Leveraging the Stereochemical Complexity of Octahedral Diastereomeric-at-Metal Catalysts to Unlock Regio-, Diastereo-, and Enantioselectivity in Alcohol-Mediated C-C Couplings via Hydrogen Transfer.

Experimental and computational studies illuminating the factors that guide metal-centered stereogenicity and, therefrom, selectivity in transfer hydrogenative carbonyl additions of alcohol proelectrophiles catalyzed by chiral-at-metal-and-ligand octahedral d6 metal ions, iridium(III) and ruthenium(II), are described. To augment or invert regio-, diastereo-, and enantioselectivity, predominantly one from among as many as 15 diastereomeric-at-metal complexes is required. For iridium(III) catalysts, cyclometalation assists in defining the metal stereocenter, and for ruthenium(II) catalysts, iodide counterions play a key role. Whereas classical strategies to promote selectivity in metal catalysis aim for high-symmetry transition states, well-defined low-symmetry transition states can unlock selectivities that are otherwise difficult to achieve or inaccessible.

Iridium-Catalyzed [2 + 2 + 2] Cycloaddition of Bithiophen-Linked Diynes with Nitriles: Scope and Mechanistic Study with Quantum Chemical Calculation.

We report a simple and atom-efficient method for the synthesis of bithiophene-fused isoquinolines by iridium-catalyzed [2 + 2 + 2] cycloaddition of bithiophene-linked diynes with nitriles. All three structural isomers of bithiophene-linked diynes underwent [2 + 2 + 2] cycloaddition, and the trend in the reactivity for cycloaddition was diyne 1 = diyne 3 > diyne 2. Dibenzothiophene-linked diyne also reacted with nitriles to form a variety of cycloadducts. Cycloaddition of bithiophene-linked diynes with alkynes and an isocyanate formed naphthodithiophenes and a 2-pyridone derivative, respectively. Cycloadducts bearing a 2-aminopyridine moiety and benzothiophene rings showed intense fluorescence at around 530 nm and gave a fluorescence quantum yield of 0.44. Furthermore, quantum chemical calculations provided insight into the origin of the difference in reactivity of three bithiophene-linked diynes. The different reactivities of the three diynes 1-3 are believed to originate from the step where an iridacyclopentadiene reacts with a coordinated nitrile to form azairidabicyclo[3.2.0]heptatriene. HOMOs of iridacyclopentadiene play a decisive role in this step.

Excitation configuration analysis for divide-and-conquer excited-state calculation method using dynamical polarizability.

The authors previously developed a divide-and-conquer (DC)-based non-local excited-state calculation method for large systems using dynamical polarizability [Nakai and Yoshikawa, J. Chem. Phys. 146, 124123 (2017)]. This method evaluates the excitation energies and oscillator strengths using information on the dynamical polarizability poles. This article proposes a novel analysis of the previously developed method to obtain further configuration information on excited states, including excitation and de-excitation coefficients of each excitation configuration. Numerical applications to simple molecules, such as ethylene, hydrogen molecule, ammonia, and pyridazine, confirmed that the proposed analysis could accurately reproduce the excitation and de-excitation coefficients. The combination with the DC scheme enables both the local and non-local excited states of large systems with an excited nature to be treated.

Chiral-at-Ruthenium-SEGPHOS Catalysts Display Diastereomer-Dependent Regioselectivity: Enantioselective Isoprene-Mediated Carbonyl tert-Prenylation via Halide Counterion Effects.

