Concise Total Synthesis of (+)-Pleiocarpamine and Convergent Total Syntheses of (+)-Voacalgine A and (+)-Bipleiophylline via an Aerobic Oxidative Coupling.

The stereocontrolled total synthesis of (+)-pleiocarpamine and the total syntheses of (+)-voacalgine A and (+)-bipleiophylline have been achieved. The scalable and concise 10-step synthesis of (+)-pleiocarpamine features construction of stereochemistry at the C16 position by radical cyclization and that of the highly strained cage-like structure via Pd-catalyzed intramolecular aromatic C-H functionalization. By modifying the biomimetic aerobic oxidative coupling of tryptophane derivatives catalyzed by FePc(COH), the oxidative coupling of the synthesized (+)-pleiocarpamine with pyrocatechuic acid was established to produce (+)-voacalgine A.

Iron-Catalyzed Biomimetic Dimerization of Tryptophan-Containing Peptides.

Biomimetic oxidative dimerization of tryptophan derivatives in aqueous media with oxygen as a bulk oxidant catalyzed by an iron octacarboxy phthalocyanine complex was established. The discovery of the extremely active iron catalyst enables aerobic enzyme-mimetic oxidation to be performed in a flask. This method was applicable to the oxidative dimerization of a wide range of tryptophan derivatives, including various dipeptides and oligopeptides, with remarkable functional-group tolerance without the protection of the amino acid residues.

Total synthesis of (±)-vinoxine: construction of the bridged pyrido[1,2-]indole skeleton TfO-mediated Bischler-Napieralski reaction and stereoselective radical cyclization.

The total synthesis of (±)-vinoxine was achieved featuring the assembly of a multi-substituted tetrahydropyrido[1,2-]indole skeleton through the TfO-mediated Bischler-Napieralski reaction. The characteristic diazabicyclo[3.3.

Synthesis of substituted anilines via a gold-catalyzed three-component reaction.

A three-component reaction for the synthesis of substituted anilines by a gold(i)-catalyzed domino reaction was developed. Cationic gold catalysts selectively and sequentially activated two different alkynes, which were involved in pyrrole synthesis and subsequent Diels-Alder reaction. The sequential formal (3 + 2) annulation/Diels-Alder reaction of three components provided a variety of substituted anilines in a modular fashion.

A Concise Enantioselective Total Synthesis of (-)-Deoxoapodine.

We have established a highly convergent 10-step route for the total synthesis of (-)-deoxoapodine, which is a hexacyclic aspidosperma alkaloid. The quaternary C5 center of the characteristic tetrahydrofuran ring was constructed by a chiral-phosphoric-acid-catalyzed enantioselective bromocycloetherification in a 5-endo fashion and subsequent allylation by using the Keck protocol. Construction of the aspidosperma skeleton features the formation of a nine-membered lactam by a catalytic C-H palladation/alkylation cascade at the indole 2-position and an iron-catalyzed oxidative transannular reaction at a late-stage of the synthesis.

Aerobic Dehydrogenation of N-Heterocycles with Grubbs Catalyst: Its Application to Assisted-Tandem Catalysis to Construct N-Containing Fused Heteroarenes.

An aerobic dehydrogenation of nitrogen-containing heterocycles catalyzed by Grubbs catalyst is developed. The reaction is applicable to various nitrogen-containing heterocycles. The exceptionally high functional group compatibility of this method was confirmed by the oxidation of an unprotected dihydroindolactam V to indolactam V.

Synthetic Studies toward Dimeric Indole Alkaloids Based on Convergent Synthetic Strategy.

The total syntheses of dimeric indole alkaloids, haplophytine, and T988s are described. These dimeric compounds comprising two structurally different indole units are ubiquitous in nature, and many possess pharmaceutically important activities. To realize an efficient chemical synthesis of these dimeric indole alkaloids, the establishment of convergent synthetic strategies and development of new coupling methods are indispensable.

Identification of Emetine as a Therapeutic Agent for Pulmonary Arterial Hypertension: Novel Effects of an Old Drug.

Objective: Excessive proliferation and apoptosis resistance are special characteristics of pulmonary artery smooth muscle cells (PASMCs) in pulmonary arterial hypertension (PAH). However, the drugs in clinical use for PAH target vascular dilatation, which do not exert adequate effects in patients with advanced PAH. Here, we report a novel therapeutic effect of emetine, a principal alkaloid extracted from the root of ipecac clinically used as an emetic and antiprotozoal drug.

Synthesis of Propargylic Ethers by Gold-Mediated Reaction of Terminal Alkynes with Acetals.

