Synthesis of Branch-Type 3-Allylindoles from N-Alkyl-N-cinnamyl-2-ethynylaniline Derivatives Using π-Allylpalladium Chloride Complex as a Catalyst.

The reaction of N-alkyl-N-cinnamyl-2-ethynylaniline derivatives 1 via annulation and aza-Claisen-type rearrangement easily afforded corresponding branch-type 3-allylindoles 2 with high regioselectivities in good yields using π-allylpalladium chloride complex as a catalyst.

Formal [3 + 2] Cycloaddition of α-Imino Esters with Azo Compounds: Facile Construction of Pentasubstituted 1,2,4-Triazoline Skeletons.

1,2,4-Triazole and 1,2,4-triazoline are important components of bioactive molecules and catalysts employed in organic synthesis. Therefore, the efficient synthesis of these components has received significant research attention. However, studies on their structural diversity remain lacking. Previously, we developed chiral phase-transfer-catalyzed asymmetric reactions of α-imino carbonyl compounds with α,ß-unsaturated carbonyl compounds and haloalkanes. In this study, we demonstrate the formal [3 + 2] cycloaddition reaction of α-imino esters with azo compounds under Brønsted base catalysis, resulting in the corresponding 1,2,4-triazolines in high yields. The results revealed that a wide range of substrates and reactants can be applied, irrespective of their steric and electronic characteristics. The present reaction made the general preparation of 3-aryl pentasubstituted 1,2,4-triazolines possible for the first time. Furthermore, a mechanistic study suggested that the reaction proceeds without isomerization into the aldimine form.

Intramolecular Azo Coupling Reaction of Binaphthyl Compounds: Synthesis of Pyrazole-Containing Helicene-Like Molecules.

A method for accessing pyrazole-containing helicene-like molecules from easily accessible NOBIN derivatives was developed. The reaction proceeded efficiently via diazonium salt intermediates, which provided a series of helicene-like molecular products in yields of 77%-89% regardless of their steric and electronic natures. The photophysical properties of the products were investigated. The 3,3'-disubstituted molecules showed a characteristic blue shift in their emission spectra. Product derivatizations were conducted, and interesting reactivities toward nucleophiles were observed.

Axially chiral N-alkyl-N-cinnamoyl amide type P,olefin ligands for Pd-catalyzed reactions.

We synthesized N-alkyl-N-cinnamoyl amide type phosphine-olefin compounds 1 and found axial chirality in a C(aryl)-N(amide) bond in compounds 1 by HPLC analysis using a chiral stationary phase column. We successfully obtained enantiomeric isomers of 1 and demonstrated the use of (-)-1 for chiral ligands in Pd-catalyzed asymmetric allylic substitution reactions of allylic esters with indoles (up to 97% ee).

Chiral Bromonium Salt (Hypervalent Bromine(III)) with N-Nitrosamine as a Halogen-Bonding Bifunctional Catalyst.

There has been a great focus on halogen-bonding as a unique interaction between electron-deficient halogen atoms with Lewis basic moieties. Although the application of halogen-bonded atoms in organic chemistry has been eagerly researched in these decades, the development of chiral molecules with halogen-bonding functionalities and their utilization in asymmetric catalysis are still in the\ir infancy. We have previously developed chiral halonium salts with amide functionalities, which behaved as excellent catalysts albeit in only two reactions due to the lack of substrate activation abilities. In this manuscript, we have developed chiral halonium salts with an N-nitrosamine moiety and applied them to the Mannich reaction of isatin-derived ketimines with malonic esters. The study focused on our novel bromonium salt catalyst which provided the corresponding products in high yields with up to 80% ee. DFT calculations of the chiral catalyst structure suggested that the high asymmetric induction abilities of this catalyst are due to the Lewis basic role of the N-nitrosamine part. To the best of our knowledge, this is the first catalytic application of N-nitrosamines.

Synthesis of 3-Allylindoles via Annulation of N-Allyl-2-ethynylaniline Derivatives Using a P,Olefin Type Ligand/Pd(0) Catalyst.

Annulation of N-allyl-2-ethynylaniline derivatives easily afforded the corresponding 2-substituted 3-allylindole derivatives in good to excellent yields using P,olefin ligand/palladium catalst systems.

Chiral Symmetry Breaking of Monoacylated Anhydroerythritols and meso-1,2-Diols through Crystallization-Induced Deracemization.

We developed a chiral symmetry breaking method for monoacylated meso diols. The X-ray crystal structure analysis of monoacylated 1,4-anhydroerythritols, meso cyclic diols with a cis configuration, revealed that the O-(p-anisoyl) derivative crystallized as a racemic conglomerate of the P21 21 21 crystal system. It was confirmed that the substrate racemized by intramolecular transfer of the acyl group in the presence of a catalytic amount of base. Evaporating the solvent gradually from the solution or Viedma ripening to promote crystallization-induced deracemization efficiently led to enantiomer crystals. These results provide the first successful example of asymmetric expression and amplification by deracemization of sugar derivatives without an external chemical chiral source. Furthermore, we applied this methodology to acyclic meso-1,2-diols. Three O-monoacylated substrates were successfully deracemized to 99 % ee by Viedma ripening. We also developed asymmetric desymmetrization of meso-1,2-diols by combining acylation and crystallization-induced deracemization.