The first correlation between metal-centered stereogenicity and regioselectivity in a catalytic process is described. Alternate pseudo-diastereomeric chiral-at-ruthenium complexes of the type RuX(CO)[η3-prenyl][(S)-SEGPHOS] form in a halide-dependent manner and display divergent regioselectivity in catalytic C-C couplings of isoprene to alcohol proelectrophiles via hydrogen autotransfer. Whereas the chloride-bound ruthenium-SEGPHOS complex prefers a trans-relationship between the halide and carbonyl ligands and delivers products of carbonyl sec-prenylation, the iodide-bound ruthenium-SEGPHOS complex prefers a cis-relationship between the halide and carbonyl ligands and delivers products of carbonyl tert-prenylation. The chloride- and iodide-bound ruthenium-SEGPHOS complexes were characterized in solution and solid phase by 31P NMR and X-ray diffraction. Density functional theory calculations of the iodide-bound catalyst implicate a Curtin-Hammett-type scenario in which the transition states for aldehyde coordination from an equilibrating mixture of sec- and tert-prenylruthenium complexes are rate- and product-determining. Thus, control of metal-centered diastereoselectivity has unlocked the first catalytically enantioselective isoprene-mediated carbonyl tert-prenylations.

Coordinated regulation of TORC2 signaling by MCC/eisosome-associated proteins, Pil1 and tetraspan membrane proteins during the stress response.

MCCs are linear invaginations of the yeast plasma membrane that form stable membrane microdomains. Although over 20 proteins are localized in the MCCs, it is not well understood how these proteins coordinately maintain normal MCC function. Pil1 is a core eisosome protein and is responsible for MCC-invaginated structures. In addition, six-tetraspan membrane proteins (6-Tsp) are localized in the MCCs and classified into two families, the Sur7 family and Nce102 family. To understand the coordinated function of these MCC proteins, single and multiple deletion mutants of Pil1 and 6-Tsp were generated and their MCC structure and growth under various stresses were investigated. Genetic interaction analysis revealed that the Sur7 family and Nce102 function in stress tolerance and normal eisosome assembly, respectively, by cooperating with Pil1. To further understand the role of MCCs/eisosomes in stress tolerance, we screened for suppressor mutants using the SDS-sensitive phenotype of pil1Δ 6-tspΔ cells. This revealed that SDS sensitivity is caused by hyperactivation of Tor kinase complex 2 (TORC2)-Ypk1 signaling. Interestingly, inhibition of sphingolipid metabolism, a well-known downstream pathway of TORC2-Ypk1 signaling, did not rescue the SDS-sensitivity of pil1Δ 6-tspΔ cells. These results suggest that Pil1 and 6-Tsp cooperatively regulate TORC2 signaling during the stress response.

Iridium-Catalyzed Branch-Selective Hydroalkylation of Simple Alkenes with Malonic Amides and Malonic Esters.

We report the iridium-catalyzed branch-selective hydroalkylation of simple alkenes such as aliphatic alkenes and aromatic alkenes with malonic amides and malonic esters under neutral reaction conditions. A variety of aliphatic alkenes and aromatic alkenes bearing bromine, chlorine, ester, 2-thienylcarboxylate, silyl, and phthalimide groups were all found to be suitable for this hydroalkylation. The combination of this method with Krapcho dealkoxycarbonylation realized a one-pot synthesis of ß-substituted amide and ester from ß-amide ester and malonic ester. The hydroalkylated products derived from malonic amides are suitable for further transformation. The finely tuned reaction conditions realized the selective transformation of hydroalkylated products to 1,3-diamines or monoamides with the same reagent. Deuterium labeling experiments and measurement of the kinetic isotope effect indicated that the catalytic cycle involves a reversible step and cleavage of the C-H bond is not a rate-determining step. Density functional theory calculations provided insight into the reaction mechanism, where the carboiridation step is followed by C-H reductive elimination.

Unveiling controlling factors of the S0/S1 minimum-energy conical intersection (3): Frozen orbital analysis based on the spin-flip theory.

