A platform for discovery of functional cell-penetrating peptides for efficient multi-cargo intracellular delivery.

Cell penetrating peptides (CPPs) offer great potential to deliver therapeutic molecules to previously inaccessible intracellular targets. However, many CPPs are inefficient and often leave their attached cargo stranded in the cell's endosome. We report a versatile platform for the isolation of peptides delivering a wide range of cargos into the cytoplasm of cells.

Direct α-C-H amination using various amino agents by selective oxidative copper catalysis: a divergent access to functional quinolines.

Herein, we present, for the first time, direct dehydrogenative α-C-H amination of tetrahydroquinolines (THQs) using various amino agents by selective aerobic copper catalysis, which enables divergent access to 2-aminoquinolines, the core structures of numerous functional products. In which, the catalyst system preferentially oxidizes the tetrahydroquinolines between two amino reactants, and the presence of TEMPO significantly enhances the capability of the first oxidation of THQs and makes it a kinetically controlled process, thus favoring the C-N bond-forming step. The developed chemistry features broad substrates, excellent functional tolerance, high chemo-selectivity, and no need for pre-preparation of specific aminating agents, which offers a practical way for diverse and atom-economic synthesis of 2-aminoquinolines that are difficult to prepare or inaccessible with the existing C-H amination approaches.

Rhodium-catalyzed oxidative C-H/C-H cross-coupling of aniline with heteroarene: N-nitroso group enabled mild conditions.

The development of transition metal-catalyzed oxidative C-H/C-H cross-coupling between two (hetero)arenes to forge aryl-heteroaryl motifs under mild conditions is an appealing yet challenging task. Herein, we disclose a rhodium-catalyzed oxidative C-H/C-H cross-coupling reaction of an N-nitrosoaniline with a heteroarene under mild conditions. The judicious choice of the N-nitroso group as a directing group enables heightened reactivity.

Selective Synthesis of Aryl Nitriles and 3-Imino-1-oxoisoindolines via Nickel-Promoted C(sp)-H Cyanations.

An efficient nickel-promoted selective monocyanation of benzamides with TMSCN via 8-aminoquinoline directed ortho C-H activation has been developed. Varieties of functionalized ortho-cyanated (hetero)aryl nitriles can be selectively synthesized in moderate to good yields. These cyanation products can be easily transformed into various 3-imino-1-oxoisoindolines in a one-pot procedure.

Eosin Y as a Direct Hydrogen-Atom Transfer Photocatalyst for the Functionalization of C-H Bonds.

Eosin Y, a well-known economical alternative to metal catalysts in visible-light-driven single-electron transfer-based organic transformations, can behave as an effective direct hydrogen-atom transfer catalyst for C-H activation. Using the alkylation of C-H bonds with electron-deficient alkenes as a model study revealed an extremely broad substrate scope, enabling easy access to a variety of important synthons. This eosin Y-based photocatalytic hydrogen-atom transfer strategy is promising for diverse functionalization of a wide range of native C-H bonds in a green and sustainable manner.

Iridium-Catalyzed Annulation Reactions of Thiophenes with Carboxylic Acids: Direct Evidence for a Heck-type Pathway.

The functionalization of thiophenes is a fundamental and important reaction. Herein, we disclose iridium-catalyzed one-pot annulation reactions of (benzo)thiophenes with (hetero)aromatic or α,β-unsaturated carboxylic acids, which afford thiophene-fused coumarin-type frameworks. Dearomatization reactions of 2-substituted thiophenes with α,β-unsaturated carboxylic acids deliver various thiophene-containing spirocyclic products.

Broad-Scope Rh-Catalyzed Inverse-Sonogashira Reaction Directed by Weakly Coordinating Groups.

We report the alkynylation of C(sp)-H bonds with bromoalkynes (inverse-Sonogashira reaction) directed by synthetically useful ester, ketone, and ether groups under rhodium catalysis. Other less common directing groups such as amine, thioether, sulfoxide, sulfone, phenol ester, and carbamate are also suitable directing groups. Mechanistic studies indicate that the reaction proceeds by a turnover-limiting C-H activation step via an electrophilic-type substitution.

Construction of Axially Chiral Compounds via Asymmetric Organocatalysis.

Axially chiral compounds have received much attention from chemists because of their widespread appearance in natural products, biologically active compounds, and useful chiral ligands in asymmetric catalysis. Because of the importance of this structural motif, the catalytic enantioselective construction of axially chiral scaffolds has been intensively investigated, and great progress has been accomplished. However, the majority of methodologies in this field focus on the use of metal catalysis, whereas approaches involving organocatalysis have started to emerge only recently.

Longitudinal Changes in Disc and Retinal Lesions Among Highly Myopic Adolescents in Singapore Over a 10-Year Period.

Objectives: To examine the progression pattern of disc and retinal lesions in highly myopic Chinese adolescents over a 10-year period in Singapore.

