Biomimetic Cationic Cyclopropanation Enables an Efficient Chemoenzymatic Synthesis of 6,8-Cycloeudesmanes.

Cationic cyclopropanation involves the γ-elimination at carbocations to form a new σ-C-C bond through proton loss. While exceedingly rare in bulk solution, it is recognized as one of the main biosynthetic cyclopropanation pathways. Despite the rich history of bioinspired synthetic chemistry, cationic cyclopropanation has not been appropriated for the synthetic toolbox, likely due to the preference of carbocations to undergo competing E1 ß-elimination pathways. Here, we present an in-depth synthetic and computational study of cationic cyclopropanation, focusing on the 6,8-cycloeudesmanes as a platform for this investigation. We were able to apply biomimetic cationic cyclopropanation to the synthesis of several 6,8-cycloeudesmanes and non-natural analogues─in doing so, we showcase the power of this transformation in the preparation of complex cyclopropanes.

Azide-Enolate Cycloaddition-Rearrangement Enables Direct α-Amination of Amides and Enelactam Synthesis from Esters.

Azide-enolate cycloaddition-rearrangements offer potential for rapid access to diverse molecular frameworks from simple precursors. We report here that investigations into the cycloadditions of ester or amide enolates with vinyl azides led to the identification of two reaction processes - direct α-amination of amides and lactams, and the synthesis of ene-γ-lactams from esters. The outcomes of these reactions depended on the fate of key vinyl triazoline intermediates generated in the initial cycloaddition step. Isolation of reaction intermediates in the ene-γ-lactam synthesis revealed the unexpected addition of two enolate equivalents, one of which is later eliminated. Computational studies further suggested an unusual reaction pathway involving direct addition of an enolate to the terminal carbon of the N-vinyl triazoline. In contrast, the α-amination of amides and lactams proceeded by rearrangement of the intermediate triazoline to give an imine, hydrolysis or reduction of which gave access to primary or secondary α-amino amides or lactams.

Azide-Enolate Cycloaddition-Rearrangement Enables Direct α-Amination of Amides and Enelactam Synthesis from Esters.

Invited for the cover of this issue are Dan Furkert, Joe Bell-Tyrer and co-workers at the University of Auckland and Victoria University of Wellington. The image depicts a tandem cycloaddition-rearrangement process delivering a diverse range of molecular frameworks from simple precursors. Read the full text of the article at 10.1002/chem.202300261.

Direct Stereodivergent Olefination of Carbonyl Compounds with Sulfur Ylides.

The reactivity of phosphorus and sulfur ylides toward carbonyl compounds constitutes a well-known dichotomy that is a common educational device in organic chemistry─the former gives olefins, while the latter gives epoxides. Herein, we report a stereodivergent carbonyl olefination that challenges this dichotomy, showcasing thiouronium ylides as valuable olefination reagents. With this method, aldehydes are converted to Z-alkenes with high stereoselectivity and broad substrate scope, while N-tosylimines provide a similarly proficient entry to E-alkenes. In-depth computational and experimental studies clarified the mechanistic details of this unusual reactivity.

Brain structural correlates of schizotypal signs and subclinical schizophrenia nuclear symptoms in healthy individuals.

BACKGROUND: Subclinical psychotic-like experiences (PLE), resembling key symptoms of psychotic disorders, are common throughout the general population and possibly associated with psychosis risk. There is evidence that such symptoms are also associated with structural brain changes. METHODS: In 672 healthy individuals, we assessed PLE and associated distress with the symptom-checklist-90R (SCL-90R) scales 'schizotypal signs' (STS) and 'schizophrenia nuclear symptoms' (SNS) and analysed associations with voxel- and surfaced-based brain structural parameters derived from structural magnetic resonance imaging at 3 T with CAT12. RESULTS: For SNS, we found a positive correlation with the volume in the left superior parietal lobule and the precuneus, and a negative correlation with the volume in the right inferior temporal gyrus [p < 0.05 cluster-level Family Wise Error (FWE-corrected]. For STS, we found a negative correlation with the volume of the left and right precentral gyrus (p < 0.05 cluster-level FWE-corrected). Surface-based analyses did not detect any significant clusters with the chosen statistical threshold of p < 0.05. However, in exploratory analyses (p < 0.001, uncorrected), we found a positive correlation of SNS with gyrification in the left insula and rostral middle frontal gyrus and of STS with the left precuneus and insula, as well as a negative correlation of STS with gyrification in the left temporal pole. CONCLUSIONS: Our results show that brain structures in areas implicated in schizophrenia are also related to PLE and its associated distress in healthy individuals. This pattern supports a dimensional model of the neural correlates of symptoms of the psychotic spectrum.

