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A synthesis of 3-alkyl-2-arylindoles was performed by sequential oxidation and reduction of 2-(2-nitrophenyl)ethanols that were prepared by base-catalyzed three-component reactions of vinylarenes, aldehydes, and various pronucleophiles, including nitroalkanes, thiols, and malonates. In addition to indoles, a selective synthesis of an N-hydroxyindole was accomplished. The highly nucleophilic character of transient benzylic anions in DMSO was also clarified for the three-component reactions.

Regio-, stereo- and enantioselective cascade intramolecular aldol cyclization/acetalizations of symmetrical 1,2,7,8-tetraones were developed. The total synthesis of (±)-nesteretal A was accomplished in seven steps by this synthetic strategy.

Three-component reactions of nitroalkanes, acrylamides, and aldehydes by using a catalytic amount of KOH in DMSO gave β′-hydroxy-γ-nitro amides. Mechanistic studies suggested that the reactions proceeded by domino Michael/aldol reactions. The highly nucleophilic nature of transient amide enolates that were formed by Michael addition of nitronate anions to acrylamides in DMSO enabled the realization of catalytic intermolecular aldol reactions of amide enolates in the presence of acidic nitroalkanes.

Regioselectivity for intramolecular Diels-Alder (IMDA) reactions of 6-acetoxy-6-alkenylcyclohexa-2,4-dien-1-ones that were formed by oxidation of 2-alkenylphenols with lead tetraacetate in acetic acid were studied. Bridged regioselectivity was observed in the IMDA reactions of 6-acetoxy-6-alkenylcyclohexa-2,4-dien-1-ones having a dienophile part which could conjugate with an aromatic group. Bridged seven- and eight-membered rings and bicyclo[2.2.2]octane skeletons were constructed by the present IMDA reactions. Density functional theory (DFT) calculations suggested that conjugation of the dienophile with neighboring aromatic groups lowered the highest occupied molecular orbital-lowest unoccupied molecular orbital (HOMO-LUMO) energy gap and preceded bridged [4 + 2] adducts.

Understanding of the underlying mechanism of epilepsy is desired since some patients fail to control their seizures. The carnitine/organic cation transporter OCTN1/SLC22A4 is expressed in brain neurons and transports food-derived antioxidant ergothioneine (ERGO), L-carnitine, and spermine, all of which may be associated with epilepsy. This study aimed to clarify the possible association of this transporter with epileptic seizures. In both pentylenetetrazole (PTZ)-induced acute seizure and kindling models, ocnt1 gene knockout mice (octn1-/-) showed lower seizure scores compared with wild-type mice. Up-regulation of the epilepsy-related genes, c-fos and Arc, and the neurotrophic factor BDNF following PTZ administration was observed in the hippocampus of wild-type, but not octn1-/- mice. To find the OCTN1 substrate associated with the seizure, untargeted metabolomics analysis using liquid chromatography-quadrupole time-of-flight mass spectrometry was conducted on extracts from the hippocampus, frontal cortex, and plasma of both strains, leading to the identification of a plant alkaloid homostachydrine as a compound present in a lower concentration in octn1-/- mice. OCTN1-mediated uptake of deuterium-labeled homostachydrine was confirmed in OCTN1-transfected HEK293 cells, suggesting that this compound is a substrate of OCTN1. Homostachydrine administration increased PTZ-induced acute seizure scores and the expression of Arc in the hippocampus and that of Arc, Egr1, and BDNF in the frontal cortex. Conversely, administration of the OCTN1 substrate/inhibitor ERGO inhibited PTZ-induced kindling and reduced the plasma homostachydrine concentration. Thus, these results suggest that OCTN1 is at least partially associated with PTZ-induced seizures, which is potentially deteriorated by treatment with homostachydrine, a newly identified food-derived OCTN1 substrate.

The enantioselective synthesis of a bicyclo[4.3.0]nonene derivative bearing a quaternary carbon stereocenter is achieved by employing a desymmetrization strategy involving an intramolecular addition. The intramolecular nucleophilic addition of a highly reactive carbanion generated from an alkenyl iodide in the presence of a chiral ligand occurs with discrimination of two keto carbonyl groups to give the corresponding bicyclic compound in 81% yield and 39% ee. Asymmetric synthesis via an intramolecular desymmetrization strategy using a chiral ligand–carbanion complex represents a complementary approach to using chiral organocatalysts or chiral ligand–transition-metal complexes.