Conical intersections (CIs), which indicate the crossing of two or more adiabatic electronic states, are crucial in the mechanisms of photophysical, photochemical, and photobiological processes. Although various geometries and energy levels have been reported using quantum chemical calculations, the systematic interpretation of the minimum energy CI (MECI) geometries is unclear. A previous study [Nakai et al., J. Phys. Chem. A 122, 8905 (2018)] performed frozen orbital analysis (FZOA) based on time-dependent density functional theory (TDDFT) at the MECI formed between the ground and first electronic excited states (S0/S1 MECI), thereby inductively clarifying two controlling factors. However, one of the factors that the highest occupied molecular orbital (HOMO) and the lowest unoccupied molecular orbital (LUMO) energy gap became close to the HOMO-LUMO Coulomb integral was not valid in the case of spin-flip TDDFT (SF-TDDFT), which is frequently used as a means of the geometry optimization of MECI [Inamori et al., J. Chem. Phys. 152, 144108 (2020)]. This study revisited the controlling factors using FZOA for the SF-TDDFT method. Based on spin-adopted configurations within a minimum active space, the S0-S1 excitation energy is approximately represented by the HOMO and LUMO energy gap ΔεHL, a contribution from Coulomb integrals JHL″ and that from the HOMO-LUMO exchange integral KHL″. Furthermore, numerical applications of the revised formula at the SF-TDDFT method confirmed the control factors of S0/S1 MECI.

Metastatic basal cell carcinoma of buccal mucosa: a report of a rare case.

BACKGROUND: Basal cell carcinoma (BCC) is the most common cancer worldwide. Most of BCCs can be detected in the early stages and are generally well controlled with local resection. Despite the high incidence of BCC, metastasis is rarely observed. Metastatic BCCs generally have an aggressive phenotype and are refractory to conventional treatment. CASE PRESENTATION: We describe a rare case of BCC in which a series of local relapses culminated in metastasis into the oral cavity 10 years after the first diagnosis of cutaneous BCC. We performed surgical resection and postoperative radiotherapy in this patient; 11 months after the final course of radiotherapy, the BCC remains stable, and the patient continues to be monitored regularly. CONCLUSIONS: Because metastatic BCC is refractory to current treatment and difficult to control, his treatment history and the pathohistological features of BCC had to be considered in posttreatment planning.

Ruthenium- and Copper-Catalyzed Propargylic Substitution Reactions of Propargylic Alcohol Derivatives with Hydrazones.

Ruthenium- and copper-catalyzed propargylic substitution reactions of propargylic alcohol derivatives with N-monosubstituted hydrazones as ambident nucleophiles are achieved in which N-monosubstituted hydrazones exhibit impressive different reactivities depending on different catalytic systems, behaving as carbon-centered nucleophiles to give the corresponding propargylic alkylated products in ruthenium catalysis, or as nitrogen-centered nucleophiles to afford the corresponding propargylic aminated products in copper catalysis. DFT calculations were carried out to investigate the detailed reaction pathways of these two systems. Further transformation of propargylic substituted products affords the corresponding multisubstituted pyrazoles as cyclization products in good to high yields.

Ruthenium- and Copper-Catalyzed Propargylic Substitution Reactions of Propargylic Alcohol Derivatives with Hydrazones.

Invited for the cover of this issue are Ken Sakata, Yoshiaki Nishibayashi, and co-workers at The University of Tokyo and Toho University. The image depicts the propargylic substitution reaction of a propargylic alcohol with an N-monosubstituted hydrazone, where the nucleophilicity of the hydrazone is controlled by the choice of catalytic system. Read the full text of the article at 10.1002/chem.202103287.

Ruthenium-Catalyzed Enantioselective Propargylic Phosphinylation of Propargylic Alcohols with Phosphine Oxides.

The development of transition metal-catalyzed enantioselective propargylic substitution reactions has gained much progress in recent years, however, no successful example with phosphorus-centered nucleophiles has yet been reported until now. Herein, we report the first successful example of ruthenium-catalyzed enantioselective propargylic substitution reactions of propargylic alcohols with diarylphosphine oxides as phosphorus-centered nucleophiles. This synthetic approach provides a new method to prepare chiral phosphorus-containing organic compounds.

Total Synthesis of (-)-Graminin A Based on Asymmetric Cyclization Carbonylation of Propargyl Acetate.