Polygenic risk for schizophrenia and schizotypal traits in non-clinical subjects.

BACKGROUND: Schizotypy is a putative risk phenotype for psychosis liability, but the overlap of its genetic architecture with schizophrenia is poorly understood. METHODS: We tested the hypothesis that dimensions of schizotypy (assessed with the SPQ-B) are associated with a polygenic risk score (PRS) for schizophrenia in a sample of 623 psychiatrically healthy, non-clinical subjects from the FOR2107 multi-centre study and a second sample of 1133 blood donors. RESULTS: We did not find correlations of schizophrenia PRS with either overall SPQ or specific dimension scores, nor with adjusted schizotypy scores derived from the SPQ (addressing inter-scale variance). Also, PRS for affective disorders (bipolar disorder and major depression) were not significantly associated with schizotypy. CONCLUSIONS: This important negative finding demonstrates that despite the hypothesised continuum of schizotypy and schizophrenia, schizotypy might share less genetic risk with schizophrenia than previously assumed (and possibly less compared to psychotic-like experiences).

ent-Atisane diterpenoids: isolation, structure and bioactivity.

Covering: up to 2020 ent-Atisane diterpenoids are a class of over 150 members with diverse structures and valuable bioactivities. These compounds share a curious history in which the synthesis of the archetypal member preceded its isolation from natural sources. In this review, we provide a comprehensive summary of the isolation, structure, and bioactivity of ent-atisane diterpenoids from their discovery in 1965 to the present day.

seco-Labdanes: A Study of Terpenoid Structural Diversity Resulting from Biosynthetic C-C Bond Cleavage.

The cleavage of a C-C bond is a complexity generating process, which complements oxidation and cyclisation events in the biosynthesis of terpenoids. This process leads to increased structural diversity in a cluster of related secondary metabolites by modification of the parent carbocyclic core. In this review, we highlight the diversifying effect of C-C bond cleavage by examining the literature related to seco-labdanes-a class of diterpenoids arising from such C-C bond cleavage events.

The association of striatal volume and positive schizotypy in healthy subjects: intelligence as a moderating factor.

BACKGROUND: Schizotypy, a putative schizophrenia endophenotype, has been associated with brain-structural variations partly overlapping with those in psychotic disorders. Variations in precuneus structure have been repeatedly reported, whereas the involvement of fronto-striatal networks - as in schizophrenia - is less clear. While shared genetic architecture is thought to increase vulnerability to environmental insults, beneficial factors like general intelligence might buffer their effect. METHODS: To further investigate the role of fronto-striatal networks in schizotypy, we examined the relationship of voxel- and surface-based brain morphometry and a measure of schizotypal traits (Schizotypal Personality Questionnaire, with subscores Cognitive-Perceptual, Interpersonal, Disorganised) in 115 healthy participants [54 female, mean age (s.d.) = 27.57(8.02)]. We tested intelligence (MWT-B) as a potential moderator. RESULTS: We found a positive association of SPQ Cognitive-Perceptual with putamen volume (p = 0.040, FWE peak level-corrected), moderated by intelligence: with increasing IQ, the correlation of SPQ Cognitive-Perceptual and striatal volume decreased (p = 0.022). SPQ Disorganised was positively correlated with precentral volume (p = 0.013, FWE peak level-corrected). In an exploratory analysis (p < 0.001, uncorrected), SPQ total score was positively associated with gyrification in the precuneus and postcentral gyrus, and SPQ Disorganised was negatively associated with gyrification in the inferior frontal gyrus. CONCLUSIONS: Our findings support the role of fronto-striatal networks for schizotypal features in healthy individuals, and suggest that these are influenced by buffering factors like intelligence. We conclude that protective factors, like general cognitive capacity, might attenuate the psychosis risk associated with schizotypy. These results endorse the idea of a continuous nature of schizotypy, mirroring similar findings in schizophrenia.

Divalent cannabinoid-1 receptor ligands: A linker attachment point survey of SR141716A for development of high-affinity CB1R molecular probes.

