Practical and Facile Access to Bicyclo[3.1.1]heptanes: Potent Bioisosteres of meta-Substituted Benzenes.

There is increasing interest in replacement of the planar aromatic rings of drug candidates with three-dimensional caged scaffolds in order to improve the physical properties, but bioisosteres of meta-substituted benzenes have remained elusive. We focused on the bicyclo[3.1.1]heptane (BCH) scaffold as a novel bioisostere of meta-substituted benzenes, anticipating that [3.1.1]propellane (2) would be a versatile precursor of diversely functionalized BCHs. Here, we describe a practical preparative method for [3.1.1]propellane from newly developed 1,5-diiodobicyclo[3.1.1]heptane (1), as well as difunctionalization reactions of 2 leading to functionalized BCHs. We also report postfunctionalization reactions of these products.

A network analysis of problematic smartphone use in Japanese young adults.

BACKGROUND: We aimed to explore the overall network structure of problematic smartphone use symptoms assessed by smartphone addiction scale-short version (SAS-SV) and to identify which items could play important roles in the network. METHODS: 487 college and university students filled out the study questionnaire, including SAS-SV. We constructed a regularized partial correlation network among the 10 items of SAS-SV. We calculated three indices of node centrality: strength, closeness, and betweenness, to quantify the importance of each SAS-SV item. RESULTS: We identified 34 edges in the estimated network. In the given network, one item pertaining to withdrawal symptom hadthe highest strength and high closeness centrality. Additionally, one item related to preoccupation was also found to have high centrality indices. CONCLUSION: Our results indicating the central role of one withdrawal symptom and one preoccupation symptom in the symptom network of problematic smartphone use in young adults were in line with a previous study targeting school-age children. Longitudinal study designs are required to elicit the role of these central items on the formation and maintenance of this behavioral problem.

Associations Between Recipients' Feelings of Guilt for Donor and Depressive Symptoms Before Living Kidney Transplantation.

BACKGROUND: Recipient depression before kidney transplantation needs to be treated to reduce poor posttransplant outcomes. For recipients who receive living kidney transplantation, feelings of guilt for potential donors may be factors related to the presence of depressive symptoms. This study aimed to examine the association between recipients' feelings of guilt for the donor and depressive symptoms before living kidney transplantation. METHODS: Participants included 178 patients in Sapporo City General Hospital, Hokkaido, Japan, who completed a questionnaire before having living kidney transplantation from April 2009 to May 2016. Feelings of guilt for the donor, depressive symptoms using the Beck Depression Inventory-II (BDI-II), relationship to the donor, dialysis period, and socio-demographic characteristics were assessed via a questionnaire. Multivariate regression analyses were performed to examine the association between feelings of guilt for the donor and BDI-II score after multiple imputations. RESULTS: The results showed that feelings of guilt for donors were associated with depressive symptoms, especially cognitive factors. CONCLUSIONS: These findings indicate that medical staff needs to address recipients' feelings of guilt for donors before living kidney transplantation.

Synthetic Access to gem-Difluoropropargyl Vinyl Ethers and Their Application to Propargyl Claisen Rearrangement.

With the increasing importance of fluorine to medicinal chemistry and other areas, methods to access various fluorinated compounds are needed. Herein, we report the synthesis of difluoropropargyl vinyl ethers from ketones and aldehydes using difluoropropargyl bromide dicobalt complexes. We applied difluoropropargyl vinyl ethers to the synthesis of difluorodienone or difluoroallene under thermal conditions and trifluoro-pyran under acid-catalyzed conditions.

α-Cyclodextrin Encapsulation of Bicyclo[1.1.1]pentane Derivatives: A Storable Feedstock for Preparation of [1.1.1]Propellane.

