Highly Enantioselective Radical Cation [2 + 2] and [4 + 2] Cycloadditions by Chiral Iron(III) Photoredox Catalysis.

Radical cations show a unique reactivity that is fundamentally different from that of conventional cations and have thus attracted considerable attention as alternative cationic intermediates for novel types of organic reactions. However, asymmetric catalysis to promote enantioselective radical cation reactions remains a major challenge in contemporary organic synthesis. Here, we report that the judicious design of an ion pair consisting of a radical cation and a chiral counteranion induces an excellent level of enantioselectivity. This strategy was applied to enantio-, diastereo-, and regioselective [2 + 2] cycloadditions, as well as enantio-, diastereo-, and regioselective [4 + 2] cycloadditions, by using chiral iron(III) photoredox catalysis. We anticipate that this strategy has the potential to expand the use of several mature chiral anions to develop numerous unprecedented enantioselective radical cation reactions.

Catalytic Site-, Diastereo-, and Enantioselective Cascade Iodocyclization of 2-Geranylarenols.

A chiral amidophosphate-N-iodosuccinimide cooperative catalysis has been developed for the site-, diastereo-, and enantioselective iodocyclization of 2-geranylarenols with molecular iodine to give the corresponding iodo-containing polycyclic compounds with good levels of selectivity. This is the first example of a catalytic enantioselective iodocarbocyclization. A reactive chiral iodonium species is generated from molecular iodine via the dual halogen-bonding interactions with a chiral Lewis base and Lewis acid. The sterically demanding 3,3'-substituents of the chiral BINOL-derived amidophosphate are critical to induce the site-selective iodination at the less-hindered terminal alkenyl moiety of 2-geranylarenols.

Multifactor Control of Vinyl Monomer Sequence, Molecular Weight, and Tacticity via Iterative Radical Additions and Olefin Metathesis Reactions.

Monomer sequence control in terms of a single monomer unit, particularly in vinyl polymers, is one of the largest challenges in polymer chemistry. Furthermore, multifactor control of monomer sequence, molecular weight, and stereoregularity is an ultimate goal. In this work, we propose a strategy to prepare C-C main-chain sequence-regulated polymers with controlled molecular weights from vinyl monomers via a combination of iterative atom transfer radical additions and olefin metathesis reactions. This strategy enabled the synthesis of sequence-regulated polymers with exact styrene-acrylate-styrene sequences in the C-C main chains, controlled molecular weights of up to 104, and stereoregularities varying with syndiotacticity, isotacticity, and heterotacticity. The utility of this strategy is further demonstrated by formation of block copolymers consisting of sequence-regulated vinyl polymer segments by combining living ROMP of norbornene derivatives.

One-Pot Tandem Michael Addition/Enantioselective Conia-Ene Cyclization Mediated by Chiral Iron(III)/Silver(I) Cooperative Catalysis.

The first one-pot tandem Michael addition/enantioselective Conia-ene cyclization of N-protected prop-2-yn-1-amines with 2-methylene-3-oxoalkanoates promoted by chiral iron(III)/silver(I) cooperative catalysts has been developed. Alkyl 4-methylenepyrrolidine-3-acyl-3-carboxylates, which can be transformed into ß-proline derivatives, are obtained in high yield with high enantioselectivity.

Enantioselective 1,4-Addition Reaction of α,ß-Unsaturated Carboxylic Acids with Cycloalkanones Using Cooperative Chiral Amine-Boronic Acid Catalysts.

An enantioselective 1,4-addition of α,ß-unsaturated carboxylic acids with cycloalkanones has been developed by using chiral amine-boronic acid cooperative catalysts. In the presence of a chiral amine and boronic acid, cycloalkanones and carboxylic acids are activated as chiral enamines and mixed anhydrides, respectively. The corresponding 1,4-adducts are obtained in high yield with high enantioselectivity. Furthermore, subsequent oxylactonization of the 1,4-adducts gives spirolactones with high diastereoselectivity.

Halogen-Bonding Interaction between I2 and N-Iodosuccinimide in Lewis Base-Catalyzed Iodolactonization.

