Synthesized Research Articles

Copper-Catalyzed Asymmetric Tertiary Radical Cyanation for the Synthesis of Chiral Tetrasubstituted Monofluoroacyl Nitriles.

The construction of chiral tetrasubstituted α-fluoro-α-cyano carbonyl compounds remains a key challenge in synthetic organic chemistry because of their popularity in multiple disciplines. In this paper, we report the copper-catalyzed asymmetric fluorinated tertiary radical cyanation reaction of cyclic α-iodo-α-fluoroindanones with TMSCN to achieve chiral nitriles with carbon-fluorine quaternary stereogenic centers. Thus, an array of optically active tetrasubstituted monofluoroacyl nitriles were synthesized with high reaction efficiency and excellent enantioselectivities (up to 91% yield, 99% ee). Moreover, mechanistic investigations, including experiments, were conducted to clarify the reaction pathway and stereochemical outcomes.

Tunable Thiazolium Carbenes for Enantioselective Radical Three-Component Dicarbofunctionalizations.

Asymmetric N-heterocyclic carbene (NHC) organocatalysis is a cornerstone of synthetic organic chemistry. The emerging concept of single-electron NHC catalysis broadened the scope of C-C bond-forming reactions, facilitating the synthesis of a variety of attractive racemic compounds. However, the development of effective and selective chiral NHC catalysts for asymmetric radical-mediated reactions has been challenging. In this report, we introduce a family of highly tunable chiral thiazolium carbenes with three distinct positions for broad electronic and steric modulation featuring bulky chiral flanking groups. We demonstrate the catalytic efficacy of these chiral carbenes in an enantioselective SET-type three-component acyl-difluoroalkylation of olefins using a broad range of aldehydes and difluoroalkyl bromides. This method provides straightforward access to a diverse set of β-difluoroalkylated α-chiral ketones (65 examples) with an up to 87% yield and excellent enantioselectivities of up to >99:1 er. The utility of this methodology is further outlined by enantio- and diastereoselective late-stage modifications of pharmaceutically relevant compounds and selective twofold orthogonal acyl-difluoroalkylations of linchpin reagents.

Synthesis and Evaluation of 9-epi-Koshidacin B as Selective Inhibitor of Histone Deacetylase 1.

A concise synthetic route to an epimer of the recently isolated biologically active cyclic tetrapeptide koshidacin B has been developed, which featured a late-stage functionalization of a macrocyclic scaffold through a cross metathesis reaction. The synthetic 9-epi-koshidacin B showed marginal differences in spectroscopic behavior with that of the natural product but exhibited conformational preferences similar to those reported for analogous substrate chlamydocin. Moreover, it exhibited a useful level of selective inhibition of biologically relevant enzyme histone deacetylase 1 with an IC50 value of 0.145 μM over two other isoforms. Docking studies indicate that the natural product as well as its 9-epimer binds very similarly to the active site of HDAC1 indicating little influence of the configuration of the C9-stereocenter.

One-Step Regioselective Synthesis of N-1-Substituted Dihydrouracils: A Motif of Growing Popularity in the Targeted Protein Degradation Field.

The increasing popularity of the dihydrouracil motif in cereblon (CRBN) recruiting proteolysis-targeting chimeras (PROTACs) has necessitated the development of a facile, cost-effective, and high-yielding method for its introduction into molecules. To that end, we disclose herein an N-1 selective Pd-catalyzed cross-coupling of dihydrouracil with aryl electrophiles to provide access to medicinally relevant scaffolds in a single step. This approach exhibits excellent functional group tolerance and broad applicability to an abundance of (hetero)aryl halides and phenol derivatives and utilizes readily available catalyst/ligand systems. Thus, our strategy should find broad utility in the arena of PROTAC research, as it obviates the drawbacks of previous methodologies that rely on multistep synthetic routes and protecting group strategies to achieve N-1 selectivity.