The bicyclo[1.1.1]pentane (BCP) scaffold is useful in medicinal chemistry, and many protocols are available for synthesizing BCP derivatives from [1.1.1]propellane. Here, we report (1) the α-cyclodextrin (α-CD) encapsulation of BCP derivatives, affording a stable, readily storable material from which BCPs can be easily and quantitatively recovered and (2) new and simple protocols for deiodination reaction of 1,3-diiodo BCP to afford [1.1.1]propellane in protic/aprotic/polar/non-polar solvents. The combination of these methodologies enables simple, on-demand preparation of [1.1.1]propellane in various solvents under mild conditions from α-CD capsules containing 1,3-diiodo BCP.

DFT Study of a Missing Piece in Brasilane-Type Structure Biosynthesis: An Unusual Skeletal Rearrangement.

Brasilane-type sesquiterpenes have been known for a long time, but their biosynthetic pathways and mechanisms remain elusive. Recently, two groups independently characterized a Trichoderma terpene cyclase that produces trichobrasilenol, a brasilane-type sesquiterpene, and a plausible biosynthetic pathway was proposed based on isotopic labeling experiments. In the proposed mechanism, the characteristic brasilane-type 5/6 bicyclic skeleton is synthesized from a 5/7/3 tricyclic intermediate via a complicated concerted reaction, including six chemical events of C-C σ bond metathesis and rearrangements, ring-contraction, π bond formation, and regioselective hydroxylation. However, our density functional theory (DFT) calculations do not support this mechanism. On the basis of DFT calculations, we propose a new pathway for trichobrasilenol biosynthesis, involving a multistep carbocation cascade in which cyclopropylcarbinyl cations in equilibrium with homoallyl cations play a pivotal role. This pathway and mechanism is in good agreement with previous biosynthetic studies on brasilane-type compounds and related terpenoids, including isotope-labeling experiments and byproducts analysis.

Biosynthesis of Indole Diterpene Lolitrems: Radical-Induced Cyclization of an Epoxyalcohol Affording a Characteristic Lolitremane Skeleton.

Lolitrems are tremorgenic indole diterpenes that exhibit a unique 5/6 bicyclic system of the indole moiety. Although genetic analysis has indicated that the prenyltransferase LtmE and the cytochrome P450 LtmJ are involved in the construction of this unique structure, the detailed mechanism remains to be elucidated. Herein, we report the reconstitution of the biosynthetic pathway for lolitrems employing a recently established genome-editing technique for the expression host Aspergillus oryzae. Heterologous expression and bioconversion of the various intermediates revealed that LtmJ catalyzes multistep oxidation to furnish the lolitrem core. We also isolated the key reaction intermediate with an epoxyalcohol moiety. This observation allowed us to establish the mechanism of radical-induced cyclization, which was firmly supported by density functional theory calculations and a model experiment with a synthetic analogue.

Shelf-Stable (E)- and (Z)-Vinyl-λ3-chlorane: A Stereospecific Hyper-vinylating Agent.

We report the first stereoselective synthesis of stable (E)- and (Z)-ß-chlorovinyl-λ3-chlorane via direct mesitylation of 1,2-dichloroethylene with mesityldiazonium tetrakis(pentafluorophenyl)borate under mild reaction conditions. The structure of the (E)-vinyl-λ3-chlorane was established by single-crystal X-ray analysis. Because of the enormously high leaving group ability of the aryl-λ3-chloranyl group, vinyl-λ3-chloranes undergo not only SNVσ-type reaction with extremely weak nucleophiles such as perfluoroalkanesulfonate, iodobenzene, and aromatic hydrocarbons but also coupling with phenylcopper(I) species.

Synthetic Studies on Pactamycin: A Synthesis of Johnson's Intermediate.

A formal total synthesis of pactamycin (1) has been accomplished by face-selective and regioselective nitroso Diels-Alder (NDA) reaction of acyl nitroso compound 14, which contains a camphorsultam chiral auxiliary, and chiral cyclopentadiene 12. Construction of the chiral secondary alcohol of 12 was performed by (S,S)-Ts-DENEB catalyst-mediated reduction, and the NDA adduct 15a was readily converted to Johnson's intermediate 21.

