Multicomponent Synthesis of 3(2H)-Furanones Initiated by Copper(II)-Catalyzed Alkyne-Carbonyl Cross Metathesis.

The cooperative Lewis and Brønsted acid catalysis makes convergent synthesis of 3(2H)-furanones through a three-component coupling of 1,3-diynes, alkyl glyoxylates and water. Control experiments support that Lewis acid-catalyzed highly chemo-, regio- and stereoselective alkyne-carbonyl metathesis of 1,3-diynes and alkyl glyoxylates might be the initial step of this multicomponent annulation. Further chemo- and regioselective hydration of the alkyne-carbonyl metathesis product and subsequent oxa-Michael addition promoted by Brønsted acid results in the formation of two C-O bonds of the five-membered oxygen heterocycle.

Generation of Carbonyl Compounds from Oximes through Electrooxidative Deoximation.

An electrochemical protocol was developed to generate carbonyl compounds from oximes with excellent functional group compatibility. Mechanistic experimental studies support the idea that an electrooxidative pathway of oximes might be involved, in which the water may serve as an oxygen nucleophile and the oxygen source for the final carbonyl compounds.

Access to Chiral O,O-Acetals Enabled by Palladium-Catalyzed Asymmetric Addition of Oximes to Alkoxyallenes.

Enantiomerically pure acyclic O,O-acetal compounds (up to 97 % ee) have been accessed through chemo-, regio- and enantioselective palladium-catalyzed addition of oximes to alkoxyallenes. DFT calculations support that a protonative hydropalladation pathway is favourable, in which the hydrogen bonding interaction between the amide group of the diphosphine ligand and the alkoxyallene is critical for the highly stereoselective formation of the dioxygenated stereogenic center.

Gold(I)-Catalyzed Ring-Closing Alkyne-Carbonyl Metathesis for the Synthesis of Butenolides.

Alkyne-carbonyl metathesis is a type of carbon-carbon forming reaction involving the construction a carbon-carbon double bond and a carbonyl group in one transformation. Herein, a Au(I)-catalyzed ring-closing alkyne-carbonyl metathesis protocol has been developed to make densely substituted γ-butenolides from propargyl α-ketoesters. It features 100 % atom economy, excellent substrate flexibility and benign functional group tolerance. Mechanistic studies demonstrate that the coordinative interaction between the gold catalyst and the alkyne might initiate the transfer of an oxygen atom and the formation of the carbon-carbon double bond. By using this gold-catalyzed ring-closing alkyne-carbonyl metathesis as a key step reaction, four naturally occurring butenolide-type compounds including decumbic acid (45 % yield for 3 steps), deoxyisosporothric acid (32 % yield for 5 steps), lichesterinic acid (34 % yield for 5 steps) and isomuronic acid (6 % yield for 8 steps) have been synthesized starting from commercially available starting materials.

Construction of Cyclic Nitrones Enabled by Photodriven and Gold-Catalyzed 1,3-Azaprotio Transfer of Allenyloximes.

A protocol was developed to construct five- to seven-membered cyclic nitrones through the gold-catalyzed 1,3-azaprotio transfer of allenyloximes under photoirradiation. The photoisomerization of oximes was suggested to convert the inert stereoisomer to a reactive one. This photodriven and gold-catalyzed ring formation could be further extended to the thermodynamically stable aryl ketoximes with an E-configuration, which previously displayed chemical inertness in the absence of light irradiation.

Construction of 4-Acyl-2-quinolones through Sc(OTf)3-Catalyzed Ring-Closing Alkyne-Carbonyl Metathesis.

An atom-economical protocol to construct densely substituted 4-acyl-2-quinolones from N-(2-alkynylphenyl)-α-ketoamides has been developed through Sc(OTf)3-catalyzed ring-closing alkyne-carbonyl metathesis. Mechanistic experimental studies support that coordinative interaction between Sc(OTf))3 and the substrate, the formation of an oxetene intermediate, and an electrocyclic ring-opening of the oxetene might be involved.

Total Synthesis of Marine Alkaloids Cystodytins A-K.