Construction of N‐Sulfonyl Amidines: Self‐Assembly through Synergy between Hydrogen Bonding and Lewis Pairs

Abstract: Self‐assembly with non‐covalent interactions (NCIs) is a ubiquitous phenomenon observed in biology and materials chemistry, while its application in synthetic chemistry is still in its infancy. Herein, a self‐assembly condensation method from sulfonamides and imides is reported, leading to the formation of N‐acyl‐N’‐sulfonyl amidines. DFT calculations and NMR investigations suggest that the process is facilitated by cooperative assisted NCIs, including hydrogen bonding and Lewis pairs. Moreover, this methodology can be applied in the late‐stage derivatization of bioactive and complex sulfonamides, offering a potential avenue for the discovery of drug molecules. Extension of this methodology to the condensation of various sulfonamides and amides has also been successfully achieved.

An Alkyne-Containing Isoprenoid Analogue Based on a Farnesyl Diphosphate Scaffold Is a Biologically Functional Universal Probe for Proteomic Analysis.

Prenylation consists of the modification of proteins with either farnesyl diphosphate (FPP) or geranylgeranyl diphosphate (GGPP) at a cysteine near the C-terminus of target proteins to generate thioether-linked lipidated proteins. In recent work, metabolic labeling with alkyne-containing isoprenoid analogues including C15AlkOPP has been used to identify prenylated proteins and track their levels in different diseases. Here, a systematic study of the impact of isoprenoid length on proteins labeled with these probes was performed. Chemical synthesis was used to generate two new analogues, C15hAlkOPP and C20AlkOPP, bringing the total number of compounds to eight used in this study. Enzyme kinetics performed in vitro combined with metabolic labeling in cellulo, resulted in the identification of 8 proteins for C10AlkOPP, 70 proteins for C15AlkOPP, 41 proteins for C15hAlkOPP, and 7 proteins for C20AlkOPP. While C10AlkOPP was the most selective for farnesylated proteins and C20AlkOPP was most selective for geranylgeranylated proteins, the number of proteins identified using those probes was relatively small. In contrast, C15AlkOPP labeled the most proteins including representatives from all classes of prenylated proteins. Functional analysis of these analogues demonstrated that C15AlkOPP was particularly well suited for biological studies since it was efficiently incorporated in cellulo, was able to confer correct plasma membrane localization of H-Ras protein and complement the effects of GGPP depletion in macrophages to yield correct cell polarization and filopodia. Collectively, these results indicate that C15AlkOPP is a biologically functional, universal probe for metabolic labeling experiments that has minimal effects on cellular physiology.

Abstract PR005: Helping academic investigators develop small molecules for the clinic: The NCI Developmental Therapeutics Program and Stepping-Stones

Abstract Academic researchers working in small molecule drug discovery and development face unique challenges – key among these include limited access to the full range of resources needed, inadequate funding which does not cover costs for routine/iterative product development tasks, and unavailability of expertise for the full range of regulatory critical path steps required for an IND. For academic institutions which lack deep resources, specialized core facilities, or endowments, these challenges are even more dire. In recognition of these realities, the NCI Developmental Therapeutics Program (DTP) expanded its capability through creation of the Stepping-Stones program, which provides resources to academic-based researchers who are working towards advancing their small molecule therapeutic candidates from ‘bench to bedside’. Through the Stepping-Stones program, NCI grant-supported small molecule therapeutics focused projects demonstrating high productivity are eligible to obtain access to NCI/DTP drug development capabilities and resources to fill in ‘gaps’ for specific activities that are not covered through their existing funding, but which are necessary to facilitate advancement along the critical path. Examples of services provided have included molecular profiling for ADME/DMPK studies, screens for secondary pharmacology and in vitro safety, synthesis optimization and chemical synthesis, and formulation development, to name a few. By filling in such discrete ‘gaps’, project teams can ‘de-risk’ a candidate earlier and develop stronger data packages to better position themselves for attracting additional investment for development toward clinical testing, or as the data warrants pursue an earlier re-direction of effort before going too far down the critical path. An overview of Stepping-Stones including details for how to be considered for this program and its interactions with other programs at NCI that support drug discovery and development is described, in addition to an overview of DTP’s discovery and development services which usher R&D programs from discovery through preclinical development and IND-enabling studies to support first-in-human trials. From this presentation, academic based ‘drug hunters’ will obtain knowledge about the Stepping-Stones program as a support mechanism to enable their continued efforts and gain an improved understanding about the ‘ecosystem’ of drug discovery and development programs offered by the NCI for the extramural community of researchers. Citation Format: Sharad Verma, Morgan O' Hayre, Rose Aurigemma. Helping academic investigators develop small molecules for the clinic: The NCI Developmental Therapeutics Program and Stepping-Stones [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Optimizing Therapeutic Efficacy and Tolerability through Cancer Chemistry; 2024 Dec 9-11; Toronto, Ontario, Canada. Philadelphia (PA): AACR; Mol Cancer Ther 2024;23(12_Suppl):Abstract nr PR005

