Highly Efficient Electrosynthesis of Glycine over an Atomically Dispersed Iron Catalyst.

Glycine is a nonessential amino acid that plays a vital role in various biological activities. However, the conventional synthesis of glycine requires sophisticated procedures or toxic feedstocks. Herein, we report an electrochemical pathway for glycine synthesis via the reductive coupling of oxalic acid and nitrate or nitrogen oxides over atomically dispersed Fe-N-C catalysts. A glycine selectivity of 70.7% is achieved over Fe-N-C-700 at -1.0 V versus RHE. Synergy between the FeN3C structure and pyrrolic nitrogen in Fe-N-C-700 facilitates the reduction of oxalic acid to glyoxylic acid, which is crucial for producing glyoxylic acid oxime and glycine, and the FeN3C structure could reduce the energy barrier of *HOOCCH2NH2 intermediate formation thus accelerating the glyoxylic acid oxime conversion to glycine. This new synthesis approach for value-added chemicals using simple carbon and nitrogen sources could provide sustainable routes for organonitrogen compound production.

Effective delivery of miR-150-5p with nucleus pulposus cell-specific nanoparticles attenuates intervertebral disc degeneration.

BACKGROUND: The use of gene therapy to deliver microRNAs (miRNAs) has gradually translated to preclinical application for the treatment of intervertebral disc degeneration (IDD). However, the effects of miRNAs are hindered by the short half-life time and the poor cellular uptake, owing to the lack of efficient delivery systems. Here, we investigated nucleus pulposus cell (NPC) specific aptamer-decorated polymeric nanoparticles that can load miR-150-5p for IDD treatment. METHODS: The role of miR-150-5p during disc development and degeneration was examined by miR-150-5p knockout (KO) mice. Histological analysis was undertaken in disc specimens. The functional mechanism of miR-150-5p in IDD development was investigated by qRT-PCR assay, Western blot, coimmunoprecipitation and immunofluorescence. NPC specific aptamer-decorated nanoparticles was designed, and its penetration, stability and safety were evaluated. IDD progression was assessed by radiological analysis including X-ray and MRI, after the annulus fibrosus needle puncture surgery with miR-150-5p manipulation by intradiscal injection of nanoparticles. The investigations into the interaction between aptamer and receptor were conducted using mass spectrometry, molecular docking and molecular dynamics simulations. RESULTS: We investigated NPC-specific aptamer-decorated polymeric nanoparticles that can bind to miR-150-5p for IDD treatment. Furthermore, we detected that nanoparticle-loaded miR-150-5p inhibitors alleviated NPC senescence in vitro, and the effects of the nanoparticles were sustained for more than 3 months in vivo. The microenvironment of NPCs improves the endo/lysosomal escape of miRNAs, greatly inhibiting the secretion of senescence-associated factors and the subsequent degeneration of NPCs. Importantly, nanoparticles delivering miR-150-5p inhibitors attenuated needle puncture-induced IDD in mouse models by targeting FBXW11 and inhibiting TAK1 ubiquitination, resulting in the downregulation of NF-kB signaling pathway activity. CONCLUSIONS: NPC-targeting nanoparticles delivering miR-150-5p show favorable therapeutic efficacy and safety and may constitute a promising treatment for IDD.

Manganese-Catalyzed Hydrogenative Desulfurization of Thioamides.

Earth-abundant transition metal catalysis has emerged as an important alternative to noble transition metal catalysis in hydrogenation reactions. However, there has been no Earth-abundant transition metal catalyzed hydrogenation of thioamides reported so far, presumably due to the poisoning of catalysts by sulfur-containing molecules. Herein, we described the first manganese-catalyzed hydrogenative desulfurization of thioamides to amines or imines. The key to success is the use of MnBr(CO)5 instead of commonly-employed pincer-manganese catalysts, together with simple NEt3 and CuBr. This protocol features excellent selectivity on sole cleavage of the C=S bond of thioamides, in contrast to the only known Ru-catalyzed hydrogenation of thioamides, and unprecedented chemo-selectivity tolerating vulnerable functional groups such as nitrile, ketone, aldehyde, ester, sulfone, nitro, olefin, alkyne and heterocycle, which are usually susceptible to common hydride-type reductive protocols.

Clinicopathological Analysis of Acquired Melanocytic Nevi and a Preliminary Study on the Possible Origin of Nevus Cells.