A gold-catalyzed introduction of various terminal alkynes to acetals was investigated. Extensive optimization of the reaction conditions revealed that thermally stable cationic gold catalysts bearing bulky ligands such as 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene 3-1H-benzo[d][1,2,3]triazolyl gold trifluoromethanesulfonate (IPrAu(BTZ-H)OTf) were particularly suitable for the reaction. Additionally, significant solvent effects were observed.

Construction of Indole Structure on Pyrroloindolines via AgNTf-Mediated Amination/Cyclization Cascade: Application to Total Synthesis of (+)-Pestalazine B.

An N-linked indole structure was constructed on the 3a-position of pyrroloindoline derivatives via a cascade process involving silver-mediated amination of bromopyrroloindolines with 2-ethynylanilines with subsequent 5- endo-dig cyclization. In this reaction, AgNTf was used as a tandem reagent, which activated the bromo group as a σ-Lewis acid and the alkyne moiety as a π-Lewis acid. Switching from the initial step to the second step was conducted by controlling the temperature.

Stenosis after esophagojejunostomy with the hemi-double-stapling technique using the transorally inserted anvil (OrVil™) in Roux-en-Y reconstruction with its efferent loop located on the patient's left side following laparoscopic total gastrectomy.

Background: The drawback of intracorporeal esophagojejunostomy with the double-stapling technique (DST) using a transorally inserted anvil (OrVil™, Covidien, Mansfield, MA, USA) following laparoscopic total gastrectomy (LTG) is not only the high incidence of stenosis but also the presence of intractable stenosis that is refractory to endoscopic treatments.

Methods: From November 2013 to December 2016, 24 patients with gastric cancer underwent intracorporeal circular-stapled esophagojejunostomy with the hemi-double-stapling technique (hemi-DST) using the OrVil™ in antecolic Roux-en-Y reconstruction with its efferent loop located on the left side of the patient following LTG to prevent twisting of the esophagojejunostomy and lifted jejunum, which might cause intractable stenosis of the esophagojejunostomy.

Results: In this patient series, no twisting of the esophagojejunostomy and lifted jejunum was encountered intraoperatively or postoperatively.

Novel Potent ABCB1 Modulator, Phenethylisoquinoline Alkaloid, Reverses Multidrug Resistance in Cancer Cell.

ATP-binding cassette (ABC) transporters, which are concerned with the efflux of anticancer drugs from cancer cells, have a pivotal role in multidrug resistance (MDR). In particular, ABCB1 is a well-known ABC transporter that develops MDR in many cancer cells. Some ABCB1 modulators can reverse ABCB1-mediated MDR; however, no modulators with clinical efficacy have been approved.

An option for delta-shaped gastroduodenostomy in totally laparoscopic distal gastrectomy for gastric cancer: A single-layer suturing technique for the stapler entry hole using knotless barbed sutures combined with the application of additional knotted sutures.

We report an option for delta-shaped gastroduodenostomy in totally laparoscopic distal gastrectomy (TLDG) for gastric cancer. We detail a single-layer suturing technique for the endoscopic linear stapler entry hole using knotless barbed sutures combined with the application of additional knotted sutures. From June 2013 to February 2017, we performed TLDG with delta-shaped gastroduodenostomy in 20 patients with gastric cancer.

AgNTf-Mediated Allylation with Allylsilanes at C3a-Position of Hexahydropyrroloindoles: Application to Total Syntheses of Amauromine Alkaloids.

A protocol for the allylation at the C3a-position of hexahydropyrroloindole using allylsilanes is developed. AgNTf proved to be an efficient activator of halopyrroloindoline substrates. This method is applicable to the introduction of various allyl groups including the reverse prenyl group.

A novel option for preoperative endoscopic marking with India ink in totally laparoscopic distal gastrectomy for gastric cancer: A useful technique considering the morphological characteristics of the stomach.

In totally laparoscopic distal gastrectomy (TLDG) for gastric cancer, accurately determining the proximal resection line may be difficult. This is because identifying the lesion intracorporeally is impossible, due to the lack of tactile sense, and, in addition, unlike the intestine, the most proximal site of the lesion is often different from the main site due to the distorted shape of the stomach. The aim of this study was to introduce a novel method of preoperative endoscopic marking with India ink, taking into consideration the morphological characteristics of the stomach.

Bioinspired Total Synthesis of the Dimeric Indole Alkaloid (+)-Haplophytine by Direct Coupling and Late-Stage Oxidative Rearrangement.

A bioinspired convergent total synthesis of (+)-haplophytine, a dimeric indole alkaloid with diazabicyclo[3.3.1]nonane and hexacyclic aspidosperma segments, is described.

Condensation of Carboxylic Acids with Non-Nucleophilic N-Heterocycles and Anilides Using BocO.