The halogen-bonding interaction between I2 and N-iodosuccinimide (NIS) stabilized by a Lewis base (LB) has been explored. 1H NMR, nuclear Overhauser effect (NOE), and diffusion-ordered NMR spectroscopy (DOSY) suggest the generation of a 1:1:1 assembly, LB-I2-NIS. In contrast, when N-iodotrifluoromethanesulfonimide (INTf2) is used instead of NIS, LB-I5+-LB is generated. On the basis of these results in combination with density functional theory (DFT) calculations, we propose a mechanism for the formation of I2-NIS and the subsequent generation of an active iodinating species LB-I+.

An enantioselective oxidative coupling reaction of 2-naphthol derivatives catalyzed by chiral diphosphine oxide-iron(ii) complexes.

An enantioselective oxidative coupling of 2-naphthol derivatives is developed with the use of chiral Fe(ii)-diphosphine oxide complexes. Optically active 1,1-bi-2-naphthol derivatives can be synthesized in high yields when a 2 : 1 complex of (S)-xylyl-iPrO-BIPHEP-oxide and Fe(OTf)2 is used in the presence of t-butyl hydroperoxide as an oxidant. The non-linear effect, X-ray crystal structure and ESI-MS suggest that a 2 : 1 complex of (S)-xylyl-iPrO-BIPHEP-oxide and Fe(OTf)2 is a pre-catalyst for a Fe(iii)/Fe(iv) redox cycle.

Structure and Reactivity of Aromatic Radical Cations Generated by FeCl3.

This paper describes the isolation and characterization of an aromatic radical cation generated by FeCl3. X-ray crystallographic analysis and kinetic studies reveal the mechanism of the generation of aromatic radical cation. In the solid state, a tight ion-pair of a radical cation with FeCl4- is observed. Leveraging the efficient generation of the radical cation-FeCl4- ion pair, we explore a radical cation-induced cycloaddition of trans-anethole initiated by catalytic amount of FeCl3. Both [4+2] cycloaddition and [2+2] cycloaddition with a broad substrate scope are also described. Moreover, a 100 g-scale reaction is demonstrated with the use of 1 mol % of FeCl3 as a simple and a highly active initiator.

Selenium-Iodine Cooperative Catalyst for Chlorocyclization of Tryptamine Derivatives.

Chlorocyclization of tryptamine derivatives has been developed with the use of a diphenyl diselenide-iodine cooperative catalyst. Various tryptamine derivatives can be smoothly converted to the corresponding C3a-chlorohexahydropyrrolo[2,3-b]indoles. Additionally, we demonstrate the formal total syntheses of (-)-psychotriasine and (-)-acetylardeemin by introducing nucleophiles to the C3a position of the products.

Enantioselective Cyanosilylation of Ketones with Lithium(I) Dicyanotrimethylsilicate(IV) Catalyzed by a Chiral Lithium(I) Phosphoryl Phenoxide.

A highly enantioselective cyanosilylation of ketones was developed by using a chiral lithium(I) phosphoryl phenoxide aqua complex as an acid/base cooperative catalyst. The pentacoordinate silicate generated in situ from Me3SiCN/LiCN acts as an extremely reactive cyano reagent. Described is a 30 gram scale reaction and the synthesis of the key precursor to (+)-13-hydroxyisocyclocelabenzine.

Gold(I)-catalyzed enantioselective [3+2] and [3+3] cycloaddition reactions of propargyl acetals/ketals.

An asymmetric gold(I)-catalyzed [3+2] cycloaddition of propargyl acetals/ketals and aldehydes is reported, which proceeds via stepwise migration-fragmentation of acetals/ketals and cycloaddition of the in situ generated gold-carbenoid intermediate. Various functionalized 2, 5-dihydrofurans were obtained in good yields and high enantioselectivities. Furthermore, an example of the first gold(I) catalyzed [3+3] cycloaddition of secondary propargyl ketals and nitrones is presented.

Stable gold(III) catalysts by oxidative addition of a carbon-carbon bond.

