Atroposelective Synthesis of Isoriccardin C through a C−H Activated Heck Type Macrocyclization

Macrocyclization is typically the key step in syntheses of cyclophane‐type natural products. Considering compounds with axially chiral biaryl moieties, the control of atroposelectivity is essential for biological activity and is synthetically challenging. Herein we report on atroposelective macrocyclization involving an oxidative Heck type process and enabling the first atropo‐enantiopure synthesis of isoriccardin C. A chiral sulfinyl auxiliary in the ortho‐position of a biaryl axis (still flexible) was used to induce a C−H activated atropodiastereoselective oxidative Heck coupling (>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

Transition-Metal-Free Synthesis of a Known Intermediate in the Formal Synthesis of (-)-Steganacin

International audienceThe formal synthesis of both enantiomers of a natural axially chiral biaryl, steganacin is reported. The previously developed atropo-diastereoselective coupling of an aryne and an aryllithium (the 'ARYNE coupling') allows for this synthesis. In each step, the axial configuration of the biaryl could be maintained. The key intermediate of literature was accessed without using transition metals, demonstrating the interest of the ARYNE coupling as a complement or an alternative to transition metal-catalyzed couplings

[7,0]-metacyclophanes from biaryl coupling/macrocyclisation

The biaryl structural motif is a predominant feature in many pharmaceutically relevant and biologically active compounds. As a result, for over a century organic chemists have sought to develop new and more efficient aryl-aryl bond-forming methods (1). Cyclophanic natural products comprise an intriguing class of structurally diverse compounds. As inherent for all cyclic compounds regardless of their origin, macrocyclization is naturally the most decisive step, which defines the overall efficiency of the synthetic pathway. Especially in small cyclophanic molecules, this key step constitutes an even greater challenge. Due to the strain imparted by the macrocyclic system, free rotation of the benzene ring(s) is often restricted depending on both the constitution of the tether and the aromatic portions (2). Among cyclophanic natural products, the diarylheptanoids are a structurally sub-class with their scaffold consisting of two benzene rings tethered by an oxygenated aliphatic heptyl chain. In this work we reported different metal catalysed approaches to obtain the biaryl motif of myricanol, a natural [7,0]-metacyclophane with very important and recently discovered biological activities (3),(4),(5),(6). (Figure 1) Figure 1 The desired product 1could be obtained from the functionalized linear diarylheptanoid 2 by Suzuki domino process (macrocyclisation by linkage of aryl moieties) or could be synthesized from ring closing metathesis of product 3 which derived from a biaryl coupling of fragments 4 and 5. (1) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107 (1), 174–238. (2) Gulder, T.; Baran, P. S. Nat. Prod. Rep. 2012, 29 (8), 899-934. (3) Jones, J. R.; Lebar, M. D.; Jinwal, U. K.; Abisambra, J. F.; Koren, J.; Blair, L.; O’Leary, J. C.; Davey, Z.; Trotter, J.; Johnson, A. G.; Weeber, E.; Eckman, C. B.; Baker, B. J.; Dickey, C. A. J. Nat. Prod. 2011, 74 (1), 38–44. (4) Martin, M. D.; Calcul, L.; Smith, C.; Jinwal, U. K.; Fontaine, S. N.; Darling, A.; Seeley, K.; Wojtas, L.; Narayan, M.; Gestwicki, J. E.; Smith, G. R.; Reitz, A. B.; Baker, B. J.; Dickey, C. A. ACS Chem. Biol. 2015, 10 (4), 1099–1109. (5) Dai, G. H.; Meng, G. M.; Tong, Y. L.; Chen, X.; Ren, Z. M.; Wang, K.; Yang, F. Phytomedicine 2014, 21 (11), 1490–1496. (6) Dai, G.; Tong, Y.; Chen, X.; Ren, Z.; Ying, X.; Yang, F.; Chai, K. Int. J. Mol. Sci. 2015, 16 (2), 2717–2731

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.We acknowledge support by the Open Access Publication Funds of the SLUB/TU Dresden (Grant No. IN-1502335)

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

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

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 bipolar disorder diagnosis 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

Nouvelles superbases unimétalliques lithiées et sodées : réactivité vis-à-vis de l'allylphénylsulfure et des 2-, 3- et 4- chloropyridines

Non disponible/Not avialable.Le travail présente dans ce mémoire a montré l'efficacité, la sélectivité ainsi que le potentiel synthétique de nouvelles superbases unimétalliques lithiées et sodées dans des réactions de métallation. La première partie est consacrée à la métallation de l'allylphenylsulfure par des superbases unimetalliques sodées et lithiées. Il a en particulier été montré que l'activation de NANH 2 par un amino-alcoolate de sodium permet d'obtenir une nouvelle réaction de bisfonctionnalisation directe du substrat. Cette réaction originale donne un accès aisé à des cétones dissymétriques. La recherche d'une explication au phénomène d'activation à montrer que l'amidure de sodium pouvait également être activé par une espèce non anionique, le DME. L'utilisation de superbases unimétalliques lithiées, N-BULI-ROLI, conduit à des systèmes d'efficacité et de sélectivité comparables à celles des systemes bimétalliques de type LICKOR ou les systèmes de type base/activant tel que N-BULI/DABCO. Dans une seconde partie, il a été montré que le système unimétallique lithie n-buli-dimethylaminoethylate de lithium noté N-BULI-LIDMAE permet d'accéder à une métallation-fonctionnalisation chimio- et regioséléctive en ortho de l'azote des chloropyridines. La méthodologie développée permet un accès original à des précurseurs de molécules polyhétérocycliques à activité biologique potentielle, d'agents chélatants et de ligands de métaux de transition. Des calculs théoriques et des expériences réalisées sur des espèces deuterées ont ensuite montré que le site initial de déprotonnation des 2-, 3- et 4-chloropyridines est probablement le site situé en alpha de l'azote pyridinique et ceci quel que soit le système basique utilisé. Par ailleurs, la formation d'agrégats au voisinage de cet azote pyridinique peut être rendue responsable de la stabilité particulière des lithiens issus des 2-, 3- et 4-chloropyridines en présence du système N-BULI-LIDMAE. Il a enfin été montré que les méthodes de métallation sélective par N-BULI-LIDMAE, couplées a des réactions pallado-catalysées de type negishi et stille permettent un accès original et très efficace à des composés polyhétérocycliques refonctionnalisables