A novel condensation reaction of carboxylic acids with various non-nucleophilic N-heterocycles and anilides was developed. The reaction proceeds in the presence of di-tert-butyl dicarbonate (BocO), catalytic 4-(dimethylamino)pyridine (DMAP), and 2,6-lutidine and is applicable to the acylation of a wide range of non-nucleophilic nitrogen compounds, including indoles, pyrroles, pyrazole, carbazole, lactams, oxazolidinones, and anilides with high functional group compatibility. The scope of indoles, carboxylic acids, and anilides was also studied.

Convergent Synthesis of 2-Aryl-Substituted Quinolines by Gold-Catalyzed Cascade Reaction.

Gold-catalyzed auto-tandem catalysis has been developed for synthesizing 2-aryl-substituted quinolines. The reaction of an aniline bearing an acetal moiety with an aryl alkyne proceeded via formal [4+2]-cycloaddition, which involved the addition of gold acetylide to an oxonium ion to give amino alkyne intermediate and sequential 6-endo-dig cyclization of amino alkyne intermediate by attacking of nitrogen to alkyne moiety activated by gold catalyst. The cationic gold catalyst promoted two different processes by enhancing the nucleophilicity and electrophilicity of alkyne.

Structure and biological function of ENPP6, a choline-specific glycerophosphodiester-phosphodiesterase.

Choline is an essential nutrient for all living cells and is produced extracellularly by sequential degradation of phosphatidylcholine (PC). However, little is known about how choline is produced extracellularly. Here, we report that ENPP6, a choline-specific phosphodiesterase, hydrolyzes glycerophosphocholine (GPC), a degradation product of PC, as a physiological substrate and participates in choline metabolism.

Total syntheses of codonopsinine and 4-epi-codonopsinine via gold-mediated tandem-catalyzed pyrrole synthesis.

The total syntheses of codonopsinine (1) and 4-epi-codonopsinine (2) were accomplished. The key substituted pyrrole intermediate was constructed via gold-catalyzed addition-cyclization cascade of an aminoacetaldehyde acetal derivative and a terminal alkyne. After diastereoselective reduction of the pyrrole intermediate to the corresponding 3-pyrroline derivative with zinc dust and sulfonic acid, the total synthesis of 4-epi-codonopsinine (2) was achieved via stereoselective construction of the diol by dihydroxylation.

Total Synthesis of (-)-Isoschizogamine.

The total synthesis of (-)-isoschizogamine was accomplished, featuring the construction of the quaternary carbon center by the modified Johnson-Claisen rearrangement in basic media and the facile assembly of the key tetracyclic quinolone intermediate through a cascade cyclization. The characteristic cyclic aminal was constructed by late-stage C-H functionalization at the position adjacent to the lactam nitrogen using a combination of CrO3 and nBu4 NIO4 and subsequent Bi(OTf)3 -mediated cyclization.

A new option for intracorporeal circular-stapled esophagojejunostomy in laparoscopic total gastrectomy: Roux-en-Y reconstruction with its efferent loop located at the left side of the patient to prevent twisting of the esophagojejunostomy.

Background/aims: Laparoscopic total gastrectomy (LTG) has not gained widespread acceptance because of the difficult reconstruction technique, especially for esophagojejunostomy. Although various modified procedures using a circular stapler for esophagojejunostomy have been reported, an optimal technique has not yet been established. In addition, in intracorporeal techniques, twisting of the esophagojejunostomy, which might be the cause of stenosis, is often encountered because application of the shaft is restricted.

Autotandem catalysis: synthesis of pyrroles by gold-catalyzed cascade reaction.

A novel synthesis of substituted pyrroles by a gold(I)-catalyzed cascade reaction has been developed. The reaction proceeded with an autotandem catalysis consisting of an initial addition of gold-acetylide to an acetal moiety and was followed by gold-catalyzed 5-endo-dig cyclization and aromatization. Gold catalysts play a dual role in activating nucleophilicity or electrophilicity of terminal acetylenes by forming gold-acetylides or by π-coordination.

Acetic acid promoted metal-free aerobic carbon-carbon bond forming reactions at α-position of tertiary amines.

The oxidative functionalization of the benzylic C-H bonds in tetrahydroisoquinolines and tetrahydro-β-carboline derivatives was investigated. C-C bond forming reactions proceeded with a range of nucleophiles (nitroalkane, enol silyl ether, indole, allylstannane, and tetrabutylammonium cyanide) under metal-free conditions and an oxygen atmosphere. Acetic acid caused a significant acceleration effect.

Total syntheses of leuconoxine, leuconodine B, and melodinine E by oxidative cyclic aminal formation and diastereoselective ring-closing metathesis.

Total syntheses of leuconodine B, melodinine E, and leuconoxine were accomplished via a divergent route. The [5.5.