BACKGROUND: The pathogenesis of acquired melanocytic nevi (AMN) is still unclear, and the origin of nevus cells has not been clarified. OBJECTIVE: To analyze the clinical features and pathological types of AMN and identify the possible origin of nevus cells. METHODS: A retrospective study of 2929 cases of AMN was conducted, and 96 specimens of intradermal and junctional nevi were selected. Immunohistochemical assays were performed to detect the expression of basement membrane component receptor DDR-1 and the molecular markers on epidermal melanocytes, dermal stem cells (DSCs), and hair follicle stem cells. RESULTS: Junctional nevi and compound nevi were prone to occur on glabrous skin, such as the palms, soles, and vulva, and on the extremities in children, whereas intradermal nevi tended to develop on the trunk, head, and face of adults. The immunohistochemical data revealed that both junctional nevi and intradermal nevi expressed the epidermal melanocyte surface markers E-cadherin, DDR-1, and integrin α6 and the DSC molecular markers NGFRp-75 and nestin. CD34 was expressed only in junctional nevi, whereas K19 was not expressed in any type of melanocytic nevi. There was no significant difference in molecular expression at different sites or in different ages of onset. Nestin expression was markedly stronger in the intradermal nevi than in the junctional nevi, but there was no difference between the superficial and deep nevus cell nests of intradermal nevi. CONCLUSION: AMN may have a multicellular origin that commonly follows the mode of Abtropfung. Furthermore, DSCs may partly or independently participate in the formation of nevus cells.

Manganese-Catalyzed Hydroarylation of Unactivated Alkenes.

Transition-metal-catalyzed hydroarylation of unactivated alkenes with strategic use of remote coordinating functional groups has received significant attention recently to address the issues of both low reactivity and poor selectivity. The bidentate 8-aminoquinoline amide group is the most successfully adopted in unactivated alkenes for Pd and Ni catalysis. We describe the first manganese-catalyzed hydroarylation of unactivated alkenes bearing diverse simple functionalities with arylboronic acids. A series of δ- and γ-arylated amides, ketones, pyridines, and amines was accessed with excellent regioselectivity and in high yields. Hydroalkenylation of unactivated alkenes was also shown to be applicable under this manganese-catalysis regime. The method features earth-abundant manganese catalysis, easily available substrates, broad functional-group tolerance, and excellent regioselective control.

Inert C-H Bond Transformations Enabled by Organometallic Manganese Catalysis.

Traditional organic synthesis relies heavily on the transformations of various preinstalled functional groups, such as cross-coupling reactions using organohalides and organometallic reagents. The strategy of C-H activation enables the direct formation of C-C/C-X (X = heteroatom) bonds from inert C-H bonds, which can enhance the atom- and step-economy of organic synthesis. To date, precious metals have overwhelmingly dominated the C-H activation field; however, the rarity and high cost of these metals necessitate the development of more sustainable catalysts. In this regard, catalysts based on manganese are highly desirable owing to the abundant reserve of manganese in the earth's crust and its economic benefits, low toxicity, and potentially unique reactivity. Although the first stoichiometric manganese-mediated C-H activation reaction was reported as early as 1970, manganese-catalyzed C-H activation reactions are largely underdeveloped. How to construct an efficient catalytic cycle for manganese in C-H activation reactions remains as a key issue to be addressed. In this Account, we summarize our recent advances in the manganese-catalyzed transformations of inert C-H bonds. To overcome the challenges associated with building manganese-based catalytic cycles, we developed two novel strategies, namely, synergy between manganese catalysts and bases and between manganese catalysts (with or w/o bases) and acids. By implementing the former strategy, we developed cooperative manganese/base catalytic systems that facilitate a new mode of C-H bond activation by manganese via a redox-neutral base-assisted deprotonation mechanism. As such, the requirement for the tedious preparation of MnR(CO)5 complexes (R = Me, Bn, Ph) in stoichiometric reactions was eliminated, and a series of manganese-catalyzed C-H activation reactions of arenes with various reaction partners having C≡C and C═C bonds were achieved. Through the latter strategy of synergy between manganese catalysts (with or w/o bases) and acids, we disclosed a "dual activation" mode for performing manganese-catalyzed C-H bond transformations, that is, merging C-H activation by manganese catalysts and C-X multiple bond activation by Lewis acids. Consequently, the scope of C-H substrates could be expanded to include challenging ketones and olefinic C-H compounds. Additionally, the range of reaction partners could be significantly broadened to include those bearing more polarized C═O, C═N, and C≡N bonds such as aldehydes, imines, and nitriles. Remarkably, the innate reactivity of different C-H bonds in ketones could be reversed by manganese catalysis, and the reactions could even be carried out at room temperature. Our findings provide guiding information for the future development of manganese-catalyzed C-H activation reactions and beyond. Related important contributions from other groups are mentioned, and the remaining challenges and future perspective in this emerging area are also presented.

Re-Catalyzed Annulations of Weakly Coordinating N-Carbamoyl Indoles/Indolines with Alkynes via C-H/C-N Bond Cleavage.

