Synthetic Approach Research Articles

Synthetic Approaches, Properties, and Applications of Acylals in Preparative and Medicinal Chemistry.

Diesters of geminal diols (R-CH(O-CO-R')2, RR'C(OCOR″)2, etc. with R = H, aryl or alkyl) are termed acylals according to IUPAC recommendations (Rule P-65.6.3.6 Acylals) if the acids involved are carboxylic acids. Similar condensation products can be obtained from various other acidic structures as well, but these related "non-classical acylals", as one might call them, differ in various aspects from classical acylals and will not be discussed in this article. Carboxylic acid diesters of geminal diols play a prominent role in organic chemistry, not only in their application as protective groups for aldehydes and ketones but also as precursors in the total synthesis of natural compounds and in a variety of organic reactions. What is more, acylals are useful as a key structural motif in clinically validated prodrug approaches. In this review, we summarise the syntheses and chemical properties of such classical acylals and show what potentially under-explored possibilities exist in the field of drug design, especially prodrugs, and classify this functional group in medicinal chemistry.

Small Ring Molecules Comprising 3-6 Boron Atoms: An Account on Synthesis, Structure, and Orbital Engineering.

ConspectusUnlike carbon, boron does not usually form ring compounds due to its electron-deficiency-driven affinity toward polyhedral geometries. The polyhedral boranes having closo-, nido-, arachno-, or hypho-shapes can be structurally and electronically correlated using various electron counting rules developed by Wade, Mingos, and one of us. However, in the last few decades, boron chemistry progressed significantly toward ring systems. In this regard, three of our research groups have made significant contributions to the development of boron ring molecules through different synthetic approaches. While the Ghosh group generally starts from transition metal (TM) stabilized boron species, the Himmel group typically starts from electron-deficient TM-free boron ring compounds. On the other hand, the Jemmis group studies boron rings and their analogous structures computationally and develops electron counting rules to describe them. Over the past few years, through different synthetic approaches, several boron ring molecules have been prepared by our research groups and others. Recently, the Ghosh group has reported the synthesis of an almost planar B6-ring that is stabilized by a TM template. Similarly, the B3-, B4-, and B5-rings have also been stabilized in the coordination spheres of early and late TMs. The recent work of Himmel has uncovered some remarkable diversity in the structures and bonding of B3 and B4 rings, along with their redox reactions. The well-known hydrocarbon analogues of these borane rings, i.e., two-dimensional aromatic compounds [C3H3]+, [C5H5]-, [C6H6], etc., are governed by Hückel's (4n + 2) π-electron rule. However, planar or nearly planar borane rings are not seriously thought of as achievable targets. One of the reasons for this is the influence of the Rudolph diagram in the thought process of chemists that the nido- and arachno-structures generated from closo-polyhedral boranes must also be three-dimensional (3D) fragments. However, this is not the only possibility. Flat arachno- and nido-boranes reminiscent of their organic counterparts follow from an equivalent of the Rudolph diagram. Therefore, this Account is very much necessary for the boron community, in particular, to design and synthesize 3-6 membered boron rings or beyond. This Account aims to highlight significant ongoing experimental and theoretical results in this area from our groups, in addition to relevant works from other groups wherever appropriate. This will also bring into focus various ways in which the flat Bn-systems can be stabilized, such as the utilization of TM or main group caps, utilization of various Lewis bases, edge-condensation of small rings, control over the electron count, and orbital engineering.

Metabolic engineering-enabled dual-color biosensor for discriminative and sensitive detection of toxic lead and mercury in environmental waters

The ubiquity of toxic heavy metals, particularly lead (Pb) and mercury (Hg), in environmental waters severely threatens ecosystems and human health. We developed a metabolic engineering-based dual-color bacterial biosensor for the sensitive and discriminative detection of Pb(II) and Hg(II) at nanomolar levels. The biosensor leverages the synthetic biology approach to integrate two pigments, prodeoxyviolacein (PDV) and deoxyviolacein (DV), into a single construct that responds distinctly to Pb(II) and Hg(II), respectively. The engineered E. coli biosensor exhibits a detection range of 0.732–3000 nM for Pb(II) and 0.183–750 nM for Hg(II), with low detection limits of 0.732 nM for Pb(II) and 0.183 nM for Hg(II). The biosensor demonstrated high sensitivity, selectivity, and accuracy with a recovery rate close to 1 in freshwater and seawater matrices. Notably, the biosensor's visual readout allows for rapid, equipment-free assessment. It is a practical tool for real-world monitoring of heavy metal pollution, especially in remote or resource-limited settings. This study underscores the potential of whole-cell biosensors as a sustainable and effective alternative to traditional heavy metal detection methods.