Synthesis of Trifluoromethylthio Compounds from Sulfur Containing Precursors

The trifluoromethylthio group (–SCF3) exhibits several distinctive physicochemical properties and can alter the molecular lipophilicity and other pharmacokinetic properties of functional molecules. Moreover, its potent electron‐withdrawing capability confers enhanced metabolic stability to functional molecules. Molecules containing trifluoromethylthio groups are extensively applied in the synthesis of pharmaceuticals or agrochemicals and have garnered significant attention in recent years. The synthetic routes to trifluoromethylthio groups primarily fall into two categories: direct introduction of –SCF3 into target molecules, and indirect construction of –SCF3 through the introduction of –CF3 into sulfur containing precursors. In this review, we delineate approaches developed over the past seven years for the indirect construction of SCF3 groups via electrophilic, nucleophilic, radical, or other types of reactions involving –CF3 groups and sulfur‐containing precursors. These reactions are classified into seven categories depending on the employed: thiols, disulfides, thiosulfates, sodium sulfinates, sulfonyl chlorides, sulfoxides, and other sulfur‐containing precursors.

Asymmetric Hydrogenation of Exocyclic α,β-Unsaturated Nitriles: An Access to Chiral 2-Benzocyclic Acetonitriles and Ramelteon.

A highly efficient and enantioselective hydrogenation of exocyclic α,β-unsaturated nitriles catalyzed by the Rh-JosiPhos complex for synthesis of the chiral 2-benzocyclic acetonitriles has been developed. Both (Z)- and (E)-isomers of exocyclic α,β-unsaturated nitriles with various benzocyclic structures, including heterocyclic (chroman and tetrahydroquinoline) scaffolds, were hydrogenated successfully, achieving excellent enantioselectivities (up to 97% ee) and high turnover numbers (TON up to 4000). Furthermore, this methodology provides an efficient, concise, and practical synthetic route to the sleep agent (S)-Ramelteon.

Guanidine Derivative ADS1017, a Potent Histamine H3 Receptor Antagonist with Promising Analgesic Activity and Satisfactory Safety Profile.

In this study, we selected 12 guanidine derivatives from the previously described ligand library and determined their affinity at histamine H3 and H4 receptors (H3R and H4R, respectively). Moreover, we also checked their intrinsic activity toward H3R and muscarinic M1, M2, and M4 receptors (M1R, M2R, and M4R, respectively). Since ADS1017 has been proved to be the most selective and highly potent H3 antagonist in our series, we chose it as the lead structure for further biological evaluation. To extend the study of its in vivo efficacy, we proposed an alternative synthetic route that resulted in an increased yield. Interestingly, ADS1017 showed a broad spectrum of analgesic activity in both nociceptive and neuropathic pain models. Finally, as a result of comprehensive analysis of its off-target activity and ADMETox parameters, we confirmed the moderate selectivity of ADS1017 and its promising drug-like properties.