Methods: This longitudinal study included Chinese participants who showed high myopia (spherical equivalent [SE] worse than or equal to -5 diopters [D]), no history of refractive surgery, and available fundus photographs at both 2006 (baseline) and 2016 (10-year follow-up) visits. Forty-four adolescents (aged 12-16 years at baseline) who were re-examined later at follow-up were included.

Organocatalytic asymmetric arylation of indoles enabled by azo groups.

Arylation is a fundamental reaction that can be mostly fulfilled by electrophilic aromatic substitution and transition-metal-catalysed aryl functionalization. Although the azo group has been used as a directing group for many transformations via transition-metal-catalysed aryl carbon-hydrogen (C-H) bond activation, there remain significant unmet challenges in organocatalytic arylation. Here, we show that the azo group can effectively act as both a directing and activating group for organocatalytic asymmetric arylation of indoles via formal nucleophilic aromatic substitution of azobenzene derivatives.

Thioamide-Directed Cobalt(III)-Catalyzed Selective Amidation of C(sp )-H Bonds.

A mild, oxidant-free, and selective Cp*Co -catalyzed amidation of thioamides with robust dioxazolone amidating agents via C(sp )-H bond activation to generate the desired amidated products is reported. The method is efficient and allows for the C-H amidation of a wide range of functionalized thioamides with aryl-, heteroaryl-, and alkyl-substituted dioxazolones under the Cp*Co -catalyzed conditions. The observed regioselectivity towards primary C(sp )-H activation is supported by computational studies and the cyclometalation is proposed to proceed by means of an external carboxylate-assisted concerted metalation/deprotonation mechanism.

Rhodium/Copper Cocatalyzed Highly trans-Selective 1,2-Diheteroarylation of Alkynes with Azoles via C-H Addition/Oxidative Cross-Coupling: A Combined Experimental and Theoretical Study.

Transition metal-catalyzed addition of diaryl alkynes with arylating reagents for the synthesis of tetraarylethylenes generally encounters rigorous reaction conditions and relies on the use of prefunctionalized substrates such as organic halides or surrogates and organometallic reagents. In this work, we establish a highly trans-selective 1,2-diheteroarylation of alkynes with azoles via a rhodium/copper cocatalyzed C-H addition/oxidative coupling process. Moreover, the diheteroarylation developed herein could open a door for the synthesis of heteroarene-doped tetraarylethylenes, and the photoluminescence (PL) spectra in THF-water mixtures and solid powder verify that these tetra(hetero)arylethylenes are aggregation-induced emission (AIE) active, building a new AIE molecule library.

Understanding Flavin-Dependent Halogenase Reactivity via Substrate Activity Profiling.

The activity of four native FDHs and four engineered FDH variants on 93 low molecular weight arenes was used to generate FDH substrate activity profiles. These profiles provided insights into how substrate class, functional group substitution, electronic activation, and binding impact FDH activity and selectivity. The enzymes studied could halogenate a far greater range of substrates than previously recognized, but significant differences in their substrate specificity and selectivity were observed.

ABCA8 Regulates Cholesterol Efflux and High-Density Lipoprotein Cholesterol Levels.

Objective: High-density lipoproteins (HDL) are considered to protect against atherosclerosis in part by facilitating the removal of cholesterol from peripheral tissues. However, factors regulating lipid efflux are incompletely understood. We previously identified a variant in adenosine triphosphate-binding cassette transporter A8 () in an individual with low HDL cholesterol (HDLc).

Synthesis of Phenalenyl-Fused Pyrylium Cations: Divergent C-H Activation/Annulation Reaction Sequence of Naphthalene Aldehydes with Alkynes.

Described herein is the synthesis of stable oxonium-doped polycyclic aromatic hydrocarbons (PAHs) by the rhodium-catalyzed C-H activation/annulations of naphthalene-type aldehydes with internal alkynes. This protocol provides four divergent reaction types, including two unexpected annulations with an oxygen transposition process, which lead to diverse types of phenalenyl-fused pyrylium cations comprising a four-, five-, or six-ring-fused π-conjugated core. The annulations exhibit an exquisite regioselectivity and a high tolerance of sensitive functional groups.

Synthesis of Silicon and Germanium-Containing Heterosumanenes via Rhodium-Catalyzed Cyclodehydrogenation of Silicon/Germanium-Hydrogen and Carbon-Hydrogen Bonds.

A three-step synthesis of C-symmetric trisilasumanene and trigermasumanene, heteroanalogues of the π-bowl sumanene, was achieved using a threefold rhodium-catalyzed cyclodehydrogenation of Si/Ge-H and C-H bonds as the key step. Trigermasumanene was proven to adopt a planar geometry by single crystal X-ray diffraction for the first time. The optical properties were also investigated by UV-vis and fluorescence spectroscopy.

Intermolecular cascade annulations of N-(arylsulfonyl)acrylamides with dual C(sp)-H bonds: divergent access to indanes and pyrrolidin-2-ones.