BF3-Catalyzed Skeletal Rearrangement of 7-En-2-ynones to endo-Type Cyclic Dienes.

Transition-metal-catalyzed cycloisomerization reactions with skeletal rearrangement of 1,n-enynes to afford cyclic dienes (particularly exo-cyclization products) have been well studied. However, there are few reports on the nonmetal-catalyzed skeletal rearrangement of enynes and skeletal rearrangement of electron-deficient enynes such as n-en-2-ynones. Here, we describe BF3·MeCN-catalyzed synthesis of 3-alkylidenecyclohexenes from 7-en-2-ynones, representing the first nonmetal-catalyzed skeletal rearrangement of 1,6-enynes to endo-type cyclic dienes.

Shimalactone Biosynthesis Involves Spontaneous Double Bicyclo-Ring Formation with 8π-6π Electrocyclization.

Shimalactones A and B are neuritogenic polyketides possessing characteristic oxabicyclo[2.2.1]heptane and bicyclo[4.2.0]octadiene ring systems that are produced by the marine fungus Emericella variecolor GF10. We identified a candidate biosynthetic gene cluster and conducted heterologous expression analysis. Expression of ShmA polyketide synthase in Aspergillus oryzae resulted in the production of preshimalactone. Aspergillus oryzae and Saccharomyces cerevisiae transformants expressing ShmA and ShmB produced shimalactones A and B, thus suggesting that the double bicyclo-ring formation reactions proceed non-enzymatically from preshimalactone epoxide. DFT calculations strongly support the idea that oxabicyclo-ring formation and 8π-6π electrocyclization proceed spontaneously after opening of the preshimalactone epoxide ring through protonation. We confirmed the formation of preshimalactone epoxide in vitro, followed by its non-enzymatic conversion to shimalactones in the dark.

Silaboration of [1.1.1]Propellane: A Storable Feedstock for Bicyclo[1.1.1]pentane Derivatives.

The silaboration of [1.1.1]propellane enables direct introduction of B and Si functional groups onto the bicyclo[1.1.1]pentane (BCP) scaffold in high yield under mild, additive-free conditions. The silaborated BCP can be obtained on a gram-scale in a single step without the need for column-chromatographic purification, and is storable and easy to handle, providing a versatile synthetic intermediate for BCP derivatives. We also describe various conversions of the C-B/C-Si bonds on the BCP scaffold, including development of a modified Suzuki-Miyaura cross-coupling reaction at the highly sterically hindered bridgehead sp3 carbon center of the BCP skeleton using a combination of highly activated BCP boronic esters, copper(I) oxide, and a PdCl2 (dppf) catalyst system.

Gambling symptoms, behaviors, and cognitive distortions in Japanese university students.

BACKGROUND: This study was conducted to investigate the relationship between symptoms of gambling problems, gambling behaviours, and cognitive distortions among a university student population in Japan ages 20 to 29 years. We aimed to address the gap in knowledge of gambling disorders and treatment for this population. METHODS: Data were obtained from 1471 Japanese undergraduate students from 19 universities in Japan. Descriptive statistics and hierarchical multivariate regression analysis were used to investigate whether the factors of gambling cognitive distortions would have predictive effects on gambling disorder symptoms. RESULTS: Results indicated that 5.1% of the participants are classifiable as probable disordered gamblers. The bias of the gambling type to pachinko and pachislot was unique to gamblers in Japan. Of the students sampled, 342 self-reported gambling symptoms via the South Oaks Gambling Screen. Hierarchical multivariate regression analysis indicated that one domain of gambling cognitive distortions was associated significantly with gambling symptoms among the 342 symptomatic participants: gambling expectancy (ß = 0.19, p < .05). The multivariate model explained 47% of the variance in the gambling symptoms. CONCLUSION: This study successfully contributed to the sparse research on university student gambling in Japan. Specifically, our results indicated a statistically significant relationship between gambling cognitive distortions and gambling disorder symptoms. These results can inform the development of preventive education and treatment for university students with gambling disorder in Japan. The report also describes needs for future research of university students with gambling disorder.

