Nickel-Catalyzed Hydrofluorination in Unactivated Alkenes: Regio- and Enantioselective C-F Bond Formation.

Catalytic formation of a regio- and enantioselective C-F bond chiral center from readily available alkenes is a crucial goal, yet it continues to pose significant challenges in organic synthesis. Here, we report the regioselective formation of C-F bonds facilitated by NiH catalysis and a coordination directing strategy that enables precise hydrofluorination of both terminal and internal alkenes. Notably, we have optimized this methodology to achieve high enantioselectivity in creating aliphatic C-F stereogenic centers especially with ß,γ-alkenyl substrates, using a tailored chiral Bn-BOx ligand. Another pivotal finding in our research is the identification of the (+)-nonlinear effect under optimized conditions, allowing for high enantioselectivity even with moderately enantiomerically enriched chiral ligands. Given the significant role of fluorine in pharmaceuticals and synthetic materials, this research offers essential insights into the regioselective and enantioselective formation of C-F bond chiral centers, paving the way for the efficient production of valuable fluorinated compounds.

Unlocking the Potential of ß-Fragmentation of Aminophosphoranyl Radicals for Sulfonyl Radical Reactions.

Exploiting ß-scission in aminophosphoranyl radicals for radical-mediated transformations has been a longstanding challenge. In this study, we investigated the untapped potential of ß-fragmentation in aminophosphoranyl radicals by leveraging the unique properties of the P-N bond and the substituents of P(III) reagents. Our approach carefully considers factors such as cone angle and electronic properties of phosphine and employs density functional theory (DFT) calculations to probe structural and molecular orbital influence. We successfully induced ß-fragmentation through N-S bond cleavage of aminophosphoranyl radicals under visible light and mild conditions, generating a range of sulfonyl radicals derived from pyridinium salts via the photochemical activity of electron donor-acceptor (EDA) complexes. This innovative synthetic strategy exhibits broad applicability, including late-stage functionalization, and paves the way for valuable sulfonyl radical-mediated reactions, such as alkene hydrosulfonylation, difunctionalization, and pyridylic C-H sulfonylation.

Regio- and Enantioselective Catalytic δ-C-H Amidation of Dioxazolones Enabled by Open-Shell Copper-Nitrenoid Transfer.

Controlling regio- and enantioselectivity in C-H functionalization reactions is of paramount importance due to their versatile synthetic utilities. Herein, we describe a new approach for the asymmetric δ-C(sp3)-H amidation catalysis of dioxazolones using a Cu(I) precursor with a chiral bisoxazoline ligand to access six-membered lactams with high to excellent regio- and enantioselectivity (up to >19:1 rr and >99:1 er). Combined experimental and computational mechanistic studies unveiled that the open-shell character of the postulated Cu-nitrenoids enables the regioselective hydrogen atom abstraction and subsequent enantio-determining radical rebound of the resulting carbon radical intermediates. The synthetic utility of this asymmetric cyclization was demonstrated in the diastereoselective introduction of additional functional groups into the chiral δ-lactam skeleton as well as in the rapid access to biorelevant azacyclic compounds.

N-Functionalized Pyridinium Salts: A New Chapter for Site-Selective Pyridine C-H Functionalization via Radical-Based Processes under Visible Light Irradiation.

The radical-mediated C-H functionalization of pyridines has attracted considerable attention as a powerful tool in synthetic chemistry for the direct functionalization of the C-H bonds of the pyridine scaffold. Classically, the synthetic methods for functionalized pyridines often involve radical-mediated Minisci-type reactions under strongly acidic conditions. However, the site-selective functionalization of pyridines in unbiased systems has been a long-standing challenge because the pyridine scaffold contains multiple competing reaction sites (C2 vs C4) to intercept free radicals. Therefore, prefunctionalization of the pyridine is required to avoid issues observed with the formation of a mixture of regioisomers and overalkylated side products.Recently, N-functionalized pyridinium salts have been attracting considerable attention in organic chemistry as promising radical precursors and pyridine surrogates. The notable advantage of N-functionalized pyridinium salts lies in their ability to enhance the reactivity and selectivity for synthetically useful reactions under acid-free conditions. This approach enables exquisite regiocontrol for nonclassical Minisci-type reactions at the C2 and C4 positions under mild reaction conditions, which are suitable for the late-stage functionalization of bioactive molecules with greater complexity and diversity. Over the past five years, a variety of fascinating synthetic applications have been developed using various types of pyridinium salts under visible light conditions. In addition, a new platform for alkene difunctionalization using appropriately designed N-substituted pyridinium salts as bifunctional reagents has been reported, offering an innovative assembly process for complex organic architectures. Intriguingly, strategies involving light-absorbing electron donor-acceptor (EDA) complexes between pyridinium salts and suitable electron-rich donors further open up new reactivity under photocatalyst-free conditions. Furthermore, we developed enantioselective reactions using pyridinium salts to afford enantioenriched molecules bearing pyridines through single-electron N-heterocyclic carbene (NHC) catalysis.Herein, we provide a broad overview of our recent contributions to the development of N-functionalized pyridinium salts and summarize the cornerstones of organic reactions that successfully employ these pyridinium salts under visible light conditions. The major advances in the field are systematically categorized on the basis of the pyridines' N-substituent, N-X (X = O, N, C, and SO2CF3), and its reactivity patterns. Furthermore, the identification of new activation modes and their mechanistic aspects are discussed by providing representative contributions to each paradigm. We hope that this Account will inspire broad interest in the continued innovation of N-functionalized pyridinium salts in the exploration of new transformations.

