Complex Molecules Research Articles

Retrosynthesis Zero: Self-Improving Global Synthesis Planning Using Reinforcement Learning.

The field of computer-aided synthesis planning (CASP) has witnessed significant growth in recent years. Still, many CASP programs rely on large data sets to train neural networks, resulting in limitations due to the data quality and prior knowledge from chemists. In response, we propose Retrosynthesis Zero (ReSynZ), a reaction template-based method that combines Monte Carlo Tree Search with reinforcement learning inspired by AlphaGo Zero. Unlike other single-step reaction template-based CASP methods, ReSynZ takes complete synthesis paths for complex molecules, determined by reaction rules, as input for training the neural network. ReSynZ enables neural networks trained with relatively small reaction data sets (tens of thousands of data) to generate multiple synthesis pathways for a target molecule and suggest possible reaction conditions. On multiple data sets of molecular retrosynthesis, ReSynZ demonstrates excellent predictive performance compared to existing algorithms. The advantages, such as self-improving model features, flexible reward settings, the potential to surpass human limitations in chemical synthesis route planning, and others, make ReSynZ a valuable tool in chemical synthesis design.

Copper-Nitroxyl-Catalyzed α-Oxygenation of Cyclic Secondary Amines Including Application to Late-Stage Functionalization.

Cyclic secondary amines are prominent subunits in pharmaceutical compounds. Methods for direct functionalization of N-unprotected/unsubstituted piperidines and related heterocycles have limited precedent despite their potential to impact medicinal chemistry and organic synthesis. Herein, we report a Cu/nitroxyl co-catalyzed method for direct conversion of cyclic secondary amines to the corresponding lactams via aerobic dehydrogenation and oxidative coupling with water. The mild reaction conditions tolerate diverse functional groups, enabling application to molecules that cover broad chemical space. The method is showcased in selective functionalization of building blocks and complex molecules, including late-stage functionalization of bromodomain inhibitors.

Photochemical Synthesis and Ring‐Opening of Aziridines and Epoxides: State‐of‐the‐Art

The development of greener methods for the preparation of three‐membered rings has increased in the last decade, not only due to their biological activity, but also by the ring strain of those heterocycles that make them useful precursors of more complex molecules. In this work, the visible‐light‐promoted synthesis and ring‐opening of aziridines and epoxides, reported in the last five years, were reviewed. Both homogeneous and heterogeneous catalysts were discussed and, in addition, the plausible mechanism pathways were highlighted.

Recent Advances in Manganese(III)-Assisted Radical Cyclization for the Synthesis of Natural Products: A Comprehensive Review

Natural products play an important part in synthetic chemistry since they have many pharmacological properties and are used as active drug compounds in pharmaceutical chemistry. However, synthesis of these complex molecules is difficult due to the requirement of various synthetic steps, which include highly regio- and stereoselectivity. Therefore, oxidative radical cyclization assisted by manganese(III) acetate serves as an important step in obtaining spiro-, tricyclic, tetracyclic, and polycyclic derivatives of these compounds. Manganese(III)-based reactions offer a single-step regio- and stereoselective cyclizations and α-acetoxidations, reducing the number of synthetic steps. Also, the manganese(III)-mediated oxidative free radical cyclization method has been successfully applied for the synthesis of cyclic structures found in many natural products. This article presents a broad overview of manganese(III)-based radical reactions of natural products as a key step in overall synthesis. The authors have classified natural product synthesis processes assisted by manganese(III) acetate as intermolecular, intramolecular, oxidation, acetoxidation, aromatization, and polymerization reactions, respectively.

Perfluorooxosulfate Salts as SOF4‐Gas‐Free Precursors to Multidimensional SuFEx Electrophiles

AbstractSulfur(VI) Fluoride Exchange (SuFEx) chemistry stands as a well‐established method for swiftly constructing complex molecules in a modular fashion. An especially promising segment of this toolbox is reserved for multidimensional SuFEx hubs: three or more substituents pluggable into a singular SVI centre to make ‘beyond‐linear’ clicked constructions. Sulfurimidoyl difluorides (RNSOF2) stand out as the prime example of this, however their preparation from the scarcely available thionyl tetrafluoride (SOF4) limits this chemistry to only a few laboratories with access to this gas. In this work, we identify silver pentafluorooxosulfate (AgOSF5) as a viable SuFEx hub with reactivity equal to SOF4. The AgF2‐mediated oxidation of SOCl2 gives rise to the hexacoordinate AgOSF5 adduct, which in contact with primary amines produces the sulfurimidoyl fluorides in high yields. In addition, we have found this workflow to be fully extendable to the trifluoromethyl homologue, AgOSF4CF3, and we propose the use of AgOSF4X salts as a general route to azasulfur SuFEx electrophiles from commercial starting materials.