The total synthesis of marine alkaloids cystodytins A-K has been accomplished in five to six steps starting from commercially available compounds. The highlights of the synthesis include an oxidative amination-cyclization of tryptamine and para-hydroquinones to build a tetracyclic pyridoacridinone ring with different side chains and a copper(II)-catalyzed enantioselective Henry reaction to construct an oxygenated stereogenic carbon center. For the first time, the absolute configuration of the stereogenic centers embedded in cystodytins D-I and K was established as R. Moreover, the stereochemistry of the olefin unit in the side chain of cystodytins H and I was revised to the Z configuration from the originally assigned E configuration.

Diastereoselective Access to Tetracyclic Eight-Membered Lactams through a Dearomative Heck Reaction and an Alkylative Ring-Opening Driven by Photoexcited Spiroindolines.

An external-photocatalyst-free, light-driven alkylative ring-opening of stable spiroindolines was developed to construct indolo- and benzoannulated eight-membered lactams. The spiroindolines were prepared from tetrahydro-ß-carbolines by a dearomative Heck reaction. Mechanistic experimental studies on the alkylative ring opening suggested that a photoredox pathway was involved, in which the spiroindoline performed as both reagent and photosensitizer. DFT calculations showed that the radical addition toward a cyclic alkene was the key to the diastereoselective formation of tetracyclic medium-sized lactams.

Oxidative Cyclization of Kynuramine and Ynones Enabling Collective Syntheses of Pyridoacridine Alkaloids.

A cerium(III)-catalyzed oxidative cyclization of kynuramine and ynones has been reported as a key reaction in the total synthesis of marine pentacyclic pyridoacridine alkaloids featuring different ring connectivity patterns. The formation of tricyclic benzonaphthyridine rings was identified in the oxidative process. By combining with an intramolecular acylation and the chemoselective late-stage functionalization of pyridine rings, different approaches with 4-10 steps have been designed to accomplish the synthesis of alkaloids demethyldeoxyamphimedine (1), amphimedine (2), meridine (3), isocystodamine (4), N-methylisocystodamine (5), N-hydroxymethylisocystodamine (6), 9-hydroxyisoacididemin (7), neolabuanine A (8), and ecionine A (9).

Gold-Catalyzed Cycloisomerization of Propargyl Pyruvates Enabling Unified Access to Tricladolides C and D, Chaetomellic Anhydride A, and Tyromycin A.

Gold-catalyzed cycloisomerization of propargyl pyruvates has been developed as a key reaction to prepare maleic anhydride-type natural products. By combining with chemoselective epoxidation of the formed γ-alkylidenebutenolides and oxidative cleavage of epoxides, the first synthesis of tricladolide D and racemic tricladolide C has been achieved in 52 and 16% overall yields with five to seven steps starting from commercially available compounds. Further catalytic hydrogenation of alkenylated maleic anhydrides derived from γ-alkylidenebutenolides produced chaetomellic anhydride A (19% yield for six steps) and tyromycin A (15% yield for six steps), which provides flexible synthetic approaches to these naturally occurring dialkylated maleic anhydrides distinct from the documented ones.

LncRNA SNHG7 promotes the proliferation of nasopharyngeal carcinoma by miR-514a-5p/ELAVL1 axis.

BACKGROUND: Nasopharyngeal carcinoma (NPC), with distinct geographical distribution, has gathered public attention. Despite that radiotherapy and chemotherapy are applied to treat NPC, cell metastasis still cannot be avoided. Numerous works have elucidated that lncRNAs are essential players in the development of multiple cancers. LncRNA SNHG7 has been reported as a contributing factor in the occurrence of certain cancers, but its mechanism in NPC deserves further investigation. The purpose of the study is to figure out the role and molecular regulation mechanism of SNHG7 in NPC. METHODS: The role of SNHG7 in NPC was verified by CCK-8, colony formation, EdU staining, western blot and capase-3 assays. The interactions between SNHG7/ELAVL1 and miR-514a-5p were confirmed by RNA pull down, RT-qPCR, RIP and luciferase reporter assays. RESULTS: SNHG7 was upregulated in NPC cells, and absence of SNHG7 suppressed cell proliferation as well as promoted cell apoptosis in NPC. Furthermore, SNHG7 was confirmed to bind with miR-514a-5p and negatively modulate miR-514a-5p expression. Besides, miR-514a-5p was found to be able to bind with ELAVL1 and negatively regulate ELAVL1 mRNA and protein expressions. In the end, rescue assays demonstrated that the miR-514a-5p deficiency restored the NPC progression inhibited by SNHG7 silence, and ELAVL1 partly counteracted the restoration caused by miR-514a-5p inhibitor in HNE1 cells. CONCLUSIONS: LncRNA SNHG7 promotes the proliferation and migration of nasopharyngeal carcinoma by miR-514a-5p/ ELAVL1 axis.