The cannabinoid-1 receptor (CB1R) inverse agonist SR141716A has proven useful for study of the endocannabinoid system, including development of divalent CB1R ligands possessing a second functional motif attached via a linker unit. These have predominantly employed the C3 position of the central pyrazole ring for linker attachment. Despite this precedent, a novel series of C3-linked CB1R-D2R divalent ligands exhibited extremely high affinity at the D2R, but only poor affinity for the CB1R. A systematic linker attachment point survey of the SR141716A pharmacophore was therefore undertaken, establishing the C5 position as the optimal site for linker conjugation. This linker attachment survey enabled the identification of a novel divalent ligand as a lead compound to inform ongoing development of high-affinity CB1R molecular probes.

Catalyst-Free Deaminative Functionalizations of Primary Amines by Photoinduced Single-Electron Transfer.

The use of pyridinium-activated primary amines as photoactive functional groups for deaminative generation of alkyl radicals under catalyst-free conditions is described. By taking advantage of the visible light absorptivity of electron donor-acceptor complexes between Katritzky pyridinium salts and either Hantzsch ester or Et3 N, photoinduced single-electron transfer could be initiated in the absence of a photocatalyst. This general reactivity platform has been applied to deaminative alkylation (Giese), allylation, vinylation, alkynylation, thioetherification, and hydrodeamination reactions. The mild conditions are amenable to a diverse range of primary and secondary alkyl pyridiniums and demonstrate broad functional group tolerance.

Specific Reaction Patterns to Distinct Positive Emotional Cues Related to Incentive Motivation in Dependence of the Taq1A-Polymorphism: Molecular Genetic Associations of Early and Late Event-Related Potentials.

BACKGROUND/AIMS: Early and late event-related potential (ERP) responses, representing early subconscious and late motivational processes, were recorded for positive emotional words related to 'wanting' and 'liking', in dependence of the dopamine-related Taq1A genotype (ANKK1/DRD2). Research suggests that 'wanting' as opposed to 'liking' is related to dopaminergic processes. Therefore, it was hypothesized that risk allele carriers of the Taq1A polymorphism exhibit late ERP changes in reaction to words representing incentive motivation, i.e. 'wanting' (word categories 'lust' and 'anticipation'), but not to words representing 'liking' ('closeness'). METHODS: Seventy-two male participants performed an emotional-word Stroop task during EEG recording and were genotyped according to the Taq1A polymorphism of ANKK1/DRD2. RESULTS: Positive emotional words related to anticipation and lust revealed blunted responses in the late positive potential (LPP) in carriers of the A1 allele, an effect absent in response to 'liking'-related words. These differences were not evident in the earlier posterior negativity (EPN). CONCLUSION: As no differences in dependence of the Taq1A genotype were observed in reaction to 'wanting'- and 'liking'-related words in the EPN, but merely in the LPP, it can be assumed that incentive-motivational stimuli only modify motivation-related ERP responses in carriers of the A1 allele of the Taq1A polymorphism, indicating the role of dopamine in late ERP components.

Neural mechanisms of smooth pursuit eye movements in schizotypy.

Patients with schizophrenia as well as individuals with high levels of schizotypy are known to have deficits in smooth pursuit eye movements (SPEM). Here, we investigated, for the first time, the neural mechanisms underlying SPEM performance in high schizotypy. Thirty-one healthy participants [N = 19 low schizotypes, N = 12 high schizotypes (HS)] underwent functional magnetic resonance imaging at 3T with concurrent oculographic recording while performing a SPEM task with sinusoidal stimuli at two velocities (0.2 and 0.4 Hz). Behaviorally, a significant interaction between schizotypy group and velocity was found for frequency of saccades during SPEM, indicating impairments in HS in the slow but not the fast condition. On the neural level, HS demonstrated lower brain activation in different regions of the occipital lobe known to be associated with early sensory and attentional processing and motion perception (V3A, middle occipital gyrus, and fusiform gyrus). This group difference in neural activation was independent of target velocity. Together, these findings replicate the observation of altered pursuit performance in highly schizotypal individuals and, for the first time, identify brain activation patterns accompanying these performance changes. These posterior activation differences are compatible with evidence of motion processing deficits from the schizophrenia literature and, therefore, suggest overlap between schizotypy and schizophrenia both on cognitive-perceptual and neurophysiological levels. However, deficits in frontal motor areas observed during pursuit in schizophrenia were not seen here, suggesting the operation of additional genetic and/or illness-related influences in the clinical disorder.

