Substrate Tolerance Research Articles

Photoredox/Cr-catalyzed enantioselective radical-polar crossover transformation via C-H functionalization

Asymmetric multicomponent reactions that aim to control multiple chiral centers with high selectivity in a single step remain an on-gonging challenge. The realm of enantioselective radical-polar crossover transformation achieved through C-H Functionalization has yet to be fully explored. Herein, we present a successful description of a photoredox/Cr-catalyzed enantioselective three-component (hetero)arylalkylation of 1,3-dienes through C-H functionalization. A diverse array of chiral homoallylic alcohols could be obtained in good to excellent yields, accompanied by outstanding enantioselectivity. The asymmetric radical-polar crossover transformation could build two chiral centers simultaneously and demonstrates broad substrate tolerance, accommodating various drug-derived aldehydes, (hetero)aromatics, and 1,3-diene derivatives. Preliminary mechanistic studies indicate the involvement of a radical intermediate, with the chiral allylic chromium species reacting with various aliphatic and aromatic aldehydes through Zimmerman–Traxler transition states enabled by dual photoredox and chiral chromium catalysis.

Catalyst‐Free Sequential Wolff Rearrangement and [3+3] Annulation of Enaminones and Diazo Compounds Enabling the Assembly of Highly Functionalized Pyridin‐4‐Ones

AbstractA general protocol for the efficient synthesis of a variety of highly functionalized pyridin‐4‐ones has been developed through a sequential Wolff rearrangement and [3+3] annulation reaction of enaminones and diazo compounds. This straightforward approach features wide substrate applicability, good substrate tolerance, moderate to excellent yields, and without any catalyst, and enables access to structurally diverse pyridin‐4‐one skeletons. Additionally, scale‐up experiments and synthetic derivatizations demonstrated the potential synthetic utility of the transformations.

Iron-Photocatalyzed Decarboxylative Oxygenation of Aliphatic Carboxylic Acids

AbstractCarboxylic acids, a bench-stable, readily available, and structurally diverse class of compounds, represent ideal starting materials for organic synthesis. In this article, we highlight an iron-catalyzed, decarboxylative, C(sp3)–O bond-forming reaction that takes place under mild, photocatalytic, base-free conditions using 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO) derivatives as oxygenation reagents. The reaction is enabled by the ability of iron complexes to generate carbon-centered radicals directly from carboxylic acids through a sequence involving a photoinduced carboxylate-to-iron charge transfer, homolysis, and loss of carbon dioxide. The developed transformation displays exquisite substrate tolerance and was applied to various bioactive molecules. We performed an extensive mechanistic investigation through kinetic studies; electrochemistry, EPR, UV/Vis, and HRMS analyses; and DFT calculations. Those studies suggest that TEMPO plays three different roles in the reaction: it acts as an oxygenation reagent, serves as an oxidant to regenerate the Fe catalyst, and functions as an internal base for carboxylic acid deprotonation. The resulting TEMPO adducts are versatile synthons that can be subsequently utilized in C–C and C–heteroatom bond-forming reactions employing commercially available organophotocatalysts and nucleophilic reagents.1 Introduction2 Background on the LMCT Reactivity of Iron Complexes3 Direct Iron-Photocatalyzed Decarboxylative Oxygenation: Reaction Concept4 Substrate Scope Assessment of Decarboxylative Oxygenation5 Mechanistic Considerations6 Conclusion

Recent advances in biocatalytic and chemoenzymatic synthesis of oligonucleotides.

Access to synthetic oligonucleotides is crucial for applications in diagnostics, therapeutics, synthetic biology, and nanotechnology. Traditional solid phase synthesis is limited by sequence length and complexities, low yields, high costs and poor sustainability. Similarly, polymerase-based approaches such as in vitro transcription and primer extension reactions do not permit any control on the positioning of modifications and display poor substrate tolerance. In response, biocatalytic and chemoenzymatic strategies have emerged as promising alternatives, offering selective and efficient pathways for oligonucleotide synthesis. These methods leverage the precision and efficiency of enzymes to construct oligonucleotides with high fidelity. Recent advancements have focused on optimized systems and/or engineered enzymes enabling the incorporation of chemically modified nucleotides. Biocatalytic approaches, particularly those using DNA/RNA polymerases provide advantages in milder reaction conditions and enhanced sustainability. Chemoenzymatic methods, combining chemical synthesis and enzymes, have proven to be effective in overcoming limitations of traditional solid phase synthesis. This review summarizes recent developments in biocatalytic and chemoenzymatic strategies to construct oligonucleotides, highlighting innovations in enzyme engineering, substrate and reaction condition optimization for various applications. We address crucial details of the methods, their advantages, and limitations as well as important insights for future research directions in oligonucleotide production.