3-Hydroxy-3-vinylcycloalkanones, which were prepared from the corresponding cyclic 1,3-diketones by mono-vinylation, were rearranged to two-carbon ring enlarged cyclic 1,5-diketones by treatment with a catalytic amount of potassium tert-butoxide.

We present the orientation order of push-pull chromophores consisting of phenyl vinylene thiophene vinylene (FTC) bridges between the N,-N-bis-(2-hydroxyethyl)-amine electron donor and phenyl-trifl...

Intramolecular Buchner reaction of 1-diazo-5-phenylpentan-2-ones followed by oxidation with SeO2 or O2 in the presence of silica gel regioselectively gave 8-formyl-1-tetralones or one-carbon-lacking 1-tetralones, respectively.

The nitrolactonization of alkenyl carboxylic acids mediated by Fe(NO3)3·9H2O has been developed. Nitrolactones were obtained in up to 93% yield by treatment of alkenyl carboxylic acids with Fe(NO3)3·9H2O. Mechanistic studies disclosed that the reaction proceeded through a radical intermediate generated from addition of NO2 to alkenyl carboxylic acids.

Understanding of the underlying mechanism of epilepsy is desired since some patients fail to control their seizures. The carnitine/organic cation transporter OCTN1/SLC22A4 is expressed in brain neurons and transports food-derived antioxidant ergothioneine (ERGO), L-carnitine, and spermine, all of which may be associated with epilepsy. This study aimed to clarify the possible association of this transporter with epileptic seizures. In both pentylenetetrazole (PTZ)-induced acute seizure and kindling models, ocnt1 gene knockout mice (octn1

The Suzuki reaction of both (E)- and (Z)-α-chloro-γ-hydroxyenamides with benzeneboronic acid by using Pd2(dba)3, tBu3P, and Cs2CO3 proceeded stereoselectively to afford only (E)-trisubstituted enamides. Also, palladium-catalyzed intramolecular cyclization of (E)- and (Z)-α-chloro-γ-hydroxyenamides bearing an N-arylsulfonyl group took place stereoselectively to give the corresponding (E)-2,3-dihydrobenzoisothiazole 1,1-dioxides. The γ-hyroxy group in α-chloroenamides was found to accelerate the present palladium-catalyzed carbon-carbon bond forming reactions.

In DMSO, a catalytic amount of Barton's base (2-t-butyl-1,1,3,3-tetramethylguanidine, BTMG) effectively catalyzed intermolecular three-component reactions of α,β-unsaturated esters, aldehydes, and carbon-, sulfur-, or nitrogen-pronucleophiles to give three-component addition products with the formation of two new σ-bonds: pronucleophiles and aldehydes reacted with α,β-unsaturated esters at their β-positions and α-positions, respectively. Mechanism studies suggested that these reactions proceeded by the first intermolecular Michael addition of anionic nucleophiles that were formed from pronucleophiles with a catalytic amount of BTMG, followed by intermolecular aldol reactions of transient ester enolates even in the presence of more than stoichiometric amounts of acidic pronucleophiles. High nucleophilicity over Bronsted basicity of transient enolates in polar solvents was observed for transient ester enolates rather than ketone enolates.

Ring cleavage of 3-arylcyclobutanones and successive Friedel–Crafts alkylation of methoxy- or alkyl-substituted benzene derivatives proceeded to give 3,3-diarylbutan-2-ones by activation with titanium tetrachloride.

Formal [4+2] cycloaddition between 3-ethoxy-2-alkylcyclobutanones and nitrosobenzene proceeded by activation with Me3SiOTf to afford 6-alkyl-2-phenyl-2H-1,2-oxazin-5(6H)-one by regioselective cleavage of the more substituted C2–C3 bond of the cyclobutanone ring. On the other hand, reactions of 3-phenylcyclobutanones and 2-benzyloxycyclobutanone with nitrosobenzene gave γ,δ-unsaturated and cyclic hydroxamic acid derivatives, respectively, by cleavage of a cyclobutanone C1–C2 bond.

Various 3-phenylcyclobutanones reacted with aliphatic and aromatic nitriles in the presence of Me3SiOTf to afford dihydropyridones by formal [4+2] cycloaddition.