Visible‐Light‐Induced Three‐Component Alkylpyridylation of Alkenes Enabled by Electron Donor‐Acceptor Complex

Visible‐light‐induced difunctionalization of alkenes is a powerful strategy for constructing complex molecules. Herein, we disclose a three‐component 1,2‐alkylpyridylation of alkenes under mild and photosensitizers‐free conditions. UV‐vis absorption spectroscopy studies and NMR titration experiments indicate that the formation of an EDA complex between 4‐alkyl‐DHPs and 4‐cyanopyridines. Primary, secondary, and tertiary C(sp3)‐centered radicals were formed by homolytic cleavage of 4‐alkyl‐DHPs. Gram‐scale synthesis and late‐stage functionalization of medicinally relevant molecules showed the synthetic potential of our methodology.

Photocatalytic Generation of Carbocation from Thiols and Application to Cross-Nucleophile Coupling.

Represented herein is a simple thiol identified as an effective precursor to photochemically form a carbocation. Thanks to the thiyl radical rapid transformation to disulfide, which serves not only to stabilize the generated thiyl radical but also to allow the second electron transfer to form a carbocation. The resulting carbocations, including primary benzylic, secondary, and tertiary carbocations, can smoothly couple with nitrogen, oxygen, and carbon nucleophilic coupling partners as well as complex drug molecules, accompanied by elemental sulfur formation in air.

Recent advances in catalytic asymmetric synthesis

Asymmetric catalysis stands at the forefront of modern chemistry, serving as a cornerstone for the efficient creation of enantiopure chiral molecules characterized by their high selectivity. In this review, we delve into the realm of asymmetric catalytic reactions, which spans various methodologies, each contributing to the broader landscape of the enantioselective synthesis of chiral molecules. Transition metals play a central role as catalysts for a wide range of transformations with chiral ligands such as phosphines, N-heterocyclic carbenes (NHCs), etc., facilitating the formation of chiral C-C and C-X bonds, enabling precise control over stereochemistry. Enantioselective photocatalytic reactions leverage the power of light as a driving force for the synthesis of chiral molecules. Asymmetric electrocatalysis has emerged as a sustainable approach, being both atom-efficient and environmentally friendly, while offering a versatile toolkit for enantioselective reductions and oxidations. Biocatalysis relies on nature’s most efficient catalysts, i.e., enzymes, to provide exquisite selectivity, as well as a high tolerance for diverse functional groups under mild conditions. Thus, enzymatic optical resolution, kinetic resolution and dynamic kinetic resolution have revolutionized the production of enantiopure compounds. Enantioselective organocatalysis uses metal-free organocatalysts, consisting of modular chiral phosphorus, sulfur and nitrogen components, facilitating remarkably efficient and diverse enantioselective transformations. Additionally, unlocking traditionally unreactive C-H bonds through selective functionalization has expanded the arsenal of catalytic asymmetric synthesis, enabling the efficient and atom-economical construction of enantiopure chiral molecules. Incorporating flow chemistry into asymmetric catalysis has been transformative, as continuous flow systems provide precise control over reaction conditions, enhancing the efficiency and facilitating optimization. Researchers are increasingly adopting hybrid approaches that combine multiple strategies synergistically to tackle complex synthetic challenges. This convergence holds great promise, propelling the field of asymmetric catalysis forward and facilitating the efficient construction of complex molecules in enantiopure form. As these methodologies evolve and complement one another, they push the boundaries of what can be accomplished in catalytic asymmetric synthesis, leading to the discovery of novel, highly selective transformations which may lead to groundbreaking applications across various industries.