Cinnamoyl amide type chiral P,olefin ligands for Pd-catalyzed reactions.

We synthesized cinnamoyl amide type chiral P,olefin ligand (S)-4. We successfully obtained separable diastereomers of 4d and demonstrated Pd-catalyzed asymmetric allylic substitution reactions of indoles using (S,aS)-4d as a chiral ligand with high enantioselectivities (up to 98% ee).

Asymmetric Synthesis of Indoline from Achiral Phthalimide Involving Crystallization-Induced Deracemization.

Asymmetric synthesis was performed by combining the photochemical reaction of an achiral substrate followed by crystallization-induced deracemization. The results indicated that a fused indoline produced by photochemical intramolecular δ-hydrogen abstraction and cyclization of N-(5-chloro-2-methylphenyl)phthalimide crystallized as a racemic conglomerate. Since this substrate has an aminal skeleton, racemization involving a ring-opening and ring-closing equilibrium process occurred under suitable conditions. Efficient racemization was observed in acetone containing a catalytic base, 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU). Crystallization-induced dynamic deracemization by Viedma ripening from racemic indoline was performed with an excellent enantioselectivity of 99 % ee. Furthermore, one-pot asymmetric synthesis of the indoline was achieved by the photochemical reaction of achiral phthalimide followed by continuous attrition-enhanced deracemization converging to 99 % ee of enantiomeric crystals. This is the first example of asymmetric expression and amplification by photochemical hydrogen abstraction and crystallization-induced dynamic deracemization.

Unexpected formation of poly-functionalized fulvenes by the reaction of a tetraaryl[5]cumulene with iodine.

Longer cumulenes have come to draw considerable attention due to their unique properties and reactivities, leading to various hydrocarbons. In this manuscript, we describe the reaction of tetrakis(p-methoxyphenyl)[5]cumulene with iodine to afford poly-functionalized fulvenes via unexpected migration of a terminal aryl ring under ambient conditions. The obtained iodinated fulvenes were utilized in Suzuki-Miyaura cross-coupling reactions affording penta- and fully-arylated fulvenes successfully.

Synthesis of D-π-A type benzothiazole-pyridinium salt composite and its application as photo-degradation agent for amyloid fibrils.

We have synthesized a cyan fluorescent benzothiazole-pyridinium salt composite based on D-π-A architecture. This salt was found to work as not only a two- and three-photon excitable fluorophore but also a degradation agent against amyloid fibrils under LED irradiation conditions.

Phase-transfer catalysed asymmetric synthesis of α-chiral tetrasubstituted α-aminothioesters.

Chiral amino thioesters are important scaffolds owing to their widespread use in organic synthesis and biosynthesis. Despite their usefulness, their asymmetric synthesis, especially the catalytic asymmetric synthesis of α-chiral tetrasubstituted α-aminothioesters, is limited, with only one example reported so far. Herein, we report the first phase-transfer catalysed asymmetric synthesis of α-chiral tetrasubstituted α-aminothioesters to afford the corresponding products in up to 81% ee.

Iminophosphorane-mediated regioselective umpolung alkylation reaction of α-iminoesters.

Umpolung reactions of imines, especially the asymmetric reactions, have been extensively studied as they provide access to important chiral amines in an efficient manner. The reactions studied range from simple Michael reactions to several kinds of other reactions such as the aza-benzoin reaction, aza-Stetter reaction, addition with MBH carbonate, and Ir-catalysed allylation. Herein, we report the first umpolung alkylation reaction of α-iminoesters with alkyl halides mediated by iminophosphorane as an organic superbase. The desired products were obtained in up to 82% yield with almost perfect regioselectivities. The key to the regioselectivity of this reaction was the use of 4-trifluoromethyl benzyl imines as a substrate. The products were successfully derivatised into the more functionalised molecules in good yields.

Chirogenesis and Amplification of Molecular Chirality Using Optical Vortices.

The study of chirogenesis of organic molecules is important to elucidate the origin of the homochirality of biomolecules on Earth. Here, we have accomplished chiral symmetry breaking from a racemate using optical vortices with orbital angular momentum and a helical wavefront. We propose a new methodology of asymmetric transformation by the combination of enantioselective crystal nucleation by irradiation with optical vortices and crystallization-induced dynamic optical resolution of conglomerate crystals. Chiral green vortices generated using a spiral phase plate (SPP) with a 532 nm CW-laser were used to irradiate a supersaturated solution of a racemic isoindolinone, leading to crystal nucleation. The handedness of the crystals were controlled by the winding direction of the chiral optical vortices. The molecular chirality of the isoindolinone was then amplified by dynamic crystallization.

Bromonium salts: diaryl-λ3-bromanes as halogen-bonding organocatalysts.