Low-valent late transition-metal catalysis has become indispensable to chemical synthesis, but homogeneous high-valent transition-metal catalysis is underdeveloped, mainly owing to the reactivity of high-valent transition-metal complexes and the challenges associated with synthesizing them. Here we report a carbon-carbon bond cleavage at ambient conditions by a Au(i) complex that generates a stable Au(iii) cationic complex. In contrast to the well-established soft and carbophilic Au(i) catalyst, this Au(iii) complex exhibits hard, oxophilic Lewis acidity. For example, we observed catalytic activation of α,ß-unsaturated aldehydes towards selective conjugate additions as well as activation of an unsaturated aldehyde-allene for a [2 + 2] cycloaddition reaction. The origin of the regioselectivity and catalytic activity was elucidated by X-ray crystallographic analysis of an isolated Au(iii)-activated cinnamaldehyde intermediate. The concepts revealed suggest a strategy for accessing high-valent transition-metal catalysis from readily available precursors.

Chiral magnesium(II) binaphtholates as cooperative Brønsted/Lewis acid-base catalysts for the highly enantioselective addition of phosphorus nucleophiles to α,ß-unsaturated esters and ketones.

A little cooperation goes a long way: The cooperative Brønsted/Lewis acid-base supramolecular catalysts formed in situ from simple chiral magnesium(II) binaphtholate aqua complexes promoted the highly enantioselective 1,4-hydrophosphinylation of α,ß-unsaturated esters with diaryl phosphine oxides and 1,2-hydrophosphonylation of α,ß-unsaturated ketones with dialkyl phosphites (see scheme).

Magnesium(II)-binaphtholate as a practical chiral catalyst for the enantioselective direct Mannich-type reaction with malonates.

A highly enantioselective direct Mannich-type reaction of aldimines with dialkyl malonates was developed with the use of a Mg(II)-BINOLate salt, which was designed as a cooperative acid-base catalyst that can activate both aldimines and malonates. Optically active beta-aminoesters and alpha-halo-beta-aminoesters could be synthesized in high yields and with high enantioselectivities. This inexpensive and practical Mg(II)-BINOLate salt could be used in gram-scale catalysis.

Chiral lithium(I) binaphtholate salts for the enantioselective direct Mannich-type reaction with a change of syn/anti and absolute stereochemistry.

A highly diastereo- and enantioselective direct Mannich-type reaction of aldimines with 1,3-dicarbonyl compounds using Li(I) BINOLate salts as effective Lewis acid-Brønsted base catalysts has been developed. Li(I) BINOLate salts offered high catalytic activity toward 1,3-dicarbonyl compounds such as diketone, ketoester, ketothioester, ketoamide, and ketolactone. The reactions proceeded at -78 degrees C within 1-2 h in the presence of 1-10 mol % catalyst, which showed a catalytic activity (turnover frequency = 284 h(-1)) quite unlike those of other previous catalysts. Anti products were selectively obtained from acyclic ketoesters without epimerization at an alpha-tertiary-carbon center, and these are valuable since previous catalysts often gave syn/anti mixtures or the stereochemistry has not yet been determined.

Primary cutaneous aggressive epidermotropic CD8+ T-cell lymphoma with a CD15(+)CD30(-) phenotype.

Primary cutaneous aggressive epidermotropic CD8(+) T-cell lymphoma (CD8(+)TCL) is an extremely rare entity with distinct clinicopathological features. While the CD15 antigen is typically associated with classic Hodgkin's lymphoma, aggressive peripheral T-cell lymphomas, including advanced stage cutaneous T-cell lymphomas, rarely express this molecule. We report a case of primary cutaneous aggressive epidermotropic CD8(+)TCL, in which lymphoma cells are CD15(+)CD30(-) with a medium-to-large pleomorphic phenotype. Although the functional characteristics of CD15 expression in the cutaneous lymphomas are not fully understood, the poor prognosis of primary cutaneous aggressive epidermotropic CD8(+)TCL might be associated with the presence of this molecule in our case.

Induction of therapeutically relevant cytotoxic T lymphocytes in humans by percutaneous peptide immunization.