FASTMAP—a flexible and scalable immunopeptidomics pipeline for HLA- and antigen-specific T-cell epitope mapping based on artificial antigen-presenting cells

The study of peptide repertoires presented by major histocompatibility complex (MHC) molecules and the identification of potential T-cell epitopes contribute to a multitude of immunopeptidome-based treatment approaches. Epitope mapping is essential for the development of promising epitope-based approaches in vaccination as well as for innovative therapeutics for autoimmune diseases, infectious diseases, and cancer. It also plays a critical role in the immunogenicity assessment of protein therapeutics with regard to safety and efficacy concerns. The main challenge emerges from the highly polymorphic nature of the human leukocyte antigen (HLA) molecules leading to the requirement of a peptide mapping strategy for a single HLA allele. As many autoimmune diseases are linked to at least one specific antigen, we established FASTMAP, an innovative strategy to transiently co-transfect a single HLA allele combined with a disease-specific antigen into a human cell line. This approach allows the specific identification of HLA-bound peptides using liquid chromatography–tandem mass spectrometry (LC-MS/MS). Using FASTMAP, we found a comparable spectrum of endogenous peptides presented by the most frequently expressed HLA alleles in the world’s population compared to what has been described in literature. To ensure a reliable peptide mapping workflow, we combined the HLA alleles with well-known human model antigens like coagulation factor VIII, acetylcholine receptor subunit alpha, protein structures of the SARS-CoV-2 virus, and myelin basic protein. Using these model antigens, we have been able to identify a broad range of peptides that are in line with already published and in silico predicted T-cell epitopes of the specific HLA/model antigen combination. The transient co-expression of a single affinity-tagged MHC molecule combined with a disease-specific antigen in a human cell line in our FASTMAP pipeline provides the opportunity to identify potential T-cell epitopes/endogenously processed MHC-bound peptides in a very cost-effective, fast, and customizable system with high-throughput potential.

ß‐Phenethylamine Synthesis via Latent Dual Electrophilicity of N‐Pyridinium Aziridines

ß‐Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N‐pyridinium aziridines as latent dual electrophiles for the synthesis of ß‐phenethylamines. Bromide‐promoted ring opening generates ß‐halopyridinium amines. Selective Ni‐catalyzed C–C cross‐coupling between organozinc nucleophiles and the benzylic C–Br electrophile affords a diverse family of ß‐functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni‐catalyzed reductive N–N bond activation within the b‐functionalized phenethylamino‐pyridinium salts furnishes the products of formal olefin carboamination. Other reductive N–N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N‐centered radical chemistry. The developed reaction sequence can be implemented in the context of complex molecules and natural product derivatives. Together, the described results provide a general and modular synthesis of ß‐phenethylamines and significantly expand the utility of N‐pyridinium aziridines as linchpins in chemical synthesis

ß-Phenethylamine Synthesis via Latent Dual Electrophilicity of N-Pyridinium Aziridines.

ß-Phenethylamines are widely represented in biologically and pharmacologically active organic small molecules. Here, we introduce N-pyridinium aziridines as latent dual electrophiles for the synthesis of ß-phenethylamines. Bromide-promoted ring opening generates ß-halopyridinium amines. Selective Ni-catalyzed C-C cross-coupling between organozinc nucleophiles and the benzylic C-Br electrophile affords a diverse family of ß-functionalized phenethylaminopyridinium salts, and coupling is stereoconvergent in the presence of chiral ligands. Subsequent Ni-catalyzed reductive N-N bond activation within the b-functionalized phenethylamino-pyridinium salts furnishes the products of formal olefin carboamination. Other reductive N-N cleavage reactions are demonstrated to provide access to free primary amines, alkylated amines, heterocycles, and products derived from N-centered radical chemistry. The developed reaction sequence can be implemented in the context of complex molecules and natural product derivatives. Together, the described results provide a general and modular synthesis of ß-phenethylamines and significantly expand the utility of N-pyridinium aziridines as linchpins in chemical synthesis.

A deconstruction-reconstruction strategy for pyrimidine diversification.

Structure-Activity Relationship (SAR) studies are fundamental to drug and agrochemical development, yet only a few synthetic strategies apply to the nitrogen heteroaromatics frequently encountered in small molecule candidates.1-3 Here, we present an alternative approach where we convert pyrimidine-containing compounds various other nitrogen heteroaromatics. Transforming pyrmidines into their correspondingN-arylpyrimidinium salts enables cleavage into a three-carbon iminoenamine building block, used for various heterocycle-forming reactions. This deconstruction-reconstruction sequence diversifies the initial pyrimidine core and enables access to various heterocycles, such as azoles.4 In effect, this approach allows heterocycle formation on complex molecules, resulting in analogs that would be challenging to obtain by other methods. We anticipate this deconstruction-reconstruction strategy will extend to other heterocycle classes.

