A General Strategy for N-(Hetero)arylpiperidine Synthesis Using Zincke Imine Intermediates.

Methods to synthesize diverse collections of substituted piperidines are valuable due to the prevalence of this heterocycle in pharmaceutical compounds. Here, we present a general strategy to access N-(hetero)arylpiperidines using a pyridine ring-opening and ring-closing approach via Zincke imine intermediates. This process generates pyridinium salts from a wide variety of substituted pyridines and (heteroaryl)anilines; hydrogenation reactions and nucleophilic additions then access the N-(hetero)arylpiperidine derivatives. We successfully applied high-throughput experimentation (HTE) using pharmaceutically relevant pyridines and (heteroaryl)anilines as inputs and developed a one-pot process using anilines as nucleophiles in the pyridinium salt-forming processes. This strategy is viable for generating piperidine libraries and applications such as the convergent coupling of complex fragments.

Does preschool executive control mediate the impact of early environmental unpredictability and deprivation on the general factor of psychopathology a decade later?

BACKGROUND: Although deprivation has been consistently shown to increase risk for psychopathology through impaired executive control, the unique effects of other dimensions of early adversity, such as unpredictability, on executive control development are poorly understood. The current study evaluated whether deprivation and/or unpredictability early in life have unique effects on the general factor of psychopathology through impaired preschool executive control. METHODS: Participants included 312 children (51% female) oversampled for greater sociodemographic risk. Preschool executive control was measured using a battery of nine developmentally appropriate executive control tasks. Dimensions of adversity were measured with observational and caregiver assessments, and psychopathology was measured with caregiver and child reports. RESULTS: In separate models, both deprivation and unpredictability had significant indirect effects on the adolescent general factor of psychopathology through impaired preschool executive control. However, when both dimensions of adversity were included simultaneously, early life deprivation, but not unpredictability, was uniquely associated with the general factor of psychopathology in adolescence through impaired preschool executive control. CONCLUSIONS: Preschool executive control appears to be a transdiagnostic mechanism through which deprivation, but not unpredictability, increases risk for the general factor of psychopathology in adolescence. Results elucidate potential transdiagnostic targets for intervention efforts aimed at reducing the development and maintenance of psychopathology across the life span.

Early executive control buffers risk for adolescent psychopathology during the COVID-19 pandemic.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has had a global impact on youth mental health, and there is a critical need for research examining individual factors that contribute to increased psychopathology during the pandemic. The current study explored whether executive control (EC) abilities in early childhood interact with COVID-related stress to attenuate risk for adolescent psychopathology during the first 6 months of the pandemic. METHODS: Participants were 337 youth (49% female) living in a small midwestern city in the United States. Participants completed EC tasks when they were approximately 4.5 years old as part of a longitudinal study investigating cognitive development. At annual laboratory visits during adolescence and before the pandemic, participants (Mage = 14.57) reported on mental health symptoms. In July and August of 2020, participants (Mage = 16.57) reported on COVID-related stress and depression, anxiety, and trauma symptoms. RESULTS: COVID-related stress was associated with increased internalizing problems after controlling for prepandemic symptom levels. Further, the impact of COVID-related stress on adolescent internalizing problems was moderated by preschool EC, with higher levels of EC buffering the effects of COVID-related stress on adolescent internalizing problems. CONCLUSIONS: Findings highlight the importance of promoting EC early in development, as well as screening for EC deficits and implementing targeted intervention strategies across the lifespan to help reduce the impact of stress on adolescent internalizing problems.

Diverse Catalytic Reactions for the Stereoselective Synthesis of Cyclic Dinucleotide MK-1454.

As practitioners of organic chemistry strive to deliver efficient syntheses of the most complex natural products and drug candidates, further innovations in synthetic strategies are required to facilitate their efficient construction. These aspirational breakthroughs often go hand-in-hand with considerable reductions in cost and environmental impact. Enzyme-catalyzed reactions have become an impressive and necessary tool that offers benefits such as increased selectivity and waste limitation. These benefits are amplified when enzymatic processes are conducted in a cascade in combination with novel bond-forming strategies. In this article, we report a highly diastereoselective synthesis of MK-1454, a potent agonist of the stimulator of interferon gene (STING) signaling pathway. The synthesis begins with the asymmetric construction of two fluoride-bearing deoxynucleotides. The routes were designed for maximum convergency and selectivity, relying on the same benign electrophilic fluorinating reagent. From these complex subunits, four enzymes are used to construct the two bridging thiophosphates in a highly selective, high yielding cascade process. Critical to the success of this reaction was a thorough understanding of the role transition metals play in bond formation.