Synthesis of chiral alcohol (S)-CHBE by co-immobilization of double enzymes based on organic-inorganic hybrid nanoflower.

The chiral alcohols (S)-4-chloro-3-hydroxy-butyric acid ethyl ester ((S)-CHBE) is a critical intermediate in the synthesis of various active pharmaceutical ingredients. This study presents the first investigation of the efficient production of (S)-CHBE using organic-inorganic hybrid nanoflowers (GDH-CR@HNFs) for the co-immobilization of glucose dehydrogenase (BsGDH) and carbonyl reductase (BsCR). By optimizing immobilization conditions, we significantly enhanced the catalytic activity and immobilization efficiency of the hybrid nanoflowers. The GDH-CR@HNFs exhibited superior catalytic performance compared to the free dual enzyme system, demonstrating a higher affinity for the substrate COBE (47-fold lower Km value), increased maximum reaction rate (Vmax), and improved catalytic efficiency (Kcat/Km). Additionally, the GDH-CR@HNFs displayed enhanced temperature adaptability, pH stability, and storage stability. The GDH-CR@HNFs retained over 60% of their initial catalytic activity after 8cycles of reuse. The hydrophobic nature of the substrate COBE can lead to substrate inhibition of the free enzyme. However, GDH-CR@HNFs exhibited excellent substrate tolerance, maintaining a high conversion rate (65%) even at a substrate concentration of 200mM, significantly outperforming the free enzyme system (13.8% conversion rate). The hybrid nanoflower co-immobilization strategy offers a novel approach to addressing substrate and product inhibition issues in enzyme-catalyzed reactions, paving the way for the industrial production scale of (S)-CHBE.

Allylic Alkylation of Morita-Baylis-Hillman Carbonates with In situ Generated Azomethine Ylides

Abstract: The allylation reaction of Morita-Baylis-Hillman carbonates is an effective method for constructing C-C bonds. Yang's group has utilized azomethine ylides, which are generated in situ from 2-aminomalonate and ortho-amino benzaldehydes, to engage in allylation reactions with MBH carbonates. Despite the initial substrate specificity that confined the reaction to ortho-amino benzaldehydes, rendering benzaldehyde and salicylaldehyde ineffective for producing the desired adducts, our group has made a significant advancement. By employing diethyl amino malonate hydrochloride as the substrate, we have successfully integrated benzaldehyde and salicylaldehyde into this reaction framework, thereby broadening the versatility of the process. This strategy demonstrates excellent substrate tolerance and provides the corresponding adducts with yields up to 99%. The gram-scale synthesis and subsequent product derivatization highlight the significant applicability of this method. conclusion: an efficient allylic alkylation between MBH carbonates and azomethine ylides, in suit formed from diethyl aminomalonate hydrochloride and benzaldehyde (salicylaldehydes) was developed. The reaction showed an impressive substrate scope, successfully affording a range of allyl-alkylated products with up to 99% yield.

Biocatalytic synthesis of ribonucleoside analogues using nucleoside transglycosylase-2.

Ribonucleosides are essential building blocks used extensively in antiviral and oligonucleotide therapeutics. A major challenge in the further development of nucleoside analogues for therapeutic applications is access to scalable and environmentally sustainable synthetic strategies. This study uses the type II nucleoside 2'-deoxyribosyltransferase from Lactobacillus leichmannii (LlNDT-2) to prepare a suite of ribonucleoside analogues using naturally-occurring uridine and cytidine sugar donors. Crystal structure and mutational analyses are used to define the substrate tolerance of the nucleobase exchange and the 2'-substituent of the nucleoside sugar donor. Nucleobase profiling identified acceptance of both purine and pyrimidine nucleobases. Finally, the scalability of the approach is showcased, enabling the preparation of ribonucleosides on millimolar scales. This biocatalytic strategy opens up opportunities to establish chemoenzymatic routes to prepare nucleoside analogues incorporating 2' modifications that are of therapeutic importance.

The [4+2] Annulation of o-Acylamino-aryl MBH Carbonates with Coumarins: Facile Access to Tetrahydrochromeno[4,3-b]quinolin-6-ones

The [4+2] annulation reaction of o-acylamino-aryl MBH carbonates with 3-substituted coumarins has been developed. This method exhibits excellent substrate tolerance and constructs a series of tetrahydrochromeno[4,3-b]quinolin-6-ones with yields up to...

Stereodivergent assembly of δ-valerolactones with an azaarene-containing quaternary stereocenter enabled by Cu/Ru relay catalysis.