Dinuclear gold-catalyzed divergent dechlorinative radical borylation of gem-dichloroalkanes

The enormous and widespread use of organoboronic acids has prompted the development of innovative synthetic methodologies to meet the demands on structural diversity and functional group tolerance. The existing photoinduced defunctionalization radical borylation, typically focused on the conversion of one C-X bond (X= Br, I, or other leaving group) into only one C-B bond. Herein, we disclose a divergent radical dechloroborylation reaction enabled by dinuclear gold catalysis with visible light irradiation. A wide range of structurally diverse alkyl boronic, α-chloroboronic, and gem-diboronic esters can be synthesized in moderate to good yields (up to 92%). Its synthetic robustness is further demonstrated on a preparative scale and applied to late-stage diversification of complex molecules. The process hinges on a C-Cl bond relay activation in readily available gem-dichloroalkanes through inner-sphere electron transfer, overcoming the redox potential limits of unreactive alkyl chlorides.

SuFEx-Enabled Direct Deoxy-Diversification of Alcohols.

We introduce a new use of sulfonyl fluoride as a bifunctional reagent that facilitates the one-step deoxy-diversification of complex alcohol libraries. Our reaction design features a Sulfur(VI) Fluoride Exchange (SuFEx) mediated activation of alcohols and fluoride-induced activation of silicon-bound nucleophiles. This method enables the direct conversion of alcoholic C-O bonds in complex molecules into diverse analogues via C-C, C-N, C-Cl, and C-Br bond formation while suppressing any elimination side-products.

Carbene-Assisted Arene Ring-Opening.

Despite the significant achievements in dearomatization and C-H functionalization of arenes, the arene ring-opening remains a largely unmet challenge and is underdeveloped due to the high bond dissociation energy and strong resonance stabilization energy inherent in aromatic compounds. Herein, we demonstrate a novel carbene assisted strategy for arene ring-opening. The understanding of the mechanism by our DFT calculations will stimulate wide application of bulk arene chemicals for the synthesis of value-added polyconjugated chain molecules. Various aryl azide derivatives now can be directly converted into valuable polyconjugated enynes, avoiding traditional synthesis including multistep unsaturated precursors, poor selectivity control, and subsequent transition-metal catalyzed cross-coupling reactions. The simple conditions required were demonstrated in the late-stage modification of complex molecules and fused ring compounds. This chemistry expands the horizons of carbene chemistry and provides a novel pathway for arene ring-opening.

Bioactivity, crystal and molecular structure of vanadyl(III) complex with N-salicyloyl − N’(3,5-ditertbutyl-2-hydroxy)benzylidene hydrazine

N-salicyloyl-N’-(3,5-ditertbutyl-2-hydroxy)benzylidene hydrazine (H3sahz) and its complex with VO(III) have been synthesized. The molecular and crystal structure of the [(VO)2(sahz)2(C2H5O)2(C2H5OH)] complex by X-ray diffraction, as well as IR and electronic spectra, EPR spectrum etc., have been studied. The structure of the investigated VO(III) complex consists of binuclear units in which the monomeric complex molecules are linked to each other through vanadyl oxygen atom. Monomeric complexes differ between themselves in the character of coordination. Both vanadium atoms have a distorted octahedral environment. The biological activity of this compound has been studied. Lastly, the activities of the studied ligand against various enzyme proteins including acetylcholinesterase (AChE), butrylcholinesterase (BChE) and α-glycosidase (α-Gly) enzyme were compared. ChE inhibitory activities of the new complex against α-Gly, AChE and BChE were determined by Tao and Ellman’s methods. The new complex was shown to have IC50 values of 42.60 µM for BChE, 91.43 µM for AChE, and 196.49 µM for α-glycosidase.