Bromonium salts have been typically but infrequently used in various reactions as good leaving groups or as aryl or vinyl transfer reagents owing to their extremely high nucleofugality. Herein, we report the synthesis of novel, stable bromonium salts and their first catalytic application to the Michael reaction, with excellent product yield (up to 96%).

Attrition-Enhanced Asymmetric Transformation of Axially Chiral Nicotinamides by Dynamic Chiral Salt Formation.

Atroposelective resolution for axially chiral nicotinamides was achieved by dynamic chiral salt formation with L-DBTA using six types of nicotinamides that could not be optically resolved by the preferential crystallization method. Kinetic studies of their racemization indicated that the chiral conformation was retained for a significant period of time. Two methods of crystallization-induced asymmetric transformation were examined by dynamic diastereomeric salt formation: solvent evaporation from a supersaturated solution, and attrition-enhanced asymmetric transformation. The attrition method was more effective for asymmetric amplification of diastereomeric salts of axially chiral materials. Attrition of equimolar amount of the nicotinamide salts with L-DBTA converged to one diastereomer salts, and the corresponding enantiomers in 87-99 % ee were obtained after the chiral acid was removed. Changing the ratio of two of the nicotinamides with L-DBTA to 1 : 2 inverted the axial chirality.

Two-photon excitable boron complex based on tridentate imidazo[1,5-a]pyridine ligand for heavy-atom-free mitochondria-targeted photodynamic therapy.

We have synthesized a cyan fluorescent boron complex based on a tridentate imidazo[1,5-a]pyridine ligand. The boron complex was found to have potential applications as not only a chiroptical material but also a heavy-atom-free mitochondria-targeted photosensitizer for cancer treatment.

Two- and three-photon excitable quaternized imidazo[1,2-a]pyridines as mitochondrial imaging and potent cancer therapy agents.

We have synthesized a series of quaternized imidazo[1,2-a]pyridines in three steps from commercially available reagents. These compounds exhibit blue fluorescence emission at around 425 nm with good quantum yields. In addition, one specific compound was found to work as not only a two- and three-photon excitable mitochondria imaging agent, but also a therapeutic agent upon continuous irradiation conditions.

Subtotal gastrectomy for gastric tube cancer using intraoperative indocyanine green fluorescence method.

INTRODUCTION: Currently, the frequency of evaluating the flow of a reconstructed gastric tube using indocyanine green (ICG) fluorescence has been increasing. However, it has been difficult to decide on the operation method for patients with gastric tube cancer (GTC). We herein report a case in which ICG was effective in a patient with resection of GTC. PRESENTATION OF CASE: An 83-year-old man underwent subtotal esophagectomy with gastric tube reconstruction via the retrosternal route for esophageal cancer and right hemicolectomy for ascending colon cancer 16 years earlier. Postoperatively, the proximal part of the gastric tube had poor blood flow. Therefore, the patient underwent proximal-side resection of the gastric tube. Thereafter, free jejunal graft reconstruction was performed. The patient had not developed recurrence at that point. Recently, the patient visited the hospital complaining of nausea and chest discomfort. Upper gastrointestinal endoscopy revealed a type 0-IIa + IIc lesion located around the pylorus. A biopsy showed adenocarcinoma. Based on these findings, the patient was diagnosed with gastric tube cancer (cT1bN0M0StageI). The invasion depth of the cancer was predicted to be widespread submucosal invasion. Therefore, the patient underwent surgery. Intraoperatively, we evaluated the flow of the gastric tube after clamping the right gastroepiploic artery using ICG fluorescence. As a result, the flow of the gastric tube was deemed insufficient. Consequently, subtotal gastrectomy was performed with preservation of the right gastroepiploic artery via Roux-en-Y reconstruction. DISCUSSION: ICG fluorescence is useful for evaluating the flow of the gastric tube helping to decide the operating method. CONCLUSION: We herein report a case of subtotal gastrectomy for GTC using intraoperative ICG fluorescence.

[A Case of Long-Term Survival after Chemotherapy and Ablation Therapy Using Various Approaches for Multiple Colon Cancer Liver Metastases].

A 58-year-old man with unresectable sigmoid colon cancer and multiple liver metastases(H2, more than 30)received chemotherapy for 2 years. Subsequently, the patient was diagnosed with stenosis of the primary lesion and 5 bilobar, metastatic tumors. Simultaneous resection was unsuitable because of the performance status and comorbidities of the patient. The first surgery consisted of laparoscopic-assisted sigmoidectomy, laparoscopic microwave coagulation therapy(MCT), and percutaneous radiofrequency ablation(RFA). Percutaneous RFA was additionally performed after 2 months. Since 2 liver metastases(S3 and S8)were inadequately treated, 3 courses of P-mab plus FOLFIRI were administered. Finally, laparoscopic- assisted RFA was performed. Subsequently, serum CEA reduced from 288.3 ng/mL to the normal level. We used fusion imaging US, sonazoid US, laparoscopic convex probe, and ICG fluorescence imaging for ablation therapy. Chemotherapy and ablation therapy using various approaches can control unresectable multiple liver metastases and prolong survival by more than 3 years.