Unified Divergent Total Synthesis of Discorhabdin B, H, K, and Aleutianamine via the Late-Stage Oxidative N,S-Acetal Formation.

This study achieved the total syntheses of (+)-discorhabdin B, (-)-discorhabdin H, (+)-discorhabdin K, and (-)-aleutianamine. A phenethylamine fragment bearing a o-pivaloylthio group, corresponding to the D/E/G ring moiety, was prepared from benzothiophen-2-carboxylic acid methyl ester and condensed with a known pyrroloiminoquinone derivative. The adduct was subjected to [bis(trifluoroacetoxy)iodo]benzene (PIFA)-promoted oxidative spirocyclization to furnish the A/B/C/D/E spirocyclohexadienone fused with pyrroloiminoquinone. The total synthesis of (±)-discorhabdin B was completed via the key construction of the highly strained G ring with the N,S-acetal moiety featuring a newly developed CuBr2-mediated oxidative cascade cyclization. The stereocontrolled total synthesis of (+)-discorhabdin B was accomplished by a diastereoselective PIFA-promoted oxidative spirocyclization using a chiral thioester. (-)-Disocrhabdin H and (+)-discorhabdin K were synthesized by the site- and face-selective thia-Michael addition of l-ovothiol A to (+)-N-Ts-discorhabdin B with the concomitant formation of the F ring by forming the C2-N18 bond. The total synthesis of (-)-aleutianamine was achieved via a skeletal rearrangement initiated by the Luche reduction of the dienone moiety of (+)-N-Ts-discorhabdin B.

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(CO2H)8, the oxidative coupling of the synthesized (+)-pleiocarpamine with pyrocatechuic acid was established to produce (+)-voacalgine A. The total synthesis of (+)-bipleiophylline was completed by the second coupling of (+)-voacalgine A with (+)-pleiocarpamine or one-pot couplings of 2 equiv of (+)-pleiocarpamine with pyrocatechuic acid.

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. Furthermore, oxidative dimerization of tryptophan derivatives bearing dioxopiperazine units enabled the convergent total synthesis of five natural pyrroloindole compounds and unnatural congeners. The established chemical method provides facile access to a broad range of dimerized peptides with a unique scaffold to link two turn structures, which will serve as a powerful tool to create new small- and medium-sized-molecules as drug candidates.

Total synthesis of (±)-vinoxine: construction of the bridged pyrido[1,2-a]indole skeleton via Tf2O-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-a]indole skeleton through the Tf2O-mediated Bischler-Napieralski reaction. The characteristic diazabicyclo[3.3.1]nonane skeleton was stereoselectively constructed via radical cyclization based on the one stereochemistry of the C3 position. The established methodology provides new options for the synthesis of natural products and pharmaceuticals containing the multi-substituted pyrido[1,2-a]indole skeleton.

Photoredox-catalyzed intramolecular cyclopropanation of alkenes with α-bromo-ß-keto esters.

A mild photoredox-catalyzed intramolecular cyclopropanation of alkenes with α-bromo-ß-keto esters in an aqueous medium was developed. The sequential reaction process comprising the intramolecular radical addition of α-bromo-ß-keto esters to olefins under photoredox catalysis, and subsequent cyclization to form cyclopropane proceeds in one-pot under exceptionally mild conditions at room temperature in the presence of 2,6-lutidine. A broad range of substrates consisting of various alkenes and both base- and acid-sensitive functionalized esters were feasible under the reaction conditions, resulting in a wide range of functionalized bicyclic cyclopropanes.

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. Moreover, utility of the aniline products was demonstrated by derivatization to substituted benzoxazines, which are pharmaceutically important heterocycles.

Construction of N-Heterocycles Fused with a Highly Substituted Benzene Ring by a Benzyne-Mediated Cyclization/Functionalization Cascade Reaction and Its Application to the Total Synthesis of Marine Natural Products.

