Intramolecular Cyclopropanation of Active Methylene Derivatives Based on FeCl2 or FeCl3-Promoted Radical-Polar Crossover Reactions.

Radical-polar crossover reactions were studied for the intramolecular cyclopropanation of active methylene derivatives. In the presence of FeCl3 as a stoichiometric oxidant and K2HPO4 as a base, the dehydrogenative cyclopropanation of active methylenes proceeded through the FeCl3-promoted oxidative radical cyclization followed by the ionic cyclization to give the bicyclic cyclopropanes. The use of α-chloro-active methylenes leads the subcatalytic cyclopropanation involving two redox pathways. In the presence of K2HPO4, the redox cyclopropanation proceeded by using FeCl2 (20 mol%) in combination with ligand (20 mol%).

Regiocontrol Using Fluoro Substituent on 3,6-Disubstituted Arynes.

The effect of fluoro substituent on the regioselectivity of several reactions of 3,6-disubstituted arynes was studied. These arynes contained another inductively electron-withdrawing substituent other than fluorine. A reasonable degree of regiocontrol was achieved in the (3 + 2) cycloaddition reaction of 3,6-disubstituted aryne containing both fluorine and bromine atoms with benzyl azide. Furthermore, the insertion reaction of aryne into Sn-F σ-bonds and the three-component coupling reaction involving the insertion of aryne into C=O π-bonds also led to the high degree of regiocontrol.

Aryne Precursors for Selective Generation of 3-Haloarynes: Preparation and Application to Synthetic Reactions.

The synthesis and reaction of new 3-haloaryne precursors 2a-2h were studied. The ortho-(trimethylsilyl)aryl triflate precursors 2a-2h were prepared by a simple procedure involving O-trimethylsilylation and migration of a trimethylsilyl group followed by triflation. The remarkable feature of new precursors is the selective generation of 3-haloarynes by suppressing the competitive thia-Fries rearrangement, which is the problem in the reaction using the well-known 3-haloaryne precursors. The advantage of new precursor 2a over a typical precursor 1 was confirmed by the direct comparisons in several reactions. The application of precursors 2a-2h to the syntheses of heterocycles was also reported.

Oxidative Functionalization of Cinnamaldehyde Derivatives: Control of Chemoselectivity by Organophotocatalysis and Dual Organocatalysis.

The catalytic and chemoselective oxidation of cinnamaldehyde derivatives having a C═C bond and formyl group was studied by using two organocatalysts. The visible-light-induced catalysis using rhodamine 6G as an organophotocatalyst promoted the methoxyhydroxylation of the C═C bond in a chemoselective manner. In contrast, the cooperation between rhodamine 6G and N-heterocyclic carbene (NHC) allowed the oxidative esterification of formyl group.

Transition-Metal-Free Activation of Amide Bond by Arynes.

Highly reactive arynes activate the N⁻C and C=O bonds of amide groups under transition metal-free conditions. This review highlights the insertion of arynes into the N⁻C and C=O bonds of the amide group. The insertion of arynes into the N⁻C bond gives the unstable four-membered ring intermediates, which are easily converted into ortho-disubstituted arenes. On the other hand, the selective insertion of arynes into the C=O bond is observed when the sterically less-hindered formamides are employed to give a reactive transient intermediate. Therefore, the trapping reactions of transient intermediates with a variety of reactants lead to the formation of oxygen atom-containing heterocycles. As relative functional groups are activated, the reactions of arynes with sulfinamides, phosphoryl amides, cyanamides, sulfonamides, thioureas, and vinylogous amides are also summarized.

Progress in Enantioselective Radical Cyclizations.

The control of stereoselectivity in radical reactions is of great importance to organic synthesis. Hence, new concepts and strategies for controlling stereochemistry of radical reactions are emerging continuously. This Review highlights the recent remarkable progress in enantioselective radical cyclization reactions. Initially, the chiral Lewis acid-catalyzed method became a field of central importance for enantioselective radical cyclizations. In recent years, significant progress has been made in enantioselective organocatalysis. In contrast to intermolecular reactions, the successful examples for enantioselective radical cyclizations are still limited. In this Review, the radical cyclizations controlled by chiral Lewis acids, chiral metallic reagents, chiral imidazolidinone catalysts, chiral non-covalent organocatalysts, and chiral thiols are summarized.

Photo-Induced Atom-Transfer Radical Reactions Using Charge-Transfer Complex between Iodine and Tertiary Amine.

In the presence of charge-transfer complexes between iodine and tertiary amines, the aqueous-medium atom-transfer radical reactions proceeded under visible light irradiation without the typical photocatalysts.