Synthetic Likelihood in Misspecified Models

Bayesian synthetic likelihood is a widely used approach for conducting Bayesian analysis in complex models where evaluation of the likelihood is infeasible but simulation from the assumed model is tractable. We analyze the behavior of the Bayesian synthetic likelihood posterior when the assumed model differs from the actual data generating process. We demonstrate that the Bayesian synthetic likelihood posterior can display a wide range of nonstandard behaviors depending on the level of model misspecification, including multimodality and asymptotic non-Gaussianity. Our results suggest that likelihood tempering, a common approach for robust Bayesian inference, fails for synthetic likelihood whilst recently proposed robust synthetic likelihood approaches can ameliorate this behavior and deliver reliable posterior inference under model misspecification. All results are illustrated using a simple running example. Supplementary materials for this article are available online, including a standardized description of the materials available for reproducing the work.

The evolution of veteran educational attainment gaps over the life cycle

Abstract Individuals who serve in the military substitute work experience for post-secondary educational attainment after high school, leading to large educational attainment gaps between new veterans and observably similar nonveterans. Little is known about the evolution of these gaps by age and across cohorts. We investigate the life-cycle attainment of veterans relative to nonveterans using a synthetic panel data approach. Following five multiyear birth cohorts we find that, on average, veterans close a 20-percentage point gap in attainment of a bachelor's or greater over time and significantly outpace observably similar nonveterans in attainment of an associate's degree. Female and minority veterans exceeded the attainment of similar nonveterans over time, and more recent birth cohorts began with larger gaps but closed them at younger ages due to increasing levels of both enrollment and enrollment intensity. Our findings highlight the important role of military service in facilitating social mobility through educational attainment.

Synthesis, characterization, photophysical and electrochemical properties of new thiadiazole-based olefins for OLED applications

A three–step synthetic approach was employed to synthesize new thiadiazole-based olefins integrating customized functional groups. This methodology consistently delivered satisfactory overall yields ranging from 44 % to 57 %. Comprehensive structural characterization of the synthesized compounds was conducted using FT–IR and NMR (1H, 13C) spectroscopic techniques. The resulting thiadiazole-based olefins exhibited notable UV absorption (λmax = 309–382 nm). Among these, one compound displayed a green emission, while others exhibited red-orange emission, indicating a Stokes shift ranging from 5423 to 6835 cm–1. Their electrochemical behavior was analyzed, revealing an irreversible redox-active response and experimentally determined HOMO and LUMO energy levels indicated an electrochemical gap of <2.32 eV. Our comprehensive investigation, integrating experimental and theoretical methodologies with TD–DFT calculations, aimed to deepen the understanding of the photophysical properties of the target compounds. This comparative analysis between computational results and experimental data highlights the potential of these N-heteroaromatic compounds as organic small-molecule fluorophores for applications in electroluminescent devices.

Spokewise Total Syntheses of Four Erythrina Alkaloids and Telescoped Syntheses of Six Additional Alkaloids.

Based on rich sulfur-involving chemical transformations, a novel spokewise synthetic strategy, a subclass of the collective strategies, has been developed to concisely synthesize four erythrina alkaloids through a single-step transformation from a common synthetic precursor. Moreover, six additional erythrina alkaloids have also been synthesized by subsequent 1-2 steps chemical transformations. The current synthetic approaches provide a valuable platform for collective total syntheses of erythrina alkaloids and pseudo-natural erythrina alkaloids.

Tunable cell differentiation via reprogrammed mating-type switching

This study introduces a synthetic biology approach that reprograms the yeast mating-type switching mechanism for tunable cell differentiation, facilitating synthetic microbial consortia formation and cooperativity. The underlying mechanism was engineered into a genetic logic gate capable of inducing asymmetric sexual differentiation within a haploid yeast population, resulting in a consortium characterized by mating-type heterogeneity and tunable population composition. The utility of this approach in microbial consortia cooperativity was demonstrated through the sequential conversion of xylan into xylose, employing haploids of opposite mating types each expressing a different enzyme of the xylanolytic pathway. This strategy provides a versatile framework for producing and fine-tuning functionally heterogeneous yet isogenic yeast consortia, furthering the advancement of microbial consortia cooperativity and offering additional avenues for biotechnological applications.