A novel and concise synthesis of 1,3,5-cycloheptatrienes has been developed. The reaction of 4-substituted-4-pentenal derivatives with the Wittig reagent prepared from pyruvic ester under the optimal conditions proceeded to give 1,6-di- and 1,6,7-trisubstituted-1,3,5-cycloheptatrienes in moderate yield. The synthesis is advantageous through its use of readily available reagents, milder reaction conditions compared to those previously reported, and simple manipulations. Additionally, a plausible mechanism via intramolecular [4+2]cycloaddition followed by the ring-expansion of norcarene is proposed based on the products of the reaction.

1,3-Cyclobutanediones (dialkyl ketene dimer) reacted with various aromatic aldehydes to give six-membered cyclic β-keto esters by using a catalytic amount of potassium ethoxide. Effects of alkoxide catalysts and spiro cyclic groups at the 2,4-positions of 1,3-cyclobutanediones were investigated.

Nucleophilic alkynes bearing sulfonamide, trimethylsilyl, or p-methoxyphenyl groups at the sp carbon reacted with 3-ethoxycyclobutanones to give formal [4 + 2] cycloadducts by activation with TiCl4. Reactions with 2-monoalkyl and 2-nonsubstituted 3-ethoxycyclobutanones gave phenol derivatives directly by benzannulation, while the use of 2,2-dimethyl-3-ethoxycyclobutanone gave the corresponding dienones, which were converted to pentasubstituted phenols by dienone-phenol rearrangement. Regioselectivity that depended on the activation conditions of dienone-phenol rearrangement is also described.

Azobenzenes reacted with 3-ethoxycyclobutanoes to give 2,3-dihydro-pyridazin-4(1 H )-ones by using EtAlCl 2 as a Lewis acid. Thus, ring cleavage of 3-ethoxycyclobutanones took place to form a zwitterionic intermediate by activation with EtAlCl 2 , and intermolecular formal [4+2] cycloaddition of the zwitterionic intermediate proceeded with azobenzenes to give 2,3-dihydro-pyridazin-4(1 H )-ones after elimination of ethanol. Regioselectivity for cycloaddition of unsymmetrical azobenzenes, ring contraction and chemoselective reduction of 2,3-dihydro-pyridazin-4(1 H )-ones, and [4+2] cycloaddition to 4-phenyl-1,2,4-triazolin-3,5-dione are also described.

1,4,5,6-Tetrahydro-1-tosyl-6-tosylhydrazinopyridazines were prepared by reaction of a 1,4-ketoaldehyde with two equivalents of tosylhydrazine. Thus-obtained hydropyridazines were utilized as a substrate for synthesis of various 1,4,5,6-tetrahydropyridazine derivatives by activation with a Lewis acid, and various nucleophiles reacted to give the corresponding 6-substituted 1,4,5,6-tetrahydropyridazine derivatives. Self-reaction of a 1,4,5,6-tetrahydro-6-tosylhydrazinopyridazine in the presence of 0.5 equivalent of titanium tetrachloride gave a 1,4,5,6-tetrahydropyridazine bearing a pyrrole ring at the 6-position.

α-Chloro- or α-bromo-γ-hydroxyenamides were synthesized by the reaction of an ynamide, titanium tetrahalide, and an aldehyde or a ketone. A γ-hydroxy trisubstituted enamide was prepared stereoselectively by Suzuki coupling of an obtained α-chloro-γ-hydroxyenamide with phenyl boronic acid. Intramolecular cyclization of α-chloro-γ-hydroxyenamide took place to provide a 2,3-dihydrobenzoisothiazole 1,1-dioxide derivative by palladium-catalyzed C-H activation of the tosyl group. Hydrochlorination of ynamides proceeded to give α-chloroenamides by treatment with titanium tetrachloride followed by addition of water.

3-Ethoxycyclobutanones reacted with pyridines, quinolines, and isoquinolines to give the corresponding formal [4+2] cycloadducts, 9a-hydro-2H-quinolizin-2-one derivatives, by using Me3SiOTf in acetonitrile. Cycloaddition of 3-ethoxy-2-monoalkylcyclobutanones to 5-nitroquinoline or 4-cyanopyridine proceeded stereoselectively.

Formal [4+4] cycloaddition reactions of 3-ethoxycyclobutanones and 2-silyloxy-1,3-butadienes were catalyzed with EtAlCl2 to afford eight-membered carbocyclic compounds. Steric hindrance of the silyl group of dienes influenced the reaction course for [4+4] or [4+2] cycloaddition.