Green Synthesis of Quercetin-Coated Ecofriendly Zirconium Oxide Nanoparticles and Evaluating its in vitro Biological Activities

The development of nanomaterials using green synthesis methods is gaining attention due to their potential to reduce environmental pollution and health risks associated with traditional chemical synthesis methods. Among the various transition metals, zirconia has gained significant interest as filling materials and implants in dentistry due to its excellent mechanical and chemical properties. In this study, we developed ecofriendly zirconium oxide nanoparticles using Biancaea sappan extract as a capping agent and then functionalized them with Quercetin. Further, their anti-inflammatory property and hemocompatibility were evaluated to target their application as filling materials. The biogenic zirconium oxide nanoparticles (B-ZrO2NPs) and quercetin functionalized biogenic zirconium oxide nanoparticles (BQZN) were characterized by UV–Vis Spectroscopy (UV–Vis), Fourier Transform Infrared Spectroscopy (FTIR), X-ray diffraction (XRD), scanning electron microscopy (SEM) and energy X-ray analysis (EDX). B-ZrO2NPs showed maximum absorbance at 267[Formula: see text]nm and 383[Formula: see text]nm. FTIR showed characteristic stretching at 3381[Formula: see text]cm[Formula: see text], confirming the O–H group in the extract and Quercetin used for BQZN formation. The FTIR spectra of BQZN displayed the presence of the characteristic peaks observed in the spectra of B-ZrO2NPs and Quercetin. The broad XRD pattern confirmed the amorphous nature of the zirconia. SEM revealed the spherical morphology of B-ZrO2NPs and BQZN with a size range of around 90[Formula: see text]nm and 120[Formula: see text]nm, respectively. EDAX of BQZN revealed the presence of 45.7[Formula: see text]wt.% Zr, 32.9% oxygen and 21.4% of carbon. In vitro bioactivity studies revealed that BQZN exhibited significant anti-inflammatory activity, as evidenced by the inhibition of protein denaturation. The nanoparticles were also demonstrated for their hemocompatibility with erythrocytes. These findings highlight the potential of BQZN as a promising hemocompatible dental filling with significant anti-inflammatory properties. Further in-depth in vivo studies are required to fully understand their efficacy and toxicity.

Chemical Synthesis of ~1 nm Multilevel Capacitor‐like Particles with Atomic Precision

AbstractCan the chemically synthesized nanoparticles act as nanodevices or nanomachines? Herein, we demonstrated this feasibility. A novel nanocluster (ultrasmall nanoparticle) [Au44Cd20(m‐MBT)40][N(C8H17)4]2 (Au44Cd20 in short, m‐MBTH: m‐methylbenzenethiol) obtained via developing a synthesis method has a cannula‐like structure of the outer shell and an internal sleeve, revealed by single‐crystal X‐ray diffraction. Natural population analysis (NPA) charge calculations, charge carrier transport of Au44Cd20 (during which an intra‐nanocluster anti‐galvanic reaction was observed) after unneutral charging using NaBH4 as well as voltammetry proved the capacitor‐like character of Au44Cd20. The subsidiary capacitor‐like character of the outer shell of Au44Cd20 was further probed via NPA charge calculations and electrocatalytic reduction of CO2 to CO. Thus, this study predicts a new era of engineering metal nanoparticles for realizing atomically precise ultrasmall nanodevices and nanomachines.

A Supramolecular Approach to Engineering Living Cells with Enzymes for Adaptive and Recyclable Cascade Synthesis.

Biocatalytic transformation in nature is inherently dynamic, spontaneous, and adaptive, enabling complex chemical synthesis and metabolism. These processes often involve supramolecular recognition among cells, enzymes, and biomacromolecules, far surpassing the capabilities of isolated cells and enzymes used in industrial synthesis. Inspired by nature, here we design a supramolecular approach to equip living cells with these capacities, enabling recyclable, efficient cascade reactions. Our two-step "plug-and-play" methodology begins by coating Escherichia coli cells with guest-containing polymers (SupraBAC) via supramolecular charge interactions, followed by the introduction of β-cyclodextrin-functionalized host enzymes through host-guest chemistry, creating a robust cell-enzyme complex. This supramolecular coating not only protects cells from various stresses, such as UV radiation, heat, and organic solvents, but also facilitates the overexpression of intracellular enzymes and the attachment of extracellular enzymes within and on SupraBAC. This combination results in efficient multienzyme cascade synthesis, enabling two- and three-step reactions in one pot. Importantly, the multienzyme system can be recycled up to five times without significant loss of activity. Our findings introduce a versatile, adaptive supramolecular coating for whole-cell catalysts, offering a sustainable and efficient solution for complex synthesis in both chemistry and industrial biotechnology.