Divergent Synthesis of Oxa-Cyclic Nitrones through Gold(I)-Catalyzed 1,3-Azaprotio Transfer of Propargylic α-Ketocarboxylate Oximes: Experimental and DFT Studies.

1,3-Azaprotio transfer of propargylic α-ketocarboxylate oximes, a new type of alkynyl oximes featuring an ester tether, has been explored by taking advantage of gold catalysis. The incorporation of an oxygen atom to the chain of alkynyl oximes led to the formation of two different oxa-cyclic nitrones. It was found that internal alkynyl oximes with an E-configuration deliver five-membered nitrones, whereas terminal alkynyl oximes with an E-configuration afford six-membered nitrones. DFT calculations on four possible pathways supported a stepwise formation of C-N and C-H bonds, in which a 1,3-acyloxy-migration competes with the 1,3-azaprotio-transfer, especially in the case of internal alkynyl oximes. The relative nucleophilic properties of oxygen in the carbonyl group and the nitrogen in the oxime, the electronic effects of alkynes, and the influence of the ring system have been investigated computationally.

Diastereoselective Synthesis of Polysubstituted Piperidines through Visible-Light-Driven Silylative Cyclization of Aza-1,6-Dienes: Experimental and DFT Studies.

A visible-light-driven radical silylative cyclization of aza-1,6-dienes featuring an acrylonitrile or acrylate moiety and an electron-neutral olefin was developed, which allows for stereoselective synthesis of densely functionalized piperidines in a highly atom-economical manner. Depending on the substitution pattern of the electron-neutral olefin, poor-to-excellent diastereoselectivity was observed. It was suggested that the 6-exo-trig cyclization was initiated by a chemoselective addition of silyl radical toward electron-deficient olefin and the geometry of the remaining olefin is closely associated with the cis-stereoselectivity. DFT calculations supported that a transition state with a cyano group locating at the axial position of the forming piperidine ring might be involved, in which either the increase of 1,3-diaxial repulsion or the lack of hydrogen bonding interaction will diminish diastereoselectivity.

Visible Light-Driven Radical trans-Hydrosilylation of Electron-Neutral and -Rich Alkenes with Tertiary and Secondary Hydrosilanes.

A visible light-driven radical hydrosilylation of electron-neutral and -rich alkenes has been investigated on the basis of a newly developed catalytic reaction system composed of eosin Y, thiol, and base additives. A variety of linear and cyclic alkenes with different substitution patterns were found to undergo such metal-free hydrosilylation with tertiary and secondary hydrosilanes in a chemo-, regio-, and stereoselective manner. Comparison of the reactivity of diene compounds and late-stage hydrosilylation of steroid drugs were also explored. Deuterium labeling experiments reveal that a stepwise formation of C-Si and C-H bonds with a trans stereochemistry is preferred, in which the thiol may behave as a hydrogen atom transfer agent.

Azepinoindole Synthesis via a N-Bromosuccinimide-Induced Cycloisomerization of Enaminoester/Enaminone.

A protocol based on a newly developed N-bromosuccinimide (NBS)-induced cycloisomerization was described to prepare tricyclic azepino[4,5-b]indoles from simple ß-enaminoesters or ß-enaminones containing an indole unit. A mechanism involving a Pictet-Spengler cyclization, an aziridine ring formation, and a regioselective C-N bond cleavage was proposed to account for the medium-sized ring formation and the migration of electron-withdrawing group (ester, ketone).

Kinetic or Dynamic Control on a Bifurcating Potential Energy Surface? An Experimental and DFT Study of Gold-Catalyzed Ring Expansion and Spirocyclization of 2-Propargyl-ß-tetrahydrocarbolines.

