An efficient perfluoroalkylation of unactivated alkenes with perfluoro acid anhydrides was developed. Copper salts play a crucial role as a catalyst to achieve allylic perfluoroalkylation with the in situ generated bis(perfluoroacyl) peroxides. Furthermore, carboperfluoroalkylation of alkene bearing an aromatic ring at an appropriate position on the carbon side chain was found to proceed under metal-free conditions to afford carbocycles or heterocycles bearing a perfluoroalkyl group. This method, which makes use of readily available perfluoroalkyl sources, offers a convenient and powerful tool for introducing a perfluoroalkyl group onto an sp³ carbon to construct synthetically useful skeletons.

An efficient perfluoroalkylation of unactivated alkenes with perfluoro acid anhydrides was developed. Copper salts play a crucial role as a catalyst to achieve allylic perfluoroalkylation with the in situ generated bis(perfluoroacyl) peroxides. Furthermore, carboperfluoroalkylation of alkene bearing an aromatic ring at an appropriate position on the carbon side chain was found to proceed under metal-free conditions to afford carbocycles or heterocycles bearing a perfluoroalkyl group. This method, which makes use of readily available perfluoroalkyl sources, offers a convenient and powerful tool for introducing a perfluoroalkyl group onto an sp³ carbon to construct synthetically useful skeletons.

Hydrotrifluoromethylation, vinylic trifluoromethylation, and iodotrifluoromethylation of simple alkenes have been achieved by using Togni reagent in the absence of any transition metal catalyst. These reactions were readily controllable by selection of appropriate salts and solvents. The addition of K₂CO₃ afforded the hydrotrifluoromethylation product, with DMF acting not only as a solvent, but also as the hydrogen source. In contrast, the use of tetra-n-butylammonium iodide (TBAI) in 1,4-dioxane resulted in vinylic trifluoromethylation, while the use of KI afforded the iodotrifluoromethylation product. The vinylic trifluoromethylation product was obtained by treatment of the iodotrifluoromethylation product with ammonium 2-iodobenzoate, indicating that it was formed through an elimination reaction of the in-situ-generated iodotrifluoromethylation product, and the solubility of the resulting 2-iodobenzoate salt plays a key role in the product switching. A radical-clock experiment showed that these reactions proceed via radical intermediates.

Die Trifluormethylgruppe ist Bestandteil vieler synthetischer bioaktiver Verbindungen, und die Difunktionalisierung von CC-Bindung wurde als wirksame Strategie zum Aufbau von Verbindungen mit verschiedenen Funktionalitäten intensiv erforscht. Folgerichtig ist die difunktionalisierende Trifluormethylierung von Alkenen auf wachsendes Interesse gestoßen, da die Produkte potenzielle Bausteine für bioaktive Moleküle darstellen. Dieser Aufsatz stellt neueste Fortschritte bei der Trifluormethylierung von Alkenen unter gleichzeitiger Einführung weiterer funktioneller Gruppen vor.

Trifluoromethylation of propargylic alcohols to provide (Z)-α-trifluoromethylated enones and β-unsubstituted α-trifluoromethylated enones proceeded with high yield and selectivity in the presence of CuI/Re₂O₇. The Z isomer was formed under kinetic control, though it is less stable than the E isomer in terms of steric repulsion.

The development of new and mild protocols for the specific enrichment of biomolecules is of significant interest from the perspective of chemical biology. A cobalt–phosphine complex immobilised on a solid-phase resin has been found to selectively bind to a propargyl carbamate tag, that is, “catch”, under dilute aqueous conditions (pH 7) at 4 °C. Upon acidic treatment of the resulting resin-bound alkyne–cobalt complex, the Nicholas reaction was induced to “release” the alkyne-tagged molecule from the resin as a free amine. Model studies revealed that selective enrichment of the alkyne-tagged molecule could be achieved with high efficiency at 4 °C. The proof-of-concept was applied to an alkyne-tagged amino acid and dipeptide. Studies using an alkyne-tagged dipeptide proved that this protocol is compatible with various amino acids bearing a range of functionalities in the side-chain. In addition, selective enrichment and detection of an amine derived from the “catch and release” of an alkyne-tagged dipeptide in the presence of various peptides has been accomplished under highly dilute conditions, as determined by mass spectrometry.

The trifluoromethyl group is found in many synthetic bioactive compounds, and the difunctionalization of a CC bond, as a powerful strategy for the construction of compounds with various functional groups, has been intensively investigated. Therefore, the difunctionalizing trifluoromethylation of alkenes has attracted growing interest because of the potential of the products as building blocks for bioactive molecules. In this review, we focus on recent advances in the trifluoromethylation of alkenes with concomitant introduction of additional functional groups.