Visible-Light-Active Coumarin- and Quinolinone-Based Photocatalysts and Their Applications in Chemical Transformations.

Organic dyes have been actively studied as useful photocatalysts because they allow access to versatile structural flexibility and green synthetic applications. The identification of a new class of robust organic chromophores is, therefore, in high demand to increase structural diversity and variability. Although coumarins and quinolinones have long been acknowledged as organic chromophores, their ability to participate in photoinduced transformations is somewhat less familiar. Fascinated by their chromophoric features and adaptable platform, our group is interested in the identification of fluorescent bioactive molecules and in the development of new photoinduced synthetic methods using coumarins and quinolinones as photocatalysts. This account provides an overview of our recent progress in the discovery and application of light-absorbing coumarin and quinolinone derivatives in photochemistry and medicinal chemistry.

Photoinduced Electron Transfer from Xanthates to Acyl Azoliums: Divergent Ketone Synthesis via N-Heterocyclic Carbene Catalysis.

Considering the prevalence of alcohols and carboxylic acids, their fragment cross-coupling reactions could hold significant implications in organic synthesis. Herein, we report a versatile method for synthesizing a diverse range of ketones from alcohols and carboxylic acid derivatives via N-heterocyclic carbene (NHC) catalysis. Mechanistic investigations revealed that photoexcited xanthates and acyl azoliums undergo single electron transfer (SET) under photocatalyst-free conditions, generating NHC-derived ketyl radicals and alkyl radicals. These open-shell intermediates subsequently undergo the radical-radical cross-coupling reaction, yielding valuable ketones. Furthermore, this approach can be employed in three-component reactions involving alkenes and enynes, resulting in structurally diverse cross-coupled ketones. The unified strategy offers a unique opportunity for the fragment coupling of a diverse range of alcohols and carboxylic acid derivatives, accommodating diverse functional groups even in complex settings.

Nickel-Catalyzed Kinetic Resolution of Racemic Unactivated Alkenes via Enantio-, Diastereo-, and Regioselective Hydroamination.

Kinetic resolution is a powerful strategy for the isolation of enantioenriched compounds from racemic mixtures, and the development of selective catalytic processes is an active area of research. Here, we present a nickel-catalyzed kinetic resolution of racemic α-substituted unconjugated carbonyl alkenes via the enantio-, diastereo-, and regioselective hydroamination. This protocol affords both chiral α-substituted butenamides and syn-ß2,3 -amino acid derivatives with high enantiomeric purity (up to 99 % ee) and selectivity factor up to >684. The key to the excellent kinetic resolution efficiency is the distinctive architecture of the chiral nickel complex, which enables successful resolution and enantioselective C-N bond construction. Mechanistic investigations reveal that the unique structure of the chiral ligand facilitates a rapid migratory insertion step with one enantiomer. This strategy provides a practical and versatile approach to prepare a wide range of chiral compounds.

Photocatalytic Enantioselective Hydrosulfonylation of α,ß-Unsaturated Carbonyls with Sulfonyl Chlorides.

