Sulfoxide-Directed or 3d-Metal Catalyzed C-H Activation and Hypervalent Iodines as Tools for Atroposelective Synthesis.

ConspectusThe expanding applications of atropisomeric compounds combined with the growing diversity of such chiral molecules translate into an urgent need for innovative synthetic strategies allowing their rapid, efficient, and sustainable synthesis. Recently, the C-H activation approach has provided new opportunities for synthesizing axially chiral compounds. The two complementary approaches allowing implementation of the C-H activation methodology toward the synthesis of the chiral molecules imply either ortho-functionalization of the preexisting prochiral or atropo-unstable biaryl substrates or direct C-H arylation of sterically encumbered aromatics. The first approach required the preinstallation of a directing group on a biaryl precursor, which drastically limits the diversity of thus generated products. To tackle this important synthetic limitation, we have envisioned using a chiral sulfoxide as both directing group and chiral auxiliary. Indeed, in addition to efficiently coordinating the Pd-catalyst thus allowing chiral induction, the sulfoxide moiety can be easily removed, via the sulfoxide/lithium exchange, after the C-H activation step, thus guaranteeing an almost unlimited postdiversification of the atropisomeric products. The efficiency and generality of this concept could be illustrated by developing atropo-diastereoselective oxidative Heck reaction, direct acetoxylation, and iodination, as well as direct arylation. Besides, the synthetic utility of this methodology was demonstrated by designing an expedient synthesis of a direct steganone precursor. This unique transformation also allowed us to build up unprecedented triaryl scaffolds with two perfectly controlled chiral axes, original chiral skeletons for new ligand design. While considering the atroposelective direct arylations, the clear antagonism between the harsh reaction conditions frequently required for the coupling of two sterically hindered compounds and the atropo-stability of the new product, resulted in the scarcity of such transformations. To solve this fundamental challenge, we have focused on the application of a low-valent cobalt catalyst, prompted to catalyze C-H activation of indoles at the C2 position under extremely mild reaction conditions (room temperature). Accordingly, atroposelective C2-arylation of indoles could be achieved using an original carbene ligand and delivering the uncommon atropoisomerically pure indoles in excellent yields and enantioselectivities. Detailed combined experimental and theoretical mechanistic studies shed light on the mechanism of this transformation, providing strong evidence regarding the origin of the enantioselectivity. Finally, the antagonism between steric hindrance required to guarantee the atropo-stability of a molecule and harsh reaction conditions required to couple two partners is a strong limitation not only for the development of atroposelective C-H arylation reaction but also for the development of direct synthesis of the C-N axially chiral compounds. Despite the long history and incredible advances achieved in Ullmann-Goldberg and Buchwald-Hartwig couplings, atroposelective versions of such transformations have remained unprecedented until recently. Our idea to tackle this challenging issue consisted in using hypervalent iodines as highly reactive coupling partners, thus allowing the desired N-arylations to occur at room temperature. This hypothesis could be validated by reporting first atropo-diastereoselective Cu-catalyzed N-arylation, using sulfoxide λ3-iodanes as the coupling partners. Subsequently, the enantioselective version of this atroposelective N-arylation was successfully established by using a chiral Cu-complex bearing a BOX ligand. In conclusion, we report herein designing tailored-made solutions to provide new synthetic strategies to construct the atropisomeric molecules, including biaryls and C-N axially chiral molecules.

Access to 12-Membered Cyclic ortho,meta-Diarylheptanoids: Total Synthesis of Actinidione via Isomyricanone.

We describe herein the first access to 12-membered cyclic[7,0]ortho,meta-diarylheptanoids. The key features of the synthesis include both a Suzuki-Miyaura coupling and a ring closing metathesis. Actinidione, a promising natural product, along with a bioactive tetracyclic derivative were obtained in 14 steps for the first time from cheap commercially available substrates with an overall yield of 18-21%. Our modus operandi complies with the principles of the synthesis ideality by using notably strategic reactions.

Towards Atropoenantiopure N-C Axially Chiral Compounds via Stereoselective C-N Bond Formation.

N-C axial chirality, although disregarded for decades, is an interesting type of chirality with appealing applications in medicinal chemistry and agrochemistry. However, atroposelective synthesis of optically pure compounds is extremely challenging and only a limited number of synthetic routes have been designed. In particular, asymmetric N-arylation reactions allowing atroposelective N-C bond forming events remain scarce, although great advances have been achieved recently. In this minireview we summarize the synthetic approaches towards synthesis of N-C axially chiral compounds via stereocontrolled N-C bond forming events. Both organo-catalyzed and metal-catalyzed transformations are described, thus illustrating the diversity and specificity of both strategies.

