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.

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.

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.

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.

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).

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.

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.

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.

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.

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.

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.

Psychosis and Schizophrenia-Spectrum Personality Disorders Require Early Detection on Different Symptom Dimensions.

Psychotic disorders and schizophrenia-spectrum personality disorders (PD) with psychotic/psychotic-like symptoms are considerably linked both historically and phenomenologically. In particular with regard to schizotypal and schizotypal personality disorder (SPD), this is evidenced by their placement in a joint diagnostic category of non-affective psychoses in the InternationaI Classification of Diseases 10th Revision, (CD-10) and, half-heartedly, the fifth edition of Diagnostic and Statistical Manual of Mental Disorders, (DSM-5). Historically, this close link resulted from observations of peculiarities that resembled subthreshold features of psychosis in the (premorbid) personality of schizophrenia patients and their biological relatives. These personality organizations were therefore called "borderline (schizophrenia)" in the first half of the 20th century. In the 1970s, they were renamed to "schizotypal" and separated from psychotic disorders on axis-I and from other PD on axis-II, including modern borderline PD, in the DSM. The phenomenological and historical overlap, however, has led to the common assumption that the main difference between psychotic disorders and SPD in particular was mainly one of severity or trajectory, with SPD representing a latent form of schizophrenia and/or a precursor of psychosis. Thus, psychosis proneness and schizotypy are often assessed using SPD questionnaires. In this perspective-piece, we revisit these assumptions in light of recent evidence. We conclude that schizotypy, SPD (and other schizophrenia-spectrum PD) and psychotic disorder are not merely states of different severity on one common but on qualitatively different dimensions, with the negative dimension being predictive of SPD and the positive of psychosis. Consequently, in light of the merits of early diagnosis, the differential early detection of incipient psychosis and schizophrenia-spectrum PD should be guided by the assessment of different schizotypy dimensions.

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.

The interrelationship between schizotypy, clinical high risk for psychosis and related symptoms: Cognitive disturbances matter.

Schizotypy and clinical high risk (CHR) criteria can identify individuals who are at increased risk for developing psychosis in community and patient samples. However, both approaches have rarely been combined, and very little is known about their associations. Therefore, we examined the factorial structure of CHR and related symptoms and schizotypy features as well as their interrelationship for the first time in a comprehensive approach. In a sample of 277 patients (22 ±â€¯6 years) from two early detection services, structural equation modeling including confirmatory factor analysis was performed to test a theory-driven model using four Wisconsin Schizotypy Scales, 14 predictive basic symptoms (BS) of the Schizophrenia Proneness Instrument, and positive, negative, and disorganized symptoms from the Structured Interview for Psychosis-Risk Syndromes. The data fitted well to the six hypothesized latent factors consisting of negative schizotypy, positive schizotypy including perceptual BS, negative symptoms, positive symptoms, disorganized symptoms and cognitive disturbances. As postulated, schizotypy features were significantly associated with positive, negative and disorganized symptoms through cognitive disturbances. Additionally, positive and negative schizotypy also had a direct association with the respective symptom-domain. While the identified factorial structure corresponds well to dimensional models of schizotypy and psychoses, our model extends earlier models by indicating that schizotypy features are associated with positive, negative and disorganized symptoms directly or indirectly via subjective cognitive disturbances. This calls for more attention to subjective cognitive deficits in combination with heightened schizotypy in the early detection and intervention of psychoses - or even of an Attenuated Psychosis Syndrome.

Synthesis of the Bicyclic Lactone Core of Leonuketal, Enabled by a Telescoped Diels-Alder Reaction Sequence.

The Diels-Alder cycloaddition reaction has become established as a fundamental approach for the preparation of complex natural products; however, successful application of the intermolecular Diels-Alder cycloaddition reaction to the synthesis of particularly congested scaffolds remains surprisingly problematic. Inspired by the terpenoid spiroketal natural product leonuketal, a challenging telescoped reaction sequence has been realized to access the core [2.2.2]-bicyclic lactone ring system and its [3.2.1] isomer. Our four-step, protecting-group-free process required detailed investigation to circumvent the problems of adduct fragmentation and intermediate instability. Successful solution of these practical issues, along with unambiguous structural determination of the target structures, provide useful insights that will facilitate future applications of the Diels-Alder cycloaddition reaction to challenging, highly congested molecular scaffolds and ongoing synthetic efforts towards this natural product.

Odd and disorganized-Comparing the factor structure of the three major schizotypy inventories.

Schizotypy is a personality-framework currently considered a comprehensive and useful construct in schizophrenia research and becoming ever more accepted within psychiatry. Thus, it is crucial to obtain a unifying and generally accepted means of its measuring. The three most commonly used psychometric schizotypy inventories, the Wisconsin Schizotypy Scales, Schizotypal Personality Questionnaire and Oxford-Liverpool Inventory of Feelings and Experiences were, however, built upon different theoretical schizotypy models, wherefore comparing results from studies that have used different inventories is difficult and sometimes questionable. Therefore, an analysis of all three inventories was conducted within the same sample of 327 healthy participants to illustrate the similarities and differences in factor structures. Results showed that findings are likely dependent on the used assessment instrument. A following item-level factor analysis was conducted to investigate the shared structure of all three inventories, in order to illustrate a framework interpretable as "common ground" between measures. This adjusted four-factor structure may be used to better aid comparisons between schizotypy-studies having used different inventories. At least, our findings illustrate the necessity of viewing individual results before the background of the theoretical framework of the respective measurement tool.