Enantioselectivity Induced by Stereoselective Interlocking: A Novel Core Motif for Tropos Ligands

Well‐defined supramolecular interactions are a powerful tool to control the stereochemistry of a catalytic reaction. In this paper, we report a novel core motif for fluxional 2,2′‐biphenyl ligands carrying (S)‐amino acid‐derived interaction sites in 5,5′‐position that cause spontaneous enrichment of the Rax rotamer. The process is based on strong non‐covalent interlocking between interaction sites, which causes diastereoselective formation of a supramolecular ligand dimer, in which the axial chirality of the two subunits is dictated by the stereochemical information in the amino acid residues. The detailed structure of the dimer was elucidated by NMR spectroscopy and single‐crystal X‐ray analysis. Three different phosphorus‐based ligand types, namely a bisphosphine, a bisphosphinite and a phosphoramidite were synthesized and characterized. Whereas the first one was found to exist in a strongly weighted equilibrium, the two others each exhibited stereoconvergent behavior transforming into the diastereopure Rax rotamer. Enriched ligands were used in rhodium‐mediated asymmetric hydrogenation reactions of prochiral olefins in which very high enantioselectivities of up to 96:4 were achieved

Design and synthesis of a stereodynamic catalyst with reversal of selectivity by enantioselective self‐inhibition

Chirality plays a pivotal role in an uncountable number of biological processes, and nature has developed intriguing mechanisms to maintain this state of enantiopurity. The strive for a deeper understanding of the different elements that constitute such self‐sustaining systems on a molecular level has sparked great interest in the studies of autoinductive and amplifying enantioselective reactions. The design of these reactions remains highly challenging; however, the development of generally applicable principles promises to have a considerable impact on research of catalyst design and other adjacent fields in the future. Here, we report the realization of an autoinductive, enantioselective self‐inhibiting hydrogenation reaction. Development of a stereodynamic catalyst with chiral sensing abilities allowed for a chiral reaction product to interact with the catalyst and change its selectivity in order to suppress its formation, which caused a reversal of selectivity over time

Optimal L1L^1-type relaxation rates for the Cahn-Hilliard equation on the line

In this paper we derive optimal algebraic-in-time relaxation rates to the kink for the Cahn-Hilliard equation on the line. We assume that the initial data have a finite distance---in terms of either a first moment or the excess mass---to a kink profile and capture the decay rate of the energy and the perturbation. Our tools include Nash-type inequalities, duality arguments, and Schauder estimates