Organocopper cross-coupling reaction for C-C bond formation on highly sterically hindered structures.

We describe a powerful, broadly applicable cross-coupling protocol that enables carbon-carbon bond formation at highly sterically hindered carbon centers (both sp2 and sp3) by employing organocopper reagents under palladium catalysis. Experimental studies and theoretical calculations indicated that the key to the unique reactivity of copper is the relatively low activation energy of the compact transmetalation transition state, due to Cu(i)-Pd(ii) interaction, which is associated with small values of deformation energy of the reactants. This reaction is applicable to a variety of bulky substrates, including compounds inert to previous cross-coupling chemistry and has high functional group tolerance.

Internet Addiction, Smartphone Addiction, and Hikikomori Trait in Japanese Young Adult: Social Isolation and Social Network.

Background: As the number of internet users increases, problems related to internet overuse are becoming more and more serious. Adolescents and youth may be particularly attracted to and preoccupied with various online activities. In this study, we investigated the relationship of internet addiction, smartphone addiction, and the risk of hikikomori, severe social withdrawal, in Japanese young adult. Methods: The subjects were 478 college/university students in Japan. They were requested to complete the study questionnaire, which consisted of questions about demographics, internet use, the Internet Addiction Test (IAT), the Smartphone Addiction Scale (SAS)-Short Version (SV), the 25-item Hikikomori Questionnaire (HQ-25), etc. We investigated the difference and correlation of the results between two groups based on the purpose of internet use or the total score of each self-rating scale, such as screened positive or negative for the risk of internet addiction, smartphone addiction, or hikikomori. Results: There was a trend that males favored gaming in their internet use while females used the internet mainly for social networking via smartphone, and the mean SAS-SV score was higher in females. Two-group comparisons between gamers and social media users, according to the main purpose of internet use, showed that gamers used the internet longer and had significantly higher mean IAT and HQ-25 scores. Regarding hikikomori trait, the subjects at high risk for hikikomori on HQ-25 had longer internet usage time and higher scores on both IAT and SAS-SV. Correlation analyses revealed that HQ-25 and IAT scores had a relatively strong relationship, although HQ-25 and SAS-SV had a moderately weak one. Discussion: Internet technology has changed our daily lives dramatically and altered the way we communicate as well. As social media applications are becoming more popular, users are connected more tightly to the internet and their time spent with others in the real world continues to decrease. Males often isolate themselves from the social community in order to engage in online gaming while females use the internet as to not be excluded from their communications online. Mental health providers should be aware of the seriousness of internet addictions and hikikomori.

Recent Progress in the Synthesis of the Monocarba-closo-dodecaborate(-) Anions.

This Concept article focuses on the rapid growth in studies of the chemistry of the monocarba-closo-dodecaborate(-) anion (C1 carborane anion). As one of the most stable anions known, the C1 carborane anion has been useful for exploring the chemistry of highly reactive cations. On the other hand, development of novel functional molecules utilizing the unique properties of C1 carborane anion (e.g., σ-aromaticity, rigid spherical skeleton) has progressed more slowly. The main reason for this is the relatively undeveloped state of synthetic chemistry in this area. Recent advances in the synthetic chemistry of C1 carborane anion are highlighted in this Concept article, focusing on cross-coupling reactions at the carbon vertex, direct conversion of B-H bonds, and the synthesis of multivalent weakly coordinating anions. These progressions move this species beyond its well-established role of highly stable "counter" monocharged anion.

Internet Addiction and Attention-Deficit/Hyperactivity Disorder Traits among Female College Students in Japan.