The first total synthesis of (-)-graminin A is described. Key features of our synthetic approach involve a palladium-catalyzed asymmetric cyclization carbonylation of prochiral propargylic acetate, conversion of the orthoester product into methyl 4-oxo-3-furancarboxylate, and copper complex-mediated aldol condensation of (+)-gregatin B bearing a diene moiety. A new synthesis of (+)-gregatin B and the first synthesis of (-)-graminin A were achieved.

Copper-Catalyzed [3+2] Cycloaddition Reactions of Isocyanoacetates with Phosphaalkynes to Prepare 1,3-Azaphospholes.

A novel copper-catalyzed synthetic method is described for phosphorous- and nitrogen-containing heterocycles such as 1,3-azaphospholes. Cycloaddition reactions of various isocyanoacetates with phosphaalkynes in the presence of copper bromide, bis(diphenylphosphino)methane (dppm), and potassium carbonate afford the corresponding 1,3-azaphospholes in high yields with complete selectivity. Some dppm-bridged dicopper complexes were identified as active species for the formation of 1,3-azaphospholes.

Force constant decomposition for penta-coordinated XH3 Cl2- (X = C, Si, Ge) structures.

Based on the energy decomposition analysis of an interacting system, we propose a method for force constant decomposition analysis with respect to the specific normal coordinate. Using the presented method, we examined the penta-coordinated XH3Cl2- system (X = C, Si, Ge), which possesses a three-center four-electron bond. The origin of the difference in the stability of the penta-coordinated D3h structures was clearly shown to be the effect of electron delocalization-polarization term. © 2018 Wiley Periodicals, Inc.

UVA- and Visible-Light-Mediated Generation of Carbon Radicals from Organochlorides Using Nonmetal Photocatalyst.

Carbon radicals are reactive species useful in various organic transformations. The C-X bond cleavage of organohalides by photoirradiation is a common method to generate carbon radicals in a controlled fashion. The use of organochloride substrates is still a formidable challenge due to the low reduction potential and the high dissociation energy of the C-Cl bond. In this report, we address these issues by using a nonmetal organic molecule with a relatively simple structure as a photocatalyst. In this catalyst (bis(dimethylamino)carbazole), the amino groups increase both the HOMO and LUMO energy levels, especially in the former. As a result, compared to the parent molecule, the new catalyst shows experimentally red-shifted absorption in the visible region and forms an excited state with better reducing capability. This photocatalyst was used in the reduction of unactivated aryl chlorides and alkyl chlorides in the presence of hydrogen atom donor at room temperature. The catalytic system can also be applied to the coupling of aryl chlorides with electron-rich arene and heteroarenes to affect the C-C bond-forming reactions. Our mechanistic study results support the assumption that carbon radicals are formed from the organochlorides via a single-electron-transfer step.

Catalytic Activity of Thiolate-Bridged Diruthenium Complexes Bearing Pendent Ether Moieties in the Oxidation of Molecular Dihydrogen.

Thiolate-bridged diruthenium complexes bearing pendent ethers have been found to work as effective catalysts toward the oxidation of molecular dihydrogen into protons and electrons in water. The pendent ether moiety in the complex plays an important role to facilitate the proton transfer between the metal center and the external proton acceptor.

Cp*CoIII-Catalyzed C-H Alkenylation/Annulation Reactions of Indoles with Alkynes: A DFT Study.

The Cp*CoIII-catalyzed C-H functionalization reaction of indoles with alkynes was examined using M06-level DFT calculations. The C≡C bond in the alkyne was inserted into the Co-C bond of an intermediate alkenyl-Co complex given by the acetate-assisted C-H bond activation step. Then the reaction pathway bifurcated into alkenylation and annulation pathways. In the case where AcOH, which was eliminated by ligand exchange for the alkyne, recoordinated to the Co atom, alkenylation proceeded via proton transfer. On the other hand, the annulation pathway to give pyrroloindolone became significant in the case where the ring-closure C-C bond formation was followed by the attachment of AcOH. At a high temperature (393 K), the difference in the Gibbs free energy between the transition state for proton transfer in the alkenylation pathway and that for the ring-closure C-C bond formation in the annulation pathway was relatively small, so both reactions could proceed. In addition, we also found another pathway to provide the directing-group migration on the way to annulation. This finding well elucidates the recent experimental report that tetrasubstituted alkenes were obtained as the major product under different conditions.