New synthesized polyoxygenated diarylheptanoids suppress lipopolysaccharide-induced neuroinflammation.

In neurodegenerative diseases, such as Alzheimer's disease, Huntington's disease, Parkinson's disease and multiple sclerosis, neuroinflammation induced by the microglial activation plays a crucial role. In effort to develop effective anti-neuroinflammatory compounds, different new linear polyoxygenated diarylheptanoids were synthesized. In LPS-triggered BV-2 microglial cells their ability to reduce the concentration of IL-6 and TNF-α pro-inflammatory cytokines was evaluated. Moreover, their effect on NF-κB and ATP citrate lyase (ACLY), a recently emerged target of metabolic reprogramming in inflammation, was assessed. Finally, we turned our attention to inflammatory mediators derived from the cleavage of citrate catalyzed by ACLY: prostaglandin E2, nitric oxide and reactive oxygen species. All compounds showed null or minimal cytotoxicity; most of them had a great anti-neuroinflammatory activity. Diarylheptanoids 6b and 6c, bearing a halide atom and benzyl ether protective groups, exhibited the best effect since they blocked the secretion of all inflammatory mediators analyzed and reduced NF-κB and ACLY protein levels.

Enantioselective Synthesis of N-C Axially Chiral Compounds by Cu-Catalyzed Atroposelective Aryl Amination.

N-C axially chiral compounds have emerged recently as appealing motifs for drug design. However, the enantioselective synthesis of such molecules is still poorly developed and surprisingly no metal-catalyzed atroposelective N-arylations have been described. Herein, we disclose an unprecedented Cu-catalyzed atroposelective N-C coupling that proceeds at room temperature. Such mild reaction conditions, which are a crucial parameter for atropostability of the newly generated products, are operative thanks to the use of hypervalent iodine reagents as a highly reactive coupling partners. A large panel of the N-C axially chiral compounds was afforded with very high enantioselectivity (up to >99 % ee) and good yields (up to 76 %). Post-modifications of thus accessed atropisomeric compounds allows further expansion of the diversity of these appealing compounds.

Synthesis, characterization, and catalytic application in aldehyde hydrosilylation of half-sandwich nickel complexes bearing (κ1-C)- and hemilabile (κ2-C,S)-thioether-functionalised NHC ligands.

Neutral nickel-N-heterocyclic carbene complexes, (κ1-C)-[NiCpBr{R-NHC-(CH2)2SR'}] [Cp = η5-C5H5; R-NHC-(CH2)2SR' = 1-mesityl-3-[2-(tert-butylthio)ethyl]- (1a), 1-mesityl-3-[2-(phenylthio)ethyl]- (1b), 1-benzyl-3-[2-(tert-butylthio)ethyl]- (1c), 1-benzyl-3-[2-(phenylthio)ethyl]-imidazol-2-ylidene (1d)], which bear a N-bound thioether side arm, were prepared by the reaction of nickelocene with the corresponding imidazolium bromides [R-NHC-(CH2)2SR'·HBr] (a-d), via conventional or microwave heating. The 1H NMR spectra of the benzyl-substituted species 1c and 1d showed signals for diastereotopic NCH2CH2S protons at room temperature. However, structural studies established the absence of coordination of the sulphur atom in the solid state, and solvent DFT calculations showed that bromide displacement by sulphur is an unfavourable process (ΔG = +13.5 kcal mol-1 for 1d), thereby suggesting that the observed disatereotopicity is more likely due to significant steric congestion rather than to a possible C,S-chelation in solution. Treatment of these complexes with KPF6 in tetrahydrofuran (THF) led to bromide abstraction to afford the cationic complexes [NiCp{R-NHC-(CH2)2SR'}](PF6) (2a-c). Alternatively, 2a-c could also be prepared by the direct reaction of nickelocene with the corresponding imidazolium hexafluorophosphate salts [R-NHC-(CH2)2SR'·HPF6]. Inversely to the neutral species, whereas X-ray crystallography established C,S-chelation in the solid state, the 1H NMR spectra (CDCl3, CD2Cl2, or thf-d8) at room temperature showed no diastereotopic NCH2CH2S protons, thus suggesting the possible displacement of the sulphur atom by the respective solvents and/or very fast sulphur inversion. DFT calculations established a low energy inversion process in all cases (+9 ≤ΔG‡≤ +13 kcal mol-1) as well as a favourable solvent coordination process (ΔG‡≈ +11 kcal mol-1; ΔG≈-7 kcal mol-1) with a solvent such as THF, thus suggesting that sulphur inversion and/or solvent coordination can both account for the absence of diastereotopy at room temperature, depending on the solvent. While all complexes catalysed the hydrosilylation of benzaldehyde in the absence of any additive, the cationic C,S-chelated complexes 2 proved more active than the sterically constrained neutral species 1. In particular, 2c proved to be the most active pre-catalyst and its catalytic charge could be lowered down to 2 mol% with PhSiH3 as the hydrogen source.