Nouvelles superbases unimétalliques lithiées et sodées (réactivité vis-à-vis de l'allylphénylsulfure et des 2-, 3- et 4- chloropyridines)

Le travail présente dans ce mémoire a montré l'efficacité, la sélectivité ainsi que le potentiel synthétique de nouvelles superbases unimétalliques lithiées et sodées dans des réactions de métallation. La première partie est consacrée à la métallation de l'allylphenylsulfure par des superbases unimetalliques sodées et lithiées. Il a en particulier été montré que l'activation de NANH 2 par un amino-alcoolate de sodium permet d'obtenir une nouvelle réaction de bisfonctionnalisation directe du substrat. Cette réaction originale donne un accès aisé à des cétones dissymétriques. La recherche d'une explication au phénomène d'activation à montrer que l'amidure de sodium pouvait également être activé par une espèce non anionique, le DME. L'utilisation de superbases unimétalliques lithiées, N-BULI-ROLI, conduit à des systèmes d'efficacité et de sélectivité comparables à celles des systemes bimétalliques de type LICKOR ou les systèmes de type base/activant tel que N-BULI/DABCO. Dans une seconde partie, il a été montré que le système unimétallique lithie n-buli-dimethylaminoethylate de lithium noté N-BULI-LIDMAE permet d'accéder à une métallation-fonctionnalisation chimio- et regioséléctive en ortho de l'azote des chloropyridines. La méthodologie développée permet un accès original à des précurseurs de molécules polyhétérocycliques à activité biologique potentielle, d'agents chélatants et de ligands de métaux de transition. Des calculs théoriques et des expériences réalisées sur des espèces deuterées ont ensuite montré que le site initial de déprotonnation des 2-, 3- et 4-chloropyridines est probablement le site situé en alpha de l'azote pyridinique et ceci quel que soit le système basique utilisé. Par ailleurs, la formation d'agrégats au voisinage de cet azote pyridinique peut être rendue responsable de la stabilité particulière des lithiens issus des 2-, 3- et 4-chloropyridines en présence du système N-BULI-LIDMAE. Il a enfin été montré que les méthodes de métallation sélective par N-BULI-LIDMAE, couplées a des réactions pallado-catalysées de type negishi et stille permettent un accès original et très efficace à des composés polyhétérocycliques refonctionnalisables.NANCY1-SCD Sciences & Techniques (545782101) / SudocSudocFranceF

Les émotions induites par la musique chez les patients bipolaires euthymiques (hyperréactivité émotionnelle, un endophénotype de la bipolarité)

La régulation de l'émotion chez les patients bipolaires est perturbée, surtout pendant les épisodes thymiques. Il a été montré des biais de reconnaissance des émotions sur le visage d'autrui. Peu d'études ont étudié le ressenti émotionnel pendant les phases de rémission, et aucune donnée n'est disponible concernant les émotions complexes. L'étude vise à tester l'hyperréactivité émotionnelle chez les patients bipolaires normothymiques. La population incluse dans l'étude est constituée de 21 patients bipolaires en phase de rémission et de 21 participants contrôles appariés. Tous les participants cotent leur ressenti émotionnel induit par la musique sur des échelles d'évaluation continue. Les quatre émotions ciblées par les extraits sont l'émerveillement, le triomphe, la mélancolie, et la tension. Il n'y a pas de différences significatives entre les deux groupes pour le jugement catégoriel des émotions cibles, ni pour l'intensité du ressenti émotionnel, mais il existe des effets spécifiques concernant les émotions agitation et tristesse ressenties plus intensément chez les patients bipolaires que chez les contrôles lorsque les stimuli ciblent l'émerveillement.There is a dysregulation of the emotional process in bipolar disorder, most prevalent during depressive and manic states. Biases have been shown in the facial recognition of emotion. Only a few studies examined induced emotions during euthymia, and there is no data concerning complex emotions. The goal of the study is to test the emotional hyperreactivity in bipolar disorder during euthymia, correlated to emotional hyperreactivity in daily life, and to clinical characteristics of bipolar disorder. The participants included in the study are composed of 21 patients with bipolar disorder during euthymia and 21 matched healthy controls. All the participants rated their emotion induced by music on 9 continuous scales. The targeted emotions were wonderful, power, melancholy and tension. The study showed no significant differences between the two groups concerning the categorical judgment and no differences concerning the emotional experience, but specific effects concerning tension and sadness felt with more intensity than healthy controls when stimuli wonderful. We found no correlation between the emotional experience and the clinical characteristics of bipolar disorder, i. e. type of bipolarity and duration of illness.RENNES1-BU Santé (352382103) / SudocSudocFranceF