Aqueous-Medium Carbon-Carbon Bond-Forming Radical Reactions Catalyzed by Excited Rhodamine B as a Metal-Free Organic Dye under Visible Light Irradiation.

The utility of rhodamine B as a water-soluble organic photocatalyst was studied in the cascade radical addition-cyclization-trapping reactions under visible light irradiation. In the presence of (i-Pr)2NEt, the electron transfer from the excited rhodamine B to perfluoroalkyl iodides proceeded smoothly to promote the carbon-carbon bond-forming radical reactions in aqueous media. When i-C3F7I was employed as a radical precursor, the aqueous-medium radical reactions proceeded even in the absence of (i-Pr)2NEt. In these reactions, the direct electron transfer from the excited singlet state of rhodamine B would take place. Furthermore, the cleavage of the C-I bond in less reactive i-PrI could be achieved by the reductive electron transfer from the excited rhodamine B, which was confirmed by the fluorescence quenching of rhodamine B with the addition of i-PrI.

Multicomponent Coupling Reaction Using Arynes: Synthesis of Xanthene Derivatives.

One-pot synthesis of xanthene derivatives was achieved by a route involving the cascade three-component coupling reaction of arynes with DMF and active methylenes followed by the SN2' reaction of three-component coupling products with thiols. The reactivity of three-component coupling products toward nucleophiles and the further conversion of oxygen heterocycles allowing facile incorporation of structural variety were studied.

Synthesis of Oxygen Heterocycles via Aromatic C-O Bond Formation Using Arynes.

Most of the synthetic approaches to the benzo-fused heterocycles containing an oxygen atom have involved the use of phenol derivatives as a starting material. This review highlights the new synthetic approaches involving the aromatic C-O bond-forming process using arynes. The insertion of arynes into the C=O bond gives the unstable intermediates, [2 + 2] cycloaddition-type adducts, which can be easily converted into a variety of oxygen atom-containing heterocycles in a single operation. In this review, the syntheses of oxygen heterocycles, such as coumarin, chromene, xanthene, dihydrobenzofuran and benzofuran derivatives, via the insertion of arynes into the C=O bond of aldehydes or formamides are summarized.

Three-component coupling reactions of arynes for the synthesis of benzofurans and coumarins.

The domino three-component coupling reaction of arynes with DMF and active methylenes or methines was studied as a highly efficient method for preparing heterocycles. Coumarin derivative 5 was formed when diethyl malonate (2) or α-bromomalonate (3) were used as a C2-unit. In contrast, dihydrobenzofurans 7a and 7b were obtained by using α-chloroenolates generated from α-chloromalonates 4a and 4b and Et2Zn. The benzofuran 15a could be obtained by using ethyl iodoacetate (14) as a C1-unit. The one-pot conversion of dihydrobenzofurans 7a, 7b and 8a into benzofurans 15a and 15b was also studied. The direct synthesis of benzofuran 15b was achieved by using the active methine 18 having ketone and ester groups.

Cascade radical reaction of substrates with a carbon-carbon triple bond as a radical acceptor.

The limitation of hydroxamate ester as a chiral Lewis acid coordination moiety was first shown in an intermolecular reaction involving a radical addition and sequential allylation processes. Next, the effect of hydroxamate ester was studied in the cascade addition-cyclization-trapping reaction of substrates with a carbon-carbon triple bond as a radical acceptor. When substrates with a methacryloyl moiety and a carbon-carbon triple bond as two polarity-different radical acceptors were employed, the cascade reaction proceeded effectively. A high level of enantioselectivity was also obtained by a proper combination of chiral Lewis acid and these substrates.

Expression and function of PD-1 in human γδ T cells that recognize phosphoantigens.

Programmed cell death-1 (PD-1) is an inhibitory receptor and plays an important role in the regulation of αß T cells. Little is known, however, about the role of PD-1 in γδ T cells. In this study, we investigated the expression and function of PD-1 in human γδ T cells. Expression of PD-1 was rapidly induced in primary γδ T cells following antigenic stimulation, and the PD-1(+) γδ T cells produced IL-2. When PD-1(+) γδ T cells were stimulated with Daudi cells with and without programmed cell death ligand-1 (PD-L1) expression, the levels of IFN-γ production and cytotoxicity in response to PD-L1(+) Daudi cells were diminished compared to the levels seen in response to PD-L1(-) Daudi cells. The attenuated effector functions were reversed by anti-PD-L1 mAb. When PD-1(+) γδ T cells were challenged by PD-L1(+) tumors pretreated with zoledronate (Zol), which induced γδ TCR-mediated signaling, the resulting reduction in cytokine production was only slight to moderate compared to the reduction seen when PD-1(+) γδ T cells were challenged by PD-L1(-) tumors. In addition, cytotoxic activity of PD-1(+) γδ T cells against Zol-treated PD-L1(+) tumors was comparable to that against Zol-treated PD-L1(-) tumors. These results suggest that TCR triggering may partially overcome the inhibitory effect of PD-1 in γδ T cells.

