Lactonization of 2-Alkynylbenzoates for the Assembly of Isochromenones Mediated by BF3·Et2O.

A general and efficient lactonization method of readily available 2-alkynylbenzoates affording biologically important isochromenones has been realized via a solely BF3·Et2O-mediated 6-endo-dig cyclization process under mild conditions. An alternative mechanistic pathway in which BF3·Et2O activates the carbonyl of the ester moiety, rather than the alkyne triple bond, was postulated on the basis of control experiment results. Gram-scale reaction and further application for the assembly of more complex molecules demonstrated the practicability of the protocol.

Synthesis of Spirooxindoles from N-Arylamide Derivatives via Oxidative C(sp2)-C(sp3) Bond Formation Mediated by PhI(OMe)2 Generated in Situ.

A class of novel spirooxindole compounds (2) were readily synthesized, in a metal-free environment, from N-arylamide derivatives (1) via intramolecular oxidative cyclization. Direct oxidative C(sp2)-C(sp3) bond formation was realized with the least-studied PhI(OMe)2 as an oxidant, formed in situ from the reaction between PhIO and MeOH.

Cascade Synthesis of Benzothieno[3,2- b]indoles under Oxidative Conditions Mediated by CuBr and tert-Butyl Hydroperoxide.

A series of biologically relevant compounds of benzothieno[3,2- b]indole derivatives were conveniently synthesized from reactions of N-protected 2-((2-bromophenyl)ethynyl)anilines and potassium ethylxanthate, mediated by cuprous bromide/ tert-butyl hydroperoxide. The method features the construction of the pyrrole and thiophene rings in a cascade sequence with the pyrrole ring being formed prior to the thiophene ring via a possible reactive Cu(III)-pyrrole intermediate.

Direct functionalization of alkyl ethers to construct hemiaminal ether skeletons (HESs).

Hemiaminal ether skeletons (HESs) are important backbones generally found in organic compounds. Compared to traditional functional group transformations, strategies for the C-H functionalization of alkyl ethers to construct HESs have drawn much attention in the past decade. In this review, we focus on the recent progress in developing various pathways to construct HESs via the direct functionalization of alkyl ethers, including: (a) the transition-metal-catalyzed nitrene insertion pathway, (b) the transition-metal-free organonitrenoid insertion pathway,

TBHP/TBAI-Mediated Oxidative Cascade Reaction Consisting of Dimerization, Cyclization, and 1,2-Aryl Migration: Metal-Free Synthesis of Pyrrolin-4-ones and Highly Substituted Pyrroles.

Treatment of enamino esters with TBHP (t-butylhydroperoxide) and TBAI (t-butylammonium iodide) in HFIP (hexafluoroisopropanol) was found to afford a variety of substituted pyrrolin-4-one compounds. This metal-free oxidative cascade reaction consists of the key steps of coupling of two radical intermediates, an intramolecular ring closure, and an exclusive 1,2-aryl radical migration. Upon treatment with a base, the obtained pyrrolin-4-ones could be converted to the highly substituted pyrrole compounds.

PhI(OCOCF3)2-Mediated Construction of a 2-Spiropseudoindoxyl Skeleton via Cascade Annulation of 2-Sulfonamido-N-phenylpropiolamide Derivatives.

A cascade annulation of 2-sulfonamido-N-phenylpropiolamide derivatives leading to the construction of the 2-spiropseudoindoxyl skeleton was realized under mild conditions with phenyliodine(III) bis(trifluoroacetate) (PIFA) as the sole oxidant. This metal-free spirocyclization process is suggested to encompass a sequential C(sp2)-C(sp) and C(sp2)-N bond formation with the concomitant introduction of a carbonyl oxygen.

Iodocyclization of N-Arylpropynamides Mediated by Hypervalent Iodine Reagent: Divergent Synthesis of Iodinated Quinolin-2-ones and Spiro[4,5]trienones.

PhI(OCOCF3)2 acts as both a nonmetal oxidant and an iodination reagent to trigger iodocyclization of N-arylpropynamides while selectively affording iodinated quinolin-2-ones or the spiro[4,5]trienone skeleton, depending on the substituent pattern. In cases where the N-arylpropynamide bears a para-fluorine on the aniline ring, the spiro compound is formed via an exclusive defluorination process; otherwise, the product was quinolin-2-one.

Chiral Aryliodine-Mediated Enantioselective Organocatalytic Spirocyclization: Synthesis of Spirofurooxindoles via Cascade Oxidative C-O and C-C Bond Formation.

