Enantioselective (3+2) Annulation of Donor-Acceptor Cyclopropanes with Aldehydes and Ketones Catalyzed by Brønsted Bases.

The substituted tetrahydrofuran core is a structural motif in many biologically active and natural compounds. However, the scarcity of enantioselective methods developed towards its synthesis makes this field challenging and attractive to explore. Herein, the first Brønsted-base catalyzed enantioselective (3+2) annulation of donor-acceptor cyclopropanes with aldehydes and ketones affording enantioenriched 2,3,5-substituted tetrahydrofurans is reported. The reaction concept is based on activation of racemic ß-cyclopropyl ketones by a chiral bifunctional Brønsted base which catalyzes the (3+2) annulation for a range of aldehydes and ketones. For aldehydes, the annulation furnished tetrahydrofurans in excellent yield, good diastereoselectivity and with excellent enantioselectivity up to >99% ee. Surprisingly, aromatic aldehydes afforded the cis-2,5-substituted tetrahydrofurans as the major diastereoisomer, while for aliphatic aldehydes the trans-cycloadduct was favored. The reaction also proceeds well for ketones affording spiro tetrahydrofurans in excellent yields and enantioselectivities (up to 99% ee). Hammett studies have been conducted to elucidate the influence of the electronic nature of benzaldehydes on the stereoselectivity. Based on the diastereochemical outcome for the aldehydes, two reaction paths for aromatic and aliphatic aldehydes are proposed. Finally, two diastereoselective synthetic transformations have been conducted to demonstrate the synthetic potential of the obtained products.

Enantioselective Synthesis of Tropane Scaffolds by an Organocatalyzed 1,3-Dipolar Cycloaddition of 3-Oxidopyridinium Betaines and Dienamines.

Tropane alkaloids constitute a compound-class which is structurally defined by a central 8-azabicyclo[3.2.1]octane core. A diverse bioactivity profile combined with an unusual aza-bridged bicyclic framework has made tropanes molecules-of-interest within organic chemistry. Enantioselective examples of (5+2) cycloadditions between 3-oxidopyridinium betaines and olefins remain unexplored, despite 3-oxidopyridinium betaines being useful reagents in organic synthesis. The first asymmetric (5+2) cycloaddition of 3-oxidopyridinium betaines is reported, affording tropane derivatives in up to quantitative yield and with excellent control of peri-, regio-, diastereo-, and enantioselectivity. The reactivity is enabled by dienamine-activation of α,ß-unsaturated aldehydes combined with in situ formation of the pyridinium reaction-partner. A simple N-deprotection protocol allows for liberation of the tropane alkaloid motif, and synthetic elaborations of the cycloadducts demonstrate their synthetic utility to achieve highly diastereoselective modification around the bicyclic framework. DFT computations suggest a stepwise mechanism where regio- and stereoselectivity are defined during the first bond-forming step in which the pyridinium dipole exerts critical conformational control over its dienamine partner. In the second bond-forming step, a kinetic preference toward an initial (5+4) cycloadduct was identified; however, a lack of catalyst turn-over, reversibility, and thermodynamic bias favoring a (5+2) cycloadduct rendered the reaction fully periselective.

Enantioselective (8+3) Cycloadditions by Activation of Donor-Acceptor Cyclopropanes Employing Chiral Brønsted Base Catalysis.

A novel enantioselective (8+3) cycloaddition between donor-acceptor cyclopropanes and heptafulvenoids catalysed by a chiral bifunctional Brønsted base is described. Importantly, the reaction, which leverages an anionic activation strategy, is divergent from prototypical Lewis-acid activation protocols. A series of cyclopropylketones react with tropones affording the desired (8+3) cycloadducts in high yield and enantiomeric excess. For barbiturate substituted heptafulvenes, the (8+3) cycloaddition with cyclopropylketones proceeds in good yield, excellent diastereoselectivity and high enantiomeric excess. The experimental work is supported by DFT calculations, which indicate that the bifunctional organocatalyst activates both the donor-acceptor cyclopropane and tropone; the reaction proceeds in a step-wise manner with the ring-closure being the stereodetermining step.

Childhood Adversity and Intimate Partner Violence in Adulthood: The Mediating Influence of PTSD in a Sample of Women Prisoners.