Internet use by older adults with bipolar disorder: international survey results.

BACKGROUND: The world population is aging and the number of older adults with bipolar disorder is increasing. Digital technologies are viewed as a framework to improve care of older adults with bipolar disorder. This analysis quantifies Internet use by older adults with bipolar disorder as part of a larger survey project about information seeking. METHODS: A paper-based survey about information seeking by patients with bipolar disorder was developed and translated into 12 languages. The survey was anonymous and completed between March 2014 and January 2016 by 1222 patients in 17 countries. All patients were diagnosed by a psychiatrist. General estimating equations were used to account for correlated data. RESULTS: Overall, 47% of older adults (age 60 years or older) used the Internet versus 87% of younger adults (less than 60 years). More education and having symptoms that interfered with regular activities increased the odds of using the Internet, while being age 60 years or older decreased the odds. Data from 187 older adults and 1021 younger adults were included in the analysis excluding missing values. CONCLUSIONS: Older adults with bipolar disorder use the Internet much less frequently than younger adults. Many older adults do not use the Internet, and technology tools are suitable for some but not all older adults. As more health services are only available online, and more digital tools are developed, there is concern about growing health disparities based on age. Mental health experts should participate in determining the appropriate role for digital tools for older adults with bipolar disorder.

Access to the Enantiopure Axially Chiral Cyclophane Isoplagiochin†D through Atropo-diastereoselective Heck Coupling.

Macrocyclization is typically the key step in the syntheses of cyclophane-type natural products. Considering cyclophanes with axially chiral biaryl moieties, the control of atroposelectivity is essential with biological activity and is synthetically challenging. We report an atroposelective approach involving Heck cyclization, which for the first time enables the total synthesis of an enantiopure macrocyclic bis(bibenzyl), namely isoplagiochin D. An enantiopure sulfinyl auxiliary in the ortho position of a biaryl axis (still flexible) was used to induce an atropo-diastereoselective Heck coupling (up to 98 % de). The traceless character of the sulfinyl auxiliary enables the introduction of a hydroxy group to give the target molecule with 98 % ee as well.

Access to Wieland-Miescher Diketone-Derived Building Blocks by Stereoselective Construction of the C-9 Quaternary Carbon Center Using the Mukaiyama Aldol Reaction.

The Mukaiyama aldol reaction has been used to efficiently install a lateral chain at the C-9 position of the Wieland-Miescher ketone derivative 3 within two steps, representing a shortcut compared to that of the classical sequences. The treatment of the silylated enol ether 8 with a wide range of acetals in the presence of tin tetrachloride led to a the diastereoselective construction of the C-9 quaternary center of 33 new building blocks derived from the Wieland-Miescher ketone derivative 3.

International multi-site survey on the use of online support groups in bipolar disorder.

BACKGROUND: Peer support is an established component of recovery from bipolar disorder, and online support groups may offer opportunities to expand the use of peer support at the patient's convenience. Prior research in bipolar disorder has reported value from online support groups. AIMS: To understand the use of online support groups by patients with bipolar disorder as part of a larger project about information seeking. METHODS: The results are based on a one-time, paper-based anonymous survey about information seeking by patients with bipolar disorder, which was translated into 12 languages. The survey was completed between March 2014 and January 2016 and included questions on the use of online support groups. All patients were diagnosed by a psychiatrist. Analysis included descriptive statistics and general estimating equations to account for correlated data. RESULTS AND CONCLUSIONS: The survey was completed by 1222 patients in 17 countries. The patients used the Internet at a percentage similar to the general public. Of the Internet users who looked online for information about bipolar disorder, only 21.0% read or participated in support groups, chats, or forums for bipolar disorder (12.8% of the total sample). Given the benefits reported in prior research, clarification of the role of online support groups in bipolar disorder is needed. With only a minority of patients using online support groups, there are analytical challenges for future studies.

Online information seeking by patients with bipolar disorder: results from an international multisite survey.