Described herein are rhenium-catalyzed [3+2] annulations of N-carbamoyl indoles with alkynes via C-H/C-N bond cleavage, which provide rapid access to fused-ring pyrroloindolone derivatives. For the first time, the weakly coordinating O-directing group was successfully employed in rhenium-catalyzed C-H activation reactions, enabled by the unique catalytic trio of Re2 (CO)10 , Me2 Zn and ZnCl2 . Mechanistic studies revealed that aminozinc species plays an important role in the reaction. Based on the mechanistic understanding, a more powerful catalytic trio of Re2 (CO)10 , [MeZnNPh2 ]2 and Zn(OTf)2 was devised and applied successfully in the [4+2] annulations of indolines and alkynes affording pyrroloquinolinone derivatives.

Dichotomy of Manganese Catalysis via Organometallic or Radical Mechanism: Stereodivergent Hydrosilylation of Alkynes.

Herein, we disclose the first manganese-catalyzed hydrosilylation of alkynes featuring diverse selectivities. The highly selective formation of E-products was achieved by using mononuclear MnBr(CO)5 with the arsenic ligand, AsPh3 . Whereas using the dinuclear catalyst Mn2 (CO)10 and LPO (dilauroyl peroxide) enabled the reversed generation of Z-products in good to excellent stereo- and regioselectivity. Such a way of controlling the reaction stereoselectivity is unprecedented. Mechanistic experiments revealed the dichotomy of manganese catalysis via organometallic and radical pathways operating in the E- and Z-selective routes, respectively.

Manganese-Catalyzed Redox-Neutral C-H Olefination of Ketones with Unactivated Alkenes.

Since 1987, stoichiometric cyclomanganation of ketones and subsequent reactions with olefins in the presence of either palladium salts or trimethylamine N-oxide (Me3 N+ O- ) have been reported, but the catalytic versions remain untouched so far. Herein, the first manganese-catalyzed redox-neutral C-H olefination of ketones with unactivated alkenes is described, and shows a distinct reactivity with its parent stoichimetric reactions. Remarkably, mechanistic experiments and DFT calculations uncovers a unique concerted bis-metalation deprotonation (CBMD) mechanism of the Mn-Zn-enabled C-H bond activation.

Copper-catalyzed three-component cascade reaction of alkynes, sulfonyl azides and simple aldehydes/ketones.

A copper-catalyzed dimethylzinc-promoted three-component cascade reaction of alkynes, sulfonyl azides, and simple aldehydes or ketones is described. Polysubstituted olefins were thus constructed expeditiously in a one-pot procedure under mild conditions.

Iron-Carbonyl-Catalyzed Redox-Neutral [4+2] Annulation of N-H Imines and Internal Alkynes by C-H Bond Activation.

Stoichiometric C-H bond activation of arenes mediated by iron carbonyls was reported by Pauson as early as in 1965, yet the catalytic C-H transformations have not been developed. Herein, an iron-catalyzed annulation of N-H imines and internal alkynes to furnish cis-3,4-dihydroisoquinolines is described, and represents the first iron-carbonyl-catalyzed C-H activation reaction of arenes. Remarkablely, this is also the first redox-neutral [4+2] annulation of imines and alkynes proceeding by C-H activation. The reaction also features only cis stereoselectivity and excellent atom economy as neither base, nor external ligand, nor additive is required. Experimental and theoretical studies reveal an oxidative addition mechanism for C-H bond activation to afford a dinuclear ferracycle and a synergetic diiron-promoted H-transfer to the alkyne as the turnover-determining step.

Rhenium-catalyzed C-H aminocarbonylation of azobenzenes with isocyanates.

The first C-H aminocarbonylation of azobenzenes with isocyanates is achieved by using rhenium-catalysis, which provides an expedient and atom-economical access to varied o-azobenzamides from readily available starting materials. The reaction efficiency can be enhanced by the catalytic use of sodium acetate via accelerated C-H bond activation.

Rhenium-catalyzed dehydrogenative olefination of C(sp(3))-H bonds with hypervalent iodine(III) reagents.

A dehydrogenative olefination of C(sp(3))-H bonds is disclosed here, by merging rhenium catalysis with an alanine-derived hypervalent iodine(III) reagent. Thus, cyclic and acyclic ethers, toluene derivatives, cycloalkanes, and nitriles are all successfully alkenylated in a regio- and stereoselective manner.

Use of Flow-Through Anterolateral Thigh Perforator Flaps in Reconstruction of Complex Extremity Defects.