Chiral induction in stereodynamic catalysts by non-covalent interactions

Enantioselektive Interaktionen zwischen Molekülen spielen in vielen biologischen Vorgängen eine entscheidende Rolle. Sind diese Wechselwirkungen von nicht-kovalenter Natur, bilden sie häufig die Grundlage für Vorgänge der molekularen Erkennung, des Chiralitätstransfers oder der Selbstorganisation. Es wird vermutet, dass solche Mechanismen an der Entstehung der Homochiralität in der Natur beteiligt waren. Das Verständnis darüber, wie solche nicht-kovalenten Interaktionen ausgenutzt werden können, um die stereochemische Kontrolle über asymmetrische Reaktionen zu erlangen, verspricht weitreichende Möglichkeiten für das zukünftige Design neuer Katalysatoren in der Chemie. Die vorliegende Dissertation beschreibt die Synthese und Untersuchung stereodynamischer Liganden und Komplexe sowie ihre Anwendung in asymmetrischen Reaktionen. Im Zentrum stand die Beeinflussung der Chiralität axial chiraler Liganden durch nicht-kovalente Wechselwirkungen zwischen am Ligandenrückgrat befestigten Bindungsstellen (Selektoren) und anderen Molekülen. Die Dissertation ist in vier Themengebiete untergliedert. Das erste Themengebiet in Kapitel 2 beinhaltet die Untersuchung chiraler, L-Aminosäure-basierter Interaktionsstellen mit sekundären Amiden, deren Natur von Interaktionsstellen der Hochleistungs-Gaschromatographiesäule CHIRASIL VAL abgeleitet wurde. Verschiedene 5,5‘-selektormodifizierte, 2,2‘-biphenyl-basierte Liganden wurden synthetisiert und es konnte gezeigt werden, dass eine derartige Substitution im Rückgrat eine spontane, mitunter quantitative Anreicherung eines Ligandrotamers bewirkt. In detaillierten strukturellen Untersuchungen konnte nachgewiesen werden, dass ein intermolekulares Netzwerk aus Wasserstoffbrückenbindungen zwischen Selektoreinheiten zur diastereoselektiven Ausbildung von Ligand-Dimerstrukturen führt, welche im Folgenden die Anreicherung nach sich zieht. Die verschiedenen Ligandtypen konnten abschließend erfolgreich in enantioselektiven Hydrierungs- und Alkylierungsreaktionen eingesetzt werden. Im darauffolgenden Kapitel 3 wird die Thematik auf achirale Bindungsstellen ausgeweitet. Nach dem Vorbild „schaltbarer“ Katalysatoren sollte die gezielte Deracemisierung von racemischen Liganden mittels chiraler Additive durchgeführt werden. Hierbei wurden unter anderem, aufbauend auf Erkenntnissen aus dem vorangegangenen Kapitel, racemische Bisphosphinite mit Glycin- sowie racemischen Phenylalanin-basierten Selektoren modifiziert. Durch Wechselwirkung mit chiralen Additiven konnte das Rotamerverhältnis der Liganden entsprechender Rhodiumkomplexe selektiv beeinflusst werden und somit Katalysatoren für enantioselektive Hydrierungsreaktionen erzeugt werden. Kapitel 4 behandelt die Entwicklung eines autoinduktiven Katalysatorsystems. In Anlehnung an eine von Trapp et al. beschriebene enantioselektive Reaktion mit autoinduktiven, selbstamplifizierenden Eigenschaften wurde ein komplementäres System entwickelt, bei dem der Selektivität einer Reaktion ein selbstinhibierender Ablauf zugrunde liegt. In einem zweistufigen Prozess wurde zunächst ein neuartiges Phenylalanin-basiertes Amidoester-Selektormotiv auf sein Potential der Stereoinduktion hin untersucht. Durch stereoselektive Interaktion mit einer Reihe chiraler L-Aminosäurederivate, die gleichzeitig potentielle Hydrierprodukte darstellten, gelang es, eine signifikante Rotameranreicherung bei einem der untersuchten Bisphosphinitliganden und seinem Rhodiumkomplex herbeizuführen. Dies führte gleichzeitig zu einer signifikanten Selektivitäts-steigerung in nachfolgenden Hydrierreaktionen, wobei verstärkt das (R)-Produktenantiomer gebildet wurde. Basierend auf diesen Ergebnissen wurden im zweiten Schritt ein hochdynamischer, selektormodifizierter Phosphoramiditligand und verschiedene Olefine synthetisiert, wobei letztere sich von einem der chiralitätsinduzierenden Aminosäurederivate ableiten. In folgenden Hydrierreaktionen konnte gezeigt werden, dass ein ursprünglich bevorzugt gebildetes Produktenantiomer durch Interaktion mit dem Katalysator seine eigene Entstehung im weiteren Verlauf der Reaktion inhibiert und so eine Selektivitätsumkehr herbeiführt. Der letzte Teil der Arbeit in Kapitel 5 beschreibt das Konzept und initiale Studien eines neuartigen, aliphatischen Ligandengrundkörpers für selektormodifizierte tropos Liganden, der auf meso-Weinsäure basiert. Die Erprobung von Synthesen für einen Bisphosphin- und einen Bisphosphinitliganden und Untersuchungen zur Konformerverteilung werden beschrieben.Enantioselective interactions between molecules play a crucial role in a wide range of biological transformations. Where these interactions are of non-covalent nature, they can form the basis for molecular recognition, chirality transfer and self-organization, processes believed to be deeply involved in the origin of natural homochirality. Understanding how non-covalent interactions can be utilized to exert stereochemical control over chemical reactions promises far-reaching opportunities for the prospective design of novel chiral catalysts in chemistry. The strive to harness this potential has sparked great efforts to find pathways that allow for enantiocontrol on a molecular level. In this dissertation, the synthesis and study of stereodynamic ligands and respective complexes as well as their application in asymmetric reactions is described. The focus is on investigating possibilities to influence the axial chirality of tropos ligands through non-covalent interactions between binding sites (selectors), covalently attached to the ligand backbone, and other chiral and achiral molecules, thus inducing enantioselectivity in subsequent asymmetric reactions. The dissertation is divided into four topics. The first topic in chapter 2 covers investigations on chiral L-amino acid-based interaction sites with secondary amides, derived from selector sites of the gas chromatography CSP CHIRASIL VAL. Different 2,2’-biphenyl-based ligands with interaction sites in 5,5’-position were devised and it was found that such a substitution entails spontaneous enrichment of one ligand rotamer. Detailed structural investigations revealed an intermolecular network of hydrogen bonds between selector units to cause diastereoselective formation of ligand dimers. Lastly, the ligands could successfully be employed in transition metal-mediated asymmetric hydrogenation and alkylation reactions yielding products in very high enantioselectivities. In chapter 3, investigations are extended to achiral binding sites for non-covalent interaction. Inspired by the model of "switchable" catalysts, hydrogen-bond driven deracemization of racemic catalysts was examined. Based on the findings in the previous chapter, bisphosphinite ligands with glycine- and racemic phenylalanine-based diamide selectors were devised. By interaction with chiral additives, the rotational distribution of the ligands in corresponding rhodium complexes could be selectively influenced and catalysts for enantioselective hydrogenation reactions could be obtained. Chapter 4 deals with the development of an autoinductive catalyst system. Based on a “by design” self-amplifying reaction previously described by Trapp et al., a complementary system was developed in which the selectivity of a reaction is based on enantioselective self-inhibiting properties. In a two-stage process, a novel, phenylalanine-based amidoester selector motif was first investigated for its potential of non-covalent stereoinduction. Using a series of chiral amino acid derivatives, all of them representing potential hydrogenation products, it was possible to induce significant rotameric enrichment in one investigated ligand and its respective rhodium complex. A concomitant increase in selectivity for the R product enantiomer in subsequent hydrogenation reactions was detected. In the second stage of the project, a highly dynamic, selector-modified phosphoramidite ligand and different olefins were synthesized, the latter being structurally based on one of the amino acid derivatives that had earlier exhibited strong stereoinducing capabilities. In subsequent hydrogenation reactions, it could be shown that over the course of the reaction, an originally preferential product enantiomer inhibited its own production by changing the catalyst’s selectivity through non-covalent interaction, thus inducing a reversal of the catalyst’s enantioselectivity. The last part of the dissertation in chapter 5 describes initial studies concerning a novel ligand motif for selector-modified tropos ligands that is based on an aliphatic ligand backbone derived from meso-tartaric acid. The synthetic outline and initial syntheses for a bisphosphine and a bisphosphinite ligand as well as preliminary studies on ligand conformers and interaction behaviour are described