BACKGROUND: Information seeking is an important coping mechanism for dealing with chronic illness. Despite a growing number of mental health websites, there is little understanding of how patients with bipolar disorder use the Internet to seek information. METHODS: A 39 question, paper-based, anonymous survey, translated into 12 languages, was completed by 1222 patients in 17 countries as a convenience sample between March 2014 and January 2016. All patients had a diagnosis of bipolar disorder from a psychiatrist. Data were analyzed using descriptive statistics and generalized estimating equations to account for correlated data. RESULTS: 976 (81 % of 1212 valid responses) of the patients used the Internet, and of these 750 (77 %) looked for information on bipolar disorder. When looking online for information, 89 % used a computer rather than a smartphone, and 79 % started with a general search engine. The primary reasons for searching were drug side effects (51 %), to learn anonymously (43 %), and for help coping (39 %). About 1/3 rated their search skills as expert, and 2/3 as basic or intermediate. 59 % preferred a website on mental illness and 33 % preferred Wikipedia. Only 20 % read or participated in online support groups. Most patients (62 %) searched a couple times a year. Online information seeking helped about 2/3 to cope (41 % of the entire sample). About 2/3 did not discuss Internet findings with their doctor. CONCLUSION: Online information seeking helps many patients to cope although alternative information sources remain important. Most patients do not discuss Internet findings with their doctor, and concern remains about the quality of online information especially related to prescription drugs. Patients may not rate search skills accurately, and may not understand limitations of online privacy. More patient education about online information searching is needed and physicians should recommend a few high quality websites.

Internet use by patients with bipolar disorder: Results from an international multisite survey.

There is considerable international interest in online education of patients with bipolar disorder, yet little understanding of how patients use the Internet and other sources to seek information. 1171 patients with a diagnosis of bipolar disorder in 17 countries completed a paper-based, anonymous survey. 81% of the patients used the Internet, a percentage similar to the general public. Older age, less education, and challenges in country telecommunications infrastructure and demographics decreased the odds of using the Internet. About 78% of the Internet users looked online for information on bipolar disorder or 63% of the total sample. More years of education in relation to the country mean, and feeling very confident about managing life decreased the odds of seeking information on bipolar disorder online, while having attended support groups increased the odds. Patients who looked online for information on bipolar disorder consulted medical professionals plus a mean of 2.3 other information sources such as books, physician handouts, and others with bipolar disorder. Patients not using the Internet consulted medical professionals plus a mean of 1.6 other information sources. The percentage of patients with bipolar disorder who use the Internet is about the same as the general public. Other information sources remain important.

Alteration of complex negative emotions induced by music in euthymic patients with bipolar disorder.

BACKGROUND: Research has shown bipolar disorder to be characterized by dysregulation of emotion processing, including biases in facial expression recognition that is most prevalent during depressive and manic states. Very few studies have examined induced emotions when patients are in a euthymic phase, and there has been no research on complex emotions. We therefore set out to test emotional hyperreactivity in response to musical excerpts inducing complex emotions in bipolar disorder during euthymia. METHODS: We recruited 21 patients with bipolar disorder (BD) in a euthymic phase and 21 matched healthy controls. Participants first rated their emotional reactivity on two validated self-report scales (ERS and MAThyS). They then rated their music-induced emotions on nine continuous scales. The targeted emotions were wonder, power, melancholy and tension. We used a specific generalized linear mixed model to analyze the behavioral data. RESULTS: We found that participants in the euthymic bipolar group experienced more intense complex negative emotions than controls when the musical excerpts induced wonder. Moreover, patients exhibited greater emotional reactivity in daily life (ERS). Finally, a greater experience of tension while listening to positive music seemed to be mediated by greater emotional reactivity and a deficit in executive functions. LIMITATIONS: The heterogeneity of the BD group in terms of clinical characteristics may have influenced the results. CONCLUSIONS: Euthymic patients with bipolar disorder exhibit more complex negative emotions than controls in response to positive music.

Psychotropic medication use in French children and adolescents.