Chemical Synthesis of ~1 nm Multilevel Capacitor-like Particles with Atomic Precision.

Can the chemically synthesized nanoparticles act as nanodevices or nanomachines? Herein, we demonstrated this feasibility. A novel nanocluster (ultrasmall nanoparticle) [Au44Cd20(m-MBT)40][N(C8H17)4]2 (Au44Cd20 in short, m-MBTH: m-methylbenzenethiol) obtained via developing a synthesis method has a cannula-like structure of the outer shell and an internal sleeve, revealed by single-crystal X-ray diffraction. Natural population analysis (NPA) charge calculations, charge carrier transport of Au44Cd20 (during which an intra-nanocluster anti-galvanic reaction was observed) after unneutral charging using NaBH4 as well as voltammetry proved the capacitor-like character of Au44Cd20. The subsidiary capacitor-like character of the outer shell of Au44Cd20 was further probed via NPA charge calculations and electrocatalytic reduction of CO2 to CO. Thus, this study predicts a new era of engineering metal nanoparticles for realizing atomically precise ultrasmall nanodevices and nanomachines.

Quantitative Formation of Octa‐substituted Cyclobutanes by the [2+2] Photocycloaddition of Stiff‐stilbenes

AbstractThe creation of new molecules with specific structural motifs is a primary goal in synthetic chemistry. In this context, cyclobutanes (CBs), the highly strained ring systems, are of great interest because of their wide applications from pharmaceutical chemistry to materials science. The [2+2] photocycloaddition is the most straightforward approach for CBs; however, access to fully substituted cyclobutanes presents a significant challenge due to the steric hindrance imposed by eight substituents. Here, we report an efficient synthesis of structurally unique, octa‐substituted cyclobutanes from stiff‐stilbene precursors, which is enabled by adaptable anion coordination through hydrogen bonding networks. The synthesized spiro‐benzocyclopentyl‐substituted cyclobutanes are confirmed by single‐crystal structures. DFT calculations indicate that these cyclobutanes have high ring‐strain energies (~20.1 kcal/mol) and can be completely converted back to stiff‐stilbenes. Such a reversible cycloaddition/reversion process offers a promising platform for applications in responsive and energy storage materials.

Chemoenzymatic Synthesis Planning Guided by Reaction Type Score.

Thanks to the growing interest in computer-aided synthesis planning (CASP), a wide variety of retrosynthesis and retrobiosynthesis tools have been developed in the past decades. However, synthesis planning tools for multistep chemoenzymatic reactions are still rare despite the widespread use of enzymatic reactions in chemical synthesis. Herein, we report a reaction type score (RTscore)-guided chemoenzymatic synthesis planning (RTS-CESP) strategy. Briefly, the RTscore is trained using a text-based convolutional neural network (TextCNN) to distinguish synthesis reactions from decomposition reactions and evaluate synthesis efficiency. Once multiple chemical synthesis routes are generated by a retrosynthesis tool for a target molecule, RTscore is used to rank them and find the step(s) that can be replaced by enzymatic reactions to improve synthesis efficiency. As proof of concept, RTS-CESP was applied to 10 molecules with known chemoenzymatic synthesis routes in the literature and was able to predict all of them with six being the top-ranked routes. Moreover, RTS-CESP was employed for 1000 molecules in the boutique database and was able to predict the chemoenzymatic synthesis routes for 554 molecules, outperforming ASKCOS, a state-of-the-art chemoenzymatic synthesis planning tool. Finally, RTS-CESP was used to design a new chemoenzymatic synthesis route for the FDA-approved drug Alclofenac, which was shorter than the literature-reported route and has been experimentally validated.