Different but Similar: Personality Traits of Surgeons and Internists. Results of a Cross-Sectional Observational Study

Objectives: Medical practice may attract and possibly enhance distinct personality profiles. We set out to describe the personality profiles of surgical and medical specialties focusing on board-certified physicians. Design: Prospective, observational. Setting: Online survey containing the Ten-Item Personality Inventory (TIPI), an internationally validated measure of the Five Factor Model of personality dimensions, distributed to board-certified physicians, residents and medical students in several European countries and Canada. Differences in personality profiles were analyzed using MANOVA and Canonical Linear Discriminant Analysis on age- and sex-standardized z-scores of the personality traits. Single personality traits were analyzed using robust t-tests. Participants: The TIPI was completed by 2345 board-certified physicians, 1453 residents and 1350 medical students, who also provided demographic information. Interventions: None. Results: Normal population and board-certified physicians’ personality profiles differed (P<0.001). The latter scored higher on conscientiousness, extraversion, and agreeableness, but lower on neuroticism (all P<0.001). There was no difference in openness to experience. Board-certified surgical and medical doctors’ personality profiles were also different (P<0.001). Surgeons scored higher on extraversion (P=0.003) and openness to experience (P=0.002), but lower on neuroticism (P<0.001). There was no difference in agreeableness and conscientiousness. These differences in personality profiles were reproduced at other levels of training, i.e., in students and training physicians engaging in surgical versus medical practice. Conclusion: These results indicate the existence of a distinct and consistent average “physician personality”. Despite high variability within disciplines, there are moderate, but solid and reproducible differences between surgical and medical specialties

In Reply to the Letter to the Editor Regarding "Distribution of Psychological Instability Among Surgeons".