An efficient synthetic route to optically pure norcantharidin analogue NCA-01, a highly selective inhibitor of protein phosphatase 2B (PP2B; calcineurin), has been developed. The absolute stereochemistry of the enantiomers was determined by X-ray crystallographic analysis. Optically pure NCA derivatives that had various substituents at the C1 position were synthesized in a similar manner. The PP2B-inhibitory activities of NCA-01 and its derivatives were independent of the enantiomeric form. NCA-01 dimethyl ester potently inhibited IL-2 production in Jurkat cells.

Direct asymmetric α-chlorination of aryl acetic acid derivatives was achieved with a novel trinary activation system consisting of a catalytic amount of NiCl₂/(R)-BINAP, Et₃SiOTf, and a tertiary amine base. The reaction smoothly afforded the chlorinated compound in good yield with up to 89 % ee. Application of this reaction to a less acidic crotonic acid derivative gave the β,γ-unsaturated α-chlorinated compound through deprotonation at the γ-position.

Epipolythiodiketopiperazine (ETP) alkaloids are structurally characterized by the presence of diketopiperazine rings having sensitive (poly)sulfide bridges, and most of them are classified as fungal secondary metabolites. Various biological activities have been reported for members of this family, including cytotoxic, antibacterial, antimicrobial, antiviral, antitumor, antiallergic, and antimalarial activities. Notably, some of the molecules were reported to show specific inhibitory activities against certain critical enzymes. Since the supply of these compounds from natural sources is quite limited, efficient chemical syntheses of ETP alkaloids would be useful for biological studies. However, total syntheses of ETP alkaloids remain a formidable challenge in current synthetic organic chemistry because of their structural complexity. In this review article, we present an overview of synthetic approaches to the ETP alkaloids during the past 50 years, and discuss significant milestones. We also summarize the biological activities of these compounds, focusing on the molecular mechanisms.

The tandem aza-Michael reaction/enantioselective protonation of α-substituted α,β-unsaturated carbonyl compounds is described in detail. The key to success is the combined use of a Brønsted basic palladium–μ-hydroxo complex and amine salts, which allows for the controlled generation of active catalyst and nucleophilic free amines. This catalytic system was applicable to various acceptors and aromatic amines, and the desired β-amino acid derivatives with a chiral center at the α position were produced in good yield with excellent enantioselectivity (up to 98 % ee). For electron-deficient amines, the introduction of free amine as an additive was effective in promoting the reaction. The results of mechanistic studies, including determination of the absolute configuration of the product, are discussed.

Since the incorporation of fluorine into biologically active compounds often enhances the properties of the parent compounds, there is a considerable demand for efficient enantioselective fluorination reactions. Over the past decade, a range of metal-catalyzed and organocatalyzed fluorination reactions has been developed. Nowadays, fluorine can be catalytically introduced into many compounds in good yield and with high enantioselectivity, and the scope of these reactions is broad. Herein, we review recent progress in the field of catalytic enantioselective fluorination reactions, including their scope and mechanism.

Oxidative stress-induced necrosis plays an important role in ischemia-reperfusion injury, such as stroke and heart attack. Here, we describe the development of selective inhibitors of necrosis, MS-1 and IM-54, as potential cardioprotective agents and biological tools for investigating the molecular mechanisms of cell death. By means of chemical modifications of kinase inhibitor BM I, its affinity for various kinases was successfully removed and a potent and selective inhibitor of necrosis, IM-54, was obtained. IM-54 inhibits necrosis induced by oxidative stress, but not apoptosis induced by anticancer drugs. © 2010 The Japan Chemical Journal Forum and Wiley Periodicals, Inc. Published online in Wiley InterScience (www.interscience.wiley.com) DOI 10.1002/tcr.201000031

This paper describes catalytic asymmetric Mannich-type reactions of β-ketoesters and malonates using chiral palladium complexes. Although readily enolizable, carbonyl compounds are attractive substrates, the use of such compounds as nucleophiles in Mannich-type reactions has not been extensively investigated. In the presence of chiral Pd aqua complexes (2.5 mol %), β-ketoesters reacted with various N-Boc imines (Boc=tert-butoxycarbonyl) to afford the desired β-aminocarbonyl compounds in good yield with high to excellent stereoselectivity (up to 96:4 d.r., 95–99 % ee in most cases). In these reactions, construction of highly crowded vicinal quaternary and tertiary carbon centers was achieved in one step. A chiral Pd enolate is considered to be the key intermediate. To elucidate the stereoselectivity observed in the reaction, possible transition-state models are discussed, taking into account steric and stereoelectronic effects. Furthermore, this catalytic system was applied to the Mannich-type reaction of malonates with N-Boc imine as well as one-pot classical aminomethylation of β-ketoesters using benzylamine salt and formalin. The reactions proceeded smoothly, and the corresponding Mannich products were obtained in high yield with moderate to good enantioselectivity.