This research explores the enantioselective hydrosulfonylation of various α,ß-unsaturated carbonyl compounds via the use of visible light and redox-active chiral Ni-catalysis, facilitating the synthesis of enantioenriched α-chiral sulfones with remarkable enantioselectivity (exceeding 99 % ee). A significant challenge entails enhancing the reactivity between chiral metal-coordinated carbonyl compounds and moderate electrophilic sulfonyl radicals, aiming to minimize the background reactions. The success of our approach stems from two distinctive attributes: 1) the Cl-atom abstraction employed for sulfonyl radical generation from sulfonyl chlorides, and 2) the single-electron reduction to produce a key enolate radical Ni-complex. The latter process appears to enhance the feasibility of the sulfonyl radical's addition to the electron-rich enolate radical. An in-depth investigation into the reaction mechanism, supported by both experimental observations and theoretical analysis, offers insight into the intricate reaction process. Moreover, the versatility of our methodology is highlighted through its successful application in the late-stage functionalization of complex bioactive molecules, demonstrating its practicality as a strategy for producing α-chiral sulfones.

Nickel-Catalyzed Regio- and Enantioselective Hydroamination of Unactivated Alkenes Using Carbonyl Directing Groups.

The asymmetric addition of an N-H bond to various alkenes via a direct catalytic method is a powerful way of synthesizing value-added chiral amines. Therefore, the enantio- and regioselective hydroamination of unactivated alkenes remains an appealing goal. Here, we report the highly enantio- and regioselective Ni-catalyzed hydroamination of readily available unactivated alkenes bearing weakly coordinating native amides or esters. This method succeeds for both terminal and internal unactivated alkenes and has a broad amine coupling partner scope. The mild reaction process is well suited for the late-stage functionalization of complex molecules and has the potential to gain modular access to enantioenriched ß- or γ-amino acid derivatives and 1,2- or 1,3-diamines. Mechanistic studies reveal that a chiral bisoxazoline-bound Ni specie effectively leverages carbonyl coordination to achieve enantio- and regioselective NiH insertion into alkenes.

Z-Portal Continuum Dark Matter.

We examine the possibility that dark matter (DM) consists of a gapped continuum, rather than ordinary particles. A weakly interacting continuum (WIC) model, coupled to the standard model via a Z portal, provides an explicit realization of this idea. The thermal DM relic density in this model is naturally consistent with observations, providing a continuum counterpart of the "WIMP miracle." Direct detection cross sections are strongly suppressed compared to ordinary Z-portal WIMP, thanks to a unique effect of the continuum kinematics. Continuum DM states decay throughout the history of the Universe, and observations of cosmic microwave background place constraints on potential late decays. Production of WICs at colliders can provide a striking cascade-decay signature. We show that a simple Z-portal WIC model provides a fully viable DM candidate consistent with all current experimental constraints.

Two-Track Virtual Screening Approach to Identify the Dual Inhibitors of Wild Type and C481S Mutant of Bruton's Tyrosine Kinase.

Bruton's tyrosine kinase (BTK) is responsible for the pathogenesis of various autoimmune diseases and chronic lymphocytic leukemia. However, the discovery of efficient medicines has seen limited success due to the constitutively active mutants that acquired the drug resistance. To disclose the dual inhibitors against the wild-type BTK and the problematic drug-resistant C481S mutant, a large chemical library was virtually screened with extensive molecular docking simulations using two target proteins. As a consequence of imposing the configurational restraint to make a hydrogen bond in the hinge region of BTK as well as modifying the ligand dehydration term in the scoring function, a total of 20 dual inhibitors were discovered with the range of the associated IC50 values from 2.5 to 15 µM. All these dual inhibitors revealed the inhibitory activity against the C481S mutant to a comparable extent to that measured for the wild type. Among the new inhibitors, N-(3,5-dimethoxyphenyl)-6,7-dimethoxyquinazolin-4-amine (1) appeared to be most suitable as a starting point of the lead optimization due to the highest biochemical potency against the C481S mutant as well as the lowest molecular weight. To increase the potential of a drug candidate, 1 was modified into 6,7-dimethoxy-N-(pyridin-3-yl)quinazolin-4-amine (12) via chemical synthesis so as to possess better physicochemical properties without loss of the biochemical potency. 12 is suggested as a new effective molecular core from which numerous druggable dual inhibitors of the wild-type BTK and the C481S mutant would be derivatized.

Structure-Based Virtual Screening and De Novo Design to Identify Submicromolar Inhibitors of G2019S Mutant of Leucine-Rich Repeat Kinase 2.