Synthesis of a CGRP Receptor Antagonist via an Asymmetric Synthesis of 3-Fluoro-4-aminopiperidine.

A practical and efficient enantioselective synthesis of the calcitonin gene-related peptide receptor antagonist 1 has been developed. The key structural component of the active pharmaceutical ingredient is a syn-1,2-amino-fluoropiperidine 4. Two approaches were developed to synthesize this important pharmacophore. Initially, Ru-catalyzed asymmetric hydrogenation of fluoride-substituted enamide 8 enabled the synthesis of sufficient quantities of compound 1 to support early preclinical studies. Subsequently, a novel, cost-effective route to this intermediate was developed utilizing a dynamic kinetic asymmetric transamination of ketone 9. This synthesis also features a robust Ullmann coupling to install a bis-aryl ether using a soluble Cu(I) catalyst. Finally, an enzymatic desymmetrization of meso-diester 7 was exploited for the construction of the γ-lactam moiety in 1.

Pd-Catalyzed Synthesis of Aryl and Heteroaryl Triflones from Reactions of Sodium Triflinate with Aryl (Heteroaryl) Triflates.

A novel method for Pd-catalyzed triflination of aryl and heteroaryl triflates using NaSO2CF3 as the nucleophile is described. The combination of Pd2(dba)3 and RockPhos formed the most effective catalyst. A broad range of functional groups and heteroaromatic compounds were tolerated under the neutral reaction conditions. The order of reactivity ArOTf ≥ ArCl ≥ ArBr is consistent with transmetalation being a slow step of the reaction.

Synthesis of ent-ketorfanol via a C-H alkenylation/torquoselective 6π electrocyclization cascade.

The asymmetric synthesis of ent-ketorfanol from simple and commercially available precursors is reported. A Rh(I) -catalyzed intramolecular CH alkenylation/torquoselective 6π electrocyclization cascade provides a fused bicyclic 1,2-dihydropyridine as a key intermediate. Computational studies were performed to understand the high torquoselectivity of the key 6π electrocyclization. The computational results demonstrate that a conformational effect is responsible for the observed selectivity. The ketone functionality and final ring are introduced in a single step by a redox-neutral acid-catalyzed rearrangement of a vicinal diol to give the requisite carbonyl, followed by intramolecular Friedel-Crafts alkylation.

Catalytic dynamic kinetic resolutions with N-heterocyclic carbenes: asymmetric synthesis of highly substituted ß-lactones.

New DKR type: An N-heterocyclic carbene (NHC)-catalyzed dynamic kinetic resolution of racemic α-substituted ß-keto esters has been developed. This method relies on the epimerization of an NHC-enol intermediate before subsequent aldol/acylation events. Highly substituted ß-lactones are produced in good yield with good to excellent selectivities (see scheme).

A Diastereoselective Method for the Construction of syn-2'-Deoxy-2'-fluoronucleosides.

A general and diastereoselective fluorination/glycosylation strategy for the synthesis of 2'-fluorinated nucleosides has been developed. Electrophilic fluorination of a glycal with NFSI provided the 1',2'-difunctionalized furanoside intermediate with high diastereoselectivity. The TBS-protected 2'-deoxyfluorosulfonimide sugar was prepared on an 80 g scale and isolated as a crystalline, bench-stable single diastereomer. This intermediate was found to undergo a subsequent glycosylation reaction with a variety of heteroaryl nucleophiles with generally good diastereoselectivities.

Empirical support for a dual process model of the p-factor: Interaction effects between preschool executive control and preschool negative emotionality on general psychopathology.

Recent work indicates that a general factor, often referred to as the p-factor, underlies nearly all forms of psychopathology. Although the criterion validity and utility of this general factor have been well supported, questions remain about the substantive meaning of the p-factor. The purpose of the present longitudinal study was to empirically test the hypothesis that the p-factor reflects dysregulation arising from a combination of high dispositional negative emotionality and low executive control. The current study examined preschool executive control, measured using a battery of 9 developmentally appropriate executive control tasks, as a moderator of the association between preschool negative emotionality and both concurrent and subsequent levels of general psychopathology in preschool and elementary school using a community sample (N = 497). Latent moderated structural equation models demonstrated that preschool executive control significantly moderated the associations between preschool negative emotionality and general psychopathology both in preschool and approximately 5 years later in elementary school. These results suggest that the general factor of psychopathology may reflect dysregulation arising from a tendency to experience high negative affect, without sufficient executive control to effectively down-regulate that affect. This work has important implications for identifying transdiagnostic targets for prevention and intervention efforts, as well as furthering understanding of the substantive meaning and construct validity of the general factor of psychopathology. (PsycInfo Database Record (c) 2022 APA, all rights reserved).