OBJECTIVES: Previous studies have reported that internet addiction (IA) is associated with attention-deficit/hyperactivity disorder (ADHD) consistently. However, in terms of gender, there are controversial findings. We aimed to investigate the relation between IA and self-acknowledged ADHD traits among female college students in Japan. METHODS: The study questionnaire consisted of questions about demographics, Adult ADHD Self-Report Scale-V1.1 Part A (ADHD screener) and Young's Internet Addiction Test (IAT). When four or more items are more frequent than the cut-off on ADHD screener, the subject was categorized into students with a positive ADHD screen. We defined students with total IAT score of 70 and higher as IA. RESULTS: A total number of respondents was 369 (mean age: 19.0±0.7 years). Seventy-seven subjects were screened positive on ADHD screener (20.9%). Students with a positive ADHD screen scored significantly higher on the IAT (54.2±14.2 vs. 42.5±11.3). The rates of IA in students with and without a positive ADHD screen were 18.2% and 1.0%, respectively. CONCLUSION: Results of this study demonstrated the relation between IA and self-evaluated ADHD traits among female college students in Japan. Appropriate education for students on how to use the internet properly will be necessary to prevent IA.

Radical Multicomponent Carboamination of [1.1.1]Propellane.

Three-dimensional, small-ring scaffolds are very important in modern drug discovery to expand the available drug-like chemical space and to optimize drug candidates. Among them, bicyclo[1.1.1]pentane (BCP) is regarded as a high-value bioisostere for a phenyl ring or tert-butyl group; it provides an option to generate drug-like molecules with good passive permeability, high aqueous solubility, and improved metabolic stability, though the lack of methodology to functionalize BCP remains a significant challenge. Here we present an efficient method, developed with the aid of density functional theory calculations, for the synthesis of multifunctionalized BCP derivatives by means of a radical multicomponent carboamination of [1.1.1]propellane. This reaction features mild conditions, one-pot operation, and gram-scale synthetic capability, and opens up a unique and highly efficient route for the synthesis of multifunctionalized BCP derivatives, including synthetically useful 3-substituted BCP-amines.

Psychometric properties of the Japanese version of the Weiss Functional Impairment Rating Scale: Self-Report.

The Weiss Functional Impairment Rating Scale Self-Report has been translated into nine languages and has been widely used in assessing functional impairment of adults with ADHD. This study is a psychometric validation of the WFIRS-S in Japanese. The WFIRS-S-J and other questionnaires were administered to 46 adults with attention-deficit-hyperactivity disorder (ADHD), 104 control adults, and 889 university students. ADHD diagnoses were made using the Japanese semi-structured diagnostic interview for adult ADHD, which is compatible with the DSM-5. All subscales of the WFIRS-S-J had Cronbach's α values of around 0.80. Total scores on the WFIRS-S-J had high test-retest reliability after a 2-week interval. The total score, subscale scores, and 59 of the individual item scores of the 70 items in the WFIRS-S-J were significantly higher in the ADHD group than in the other two groups, although more than half of the items in subdomain G (risk) showed floor effects and did not reach significance. Generally WFIRS-S-J subdomain scores were moderately correlated with scores on the Japanese version of Conners' Adult ADHD Rating Scales Self-Report subscales. WFIRS-S-J scores were also correlated (albeit more weakly; 0.31 ≤ r ≤ 0.55) with Beck Depression Inventory II total scores. The WFIRS-S-J showed acceptable psychometric properties, although further study is necessary.

Conjugation between σ- and π-Aromaticity in 1-C-Arylated Monocarba-closo-dodecaborate Anions.

Conjugation between σ- and π-aromatic moieties in 1-C-arylated monocarba-closo-dodecaborate anion derivatives 2 has been identified by means of kinetic experimental studies combined with theoretical calculations. We found that the reaction rate of iodination at the 12-B vertex of the carborane anion cage was affected by distal substituents on the benzene ring connected at the antipodal carbon vertex. Hammett and Yukawa-Tsuno plots indicated that substantial resonance effects are involved. Density functional theory calculations enabled detailed interpretation of the electronic interaction.