A new divergent intermolecular cascade annulation reaction of N-(arylsulfonyl)acrylamides with dual alkyl C(sp)-H bonds for producing two types of five-membered rings, indanes and pyrrolidin-2-ones, is described. By using cycloalkanes and common alkanes as a one-carbon unit, an intermolecular [4+1] cascade carboannulation of N-(arylsulfonyl)acrylamides was achieved via a sequence of three C-H bond functionalization/aryl migration/desulfonylation that enables the formation of three C-C bonds and one N-H bond. When the one-carbon unit was changed to cycloalkyl ethers, the alternative intermolecular [4+1] cascade heteroannulation reaction occurred and allowed the construction of two C-C bonds and one C-N bond through dual C-H bond functionalization, aryl migration and desulfonylation cascades.

Efficient syntheses of 3-hydroxyimino-1-isoindolinones and 3-methylene-1-isoindolinones via Cu-promoted C-H activation-nitroalkylation-intramolecular cyclization tandem processes.

Efficient and selective syntheses of 3-hydroxyimino-1-isoindolinones and 3-methylene-1-isoindolinones were achieved via 8-aminoquinoline assisted Cu-promoted coupling of benzamides with nitroalkanes. The reaction was found to go through C-H activation, nitroalkylation followed by intramolecular cyclization. 3-Hydroxyimino-1-isoindolinones were obtained with nitromethane whereas 3-methylene-1-isoindolinones were produced with higher nitroalkanes.

An Isolable Diboron-Centered Diradical with a Triplet Ground State.

Two new diboranes, 2,6-bis(BMes )mesitylene (1) and 3,3'-bis(BMes )bimesitylene (3), were synthesized. Two-electron reduction of 1 with elemental potassium afforded the C-H activation product [(18-c-6)K(THF) ] ⋅2 bearing a BC four-membered ring as colorless crystals, whereas the reduction of 3 with potassium led to the isolation of [(18-c-6)K(THF) ] ⋅3 as dark blue crystals. Both reduction products were characterized by structural and spectroscopic methods.

Isocyanide-Induced Activation of Copper Sulfate: Direct Access to Functionalized Heteroarene Sulfonic Esters.

A novel and direct approach to alkyl/aryl heteroarene sulfonic esters using copper sulfate as the environmentally benign inorganic sulfonation reagent was first realized with the aid of isocyanide. A variety of heterocycles reacted to afford the corresponding sulfonic esters through C-H functionalization. In this transformation, the otherwise inert copper sulfate was unusually activated by an isocyanide and employed as the source of the sulfonic substituents in an unprecedented fashion.

Cobalt-promoted selective arylation of benzamides and acrylamides with arylboronic acids.

A novel cobalt-promoted arylation of aryl C-H bonds with arylboronic acids has been realized by using 8-aminoquinoline as the directing group. The reaction tolerated a wide variety of functional groups and diversely substituted ortho-arylated benzamides were efficiently synthesized in good to excellent yields. Even though a catalytic amount of a Co-salt was enough to effect the transformation, better yields were obtained with a stoichiometric amount of the Co-salt.

KOBu-Promoted Oxidation of (Hetero)benzylic C-H to Ketones with Molecular Oxygen.

An efficient and practical (hetero)benzylic sp C-H oxidation method has been developed. Notably, this user-friendly protocol employs inexpensive potassium tert-butoxide (KOBu) as a promoter and proceeds under mild conditions using oxygen as the oxidant. A large variety of oxidation products were prepared in good to excellent yields.

Sequential C-H Arylation and Enantioselective Hydrogenation Enables Ideal Asymmetric Entry to the Indenopiperidine Core of an 11β-HSD-1 Inhibitor.

A concise asymmetric synthesis of an 11β-HSD-1 inhibitor has been achieved using inexpensive starting materials with excellent step-economy at low catalyst loadings. The catalytic enantioselective total synthesis of 1 was accomplished in 7 steps and 38% overall yield aided by the development of an innovative, sequential strategy involving Pd-catalyzed pyridinium C-H arylation and Ir-catalyzed asymmetric hydrogenation of the resulting fused tricyclic indenopyridinium salt highlighted by the use of a unique P,N-ligand (MeO-BoQPhos) with 1000 ppm of [Ir(COD)Cl].

Reaction of C with Inactive Secondary Amines and Aldehydes and the Cu(OAc)-Promoted Regioselective Intramolecular C-H Functionalization of the Generated Fulleropyrrolidines.

The thermal reaction of C with aromatic aldehydes and inactive secondary amines for the stereoselective synthesis of trans-1,2,5-trisubstituted fulleropyrrolidines has been developed. Moreover, when an o-hydroxyl group was located at the phenyl ring of the generated fulleropyrrolidines, the Cu(OAc)-promoted regioselective intramolecular C-O coupling reaction occurred to generate unique tricycle-fused fullerene derivatives.