Programmable Merged‐Net Porphyrinic Metal–Organic Frameworks for Water Sorption

AbstractPorous materials have attracted considerable interest as water sorbents due to their potential in a broad range of water sorption‐related applications. Metal–organic frameworks (MOFs) are particularly notable for their high porosity and tunability. However, their limited hydrolytic stability often results in pore collapse, which significantly hinders their water sorption performance. To address this issue, an innovative design strategy based on reticular chemistry is essential to enhance structural stability and ensure efficient water sorption. Herein, a novel synthetic approach for constructing a merged‐net MOF structure using metallolinkers is introduced. Specifically, a porphyrin linker is employed to successfully synthesize a porphyrin‐based merged‐net MOF, UPF‐5. This MOF demonstrates significantly enhanced hydrolytic stability and improved water sorption performance while maintaining high pore volume. Additionally, the structure of UPF‐5 allows for the modification of accessible Zr6 nodes, enabling control over the pore environments and fine‐tuning the water sorption properties. This programmable synthetic strategy for porphyrin‐based merged‐net MOFs not only significantly enhances the structural stability for practical applications, including water sorption, but also advances reticular chemistry by discovering unprecedented topologies in MOF chemistry.

Microwave‐Assisted Synthesis of Spiro Heterocyclic Scaffolds Using Graphite Oxide as a Heterogeneous Carbocatalyst and Study of their Anti‐Microbial Activities

AbstractEven though an astonishing variety of spirooxindole derivatives has been synthesized until now, the look for rapid, highly efficacious, environmental‐friendly and more skilful methods is yet an ongoing challenge. Here, we present a microwave‐assisted synthetic approach for the one‐pot synthesis of spirooxindole‐pyrimidine and spiro‐chromeno indoline‐trione derivatives in water using graphite oxide (GO) as a charismatic heterogeneous metal‐free carbocatalyst.Microwave‐assisted synthesis reduces the reaction times from hours (conventional heating) to minutes. The use of a heterogeneous catalyst allows for efficient recovery and reusability up to eight cycles without losing much of its effectiveness, thereby enhancing sustainability. This method offers high product yields of diverse substrates with low catalyst loading and simple work‐up and catalyst handling. In addition, the antimicrobial activities for some randomly taken compounds have also been studied against gram positive bacteria Staphylococcos aureus (MTCC96) and gram negative bacteria Escherichia coli(MTCC730).

The Pivotal Role of Germline BRCA2 Pathogenic Variants in "Apparently Sporadic" Pancreatic Cancer.

In 1996, Goggins and colleagues demonstrated the importance of germline BRCA2 pathogenic variants in the development of apparently sporadic pancreatic ductal adenocarcinoma (PDAC). Previously, the group identified homozygous deletion of the 13q region in PDACs, enabling the identification of the BRCA2 gene. This 1996 article first revealed loss of BRCA2, both germline and somatic, as a key driver of PDAC at a time when there was still doubt if PDAC even had an inherited component. Contrary to the prevailing wisdom, not all individuals with inherited pathogenic BRCA2 variants had a family history of cancer. The innovative bedside-to-bench nature of this work revealed that individuals with these variants would be missed if genetic testing was limited only to those meeting the family history criteria. Therefore, Goggins and colleagues advocated that universal genetic testing may be indicated for pancreatic cancer at a time when genetic testing was in its infancy. Twenty-three years later, in 2019, universal testing for pancreatic cancer became standard of care in the United States. Additionally, this work and future-related publications by the Kern Laboratory set the stage for targeting BRCA2 and related DNA repair mutations in pancreatic cancer via a synthetic lethal therapeutic approach. The provocative discussion initiated by this team in this publication is still inspiring the field today. In this seminal publication, Goggins and colleagues profoundly impacted the direction of pancreatic cancer research, leading to a more sophisticated approach to designing earlier detection and precision treatment strategies for pancreatic cancer. See related article by Goggins and colleagues, Cancer Res 1996;56:5360-4.

Enhancing Inter-AUV Perception: Adaptive 6-DOF Pose Estimation with Synthetic Images for AUV Swarm Sensing

The capabilities of AUV mutual perception and localization are crucial for the development of AUV swarm systems. We propose the AUV6D model, a synthetic image-based approach to enhance inter-AUV perception through 6D pose estimation. Due to the challenge of acquiring accurate 6D pose data, a dataset of simulated underwater images with precise pose labels was generated using Unity3D. Mask-CycleGAN technology was introduced to transform these simulated images into realistic synthetic images, addressing the scarcity of available underwater data. Furthermore, the Color Intermediate Domain Mapping strategy is proposed to ensure alignment across different image styles at pixel and feature levels, enhancing the adaptability of the pose estimation model. Additionally, the Salient Keypoint Vector Voting Mechanism was developed to improve the accuracy and robustness of underwater pose estimation, enabling precise localization even in the presence of occlusions. The experimental results demonstrated that our AUV6D model achieved millimeter-level localization precision and pose estimation errors within five degrees, showing exceptional performance in complex underwater environments. Navigation experiments with two AUVs further verified the model’s reliability for mutual 6D pose estimation. This research provides substantial technical support for more complex and precise collaborative operations for AUV swarms in the future.