Composite Contrast Enhancement of Hydrogel-Based Implants for Photon-Counting Computed Tomography Studies

Hydrogels have a wide range of medical applications, including use within implantable systems. However, when used in implants, their visibility under conventional medical imaging techniques is limited, creating safety risks for patients. In the current work, we assessed the possibility of enhancing hydrogels using Ln-based contrasting agents to facilitate their visualization in photon-counting computed tomography (PCCT). The contrast enhancement of gelatin, polyacrylamide (PAM), and silicone shells of implants was assessed. A novel synthetic route for producing cross-linked nanosized Ln2O3 with polyacrylamide was proposed and discussed in detail. Several prototypes of silicone implants, including silicone shell and gelatin or PAM filling with different combinations of contrasting agents, were produced and assessed in phantom PCCT studies.

Sustainable Synthesis of Palladium‐Immobilized Covalent Organic Frameworks: A One‐step Sonochemical Strategy

AbstractThe rapid and environmentally benign synthesis of metal‐immobilized covalent organic frameworks (metal/COFs) for heterogeneous catalysis is a pervasive challenge, as the mainstream synthesis is exceedingly time‐consuming (up to four days) and demands the use of hazardous solvents. Herein, we describe a sustainable and efficient one‐step sonochemical strategy for constructing diverse palladium (II)‐immobilized COFs (Pd(II)/COFs). By merging the sonochemistry‐assisted COF synthesis and in situ Pd (II) immobilization into a single step, this strategy enables the rapid formation of Pd(II)/COF hybrids within an hour under ambient conditions using water as the solvent. Notably, gram‐scale synthesis of Pd(II)/COFs is achievable. The resulting Pd(II)/COFs exhibit superb crystallinity and high surface area, leading to remarkable activity, excellent functionality tolerance, and high recyclability for the Suzuki–Miyaura cross‐coupling reaction of aryl bromides and arylboronic acids at room temperature. This one‐step sonochemical strategy effectively addresses the long‐lasting limitations of traditional multistep synthesis, paving a fast and sustainable avenue to diversified metal/COF hybrids for heterogeneous catalysis and potentially other applications.

Recent Advances in Direct Amidation via Organocatalysis

The formation of amide bonds is essential for a wide range of applications in biological and organic systems, including proteins, pesticides, polymers, and pharmaceuticals. Moreover, it plays a critical role in the synthesis of numerous bioactive compounds with anticancer, antibacterial, and antifungal properties. Due to the limitations of conventional coupling reagents for amide synthesis, there is a growing demand for environmentally sustainable methodologies, particularly the direct formation of amides from carboxylic acids and amines. Over recent years, we have developed several catalytic reactions based on organocatalysis, advancing sustainable synthetic methods in both organic and medicinal chemistry. This review comprehensively discusses catalytic amidation reactions published up to January 2024, focusing on both organocatalysis and boron‐based catalysis for the direct condensation of carboxylic acids and amines. Additionally, it highlights our recent contributions to sustainable amidation protocols, which are progressively replacing traditional catalytic approaches in modern synthetic chemistry.

Evolution of Vitamin E Production: From Chemical Synthesis and Plant Extraction to Microbial Cell Factories.

Vitamin E, comprising tocopherols and tocotrienols, is an essential antioxidant known for its numerous health benefits. This review traces the evolution of vitamin E production, from traditional chemical synthesis and plant extraction methods to cutting-edge microbial cell factories. Chemical synthesis, while well-established, fails to produce specific stereoisomers, and its application is limited to animal feed due to concerns about chemical residues and limited bioactivity. Plant extraction, although yielding natural vitamin E, is constrained by resource availability and high cultivation costs. Recent advancements in metabolic engineering and synthetic biology have revolutionized vitamin E bioproduction, particularly through the use of engineered microbial cell factories. This review highlights the progress of vitamin E biosynthesis in plants and microorganisms and the key metabolic engineering strategies adopted. We also discuss the existing challenges and future perspectives. When these challenges are overcome, microbial cell factories present a sustainable and effective method to fulfill the increasing demand for high-quality vitamin E.