Although past research documents strong linkages between adverse childhood experiences (ACEs), posttraumatic stress disorder (PTSD), and adult intimate partner violence (IPV) in the lives of women prisoners, researchers have often neglected to consider the potential mediating role of PTSD in the relationships between ACEs and adult IPV. Using data from a stratified random sample of all incarcerated women in Oklahoma (N = 334), we explore the relationships between ACEs, PTSD symptomology, and adult IPV utilizing a feminist life course theoretical framework. Results indicate that PTSD symptomology fully mediates the relationship between ACEs and adult IPV, suggesting that PTSD may be central to understanding pathways to adult IPV as well as offending and incarceration for women. Implications and suggestions for policy and future research are offered.

Native American and Non-Native American Women Prisoners, Adverse Childhood Experiences, and the Perpetration of Physical Violence in Adult Intimate Relationships.

Native American women are at an especially high risk of lifetime violence, including childhood abuse, intimate partner violence (IPV), and sexual assault, and are overrepresented in the criminal justice system. Yet few studies have examined how the long-term effects of child maltreatment and other adverse childhood experiences (ACEs) affect Native American women prisoners' perpetration of physical violence in adult intimate relationships. This is surprising because ample research illustrates that childhood adverse events, particularly childhood abuse and neglect, have far-reaching effects across the life course and that these experiences are especially apparent in the lives of women involved in the criminal justice system. Using data from a stratified random sample of Native American (n = 92) and non-Native American (n = 264) women prisoners in Oklahoma, we explore the relationships between individual, cumulative, and clusters of ACEs as they relate to the use of physical violence in adult intimate relationships. Utilizing a feminist life course theoretical framework, our findings indicate that ACEs are not only critical to understanding adult IPV but also that the mechanisms and processes underlying the relationships between ACEs and the perpetration of physical violence in adult intimate relationships differ for Native American and non-Native American women. The findings of the current study demonstrate that it is imperative that prison programming includes trauma-informed and trauma-specific interventions targeting Native Americans.

Childhood adversity, mental health, and the perpetration of physical violence in the adult intimate relationships of women prisoners: A life course approach.

BACKGROUND: Adverse childhood experiences (ACEs) are common, with nearly two-thirds of adult samples reporting exposure to at least one and one-quarter reporting exposure to three or more distinct types of ACEs. ACEs have been linked to various negative outcomes across the life course, including mental health problems, and the perpetration of physical violence in intimate relationships. However, little is known about the relationships between ACEs, PTSD symptomology, and use of physical violence against an adult intimate partner among incarcerated women. OBJECTIVE: The purpose of this paper is to examine the relationships between ACEs, PTSD symptoms, and the perpetration of the physical violence in the adult intimate relationships of women prisoners. METHODS: Using data from the 2014 Oklahoma Study of Incarcerated Mothers and Their Children (N = 349) and structural equation modeling (SEM) techniques, we investigate the potential mediating effect of PTSD symptoms in the relationship between ACEs and perpetrating violence against an intimate partner. RESULTS: Our findings indicate that PTSD symptomology fully mediates the relationship between ACEs and the perpetration of physical violence against an adult intimate partner, indicating that PTSD experiences may be central to understanding women's pathways toward violence. CONCLUSIONS: Women prisoners who were exposed to ACEs during childhood were at a particularly elevated risk of developing PTSD symptomology and perpetrating physical violence against an adult intimate partner. Based on the current study's findings, treatment programs that address these complex relationships between ACEs, particularly focusing on the central role of mental health in these processes, are needed for incarcerated women.

Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma.

There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound LDN-214117. Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds M4K2009, M4K2117, and M4K2163, each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust in vivo pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.

Life as she knows it: The effects of adverse childhood experiences on intimate partner violence among women prisoners.

Most incarcerated women suffer from adverse childhood experiences (ACEs), such as abuse (e.g., physical, sexual, emotional), neglect, (e.g., physical, emotional), and chaotic home environments (e.g., witnessing domestic violence), and adult intimate partner violence (IPV). Yet the majority of research on the relationship between ACEs and IPV has been limited to non-incarcerated populations. Using data from a stratified random sample of all incarcerated women in Oklahoma (n = 355), we explore the relationships between individual, cumulative, and clusters of ACEs as they relate to multiple forms of IPV in adulthood utilizing a feminist life course theory approach. Our findings indicate that individual ACEs, high accumulation of ACEs (five or more), and clusters of ACEs are linked to simple assault, aggravated assault, sexual abuse, and psychological abuse in adult intimate relationships in the pre-prison lives of women prisoners suggesting strong support for the use of a feminist life course theory approach in understanding these relationships.