A chemoenzymatic strategy for site-selective functionalization of native peptides and proteins.

The emergence of new therapeutic modalities requires complementary tools for their efficient syntheses. Availability of methodologies for site-selective modification of biomolecules remains a long-standing challenge, given the inherent complexity and the presence of repeating residues that bear functional groups with similar reactivity profiles. We describe a bioconjugation strategy for modification of native peptides relying on high site selectivity conveyed by enzymes. We engineered penicillin G acylases to distinguish among free amino moieties of insulin (two at amino termini and an internal lysine) and manipulate cleavable phenylacetamide groups in a programmable manner to form protected insulin derivatives. This enables selective and specific chemical ligation to synthesize homogeneous bioconjugates, improving yield and purity compared to the existing methods, and generally opens avenues in the functionalization of native proteins to access biological probes or drugs.

N-heterocyclic carbene-catalyzed conjugate additions of alcohols.

An efficient intermolecular conjugate addition of alcohols to activated alkenes catalyzed by N-heterocyclic carbenes has been developed. With 5 mol % of the free carbene derived from IMes·HCl, unsaturated ketones and esters are competent substrates, and a variety of primary and secondary alcohols can be employed as the nucleophile. No oligomerization is observed under these mild conditions for effective hydroalkoxylation. In addition to reactions with activated alkenes, IMes catalyzes the formation of vinyl ethers through the 1,4-addition of alcohols to ynones and promotes tandem conjugate addition/Michael cascade reactions. Preliminary data support a Brønsted base mechanism with the free carbene.

N-heterocyclic carbene-catalyzed enantioselective Mannich reactions with alpha-aryloxyacetaldehydes.

N-Heterocyclic carbenes (NHCs) catalyze a new Mannich-type reaction to form beta-amino acid derivatives in high yield and enantioselectivity. The reaction is initiated by the addition of an NHC to an alpha-aryloxyaldehyde followed by elimination of a phenoxide anion which generates an enol/enolate. A Mannich addition to a tosylimine proceeds with excellent control over enantioselectivity. In a new carbene catalysis concept, catalyst regeneration is promoted by return, or rebound, and acylation of the phenoxide group which served as the activating component in the first step of the catalytic cycle. The activated ester products formed in situ are manipulated to form a variety of useful compounds including beta-amino acids, beta-amino amides, and peptides.

N-Heterocyclic Carbene-Catalyzed Oxidations.

N-Heterocyclic carbenes catalyze the oxidation of allylic and benzylic alcohols as well as saturated aldehydes to esters with manganese(IV) oxide in excellent yields. A variety of esters can be synthesized, including protected carboxylates. The oxidation proceeds under mild conditions, with low loadings of a simple triazolium salt pre-catalyst in the presence of base. Substrates containing potentially epimerizable centers are oxidized while preserving stereochemical integrity. The acyl triazolium intermediate generated under catalytic conditions can be employed as a chiral acylating agent in the desymmetrization of meso-diols.

Tandem oxidation of allylic and benzylic alcohols to esters catalyzed by N-heterocyclic carbenes.

N-heterocyclic carbenes catalyze the oxidation of allylic, propargylic, and benzylic alcohols to esters with manganese(IV) oxide in excellent yields. A variety of ester derivatives can be synthesized, including protected carboxylates. This one-pot tandem oxidation represents the first organocatalytic oxidation of alcohols to esters. Saturated esters can also be accessed from aldehydes using this method. Through the utilization of a chiral catalyst, the acyl-heteroazolium intermediate becomes a chiral acylating agent, which can desymmetrize meso-1,2-diols. [reaction: see text].

Rh(I)-Catalyzed Cycloisomerization of 1,6-Enynes.

A new and unexpected Rh(I)-catalyzed cycloisomerization of 1,6-enynes is reported. Several different alkyne substitution patterns were evaluated under the reaction conditions, including a deuterated derivative that provides some insight into the reaction mechanism.

Catalytic enantioselective total syntheses of bakkenolides I, J, and S: application of a carbene-catalyzed desymmetrization.

A general strategy for the catalytic asymmetric syntheses of the bakkenolides is reported. The key bond-forming step involves an N-heterocyclic carbene catalyzed desymmetrization of a 1,3-diketone to form three new bonds in one step with excellent enantio- and diastereoselectivity. This intramolecular reaction allows direct access to the hydrindane core of the bakkenolide family and enables a facile synthesis of these natural products.