Percutaneous peptide immunization (PPI) is a simple and noninvasive immunization approach to induce potent CTL responses by peptide delivery via skin with the stratum corneum removed. After such a barrier disruption in human skin, epidermal Langerhans cells, although functionally matured through the up-regulation of HLA expression and costimulatory molecules, were found to emigrate with a reduced number of dendrites. CD8(+) populations binding to MHC-peptide tetramers/pentamers and producing IFN-gamma appeared in the blood after PPI with HLA class I-restricted antigenic peptides. PPI with melanoma-associated peptides reduced the lesion size and suppressed further development of tumors in four of seven patients with advanced melanoma. These beneficial effects were accompanied by the generation of circulating CTLs with in vitro cytolytic activity and extensive infiltration of tetramer/pentamer-binding cells into regressing lesions. PPI elicited neither local nor systemic toxicity or autoimmunity, except for vitiligo, in patients with melanoma. Therefore, PPI represents a novel therapeutic intervention for cancer in the clinical setting.

Chemokine receptor expression in cutaneous T cell and NK/T-cell lymphomas: immunohistochemical staining and in vitro chemotactic assay.

Interactions between chemokines and chemokine receptors are involved in migration and invasion of lymphoma cells. We investigated expression profiles of CXCR3 and CCR4 by immunohistochemistry and flow cytometry, and their biologic behaviors by real-time horizontal chemotaxis assay in cutaneous T cell and NK/T-cell lymphomas (TCLs). Tumor cells in mycosis fungoides (MF) constantly expressed CXCR3 at the patch stage, and expressed CCR4 at the tumor stage and in the folliculotropic variant of MF. Neoplastic cells at the plaque stage expressed CXCR3 and/or CCR4. Sezary cells in the dermis and circulation were positive for CCR4. Epidermotropic atypical cells in pagetoid reticulosis expressed CXCR3. CD30 cells exclusively expressed CCR4 in anaplastic large-cell lymphoma, and CXCR3 and/or CCR4 in lymphomatoid papulosis. In CD8TCL and extranodal NK/TCL characterized by extensive epidermotropism, tumor cells were positive for CXCR3. These data demonstrated preferential expression of CXCR3 in epidermotropic tumor cells, and of CCR4 in dermis-based lymphomas. In chemotaxis assays, CCR4 tumor cells in MF and CXCR3 tumor cells in CD8TCL migrated to thymus and activation-regulated chemokine and inducible protein-10, respectively. Therefore, spatial and temporal interactions between chemokine receptors and their ligands seem to dictate recruitment and retention of lymphoma cells in the skin.

Compartmental imbalance and aberrant immune function of blood CD123+ (plasmacytoid) and CD11c+ (myeloid) dendritic cells in atopic dermatitis.

Atopic dermatitis (AD) is a pruritic, chronically relapsing skin disease in which Th2 cells play a crucial role in cutaneous and extracutaneous immune reactions. In humans, CD11c+CD123- myeloid dendritic cells (mDC) and CD11c-CD123+ plasmacytoid DC (pDC) orchestrate the decision-making process in innate and acquired immunity. Since the number and function of these blood dendritic cell (DC) subsets reportedly reflect the host immune status, we studied the involvement of the DC subsets in the pathogenesis of AD. Patients with AD had an increased DC number and a low mDC:pDC ratio with pDC outnumbering mDC in the peripheral blood compared with normal subjects and psoriasis patients (a Th1 disease model group). The mDC:pDC ratio was correlated with the total serum IgE level, the ratio of IFN-gamma-producing blood cells:IL-4-producing blood cells, and the disease severity. In vitro allogeneic stimulation of naive CD4+ cells with atopic DC showed that the ability of pDC for Th1 induction was superior or comparable to that of mDC. In skin lesions, pDC infiltration was in close association with blood vessels expressing peripheral neural addressins. Therefore, compartmental imbalance and aberrant immune function of the blood DC subsets may deviate the Th1/Th2 differentiation and thus induce protracted allergic responses in AD.