An enantioselective organocatalytic oxidative spirocyclization of alkyl 3-oxopentanedioate monoamide derivatives leading to the formation of diverse spirofurooxindoles with high enantioselectivity has been realized via chiral aryliodine-mediated cascade C-O and C-C bond formations. The reaction is postulated to proceed via oxidative C-O bond formation followed by oxidative C-C bond formation, with the latter being the enantioselectivity-determining step.

Ring-Contraction Disproportionation/Spirocyclization Cascade Reaction of Isochromeno[4,3-b]indol-5(11H)-ones: Synthesis of N-Unsubstituted Spirocycles.

An efficient ring-contraction reaction of isochromeno[4,3-b]indol-5(11H)-ones via a nucleophile-induced disproportionation/spirocyclization cascade process has been developed under mild conditions. The process realized the conversion of isochromeno[4,3-b]indol-5(11H)-ones into N-unsubstituted spiro[indoline-2,1'-isobenzofuran]-3,3'-diones and spiro[indoline-2,1'-isoindoline]-3,3'-diones in the absence of a transition-metal catalyst or oxidant. Gram-scale reaction further demonstrated the practicability of the protocol.

Cu(OAc)2-Mediated Cascade Annulation of Diarylalkyne Sulfonamides through Dual C-N Bond Formation: Synthesis of 5,10-Dihydroindolo[3,2-b]indoles.

An unusual cascade reaction featuring annulation of diarylalkyne sulfonamides to form 5,10-dihydroindolo[3,2-b]indoles has been realized with Cu(OAc)2 as the sole oxidant. This unprecedented process encompasses two sequential C-N bond formations, allowing for an efficient synthesis of the biologically important indoloindole derivatives.

Metal-Free Synthesis of 3-Arylquinolin-2-ones from Acrylic Amides via a Highly Regioselective 1,2-Aryl Migration: An Experimental and Computational Study.

Combined experimental and theoretical investigations into the phenyliodine bis(trifluoroacetate) (PIFA)-mediated reaction of N-arylcinnamamide to produce 3-arylquinolin-2-one derivatives have been conducted. High regioselectivity during the aryl migration process was observed in 3,3-disubstituted acrylamides. Density functional theory calculation was conducted in an attempt to understand the mechanism and the origin of the regioselectivity. On the basis of both the experimental and the theoretical results, a mechanism involving an oxidative annulation, followed by an aryl migration, has been proposed. The annulation is the regioselectivity determining step.

Intramolecular Functionalization of Benzylic Methylene Adjacent to the Ring Nitrogen Atom in N-Aryltetrahydroisoquinoline Derivatives.

Functionalization at the benzylic methylene group that is adjacent to the ring nitrogen atom in a series of N-aryltetrahydroisoquinoline compounds has been realized through intramolecular cross-dehydrogenative coupling reactions. The presented transformation provided straightforward access to the formation of C(sp(3))-Y (Y = C, N or O) bond via I(III) reagent.

Mechanistic Study of Human Glucose Transport Mediated by GLUT1.

The glucose transporter 1 (GLUT1) belongs to the major facilitator superfamily (MFS) and is responsible for the constant uptake of glucose. However, the molecular mechanism of sugar transport remains obscure. In this study, homology modeling and molecular dynamics (MD) simulations in lipid bilayers were performed to investigate the combination of the alternate and multisite transport mechanism of glucose with GLUT1 in atomic detail. To explore the substrate recognition mechanism, the outward-open state human GLUT1 homology model was generated based on the template of xylose transporter XylE (PDB ID: 4GBZ), which shares up to 29% sequence identity and 49% similarity with GLUT1. Through the MD simulation study of glucose across lipid bilayer with both the outward-open GLUT1 and the GLUT1 inward-open crystal structure, we investigated six different conformational states and identified four key binding sites in both exofacial and endofacial loops that are essential for glucose recognition and transport. The study further revealed that four flexible gates consisting of W65/Y292/Y293-M420/TM10b-W388 might play important roles in the transport cycle. The study showed that some side chains close to the central ligand binding site underwent larger position changes. These conformational interchanges formed gated networks within an S-shaped central channel that permitted staged ligand diffusion across the transporter. This study provides new inroads for the understanding of GLUT1 ligand recognition paradigm and configurational features which are important for molecular, structural, and physiological research of the MFS members, especially for GLUT1-targeted drug design and discovery.

Galactose conjugated platinum(II) complex targeting the Warburg effect for treatment of non-small cell lung cancer and colon cancer.