Origin of High Regio-, Diastereo-, and Enantioselectivities in 1,6-Addition of Azlactones to Dienyl N-Acylpyrroles: A Computational Study.

Chiral P-spiro triaminoiminophosphorane (1) was developed to promote the highly regio-, diastereo-, and enantioselective 1,6- and 1,8-additions of azlactones (2·H) to dienyl and trienyl N-acylpyrroles (3 and 4). DFT calculations enabled us to gain deep insight into the whole reaction mechanism as well as the origin of the high regio- and stereoselectivities. The present reaction consists of three steps: (1) formation of the phosphonium-enolate ion-pair complex by deprotonation of 2·H with 1, (2) C-C bond formation of 2 with 3 and 4, and (3) protonation of the resulting enolate anion. The C-C bond formation is irreversible, and the rate- and stereodetermining step. The Cα-protonation preferentially proceeds rather than the thermodynamically and kinetically disfavored O- and Cγ-protonation, respectively. The high regio- and enantioselectivities are mainly attributed to the steric and electronic features of 1·H and 3/4. The hydrogen bonds (NH-O and CH-O) and the attractive CH-π interaction between 1·H and 2 and 3 play a key role in achieving high stereocontrol. The high regioselectivity is mainly controlled by the structural distortion of 1·H and the disruption of the π-conjugated system of 3 (1,4-system) and 4 (1,4- and 1,6-systems).

Stereoselective Synthesis of Tetrasubstituted Alkenes via a Cp*CoIII -Catalyzed C-H Alkenylation/Directing Group Migration Sequence.

A highly atom economical and stereoselective synthesis of tetrasubstituted α,ß-unsaturated amides was achieved by a Cp*CoIII -catalyzed C-H alkenylation/directing group migration sequence. A carbamoyl directing group, which is typically removed after C-H functionalization, worked as an internal acylating agent and migrated onto the alkene moiety of the product. The directing group migration was realized with the Cp*CoIII catalyst, while a related Cp*RhIII catalyst did not promote the migration process. The product was further converted into two types of tricyclic compounds, one of which had fluorescent properties.

Thiolate-bridged dinuclear ruthenium and iron complexes as robust and efficient catalysts toward oxidation of molecular dihydrogen in protic solvents.

Thiolate-bridged dinuclear ruthenium and iron complexes are found to work as efficient catalysts toward oxidation of molecular dihydrogen in protic solvents such as water and methanol under ambient reaction conditions. Heterolytic cleavage of the coordinated molecular dihydrogen at the dinuclear complexes and the sequential oxidation of the produced hydride complexes are involved as key steps to promote the present catalytic reaction. The catalytic activity of the dinuclear complexes toward the chemical oxidation of molecular dihydrogen achieves up to 10000 TON (turnover number), and electrooxidation of molecular dihydrogen proceeds quite rapidly. The result of the density functional theory (DFT) calculation on the reaction pathway indicates that a synergistic effect between the two ruthenium atoms plays an important role to realize the catalytic oxidation of molecular dihydrogen efficiently. The present dinuclear ruthenium complex is found to work as an efficient organometallic anode catalyst for the fuel cell. It is noteworthy that the present dinuclear complex worked not only as an effective catalyst toward chemical and electrochemical oxidation of molecular dihydrogen but also as a good anode catalyst for the fuel cell. We consider that the result described in this paper provides useful and valuable information to develop highly efficient and low-cost transition metal complexes as anode catalysts in the fuel cell.