Differential associations of dopamine-related polymorphisms with discrete components of reaction time variability: relevance for attention deficit/hyperactivity disorder.

BACKGROUND: Reaction time variability (RTV) is considered a valid endophenotype of attention deficit/hyperactivity disorder (ADHD). It is also often used to examine the efficacy of drug treatment or individual patients' treatment responses and has been furthermore suggested to significantly reduce the potential number of false-positive diagnoses. Among the most commonly investigated candidate genes for ADHD are DRD2, SLC6A3 (DAT), COMT and MAOA. Genetic associations have, however, proven inconclusive or inconsistent. METHODS: Due to the complexity of dopaminergic neurotransmission in the two distinct prosencephalic dopamine pathways, we examined whether the effects of dopamine-related candidate polymorphisms in the genes DRD2, SLC6A3, COMT and MAOA may be differentially associated with discrete subcomponents of RTV, rather than global RTV. A total of 260 healthy volunteers were genotyped for the aforementioned polymorphisms and performed a reaction time paradigm able to distinguish between sensory and motor reaction time. RESULTS: We found that functional polymorphisms in the genes encoding for dopamine-catabolizing enzymes (i.e. COMT and MAOA) are associated with motor RTV but not with sensory RTV, whereas vice versa the gene DRD2 influences sensory but not motor RTV. No significant associations for the gene SLC6A3 (DAT) were found. CONCLUSIONS: Our results give new insight into the inconsistent state of the literature regarding genetic associations of RTV and clearly show that the examination of subcomponents thereof explains far more variance compared to global RTV. This could be of great relevance to the use of RTV in basic research, clinical diagnostics and pharmacological studies examining the efficacy of novel drug treatments.

Remote proton elimination: C-H activation enabled by distal acidification.

Generally, the acidity of carbon-hydrogen bonds is most sensitive to functionality just one or two bonds away. Here, we present an approach to the formation of carbon-carbon σ bonds by remote proton elimination, a distinct mode of carbon-hydrogen activation enabled by distal acidification through five carbon-carbon bonds. Application of remote proton elimination to cyclodecyl cations unveiled an appealing method for the synthesis of decalins. The transformation is regioconvergent, proceeds without the need for a directing group or precious metal, and demonstrates exquisite site selectivity. An in-depth computational study illuminated the reaction mechanism. Additionally, we describe the complete stereoisomeric enrichment of the decalin products through epimerization mediated by hydrogen atom transfer.

The biogenesis protein PEX14 is an optimal marker for the identification and localization of peroxisomes in different cell types, tissues, and species in morphological studies.

Catalase and ABCD3 are frequently used as markers for the localization of peroxisomes in morphological experiments. Their abundance, however, is highly dependent on metabolic demands, reducing the validity of analyses of peroxisomal abundance and distribution based solely on these proteins. We therefore attempted to find a protein which can be used as an optimal marker for peroxisomes in a variety of species, tissues, cell types and also experimental designs, independently of peroxisomal metabolism. We found that the biogenesis protein peroxin 14 (PEX14) is present in comparable amounts in the membranes of every peroxisome and is optimally suited for immunoblotting, immunohistochemistry, immunofluorescence, and immunoelectron microscopy. Using antibodies against PEX14, we could visualize peroxisomes with almost undetectable catalase content in various mammalian tissue sections (submandibular and adrenal gland, kidney, testis, ovary, brain, and pancreas from mouse, cat, baboon, and human) and cell cultures (primary cells and cell lines). Peroxisome labeling with catalase often showed a similar tissue distribution to the mitochondrial enzyme mitochondrial superoxide dismutase (both responsible for the degradation of reactive oxygen species), whereas ABCD3 exhibited a distinct labeling only in cells involved in lipid metabolism. We increased the sensitivity of our methods by using QuantumDots™, which have higher emission yields compared to classic fluorochromes and are unsusceptible to photobleaching, thereby allowing more exact quantification without artificial mistakes due to heterogeneity of individual peroxisomes. We conclude that PEX14 is indeed the best marker for labeling of peroxisomes in a variety of tissues and cell types in a consistent fashion for comparative morphometry.