This account summarizes the development of a benzyne-mediated cyclization/functionalization protocol for the versatile construction of highly substituted benzene derivatives fused with an N-heterocyclic ring such as indolines, indoles, and related nitrogen-containing heterocycles. The protocol comprises sequential reactions initiated by generating a benzyne species and subsequent cyclization via addition of magnesium amide to the benzyne, followed by trapping of the resultant magnesium compound in situ with various electrophiles. The substituent scope was expanded by conducting a transmetalation on a copper species to introduce alkyl, aryl, and alkenyl substituents. The utility of the sequential reaction was demonstrated in the synthesis of a carbazole natural product (heptaphylline), pyrrolo[4,3,2-de]quinoline alkaloids (batzellines), and pyrrolo[2,3-c]carbazole alkaloids (dictyodendrines).

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. Furthermore, by taking advantage of the oxygen-mediated structural change of the Grubbs catalyst, we integrated ring-closing metathesis and subsequent aerobic dehydrogenation to develop the novel assisted-tandem catalysis using molecular oxygen as a chemical trigger. The utility of the assisted-tandem catalysis was demonstrated by the concise synthesis of N-containing fused heteroarenes including a natural antibiotic, pyocyanine.

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. Approach and Results: We performed stepwise screenings for 5562 compounds from original library. First, we performed high-throughput screening with PASMCs from patients with PAH (PAH-PASMCs) and found 80 compounds that effectively inhibited proliferation. Second, we performed the repeatability and counter assay. Finally, we performed a concentration-dependent assay and found that emetine inhibits PAH-PASMC proliferation. Interestingly, emetine significantly reduced protein levels of HIFs (hypoxia-inducible factors; HIF-1α and HIF-2α) and downstream PDK1 (pyruvate dehydrogenase kinase 1). Moreover, emetine significantly reduced the protein levels of RhoA (Ras homolog gene family, member A), Rho-kinases (ROCK1 and ROCK2 [rho-associated coiled-coil containing protein kinases 1 and 2]), and their downstream CyPA (cyclophilin A), and Bsg (basigin) in PAH-PASMCs. Consistently, emetine treatment significantly reduced the secretion of cytokines/chemokines and growth factors from PAH-PASMCs. Interestingly, emetine reduced protein levels of BRD4 (bromodomain-containing protein 4) and downstream survivin, both of which are involved in many cellular functions, such as cell cycle, apoptosis, and inflammation. Finally, emetine treatment ameliorated pulmonary hypertension in 2 experimental rat models, accompanied by reduced inflammatory changes in the lungs and recovered right ventricular functions. CONCLUSIONS: Emetine is an old but novel drug for PAH that reduces excessive proliferation of PAH-PASMCs and improves right ventricular functions.

Cyclic Sulfamidite as Simultaneous Protecting Group for Amino Alcohols: Development of a Mild Deprotection Protocol Using Thiophenol.

This study describes the novel utility of cyclic sulfamidite as a simultaneous protecting group for 1,2- or 1,3-amino alcohols. An exceptionally mild and neutral condition for the removal of the cyclic sulfamidite was developed. The deprotection condition demonstrated a broad range of functional-group compatibility, including a substrate bearing a Z-enyne structure without any loss of double-bond stereochemistry.

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.

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. Ether solvents such as tetrahydrofuran (THF), cyclo pentyl methyl ether (CPME), and 1,4-dioxane were effective for the reaction. Studies on the scope of substrates and alkynes indicated that various alkynes and acetals were feasible to provide a wide range of propargylic ethers.

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. The aim of this study was to identify novel ABCB1 modulators by using high-throughput screening. Of the 5861 compounds stored at Tohoku University, 13 compounds were selected after the primary screening via a fluorescent plate reader-based calcein acetoxymethylester (AM) efflux assay. These 13 compounds were validated in a flow cytometry-based calcein AM efflux assay. Two isoquinoline derivatives were identified as novel ABCB1 inhibitors, one of which was a phenethylisoquinoline alkaloid, (±)-7-benzyloxy-1-(3-benzyloxy-4-methoxyphenethyl)-1,2,3,4-tetrahydro-6-methoxy-2-methylisoquinoline oxalate. The compound, a phenethylisoquinoline alkaloid, was subsequently evaluated in the cytotoxicity assay and shown to significantly enhance the reversal of ABCB1-mediated MDR. In addition, the compound activated the ABCB1-mediated ATP hydrolysis and inhibited the photolabeling of ABCB1 with [125I]-iodoarylazidoprazosin. Furthermore, the compound also reversed the resistance to paclitaxel without increasing the toxicity in the ABCB1-overexpressing KB-V1 cell xenograft model. Overall, we concluded that the newly identified phenethylisoquinoline alkaloid reversed ABCB1-mediated MDR through direct interaction with the substrate-binding site of ABCB1. These findings may contribute to the development of more potent and less toxic ABCB1 modulators, which could overcome ABCB1-mediated MDR.