BACKGROUND: The flow-through flap has been widely utilized for reconstruction of complex defects of the extremities as it can be used for arterial reconstruction and soft-tissue coverage simultaneously. This study describes our clinical experience with the application of the flow-through anterolateral thigh perforator (ALTP) flap for reconstruction of complex defects of the extremities. METHODS: From January 2008 to June 2011, we retrospectively analyzed 16 patients with complex defects in the limbs. In two patients the defects occurred after undergoing wide excision of chronic ulcer, while 14 defects were due to trauma. All patients in this series underwent reconstruction with the flow-through ALTP flap. Applications of flow-through performed include preserving the recipient artery flow, rebuilding the major artery gap, bridging the artery and concomitant vein simultaneously, and combining the ALTP with another free flap. RESULTS: Flow-through ALTP flaps were used to preserve recipient flow (n = 5), rebuild the vessel gap (n = 2), bridge the artery and concomitant vein simultaneously (n = 2), and in combination with another free flap (n = 7). Follow-up ranged from 3 to 36 months (mean, 12 months). All flaps were successful; only two combination flaps required reexploration because of vessel crisis, and two patients suffered minor degrees of wound-edge necrosis. The donor sites healed well in all cases, without any complications. CONCLUSION: Our experience showed that the flow-through ALTP flap is reliable and suitable for reconstruction of complex defects of the extremities, as well as for various other clinical purposes.

Manganese-Catalyzed Direct Nucleophilic C(sp(2))-H Addition to Aldehydes and Nitriles.

Herein, a manganese-catalyzed nucleophilic addition of inert C(sp(2))-H bonds to aldehydes and nitriles is disclosed by virtue of a dual activation strategy. The reactions feature mild reaction conditions, excellent regio- and stereoselectivity, and a wide substrate scope, which includes both aromatic and olefinic C-H bonds, as well as a large variety of aldehydes and nitriles. Moreover, mechanistic studies shed light on possible catalytic cycles.

Mn-catalyzed three-component reactions of imines/nitriles, Grignard reagents, and tetrahydrofuran: an expedient access to 1,5-amino/keto alcohols.

An expedient Mn-catalyzed three-component synthesis of 1,5-amino/keto alcohols from Grignard reagents, imines/nitriles, and tetrahydrofuran (THF) is described, which deviates from the classic Grignard addition to imines/nitriles in THF solvent. THF is split and "sewn" in an unprecedented manner in the reaction, leading to the formation of two geminal C-C bonds via C-H and C-O cleavage. Mechanistic experiments and DFT calculations reveal radical and organo-Mn intermediates in the catalytic cycle and the α-arylative ring-opening of THF as the key reaction step.

Manganese-catalyzed dehydrogenative [4+2] annulation of N-H imines and alkynes by C-H/N-H activation.

Described herein is a manganese-catalyzed dehydrogenative [4+2] annulation of NH imines and alkynes, a reaction providing highly atom-economical access to diverse isoquinolines. This transformation represents the first example of manganese-catalyzed CH activation of imines; the stoichiometric variant of the cyclomanganation was reported in 1971. The redox neutral reaction produces H2 as the major byproduct and eliminates the need for any oxidants, external ligands, or additives, thus standing out from known isoquinoline synthesis by transition-metal-catalyzed CH activation. Mechanistic studies revealed the five-membered manganacycle and manganese hydride species as key reaction intermediates in the catalytic cycle.

Mn-catalyzed aromatic C-H alkenylation with terminal alkynes.

The first manganese-catalyzed aromatic C-H alkenylation with terminal alkynes is described. The procedure features an operationally simple catalyst system containing commercially available MnBr(CO)(5) and dicyclohexylamine (Cy(2)NH). The reaction occurs readily in a highly chemo-, regio-, and stereoselective manner delivering anti-Markovnikov E-configured olefins in high yields. Experimental study and DFT calculations reveal that (1) the reaction is initiated by a C-H activation step via the cooperation of manganese and base; (2) manganacycle and alkynylmanganese species are the key reaction intermediates; and (3) the ligand-to-ligand H-transfer and alkynyl-assisted C-H activation are the key steps rendering the reaction catalytic in manganese.

Alkene oxyalkylation enabled by merging rhenium catalysis with hypervalent iodine(III) reagents via decarboxylation.

Rhenium-catalyzed oxyalkylation of alkenes is described, where hypervalent iodine(III) reagents derived from widely occurring aliphatic carboxylic acids were used as, for the first time, not only an oxygenation source but also an alkylation source via decarboxylation. The reaction also features a wide substrate scope, totally regiospecific difunctionalization, mild reaction conditions, and ready availability of both substrates. Mechanistic studies revealed a decarboxylation/radical-addition/cation-trapping cascade operating in the reaction.

Re/Mg bimetallic tandem catalysis for [4+2] annulation of benzamides and alkynes via C-H/N-H functionalization.

A rhenium-magnesium cocatalyzed [4+2] annulation of benzamides and alkynes via C-H/N-H functionalization is described. The reaction features a divergent and high level of diastereoselectivities, which are readily switchable by subtle tuning of reaction conditions. Thus, a wide range of both cis- and trans-3,4-dihydroisoquinolinones is expediently synthesized in a highly atom-economical manner. Moreover, mechanistic studies unraveled a tandem mode of action between rhenium and magnesium in the catalytic cycles.