Malignant neoplasms exhibit a higher rate of glycolysis than normal cells; this is known as the Warburg effect. To target it, a galactose-conjugated (trans-R,R-cyclohexane-1,2-diamine)-2-chloromalonato-platinum(II) complex (Gal-Pt) was designed, synthesized, and evaluated in five human cancer cell lines and against two different xenograft tumour models. Gal-Pt exhibits much higher aqueous solubility (over 25 times) and improved cytotoxicity than oxaliplatin, especially in human colon (HT29) and lung (H460) cancer cell lines. The safety profile of Gal-Pt was investigated in vivo by exploring the maximum tolerated dose (MTD) and animal mortality rate. The ratios of the animal lethal dosage values to the cytotoxicity in HT29 (LD50/IC50) showed that Gal-Pt was associated with an increased therapeutic index by over 30-fold compared to cisplatin and oxaliplatin. We evaluated in vivo antitumor activity by single agent intravenous treatment comparison studies of Gal-Pt (50 mg/kg as 65% MTD) and cisplatin (3 mg/kg, as 80% MTD) in a H460 lung cancer xenograft model, and with oxaliplatin (7 mg/kg, as 90% MTD) in a HT29 colon cancer xenograft model. The results show that Gal-Pt was more efficacious against H460 than cisplatin, and had superior potency in HT29 cells compared to oxaliplatin under nontoxic dosage conditions. The dependency between cytotoxicity of Gal-Pt and glucose transporters (GLUTs) was investigated by using quercetin as an inhibitor of GLUTs in HT29 cells. The cytotoxic potency of Gal-Pt was highly reduced by the inhibitor, suggesting that the uptake of Gal-Pt was regulated by glucose transporters. The GLUT mediated transportability and cellular uptake of Gal-Pt was also demonstrated using a fluorescent glucose bioprobe in HT29 competition assay.

Hypervalent Iodine-Mediated Intramolecular trans-Aminocarboxylation and Oxoaminocarboxylation of Alkynes: Divergent Cascade Annulations of Isocoumarins under Metal-Free Conditions.

An exclusive trans-aminocarboxylation and oxoaminocarboxylation of diarylalkynes were realized through hypervalent iodine-mediated cascade annulations under metal-free conditions, leading to divergent assembly of fused or spiro polycyclic heterocycles with a dosage of the hypervalent iodine oxidant. The mechanisms for the formation of both products are proposed.

PhI(OCOCF3)2-Mediated Cyclization of o-(1-Alkynyl)benzamides: Metal-Free Synthesis of 3-Hydroxy-2,3-dihydroisoquinoline-1,4-dione.

The synthesis of an undocumented skeleton of 3-hydroxy-2,3-dihydroisoquinoline-1,4-diones has been discovered and reported. The reaction consists of an intramolecular cyclization of o-(1-alkynyl)benzamides in MeCN/H2O, mediated by metal-free, hypervalent reagent of PhI(OCOCF3)2, followed by an oxidative hydroxylation reaction. The mechanism consisting of two pathways has been proposed and discussed.

Hypervalent-iodine-mediated cascade annulation of diarylalkynes forming spiro heterocycles under metal-free conditions.

An unusual reaction featuring the cascade annulation of internal alkynes to afford spiro heterocycles as the products has been realized for the first time with a hypervalent iodine reagent as the only oxidant. This unprecedented process encompasses not only two sequential C-N/C-O-bond formations, but also the insertion of a carbonyl oxygen, all in one pot under metal-free conditions.

Synthesis of chromeno[2,3-b]indol-11(6H)-one via PhI(OAc)2-mediated intramolecular oxidative C(sp(2))­N(H2) bond formation.

Various chromeno[2,3-b]indol-11(6H)-ones were conveniently constructed via phenyliodine(III) diacetate (PIDA)-mediated intramolecular oxidative annulation. This method, while realizing a direct oxidative C­N bond formation between an aromatic ring and a pendent free-NH2 moiety, features a metal-free protocol, mild reaction conditions, simple workup, and the ready availability of the starting substrates.

Metal-free tandem oxidative aryl migration and C-C bond cleavage: synthesis of α-ketoamides and esters from acrylic derivatives.

A novel tandem metal-free oxidative aryl migration/C-C bond-cleavage reaction, mediated by hypervalent iodine reagent, has been discovered. The presented transformation provided straightforward access to important α-ketoamide and α-ketoester derivatives from readily available acrylic derivatives via a concerted process of 1,2-aryl shift concomitant with C-C bond cleavage.