In classical transition state theory, a transition state is connected to its reactant(s) and product(s). Recently, chemists found that reaction pathways may bifurcate after a transition state, leading to two or more sets of products. The product distribution for such a reaction containing a bifurcating potential energy surface (bPES) is usually determined by the shape of the bPES and dynamic factors. However, if the bPES leads to two intermediates (other than two products), which then undergo further transformations to give different final products, what factors control the selectivity is still not fully examined. This missing link in transition state theory is founded in the present study. Aiming to develop new methods for the synthesis of azocinoindole derivatives, we found that 2-propargyl-ß-tetrahydrocarbolines can undergo ring expansion and spirocyclization under gold catalysis. DFT study revealed that the reaction starts with the intramolecular cyclization of the gold-activated 2-propargyl-ß-tetrahydrocarboline with a bPES. The cyclization intermediates can not only interconvert into each other via a [1,5]-alkenyl shift, but also undergo ring expansion (through fragmentation/protodeauration mechanism) or spirocyclization (through deprotonation/protodeauration mechanism). Detailed analysis of the complex PESs for substrates with different substituents indicated that the reaction selectivity is under dynamic control if the interconversion of the intermediates is slower than the ring expansion and spirocyclization processes. Otherwise, the chemical outcome is under typical kinetic control and determined by the relative preference of ring expansion versus spirocyclization pathways. The present study may enrich chemist's understanding of the determinants for selectivities on bPESs.

Azocinoindole synthesis by a gold(I)-catalyzed ring expansion of 2-propargyl-ß-tetrahydrocarboline.

A new methodology taking advantage of gold(I)-catalyzed ring expansion has been developed to assemble tricyclic 1H-azocino[5,4-b]indoles from 2-propargyl-ß-tetrahydrocarbolines. The azocinoindoles were obtained in moderate to excellent yields; the structure of which was established by X-ray crystallographic analysis. A mechanism involving regioselective intramolecular hydroarylation, [1,2]-alkenyl migration and carbon-carbon bond-fragmentation was proposed.

Total synthesis of ascididemin-type alkaloids using alkyne building blocks.

A common approach to ascididemin-type alkaloids, including ascididemin, bromoleptoclinidinone, neocalliactine acetate, and 11-hydroxyascididemin, based on a Brønsted acid-promoted tandem annulation has been developed. Alkyne building blocks were first designed and then employed in alkaloid synthesis; these building blocks can be accessed by a Sonogashira coupling reaction on a multigram scale.

Asymmetric annulation of 3-alkynylacrylaldehydes with styrene-type olefins by synergetic relay catalysis from AgOAc and chiral phosphoric acid.

Asymmetric annulation of 3-alkynylacrylaldehydes with 2-hydroxystyrenes has been studied and achieved by synergetic catalysis from AgOAc and chiral phosphoric acid, providing the corresponding multiring products with decent total yields and moderate to excellent enantioselectivities (up to 95% ee). The developed mild multibond-formation cascade reaction involves in situ generation of pyrylium intermediate by Ag(I)-catalyzed alkyne/carbonyl cycloisomerization, counteranion-directed asymmetric oxa [4 + 2]-cycloaddition, and intramolecular nucleophilic substitution.

Asymmetric cascade annulation based on enantioselective oxa-Diels-Alder cycloaddition of in situ generated isochromenyliums by cooperative binary catalysis of Pd(OAc)2 and (S)-Trip.

An asymmetric cascade annulation between 2-hydroxystyrenes and 2-alkynylbenaldehyes or 1-(2-alkynylphenyl)ketones has been established with good to excellent enantioselectivities (up to >99.5% ee), on the basis of an enantioselective oxa-Diels-Alder cycloaddition of in situ generated metallo-isochromenylium intermediates, by cooperative binary catalysis of Pd(OAc)2 and (S)-Trip. The developed methodology is workable for a broad spectrum of substrates and shows great efficiency in establishing dense multiple chiral centers including quaternary carbons of variable bridged ring systems. The mechanism study suggests that (S)-Trip plays multiple roles in assembling the reactants and controlling the stereoselectivity.