Hybrid lipid-AuNP clusters as highly efficient SERS substrates for biomedical applications

Although Surface Enhanced Raman Scattering (SERS) is widely applied for ultrasensitive diagnostics and imaging, its potential is largely limited by the difficult preparation of SERS tags, typically metallic nanoparticles (NPs) functionalized with Raman-active molecules (RRs), whose production often involves complex synthetic approaches, low colloidal stability and poor reproducibility. Here, we introduce LipoGold Tags, a simple platform where gold NPs (AuNPs) clusters form via self-assembly on lipid vesicle. RRs embedded in the lipid bilayer experience enhanced electromagnetic field, significantly increasing their Raman signals. We modulate RRs and lipid vesicle concentrations to achieve optimal SERS enhancement and we provide robust structural characterization. We further demonstrate the versatility of LipoGold Tags by functionalizing them with biomolecular probes, including antibodies. As proof of concept, we successfully detect intracellular GM1 alterations, distinguishing healthy donors from patients with infantile GM1 gangliosidosis, showcasing LipoGold Tags as advancement in SERS probes production.

Numerical stability assessment of a mining slope using the synthetic rock mass modeling approach and strength reduction technique

Numerical stability assessment of a mining slope using the synthetic rock mass modeling approach and strength reduction technique

Brønsted Acidic Ionic Liquid: An Efficient Organocatalyst for the Synthesis of Pyrrolo[1,2‐a]indoles under Neat Conditions

A new synthetic approach has emerged for constructing the 9H-pyrrolo[1,2-a]indole scaffolds by the reactions between indoles and chalcones under metal and solvent-free conditions at 80 °C. The reaction occurs smoothly in presence of Brønsted acidic ionic liquid named 1-butane sulfonic acid-3-methylimidazolium tosylate, [BSMIM]OTs (BAIL) as a catalyst, enabling the synthesis of the desired products with satisfactory yields. The developed protocol is applicable for the construction of biologically important pyrrolo[1,2-a]indole derivatives from easily accessible chalcones having various substituents. The process commenced with Michael addition to chalcones, followed by annulations induced by the elimination of a water molecule yielded the 9H-pyrrolo[1,2-a]indole scaffolds. Few control experiments were carried out for better understanding the reaction pathway. The feasibility of catalyst recycling was also demonstrated. This method produces only water as the byproduct and represents a green synthetic protocol. Clean reaction, easily accessible reactants, and metal and solvent-free and environmentally friendly reaction conditions are the notable advantages of this procedure.

Exploring the Impact of Ring Mobility on the Macroscopic Properties of Doubly Threaded Slide-Ring Gel Networks.

The integration of mechanically interlocked molecules (MIMs) into polymeric materials has led to the development of mechanically interlocked polymers (MIPs). One class of MIPs that have gained attention in recent years are slide-ring gels (SRGs), which are generally accessed by crosslinking rings on a main-chain polyrotaxane. The mobility of the interlocked crosslinking moieties along the polymer backbone imparts enhanced properties onto these networks. An alternative synthetic approach to SRGs is to use a doubly threaded ring as the crosslinking moiety, yielding doubly threaded slide-ring gel networks (dt-SRGs). In this study, a photo-curable ligand-containing thread was used to assemble a series of metal-templated pseudo[3]rotaxane crosslinkers that allow access to polymer networks that contain doubly threaded interlocked rings. The physicochemical and mechanical properties of these dt-SRGs with varying size of the ring crosslinking moieties were investigated and compared to an entangled gel (EG) prepared by polymerizing the metal complex of the photo-curable ligand-containing thread, and a corresponding covalent gel (CG). Relative to the EG and CG, the dt-SRGs exhibit enhanced swelling behavior, viscoelastic properties, and stress relaxation characteristics. In addition, the macroscopic properties of dt-SRGs could be altered by "locking" ring mobility in the structure through remetalation, highlighting the impact of the mobility of the crosslinks.