Missense mutations of leucine-rich repeat kinase 2 (LRRK2), including the G2019S mutant, are responsible for the pathogenesis of Parkinson's disease. In this work, structure-based virtual screening of a large chemical library was carried out to identify a number of novel inhibitors of the G2019S mutant of LRRK2, the biochemical potencies of which ranged from the low micromolar to the submicromolar level. The discovery of these potent inhibitors was made possible due to the modification of the original protein-ligand binding energy function in order to include an accurate ligand dehydration energy term. The results of extensive molecular docking simulations indicated that the newly identified inhibitors were bound to the ATP-binding site of the G2019S mutant of LRRK2 through the multiple hydrogen bonds with backbone amide groups in the hinge region as well as the hydrophobic interactions with the nonpolar residues in the P-loop, hinge region, and interdomain region. Among 18 inhibitors derived from virtual screening, 4-(2-amino-5-phenylpyrimidin-4-yl)benzene-1,3-diol (Inhibitor 2) is most likely to serve as a new molecular scaffold to optimize the biochemical potency, because it revealed submicromolar inhibitory activity in spite of its low molecular weight (279.3 amu). Indeed, a highly potent inhibitor (Inhibitor 2n) of the G2019S mutant was derived via the structure-based de novo design using the structure of Inhibitor 2 as the molecular core. The biochemical potency of Inhibitor 2n surged to the nanomolar level due to the strengthening of hydrophobic interactions in the ATP-binding site, which were presumably caused by the substitutions of small nonpolar moieties. Due to the high biochemical potency against the G2019S mutant of LRRK2 and the putatively good physicochemical properties, Inhibitor 2n is anticipated to serve as a new lead compound for the discovery of antiparkinsonian medicines.

Site-Selective Pyridylic C-H Functionalization by Photocatalytic Radical Cascades.

An efficient pyridylic C(sp3 )-H functionalization has been developed through photocatalytic radical-mediated fluoroalkylation or cascade reactions. This method is enabled by the reversible formation of alkylidene dihydropyridine intermediates via the facile enolate formation of C4-alkyl N-amidopyridinium salts in the absence of an external base, thereby establishing the conditions necessary for subsequent intermolecular radical trapping. Rapid structural diversification of the pyridylic site can be achieved through photocatalytic multicomponent cascade reactions involving alkene trifluoromethylation, SO2 -reincorporation, and sulfonyl radical addition. This operationally simple method features a broad substrate scope and high chemoselectivity and offers a unique approach for the rational modification of the heterobenzylic C-H bonds of pyridines and quinolines with uniform site-selective control. Furthermore, experimental and theoretical studies were performed to elucidate the reaction mechanism.

Visible-Light-Induced C4-Selective Functionalization of Pyridinium Salts with Cyclopropanols.

The site-selective C-H functionalization of heteroarenes is of considerable importance for streamlining the rapid modification of bioactive molecules. Herein, we report a general strategy for visible-light-induced ß-carbonyl alkylation at the C4 position of pyridines with high site selectivity using various cyclopropanols and N-amidopyridinium salts. In this process, hydrogen-atom transfer between the generated sulfonamidyl radicals and O-H bonds of cyclopropanols generates ß-carbonyl radicals, providing efficient access to synthetically valuable ß-pyridylated (aryl)ketones, aldehydes, and esters with broad functional-group tolerance. In addition, the mild method serves as an effective tool for the site-selective late-stage functionalization of complex and medicinally relevant molecules.

Site-Selective Pyridine C-H Alkylation with Alcohols and Thiols via Single-Electron Transfer of Frustrated Lewis Pairs.

A unified strategy for the deoxygenative or desulfurative pyridylation of various alcohols and thiols has been developed through a single-electron transfer (SET) process of frustrated Lewis pairs (FLPs) derived from pyridinium salts and PtBu3 . Mechanistic studies revealed that N-amidopyridinium salts serve as effective Lewis acids for the formation of FLPs with PtBu3 , and the generated phosphine radical cation ionically couples with the in situ generated xanthate, eventually affording the alkyl radical through facile ß-scission under photocatalyst-free conditions. The reaction efficiency was further accelerated by visible-light irradiation. This method is conceptually appealing by using encounter complexes in FLP chemistry to promote SET, which provides a previously unrecognized opportunity for the selective heteroarylation of a diverse range of alcohols and thiols with various functional groups, even in complex settings under mild reaction conditions.

Site-Selective Direct C-H Pyridylation of Unactivated Alkanes by Triplet Excited Anthraquinone.