OBJECTIVE: The purpose of this study was to describe the patterns of psychotropic drug use in a large representative population of children and adolescents drawn from the French National Health Insurance databank. METHODS: Data were drawn from a sample of 1% of the beneficiaries of the French national health insurance, selecting those 0-17 years old in 2010 (n=128,298). In addition to age and gender, data included the identification number of each drug allowing a European Pharmaceutical Marketing Research Association (EphMRA) classification, as well as the type of the prescriber. RESULTS: Overall, 2.5% of children and adolescents had been prescribed psychotropic medication. A majority were prescribed anxiolytics (1.9%), followed by antidepressants (0.3%), antipsychotics (0.3%), and stimulants (0.2%). Between the ages of 15 and 17, 6.1% of girls were prescribed anxiolytics and 1.1% were prescribed antidepressants. For boys, the anxiolytics remained the most prescribed psychotropic medication; however, between the ages of 11 and 14, and between the ages of 15 and 17 they received more antipsychotics (0.7% and 0.8%) and between the ages of 6 and 10, and between the ages of 11 and 14 (0.7% and 0.6%), they were prescribed more stimulants than were girls. Among those who received a prescription, a majority of youth (84.6%) received only one class of drugs, and general practitioners were found to be prescribing most of these prescriptions (81.7%). CONCLUSIONS: The prevalence of psychotropic drug use in France is similar to that of the Netherlands and much lower than what is observed in the United States. Stimulants are less frequently prescribed in France than in other European countries, but anxiolytics are prescribed considerably more in France than in any other country.

Resting state fMRI entropy probes complexity of brain activity in adults with ADHD.

In patients with attention deficit hyperactivity disorder (ADHD), quantitative neuroimaging techniques have revealed abnormalities in various brain regions, including the frontal cortex, striatum, cerebellum, and occipital cortex. Nonlinear signal processing techniques such as sample entropy have been used to probe the regularity of brain magnetoencephalography signals in patients with ADHD. In the present study, we extend this technique to analyse the complex output patterns of the 4 dimensional resting state functional magnetic resonance imaging signals in adult patients with ADHD. After adjusting for the effect of age, we found whole brain entropy differences (P=0.002) between groups and negative correlation (r=-0.45) between symptom scores and mean whole brain entropy values, indicating lower complexity in patients. In the regional analysis, patients showed reduced entropy in frontal and occipital regions bilaterally and a significant negative correlation between the symptom scores and the entropy maps at a family-wise error corrected cluster level of P<0.05 (P=0.001, initial threshold). Our findings support the hypothesis of abnormal frontal-striatal-cerebellar circuits in ADHD and the suggestion that sample entropy is a useful tool in revealing abnormalities in the brain dynamics of patients with psychiatric disorders.

Recent advances in the diastereoselective Reformatsky-type reaction.

The classical Reformatsky reaction introduced for the first time in 1887 has been recognized as one among the most useful methods for C-C bond formation. Diastereoselective versions based on the use of chiral auxiliaries as well as enantioselective protocols using chiral ligands have been successfully developed during the last few years. This tutorial review highlights the main recent achievements (since 2004) in the diastereoselective Reformatsky reaction; diastereochemical control has been efficiently achieved using a large variety of chiral auxiliaries to perform the synthesis of specific cyclic and acyclic chiral moieties. The diastereoselective Reformatsky reactions employed in the total synthesis of natural products are also described.

Axial chirality control during Suzuki-Miyaura cross-coupling reactions: the tert-butylsulfinyl group as an efficient chiral auxiliary.

An efficient route to a new family of axially chiral biaryl ligands by a Suzuki-Miyaura cross-coupling reaction between ortho,ortho'-disubstituted aryl iodides bearing in ortho position a tert-butyl or p-tolylsulfinyl group and ortho-substituted phenyl boronic acids or esters is described. The comparison between the t-BuSO and p-TolSO groups as chiral controllers is reported. The modularity of the approach is demonstrated by the preparation of a variety of enantiopure axially chiral mixed S/N and S/P ligands.

Efficient and stereoselective access to the polyol fragment C9-C16 of ansamycin antibiotics.

Efficient synthesis of the fragment C9-C16 bearing the anti,syn stereotriad of ansamycin antibiotics is described. Key steps for controlling the configuration of the three stereogenic centers involve a stereoselective Reformatsky-type reaction followed by a diastereoselective reduction of a beta-ketosulfoxide.

Polysubstituted oxygen heterocycles by a Reformatsky-type reaction/reductive cyclization approach from enantiopure beta-ketosulfoxides.

The stereoselective synthesis of tetrasubstituted tetrahydrofurans and trisubstituted tetrahydropyrans bearing a sulfoxide was achieved by reductive cyclization (Et3SiH/TMSOTf) from the corresponding enantiopure hydroxy ketones protected as a dioxolane. These derivatives are easily accessible from a Reformatsky-type reaction between alpha-bromo-alpha'-sulfinyl ketones and protected alpha- or beta-ketoaldehydes, followed by diastereoselective reduction of the resulting beta-ketosulfoxide.