Polarity-mismatched addition of electrophilic carbon radicals to an electron-deficient acceptor: cascade radical addition-cyclization-trapping reaction.

The polarity-mismatched perfluoroalkyl radical addition to electron-deficient alkenes was studied. For this study, several substrates having two polarity-different radical acceptors were employed to investigate the regiochemical courses of cascade reaction. In the case of substrate 1 having a methacryloyl moiety, we found polarity-mismatched perfluoroalkylation giving 15a-e as a major course over the polarity-matched perfluoroalkylation giving 16a-e. Moreover, in the case of substrates 2-7, perfluoroalkyl radicals selectively added to an electron-deficient alkene moiety of 2-7, to give polarity-mismatched perfluoroalkylation products without the formation of regioisomers. Next, the control of enantioselectivity was studied. In the case of substrates 1 and 3, the reaction proceeded with good enantioselectivities by employing a chiral Lewis acid, prepared from chiral box ligand 24 and Zn(OTf)(2). For direct comparison, we also studied the reaction with other carbon radicals, derived from ICH(2)CO(2)Et, ICH(2)CN, BrC(CO(2)Et)(2)Me, and CCl(3)Br, which have electrophilic character.

Lewis acid-mediated radical cyclization: stereocontrol in cascade radical addition-cyclization-trapping reactions.

An efficient approach for achieving radical cyclizations by using hydroxamate ester as a coordination tether with Lewis acid was studied. The chiral Lewis acid-mediated cascade radical addition-cyclization-trapping reaction proceeded smoothly with good enantio- and diastereoselectivities, providing various chiral γ-lactams.

Regio- and enantioselective allylic substitution with less active N- or O-nucleophiles catalyzed by iridium-complex of bis(oxazolinyl)pyridine.

The utility of hydroxylamines as nitrogen nucleophiles was investigated in the iridium-catalyzed regio- and enantioselective allylic substitution. Allylic substitution with hydroxylamines proceeded with good enantioselectivities by using the iridium-complex of bis(oxazolinyl)pyridine ligand. The good regio- and enantioselectivities were also achieved in the reaction with alkylamines, p-anisidine, and 4-methoxyphenol.

Palladium- or iridium-catalyzed allylic substitution of guanidines: convenient and direct modification of guanidines.

As a convenient and direct functionalization of guanidines, the transition metal-catalyzed allylic substitution of guanidines was studied. The guanidine derivatives bearing two electron-withdrawing substituents acted as reactive nucleophiles in the allylic substitution to give the monoallylated products. The double allylic substitution was achieved by using tri-Boc-guanidine bearing three electron-withdrawing substituents as a nucleophile to give the diallylated products. The regiocontrol in the allylic substitution of unsymmetrical allylic substrates has been investigated by employing the palladium or iridium catalysts. The iridium complex of chiral pybox ligand allowed the regio- and enantioselective allylic substitution. Asymmetric double allylic substitution of tri-Boc-guanidine with phosphate bearing the 1-naphthyl group gave the diallylated product with high diastereo-, regio-, and enantioselectivities.

Stereoselective Organic Reactions in Heterogeneous Semiconductor Photocatalysis.

The most significant feature of heterogeneous semiconductor photocatalysis is that both oxidation and reduction occur in a one-pot process. Thus, photocatalysis leads to unique redox organic reactions that cannot be achieved by conventional techniques using oxidants or reductants. Semiconductor photocatalysis is expected to be a new method for fine chemical syntheses of highly valuable molecules such as chiral medicines. However, the use of semiconductor photocatalysts in stereoselective reactions has been limited so far. This mini-review highlights recent progress in stereoselective organic reactions using semiconductor photocatalysts, briefly summarizing the enantio- and diastereoselective reactions based on the currently available literature.

Chiral α-hydroxy acid-coadsorbed TiO2 photocatalysts for asymmetric induction in hydrogenation of aromatic ketones.

Modification of titanium dioxide (TiO2) photocatalysts with chiral reagents was evaluated by the hydrogenation of aromatic ketones. The strong adsorption of chiral mandelic acid (R)-MA on TiO2 was confirmed by comparing the inhibition effect IR values. The enantioselectivities were affected by not only the chiral reagents but also the TiO2 crystalline samples, suggesting that the interaction between aromatic ketones and MA on TiO2 should depend on the surface structure and morphology of TiO2 particles.