Homostachydrine is a Xenobiotic Substrate of OCTN1/SLC22A4 and Potentially Sensitizes Pentylenetetrazole-Induced Seizures in Mice.

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.

Bridged-Selective Intramolecular Diels-Alder Reactions in the Synthesis of Bicyclo[2.2.2]octanes.

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.

Development of Nitrolactonization Mediated by Iron(III) Nitrate Nonahydrate.

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.

Intramolecular Büchner Reaction and Oxidative Aromatization with SeO2 or O2.

Intramolecular Büchner 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.

Synthesis of multisubstituted phenols by formal [4 + 2] cycloaddition of nucleophilic alkynes with 3-ethoxycyclobutanones.

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.

The Mukaiyama aldol reaction: 40 years of continuous development.

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.

Asymmetric Cycloaddition Reactions of Aryne Intermediates with a Chiral Carbon-Carbon Axis: Syntheses of Axially Chiral Biaryl Compounds.

An asymmetric synthesis via an axially chiral arylaryne intermediate was developed. A cycloaddition reaction with various arynophiles was used to obtain chiral biaryl compounds while preserving the enantiomeric excess (ee) of a precursor even though the reaction proceeds through an arylaryne intermediate, whose ee decreases on a time-dependent basis. High chiral transfer from a precursor to a product was observed not only at low temperature (-78 °C) but also at room temperature.

Titanium(IV) chloride-mediated ring cleavage and Michael addition of 3,3-dialkylcyclobutanones and 3-[(trimethylsilyl)methyl]-cyclobutanones.

ß'-Chloro and ß',γ'-unsaturated trichlorotitanium enolates, which were formed in situ by titanium(IV) chloride-mediated ring cleavage of 3,3-dialkylcyclobutanones and 3-[(trimethylsilyl)methyl]cyclobutanones, reacted with enones to give Michael adducts with keeping a labile ß'-chloro or ß',γ'-unsaturated group.

Formal [4+2] cycloaddition of di-tert-butyl 2-ethoxycyclobutane-1,1-dicarboxylate with ketones or aldehydes and tandem lactonization.

A catalytic amount of tin(IV) chloride catalyzed formal [4+2] cycloaddition reaction of di-tert-butyl 2-ethoxycyclobutane-1,1-carboxylate with ketones or aldehydes to give diethyl 6-ethoxydihydro-2H-pyran-3,3(4H)-dicarboxylates, whereas two equivalents of trimethylsilyl triflate promoted tandem [4+2] cycloaddition and lactonization to afford 3-oxo-2,6-dioxabicyclo[2.2.2]octane-4-carboxylate esters.

Intramolecular [2+2] cycloaddition of homoallylketenes to bicyclo[2.1.1]hexan-5-ones.

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.

Trialkylamine-mediated intramolecular acylation of alkenes with carboxylic acid chlorides.

Trialkylamine-mediated intramolecular cyclization of pent-4-enoyl chlorides was studied. Substitution with a tertiary alkyl group at the 2-position gave cyclopent-2-en-1-ones, while substitution with an aromatic group gave enol esters, which were formed by O-acylation of initially formed 3-chlorocyclopentanones with ketenes.

Lewis acid-catalyzed intermolecular [4 + 2] cycloaddition of 3-alkoxycyclobutanones to aldehydes and ketones.

Intermolecular [4 + 2] cycloaddition between 3-alkoxycyclobutanones and aldehydes or ketones by the activation with boron trifluoride etherate is reported. The carbonyl compounds are inserted into the less substituted C2-C3 bond of the cyclobutanone ring of 6-alkyl-2-oxabicyclo[4.2.0]octan-7-ones to afford 1-alkyl-5,7-dioxabicyclo[4.4.0]decan-2-one derivatives regioselectively (>99:1) and diastereoselectively. On the other hand, [4 + 2] cycloaddition of 3-ethoxy-2,2-dialkylcyclobutanones at low temperature proceeds at the more substituted C2-C3 bond to yield 3,3-dialkyl-6-ethoxy-2,3,5,6-tetrahydro-4H-pyran-4-one derivatives with high regioselectivities. This [4 + 2] cycloaddition is developed into a one-pot synthesis of tri- or tetrasubstituted dihydro-gamma-pyrones from 3-ethoxycyclobutanones which are readily prepared from acid chloride and ethyl vinyl ether. The two regioselectivities observed in ring-opening of cyclobutanones can ascribe to thermodynamic stabilities of zwitterionic intermediates generated from tetrahydropyran-fused cyclobutanones and 3-ethoxycyclobutanones.

Oxazaborolidine-catalyzed enantioselective reduction of alpha-methylene ketones to allylic alcohols.

Oxazaborolidine-catalyzed enantioselective reduction of alpha-methylene ketones was efficiently carried out by using borane-diethylaniline as a stoichiometric reducing agent. The combination of this method and subsequent hydrogenation of thus-formed allylic alcohol improved stereoselectivity in the reduction of 24-oxocholesteryl ester to 24-(R)-hydroxycholesteryl ester.

Oxidative Mannich reaction of N-carbobenzyloxy amines with 1,3-dicarbonyl compounds.

Efficient carbon-carbon bond formation at the alpha-position of nitrogen was established by one-pot oxidative Mannich reaction of N-carbobenzyloxy (Cbz) amines with 1,3-dicarbonyl compounds using N-tert-butylbenzenesulfinimidoyl chloride as an oxidant.

Mild preparation of alkenes from phenyl sulfides: one-pot elimination of phenylthio group via sulfilimine at ambient temperature.

[Structure: see text] Various alkenes were prepared from phenyl sulfides in a one-pot manner at room temperature by converting them to the corresponding S-aminosulfonium salts with O-mesitylenesulfonylhydroxylamine, followed by treatment with potassium carbonate. Alkenes were formed by cis-elimination of in situ generated phenyl sulfilimines.

A mild and convenient synthesis of N-carbobenzyloxy ketimines.

N-Carbobenzyloxy (Cbz) ketimines were prepared conveniently from N-Cbz amines by oxidation with N-tert-butylbenzenesulfinimidoyl chloride.

Synthesis of α-Halo-γ-hydroxyenamides by Titanium Tetrahalide Mediated Addition of Aldehydes or Ketones to Ynamides.

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.

One-pot beta-substitution of enones with alkyl groups to beta-alkyl enones.

Vinylic hydrogens at the beta-position of enones were effectively substituted with alkyl groups in a one-pot procedure to afford beta-alkyl enones in good to high isolated yields by conjugate addition of higher-order dialkyl cyanocuprates to enones, followed by a reaction with N-tert-butylbenzenesulfinimidoyl chloride at -78 degree C.

Ring cleavage and successive aldol reaction of 3-[(trialkylsilyl)methyl]cyclobutanones.

3-[(Trialkylsilyl)methyl]cyclobutanones reacted with aldehydes by activation with titanium(IV) chloride to give acyclic ß,γ-unsaturated ß'-hydroxyketones.