Metallophthalocyanine as ideal antibiotics without light: Mechanisms and applications

The urgent global health problem of antimicrobial resistance (AMR) calls for the discovery of new antibiotics with innovative modes of action while considering the low toxicity to mammalian cells. This paper proposes a novel strategy for designing antibiotics with selective bacterial toxicity by exploiting the positional differences of electron transport chains (ETC) in bacterial and mammalian cells. The focus is on cytochrome c (cyt C) and its maturation system in E. coli. The catalytic oxidative activity of metallophthalocyanine (MPc), which have a distinctive M-N4 structure, is being investigated. Unlike previous applications based on light-activated reactive oxygen species (ROS) generation, this study exploits the ability of MPcs to oxidize Fe2+ to Fe3+ in cyt C and catalyze the formation of disulfide bonds between cysteine residues to interfere with cyt C maturation, disrupt the bacterial respiratory chain and selectively kills bacteria. In contrast, in mammalian cells, these MPcs are located in the lysosomes and cannot access the ETC in the mitochondria, thus achieving selective bacterial toxicity. Two MPcs that showed effective antibacterial activity in a wound infection model were identified. This study provides a valuable reference for the design of novel antibiotics based on M-N4-based metal complex molecules.

Nickel-catalysed enantioselective alkene dicarbofunctionalization enabled by photochemical aliphatic C–H bond activation

AbstractThe development of novel strategies to rapidly construct complex chiral molecules from readily available feedstocks is a long-term pursuit in the chemistry community. Radical-mediated alkene difunctionalizations represent an excellent platform towards this goal. However, asymmetric versions remain highly challenging, and more importantly, examples featuring simple hydrocarbons as reaction partners are elusive. Here we report an asymmetric three-component alkene dicarbofunctionalization capitalizing on the direct activation of C(sp3)–H bonds through the combination of photocatalysed hydrogen atom transfer and nickel catalysis. This protocol provides an efficient platform for installing two vicinal carbon–carbon bonds across alkenes in an atom-economic fashion, providing a wide array of high-value chiral α-aryl/alkenyl carbonyls and phosphonates, as well as 1,1-diarylalkanes from ubiquitous alkane, ether and alcohol feedstocks. This method exhibits operational simplicity, broad substrate scope and excellent regioselectivity, chemoselectivity and enantioselectivity. The compatibility with bioactive motifs and expedient synthesis of pharmaceutically relevant molecules highlight the synthetic potential of this protocol.

Mechanisms of tumor immunosuppressive microenvironment formation in esophageal cancer.

As a highly invasive malignancy, esophageal cancer (EC) is a global health issue, and was the eighth most prevalent cancer and the sixth leading cause of cancer-related death worldwide in 2020. Due to its highly immunogenic nature, emer-ging immunotherapy approaches, such as immune checkpoint blockade, have demonstrated promising efficacy in treating EC; however, certain limitations and challenges still exist. In addition, tumors may exhibit primary or acquired resistance to immunotherapy in the tumor immune microenvironment (TIME); thus, understanding the TIME is urgent and crucial, especially given the im-portance of an immunosuppressive microenvironment in tumor progression. The aim of this review was to better elucidate the mechanisms of the suppressive TIME, including cell infiltration, immune cell subsets, cytokines and signaling pathways in the tumor microenvironment of EC patients, as well as the downregulated expression of major histocompatibility complex molecules in tumor cells, to obtain a better understanding of the differences in EC patient responses to immunotherapeutic strategies and accurately predict the efficacy of immunotherapies. Therefore, personalized treatments could be developed to maximize the advantages of immunotherapy.

Ultrafast and efficient continuous flow organic synthesis with a modified extruder-grinder system

The study introduces a groundbreaking continuous system that combines an extruder and grinder to enable catalyst-free and solvent-free reactions under mild conditions. This temperature-controlled system facilitates the synthesis of highly functionalized chromenes, which have valuable applications in generating combinatorial libraries and complex target molecules. The newly developed mill extruder machine offers several advantages for industrial production on a large scale. It effectively reduces waste, saves energy, and enhances time efficiency. This system represents a significant advancement in the field, providing a new strategy for one-pot synthesis of various types of highly functionalized spirooxindoles and chromenes. Remarkably, these reactions can be accomplished within a short timeframe of 2–10 min, yielding impressive results of 75–98%. The results demonstrate superior performance compared to traditional reaction methods, making it an appealing tool and hotspot area of research in green chemistry.