Total Synthesis of Spiroketal Alkaloids Lycibarbarines A-C.

Lycibarbarines A-C are spirocyclic alkaloids with a unique tetracyclic framework, consisting of tetrahydroquinoline and spiro-fused oxazine-sugar spiroketal subunits. The first total syntheses of lycibarbarines A-C were achieved over 10 steps (longest linear sequence) each. Through this work, it was discovered that the spiroketal unit of lycibarbarines A-C exhibits unusually high resistance to acid-mediated isomerization and epimerization, likely due to the basic nitrogen atom. As such, the lycibarbarines present an interesting case study in preventing the interconversion of spiroketal isomers, which may prove to be instructive in efforts to obtain nonthermodynamic spiroketal frameworks.

Schizotypy in Parkinson's disease predicts dopamine-associated psychosis.

Psychosis is the most common neuropsychiatric side-effect of dopaminergic therapy in Parkinson's disease (PD). It is still unknown which factors determine individual proneness to psychotic symptoms. Schizotypy is a multifaceted personality trait related to psychosis-proneness and dopaminergic neurotransmission in healthy subjects. We investigated whether (1) PD patients exhibit lower schizotypy than controls and (2) dopamine-related neuropsychiatric side-effects can be predicted by higher schizotypy. In this cross-sectional study, we used the Oxford-Liverpool Inventory of Feelings and Experiences in 56 PD patients (12 women, mean ± sd age: 61 ± 11 years) receiving their usual dopaminergic medication and 32 age-matched healthy controls (n = 32; 18 women, mean ± sd age: 57 ± 6 years). We further compared schizotypy scores of patients with (n = 18, 32.1%) and without previously experienced psychosis. We found that patients exhibited lower schizotypy than controls. Further, patients with a history of psychosis exhibited higher schizotypy than patients without these symptoms. Using an information theoretic measure and a machine learning approach, we show that schizotypy yields the greatest predictive value for dopamine-associated hallucinations compared to other patient characteristics and disease related factors. Our results indicate an overlap between neural networks associated with schizotypy and the pathophysiology of PD and a relationship between schizotypy and psychotic side-effects of dopaminergic medication.

Schizotypy, social stress and the emergence of psychotic-like states - A case for benign schizotypy?

Schizotypy is a personality-organisation related to schizophrenia-liability as well as the emergence of psychotic symptoms and psychotic-like experiences (PLEs) in non-schizophrenic individuals. It has been suggested that some non-schizophrenic individuals may exhibit PLEs frequently, but in a fashion that is not distressing but life-enhancing ("benign schizotypy"). In schizophrenia and at-risk individuals, however, psychotic symptoms are not only distressing, but also triggered stress. To further investigate questions of causality and examine how PLEs may present as distressing symptoms in some individuals and as benign experiences in others, we explored how schizotypy-facets moderated PLEs-variability under experimentally induced social stress.We performed a standardised social stress-paradigm in 107 healthy adults (77 female, 30 male; average age 22,5 years), measuring changes in psychometrically assessed PLEs and the moderation of changes under stress through positive, negative and disorganised schizotypy. Results suggest two discrete effects: On the one hand, individuals high in disorganised and negative schizotypy showed stress-dependent increases in PLEs; without added effects of positive schizotypy. On the other, individuals low in negative and disorganised schizotypy showed higher levels of PLEs solely as a function of positive schizotypy but not stress. We discuss these findings in light of the fully-dimensional model of schizotypy and hypothesize that PLEs in individuals high in schizotypy-facets suggested to convey risk-for-schizophrenia (negative and disorganised) may reflect qualitatively different entities than PLEs in individuals with low values in these facets, but high expressions of positive schizotypy ("happy schizotypes"). Additionally, we emphasize the importance of not overlooking the disorganised schizotypy-facet in related research.

Total Synthesis of (±)-Leonuketal.

Leonuketal is an 8,9-seco-labdane terpenoid with a unique tetracyclic structure, owing to a diversity-generating biosynthetic C-C bond cleavage event. The first total synthesis of leonuketal is reported, featuring a Ti(III)-mediated reductive cyclization of an epoxy nitrile ether, an unusual ring-opening alkyne formation as part of an auxiliary ring strategy, and the previously undescribed Au(I)-catalyzed cyclization of a ß-keto(enol)lactone to assemble the core spiroketal motif.