peer reviewe

Distribution of psychological instability among surgeons

Background High emotional instability, i.e. neuroticism, is associated with poor mental health. Conversely, traumatic experiences may increase neuroticism. Stressful experiences such as complications are common in the surgical profession, with neurosurgeons being particularly affected. We compared the personality trait neuroticism between physicians in a prospective cross-sectional study. Methods 5,148). Multivariate linear regression was used to model differences between surgeons, non-surgeons and specialties with occasional surgical interventions with respect to neuroticism, adjusting for gender, age, age squared and their interactions, then testing equality of parameters of adjusted predictions separately and jointly using Wald tests. Results With an expected variability within disciplines, average levels of neuroticism are lower in surgeons than non-surgeons, especially in the first part of their career. However, the course of neuroticism across age follows a quadratic pattern, i.e., an increase after the initial decrease. The acceleration of neuroticism with age is specifically significant in surgeons. Levels of neuroticism are lowest towards mid-career, but exhibit a strong secondary increase towards the end of the surgeons’ career. This pattern seems driven by neurosurgeons. Conclusion Despite initially lower levels of neuroticism, surgeons suffer a stronger increase of neuroticism together with age. Since, beyond well-being, neuroticism influences professional performance and healthcare systems costs, explanatory studies are mandatory to enlighten causes of this burden

Intraoperative magnetic resonance imaging versus standard neuronavigation for the neurosurgical treatment of glioblastoma: A randomized controlled trial.

BACKGROUND: Although the added value of increasing extent of glioblastoma resection is still debated, multiple technologies can assist neurosurgeons in attempting to achieve this goal. Intraoperative magnetic resonance imaging (iMRI) might be helpful in this context, but to date only one randomized trial exists. METHODS: We included 14 adults with a supratentorial tumor suspect for glioblastoma and an indication for gross total resection in this randomized controlled trial of which the interim analysis is presented here. Participants were assigned to either ultra-low-field strength iMRI-guided surgery (0.15 Tesla) or to conventional neuronavigation-guided surgery (cNN). Primary endpoint was residual tumor volume (RTV) percentage. Secondary endpoints were clinical performance, health-related quality of life (HRQOL) and survival. RESULTS: Median RTV in the cNN group is 6.5% with an interquartile range of 2.5-14.75%. Median RTV in the iMRI group is 13% with an interquartile range of 3.75-27.75%. A Mann-Whitney test showed no statistically significant difference between these groups (P =0.28). Median survival in the cNN group is 472 days, with an interquartile range of 244-619 days. Median survival in the iMRI group is 396 days, with an interquartile range of 191-599 days (P =0.81). Clinical performance did not differ either. For HRQOL only descriptive statistics were applied due to a limited sample size. CONCLUSION: This interim analysis of a randomized trial on iMRI-guided glioblastoma resection compared with cNN-guided glioblastoma resection does not show an advantage with respect to extent of resection, clinical performance, and survival for the iMRI group. Ultra-low-field strength iMRI does not seem to be cost-effective compared with cNN, although the lack of a valid endpoint for neurosurgical studies evaluating extent of glioblastoma resection is a limitation of our study and previous volumetry-based studies on this topic.Peer reviewe

Different but similar: personality traits of​ surgeons and internists-results of a cross-sectional observational study

OBJECTIVES: Medical practice may attract and possibly enhance distinct personality profiles. We set out to describe the personality profiles of surgical and medical specialties focusing on board-certified physicians. DESIGN: Prospective, observational. SETTING: Online survey containing the Ten-Item Personality Inventory (TIPI), an internationally validated measure of the Five Factor Model of personality dimensions, distributed to board-certified physicians, residents and medical students in several European countries and Canada. Differences in personality profiles were analysed using multivariate analysis of variance and Canonical Linear Discriminant Analysis on age-standardised and sex-standardised z-scores of the personality traits. Single personality traits were analysed using robust t-tests. PARTICIPANTS: The TIPI was completed by 2345 board-certified physicians, 1453 residents and 1350 medical students, who also provided demographic information. RESULTS: Normal population and board-certified physicians' personality profiles differed (p<0.001). The latter scored higher on conscientiousness, extraversion and agreeableness, but lower on neuroticism (all p<0.001). There was no difference in openness to experience. Board-certified surgical and medical doctors' personality profiles were also different (p<0.001). Surgeons scored higher on extraversion (p=0.003) and openness to experience (p=0.002), but lower on neuroticism (p<0.001). There was no difference in agreeableness and conscientiousness. These differences in personality profiles were reproduced at other levels of training, that is, in students and training physicians engaging in surgical versus medical practice. CONCLUSION: These results indicate the existence of a distinct and consistent average 'physician personality'. Despite high variability within disciplines, there are moderate but solid and reproducible differences between surgical and medical specialities