Design and Synthesis of Out/Out, Out/In, and In/In Epoxides in Polycyclic Cage Frameworks

AbstractWe report a useful synthetic approach to assemble in/in epoxide, in/out epoxide, and out/out epoxide in cage systems using the Corey–Chaykovsky reaction and the Peterson olefination as key steps. In this regard, a variety of pentacycloundecane (PCUD) based cage compounds containing oxirane rings with diverse stereochemical disposition were synthesized via a simple synthetic sequence. Five cage diones were used for this purpose, and the starting cage diones were prepared with easily accessible starting materials such as 1,4-hydroquinone derivatives and cyclopentadiene. Here, we have used the Diels–Alder (DA) reaction, a [2+2] photocycloaddition, the Corey–Chaykovsky reaction, and the Peterson olefination as crucial steps to prepare the target molecules.

Exploring the Impact of Ring Mobility on the Macroscopic Properties of Doubly Threaded Slide‐Ring Gel Networks

AbstractThe integration of mechanically interlocked molecules (MIMs) into polymeric materials has led to the development of mechanically interlocked polymers (MIPs). One class of MIPs that have gained attention in recent years are slide‐ring gels (SRGs), which are generally accessed by crosslinking rings on a main‐chain polyrotaxane. The mobility of the interlocked crosslinking moieties along the polymer backbone imparts enhanced properties onto these networks. An alternative synthetic approach to SRGs is to use a doubly threaded ring as the crosslinking moiety, yielding doubly threaded slide‐ring gel networks (dt‐SRGs). In this study, a photo‐curable ligand‐containing thread was used to assemble a series of metal‐templated pseudo[3]rotaxane crosslinkers that allow access to polymer networks that contain doubly threaded interlocked rings. The physicochemical and mechanical properties of these dt‐SRGs with varying size of the ring crosslinking moieties were investigated and compared to an entangled gel (EG) prepared by polymerizing the metal complex of the photo‐curable ligand‐containing thread, and a corresponding covalent gel (CG). Relative to the EG and CG, the dt‐SRGs exhibit enhanced swelling behavior, viscoelastic properties, and stress relaxation characteristics. In addition, the macroscopic properties of dt‐SRGs could be altered by “locking” ring mobility in the structure through remetalation, highlighting the impact of the mobility of the crosslinks.

Combining propensity score methods with variational autoencoders for generating synthetic data in presence of latent sub-groups

In settings requiring synthetic data generation based on a clinical cohort, e.g., due to data protection regulations, heterogeneity across individuals might be a nuisance that we need to control or faithfully preserve. The sources of such heterogeneity might be known, e.g., as indicated by sub-groups labels, or might be unknown and thus reflected only in properties of distributions, such as bimodality or skewness. We investigate how such heterogeneity can be preserved and controlled when obtaining synthetic data from variational autoencoders (VAEs), i.e., a generative deep learning technique that utilizes a low-dimensional latent representation. To faithfully reproduce unknown heterogeneity reflected in marginal distributions, we propose to combine VAEs with pre-transformations. For dealing with known heterogeneity due to sub-groups, we complement VAEs with models for group membership, specifically from propensity score regression. The evaluation is performed with a realistic simulation design that features sub-groups and challenging marginal distributions. The proposed approach faithfully recovers the latter, compared to synthetic data approaches that focus purely on marginal distributions. Propensity scores add complementary information, e.g., when visualized in the latent space, and enable sampling of synthetic data with or without sub-group specific characteristics. We also illustrate the proposed approach with real data from an international stroke trial that exhibits considerable distribution differences between study sites, in addition to bimodality. These results indicate that describing heterogeneity by statistical approaches, such as propensity score regression, might be more generally useful for complementing generative deep learning for obtaining synthetic data that faithfully reflects structure from clinical cohorts.

Electron Release via Internal Polarization Fields for Optimal S-H Bonding States.

Transition metal dichalcogenides (TMDs) have received considerable attention as promising electrocatalysts for the hydrogen evolution reaction (HER), yet their potential is often constrained by the inertness of the basal planes arising from their poor hydrogen adsorption ability. Here, the relationship between the electronic structure of the WS2 basal plane and HER activity is systemically analyzed to establish a clear insight. The valance state of the sulfur atoms on the basal plane has been tuned to enhance hydrogen adsorption through sequential engineering processes, including direct phase transition and heterostructure that induces work function-difference-induced unidirectional electron transfer. Additionally, an innovative synthetic approach, harnessing the built-in internal polarization field at the W-graphene heterointerface, triggers the in-situ formation of sulfur vacancies in the bottom WSx (x < 2) layers. The resultant modulation of the valance state of the sulfur atom stabilizes the W-S bond, while destabilizing the S-H bond. The electronic structural changes are further amplified by the release and transfer of surplus electrons via sulfur vacancies, filling the valance state of W and S atoms. Consequently, this work provides a comprehensive understanding of the interplay between the electronic structure of the WS2 basal plane and the HER activity, focusing on optimizing S-H bonding state.