Cycloaddition reaction is an efficient organic reaction because all of the substrate components are introduced into a product skeleton. Recently, more than six-membered rings have been synthesized by Lewis acid-promoted ring cleavage of a cyclobutane ring followed by addition to an unsaturated bond. Typical examples in the literature of these types of reactions using 1-donor–2-acceptor cyclobutanes and 3-donor cyclobutanones with Lewis acids are presented in this Letter.

A reaction of 3-arylcyclobutanones with anthracene in the presence of TiCl4 gave 14-aryl-9,10-dihydro-9,10-butanoanthracen-12-ones as a formal [4 + 4] cycloadduct of anthracenes with a C4 unit formed by cleaving the more substituted C2 C3 bond of cyclobutanones. On the other hand, activation of 3-arylcyclobutanones with TfOH in the absence of nucleophiles gave 2-tetralones with skeletal rearrangement.

A directed cross-aldol reaction of silyl enol ethers with carbonyl compounds, such as aldehydes and ketones, promoted by a Lewis acid, a reaction which is now widely known as the Mukaiyama aldol reaction. It was first reported in 1973, and this year marks the 40th anniversary. The directed cross-aldol reactions mediated by boron enolates and tin(II) enolates also emerged from the Mukaiyama laboratory. These directed cross-aldol reactions have become invaluable tools for the construction of stereochemically complex molecules from two carbonyl compounds. This Minireview provides a succinct historical overview of their discoveries and the early stages of their development.

Azobenzenes reacted with 3-ethoxycyclobutanoes to give 2,3-dihydro-pyridazin-4(1 H )-ones by using EtAlCl 2 as a Lewis acid. Thus, ring cleavage of 3-ethoxycyclobutanones took place to form a zwitterionic intermediate by activation with EtAlCl 2 , and intermolecular formal [4+2] cycloaddition of the zwitterionic intermediate proceeded with azobenzenes to give 2,3-dihydro-pyridazin-4(1 H )-ones after elimination of ethanol. Regioselectivity for cycloaddition of unsymmetrical azobenzenes, ring contraction and chemoselective reduction of 2,3-dihydro-pyridazin-4(1 H )-ones, and [4+2] cycloaddition to 4-phenyl-1,2,4-triazolin-3,5-dione are also described.

Intramolecular [2+2] cycloaddition of γ,δ-unsaturated ketenes derived from hex-5-enoyl chloride derivatives gave bicyclo[2.1.1]hexan-5-ones with complete regioselectivity. © 2012 The Pharmaceutical Society of Japan.

3-[(Trialkylsilyl)methyl]cyclobutanones reacted with aldehydes by activation with titanium(IV) chloride to give acyclic β,γ;- unsaturated β′-hydroxyketones. © 2011 American Chemical Society.

An efficient sequential one-pot glycosylation has been developed with glycosyl trichlorocarbamate and trichloroacetate activated by the same Lewis acid and enabled by a change in reaction temperature. The αα-selective glycosylation was achieved using glucose, galactose, and mannose substrates after investigation into the reactivities of the two types of glycosyl donors. Sequential one-pot dehydrative glycosylation, including in situ preparation of glycosyl donors followed by generation of two glycosyl bonds, provided three types of trisaccharide.

Chiral cyclobutanone which had ethyl l-lactate as a chiral auxiliary at the 3-position reacted with aldehydes to give 2,3-dihydro-4-pyranones in up to 93% ee by combined use of titanium(IV) chloride and tin(II) chloride.

Efficient catalytic and stereoselective glycosylation was achieved by activating a glycosyl N -trichloroacetylcarbamate with a catalytic amount of Lewis acid in the presence of a glycosyl acceptor and 5 Ǻ molecular sieves. Catalytic one-pot dehydrative glycosylation of a 1-hydroxy carbohydrate was achieved stereoselectively by reaction with trichloroacetyl isocyanate, followed by activation with a catalytic amount of activators.

金沢大学医薬保健研究域薬学系, Aliphatic ketones were reduced to the corresponding secondary alcohols by using anti-1,3-diol and a catalytic amount of 2,4-dinitrobenzenesulfonic acid (DNBSA) in benzene at reflux. Addition of 1-octanethiol in that media improved the efficiency of the reduction. Asymmetric reduction of aliphatic ketones was performed by using chiral anti-pentane-2,4-diol, and highly asymmetric induction (up to >99% ee) was observed in the reduction of tert-alkyl ketones. Asymmetric reduction of acyl silanes using chiral anti-pentane-2,4-diol and DNBSA proceeded efficiently in the absence of octanethiol and the corresponding α-silyl alcohols were obtained in high yields with high ees. © 2010 Elsevier Ltd. All rights reserved.