Site-selective C-H functionalization in chemical feedstocks is a challenging and useful reaction in the broad field of chemical research. Here, we report a modular photochemical platform for the site-selective C-H pyridylation of unactivated hydrocarbons via the unique synergistic effects of triplet excited anthraquinone and an amidyl radical-based reverse hydrogen atom transfer (RHAT) agent. The selective pyridylation of tertiary and secondary C(sp3)-H bonds in abundant chemical feedstocks was achieved by employing various N-aminopyridinium salts in a highly selective fashion, thus providing a new catalytic system for the direct construction of high-value-added compounds under ambient reaction conditions. Moreover, this operationally simple protocol is applicable to a variety of linear-, branched-, and cyclo-alkanes and more complex molecules with high degrees of site selectivity under visible-light conditions, which provides rapid and straightforward access to versatile synthons for upgrading feedstocks under mild, metal-free reaction conditions.

Completing Multiparticle Representations of the Poincaré Group.

We extend the definition of asymptotic multiparticle states of the S-matrix beyond the tensor products of one-particle states. We identify new quantum numbers called pairwise helicities, or q_{ij}, associated with asymptotically separated pairs of particles. We first treat all single particles and particle pairs independently, allowing us to generalize the Wigner construction, and ultimately projecting onto the physical states. Our states reduce to tensor product states for vanishing q_{ij}, while for vanishing spins they reproduce Zwanziger's scalar dyon states. This construction yields the correct asymptotic states for the scattering of electric and magnetic charges, with pairwise helicity identified as q_{ij}=e_{i}g_{j}-e_{j}g_{i}.

Regio- and Stereoselective Functionalization Enabled by Bidentate Directing Groups.

Chelation-assisted C-H bond and alkene functionalization using bidentate directing groups offers an elegant and versatile approach to overcome regiocontrol issues by allowing the catalyst to come into close proximity with the targeted sites. In this personal account, we highlight our recent works in developing regio- and stereocontrolled functionalizations through transition-metal catalysis enabled by bidentate directing groups. We classify our results into two categories: (1) regioselective alkene functionalization using bidentate directing groups, and (2) asymmetric C-H functionalization using chiral bidentate directing groups. Furthermore, density functional theory studies to elucidate the origin of the regio- and stereoselectivity exerted by bidentate directing groups are discussed.

Discordance Between Apolipoprotein B and Low-Density Lipoprotein Cholesterol and Progression of Coronary Artery Calcification in Middle Age.

BACKGROUND: A high level of apolipoprotein B (apoB) is associated with incident coronary artery disease (CAD) when low-density lipoprotein cholesterol (LDL-C) level is discordantly low or concordantly high. However, data on the relationship of apoB with subclinical measure of CAD are limited.Methods and Results:A total of 14,205 men (mean age 41.0 years) who were free of cardiovascular disease at baseline and who underwent a health checkup exam, including measurement of coronary artery calcium (CAC), were studied. Of the study group, 2,773 participants (19.5%) had CAC at baseline, and CAC progression was observed in 2,550 (18.0%). The multivariate-adjusted CAC score ratios (95% confidence interval) comparing discordantly high apoB/low LDL-C and concordantly high apoB/high LDL-C with concordantly low apoB/low LDL-C were 1.51 (0.98-2.32) and 2.70 (2.19-3.33), respectively. The corresponding relative risks for CAC progression were 1.26 (1.02-1.56) and 1.49 (1.34-1.66), respectively. These associations did not change appreciably after adjustment for insulin resistance and subclinical inflammation. CONCLUSIONS: Discordant analysis showed that a high apoB level was strongly associated with prevalence and progression of CAC independent of LDL-C in a large cohort of healthy adults. The present study results highlighted the importance of an apoB measure as a potential target for primary prevention of coronary atherosclerosis in healthy adults.

Remote C-H Pyridylation of Hydroxamates through Direct Photoexcitation of O-Aryl Oxime Pyridinium Intermediates.

Herein, we report an efficient strategy for the remote C-H pyridylation of hydroxamates with excellent ortho-selectivity by designing a new class of photon-absorbing O-aryl oxime pyridinium salts generated in situ from the corresponding pyridines and hydroxamates. When irradiated by visible light, the photoexcitation of oxime pyridinium intermediates generates iminyl radicals via the photolytic N-O bond cleavage, which does not require an external photocatalyst. The efficiency of light absorption and N-O bond cleavage of the oxime pyridinium salts can be modulated through the electronic effect of substitution on the O-aryl ring. The resultant iminyl radicals enable the installation of pyridyl rings at the γ-CN position, which yields synthetically valuable C2-substituted pyridyl derivatives. This novel synthetic approach provides significant advantages in terms of both efficiency and simplicity and exhibits broad functional group tolerance in complex settings under mild and metal-free conditions.