple, rapid, and selective protocol for visible-light-driven generation of silyl radicals through photoredox-induced Si-C bond homolysis. Irradiating 3-silyl-1,4-cyclohexadienes with blue light in the presence of a commercially available photocatalyst smoothly generated silyl radicals bearing various substituents within 1 h, and these radicals were trapped by a broad range of alkenes to afford products in good yields. This process is also available for efficient generation of germyl radicals.

Dearomative triple elementalization of quinolines driven by visible light.

Organoboron and organosilicon compounds are used not only as synthetic building blocks but also as functional materials and pharmaceuticals, and compounds with multiple boryl and silyl groups are beginning to be used for these purposes. Especially in drug discovery, methodology providing easy stereoselective access to aliphatic nitrogen heterocycles bearing multiple boryl or silyl groups from readily available aromatic nitrogen heterocycles would be attractive. However, such transformations remain challenging, and available reactions have been mostly limited to dearomative hydroboration or hydrosilylation reactions. Here, we report the dearomative triple elementalization (carbo-sila-boration) of quinolines via the addition of organolithium followed by photo-boosted silaboration, affording the desired products with complete chemo-, regio-, and stereoselectivity. The reaction proceeds via the formation of silyl radicals instead of silyl anions. We also present preliminary studies to illustrate the potential of silaboration products as synthetic platforms.

Experimental and Computational Investigation of Facial Selectivity Switching in Nickel-Diamine-Acetate-Catalyzed Michael Reactions.

Chiral Ni complexes have revolutionized both asymmetric acid-base and redox catalysis. However, the coordination isomerism of Ni complexes and their open-shell property still often hinder the elucidation of the origin of their observed stereoselectivity. Here, we report our experimental and computational investigations to clarify the mechanism of ß-nitrostyrene facial selectivity switching in Ni(II)-diamine-(OAc)2-catalyzed asymmetric Michael reactions. In the reaction with a dimethyl malonate, the Evans transition state (TS), in which the enolate binds in the same plane with the diamine ligand, is identified as the lowest-energy TS to promote C-C bond formation from the Si face in ß-nitrostyrene. In contrast, a detailed survey of the multiple potential pathways in the reaction with α-keto esters points to a clear preference for our proposed C-C bond-forming TS, in which the enolate coordinates to the Ni(II) center in apical-equatorial positions relative to the diamine ligand, thereby promoting Re face addition in ß-nitrostyrene. The N-H group plays a key orientational role in minimizing steric repulsion.