A Cell-Targeted Non-Cytotoxic Fluorescent Nanogel Thermometer Created with an Imidazolium-Containing Cationic Radical Initiator.

A cationic fluorescent nanogel thermometer based on thermo-responsive N-isopropylacrylamide and environment-sensitive benzothiadiazole was developed with a new azo compound bearing imidazolium rings as the first cationic radical initiator. This cationic fluorescent nanogel thermometer showed an excellent ability to enter live mammalian cells in a short incubation period (10 min), a high sensitivity to temperature variations in live cells (temperature resolution of 0.02-0.84 °C in the range 20-40 °C), and remarkable non-cytotoxicity, which permitted ordinary cell proliferation and even differentiation of primary cultured cells.

Structural Determination of (-)-SCH 64874 and Hirsutellomycin by Semisynthesis.

The structure of a C2-symmetric epidithiodiketopiperazine alkaloid, SCH 64874, was determined by semisynthesis. The relative stereochemistry of the ß-hydroxy carboxylic acid chain having three chiral centers was determined by comparison of the NMR data of the four possible diastereomeric ß-hydroxy carboxylic acid fragments with those of SCH 64874. Condensation of the (-)-deacetylaranotin core with two enantiomeric ß-hydroxy carboxylic acids revealed the relative stereochemistry of SCH 64874. The relative stereochemistry of the ß-keto carboxylic acid chain of the analogous alkaloid hirsutellomycin was determined in a stepwise manner. The C4'-C6' syn relationships were predicted by comparing the NMR data of the corresponding ester fragments with that of hirsutellomycin. The relative stereochemistry of the whole molecule, including the epimerizable C2' stereocenter, was determined by introduction of four possible side chains into the bisdethiodi(methylthio)deacetylaranotin core. We found that the stereochemistry of C2' converged with that of the thermodynamically stable form influenced by the core structure.

Total Synthesis of Actinophyllic Acid.

Herein we report a total synthesis of the indolohydroazocine natural product actinophyllic acid. The target molecule was retrosynthetically deconvoluted to render a greatly simplified and symmetrical [4.4.1] bicyclic trienone, the desymmetrization of which was carefully examined under a variety of conditions, including oxidative, reductive, and transition-metal-catalyzed transformations. Ultimately, the successful synthetic strategy featured chemoselective catalytic dihydroxylation, desymmetrizing nitrile oxide dipolar cycloaddition, and palladium-catalyzed aminoarylation to sequentially modify the three olefins within the trienone, followed by a late-stage reductive cascade indolization and alkylation to complete the target molecule.

Total Synthesis of (-)-Histrionicotoxin through a Stereoselective Radical Translocation-Cyclization Reaction.

Stereoselective total syntheses of (-)-histrionicotoxin and (-)-histrionicotoxin 235A are described. The 1-azaspiro[5.5]undecane skeleton was constructed diastereoselectively by a radical translocation-cyclization reaction involving a chiral cyclic acetal; the use of tris(trimethylsilyl)silane was crucial for the high diastereoselectivity. The cyclization product was converted into (-)-histrionicotoxin 235A through a one-pot partial-reduction-allylation reaction of a derivative containing an unprotected lactam. Finally, two terminal alkenes were transformed into enynes with the 1,3-amino alcohol protected as an oxathiazolidine oxide to complete the total synthesis of (-)-histrionicotoxin.

Condensation of Carboxylic Acids with Non-Nucleophilic N-Heterocycles and Anilides Using Boc2O.

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 (Boc2O), 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. This convergent synthetic methodology enabled the synthesis of a variety of 2-aryl-substituted quinolines.

Conversion of Vindoline into 11-Mesyloxytabersonine.

Conversion of readily available vindoline to 11-mesyloxytabersonine, a versatile synthetic intermediate for indole alkaloids, has been achieved by a 9-step sequence in 39% overall yield.