Formal [4 + 2] cycloaddition between various 3-ethoxycyclobutanones and allyltrialkylsilanes proceeded to give 3-ethoxy-5-[(trialkylsilyl)methyl]cyclohexan-1-ones by catalysis with tin(VI) chloride. The use of allyl-tert-butyldiphenylsilane induced 1,5-hydride transfer, which gave 2-[3-(tert-butyldiphenylsilyl)propyl]-6-methyltetrahydro-4-pyrones.

金沢大学医薬保健研究域薬学系, Eight-membered cyclic siloxydienes, 2-(tert-butyldimethylsiloxy)-1-methyl-5-oxacycloocta-1,3-diene and 2-(tert-butyldimethylsiloxy)-5-oxacycloocta-1,3-diene, were prepared from δ-valerolactone, and their Diels-Alder reactions with various dienophiles are reported. © 2008 Elsevier Ltd. All rights reserved.

The caged structure of platensimycin, known as Nicolaou's key intermediate for total synthesis of platensimycin, was synthesized stereoselectively by using the following key steps: (i) diastereoselective Diels-Alder reaction between gamma-benzoyloxy enone and tert-butyldimethylsiloxydiene, (ii) formation of a dihydropyran ring by intramolecular catalytic oxypalladation, and (iii) transannular radical cyclization of monothioacetal with tributyltin hydride and AIBN.

金沢大学大学院自然科学研究科生理活性物質科学, A radical cascade involving 6-endo cyclization of aryl radicals generated from N-acryloyl-N-(1-methylethenyl)-9-bromophenanthren-10-ylmethylamines, followed by 5-endo-trig cyclization of the resulting α-amidoyl radicals afforded phenanthroindolizidines bearing a methyl substituent at the angular C13a position. 2,3,6-Trimethoxy derivative was synthesized by using this method, but its spectral data were not in accord with those of literature values reported for hypoestestatin 1. Further synthetic study toward hypoestestatin 1 is demonstrated. © 2007 Elsevier Ltd. All rights reserved.

金沢大学大学院自然科学研究科生理活性物質科学, 金沢大学薬学部, Enantiomerically pure N-carbobenzyloxy-N′-phthaloyl-cis-1,2-cyclohexanediamine was synthesized by the asymmetric reduction of a β-enamino ester formed from benzyl 2-oxocyclohexanecarboxylate and (R)-phenylethylamine, followed by hydrogenolysis, phthaloylation, and the Curtius rearrangement. © 2007.

金沢大学大学院自然科学研究科生理活性物質科学, 金沢大学薬学部, Treatment of N-(2-arylcyclohex-1-en-1-yl)-α-(methylthio)acetamides with N-chlorosuccinimide (NCS) gave 3a-aryl-2,3,3a,4,5,6-hexahydro-3-(methylthio)indol-2-ones. Desulfurization of the cyclization products followed by a catalytic hydrogenation of the resulting hexahydroindol-2-ones gave predominantly or exclusively trans-fused octahydroindol-2-ones. On the other hand, reduction of the desulfurization products with Et3SiH in CF3CO2H exclusively provided cis-fused octahydroindol-2-ones. A chiral induction of N-[2-(3,4-dimethoxy)phenylcyclohex-1-en-1-yl]-α-(methylthio)acetamide having an (R)-1-(1-naphthyl)ethyl group on the nitrogen atom led to the synthesis of (-)-mesembrane and (-)-trans-mesembrane. © 2007 Elsevier Ltd. All rights reserved.

金沢大学大学院自然科学研究科生理活性物質科学, 金沢大学薬学部, 金沢大学医学部附属病院薬剤部, A carbon-carbon bond was formed at the β-position of cyclic ketones in a one-pot manner by oxidation with N-tert-butylbenzenesulfinimidoyl chloride, followed by the reaction of malonic acid esters or potassium cyanide. © 2007 Elsevier Ltd. All rights reserved.

One-pot substitution of a C–H bond at the position next to the nitrogen atom of lactams with alkyl malonates proceeded effectively by dehydrogenation of lactams with N-tert-butylbenzenesulfinimidoyl chloride, followed by Mannich-type addition of alkyl malonates.