Developing methodologies for the expedient construction of biologically important δ-valerolactones bearing a privileged azaarene moiety and a sterically congested all-carbon quaternary stereocenter is important and full of challenges. We present herein a novel multicatalytic strategy for the stereodivergent synthesis of highly functionalized chiral δ-valerolactones bearing 1,4-nonadjacent quaternary/tertiary stereocenters by orthogonally merging borrowing hydrogen and Michael addition between α-azaaryl acetates and allylic alcohols followed by lactonization in a one-pot manner. Enabled by Cu/Ru relay catalysis, this cascade protocol offers the advantages of atom/step economy, redox-neutrality, mild reaction conditions, and broad substrate tolerance. Scale-up experiments and synthetic transformations further demonstrated the potential for synthetic applications. Mechanistic experiments support the envisioned bimetallic relay catalytic mechanism, and the key role of Cs2CO3 in promoting lactonization was also revealed.

Kinetic Analysis of Cyclization by the Substrate-Tolerant Lanthipeptide Synthetase ProcM.

Lanthipeptides are ribosomally synthesized and post-translationally modified peptides (RiPPs) characterized by the presence of thioether cross-links called lanthionine and methyllanthionine, formed by dehydration of Ser/Thr residues and Michael-type addition of Cys side chains onto the resulting dehydroamino acids. Class II lanthipeptide synthetases are bifunctional enzymes responsible for both steps, thus generating macrocyclic natural products. ProcM is part of a group of class II lanthipeptide synthetases that are known for their remarkable substrate tolerance, having large numbers of natural substrates with highly diverse peptide sequences. They install multiple (methyl)lanthionine rings with high accuracy, attributes that have been used to make large libraries of polycyclic peptides. Previous studies suggested that the final ring pattern of the lanthipeptide product may be determined by the substrate sequence rather than by ProcM. The current investigation on the ProcM-catalyzed modification of one of its 30 natural substrates (ProcA3.3) and its sequence variants utilizes kinetic assays to understand the factors that determine the ring pattern. The data show that changes in the substrate sequence result in changes to the reaction rates of ring formation that in some cases lead to a change in the order of the modifications and thereby bring about different ring patterns. These observations provide further support that the substrate sequence determines to a large degree the final ring pattern. The data also show that similar to a previous study on another substrate (ProcA2.8), the reaction rates of successive reactions slow down as the peptide is matured; rate constants observed for the reactions of these two substrates are similar, suggesting that they reflect the intrinsic activity of the enzyme with its 30 natural substrates. We also investigated whether rates of formation of single isolated rings can predict the final ring pattern of polycyclic products, an important question for the products of genome mining exercises, as well as library generation. Collectively, the findings in this study indicate that the rates of isolated modifications can be used for predicting the final ProcM-produced ring pattern, but they also revealed limitations. One unexpected observation was that even changing Ser to Thr and vice versa, a common means to convert lanthionine to methyllanthionine and vice versa, can result in a change in the ring pattern.

N‐Heterocyclic Carbene‐Catalyzed Enantioselective Synthesis of Spirocyclohexane Oxindoles

A variety of structurally diverse spirocyclohexane oxindoles featuring a quaternary carbon centre have been successfully constructed through an N‐heterocyclic carbene‐catalyzed [4+2] annulation of isatin‐derived enals with α cyano‐β‐methylenones. This domino process exhibits a wide substrate tolerance, operates under mild conditions, and yields products with high enantioselectivity.

Enhancement of the Degradation of Phytosterol Side Chains in Mycolicibacterium by Eliminating the Redox Sensitivity of Key Thiolase and Augmenting Cell Activity

Androstenedione (AD) is a vital intermediate in the synthesis of steroid drugs, making its efficient production critical in the steroid drug industry. Acetyl-CoA acetyltransferase (FadA5), a thiolase enzyme, plays an important role in the metabolic process of degrading phytosterol side chains in Mycolicibacterium to produce AD. This work is the first systematic analysis of the role of FadA5 in the transformation of phytosterols by Mycolicibacterium to produce AD. The relationship between redox potential and AD production was examined using resting cells, and it was confirmed that FadA5 is a key enzyme for AD production. Mutating the 87th cysteine of FadA5 to alanine reduced its redox effect, enhancing the substrate tolerance and biotransformation capacity of the strain. Co-expressing Vitreoscilla hemoglobin (VHb) and propionyl-CoA metabolized the transcription activator (PrpR), decreased intracellular reactive oxygen species levels, and improved cell viability. The AD yield of MSP-fA5C87A-VP/ΔfA5 was 2.541 g/L, an increase of 16.83% over the control strain. Using a repeated batch fermentation process, the production efficiency of the MSP-fA5C87A-VP/ΔfA5 strain was 0.658 g/L/d, which was 1.82 times higher than that of the control strain. These findings provide a theoretical basis for understanding and regulating steroid side-chain catabolism in Mycolicibacterium and offer support for the rational modification of industrial strains for steroidal drug precursor production.

Reusable Iron-Copper Catalyzed Cross-Coupling of Primary Amides with Aryl and Alkyl Halides: Access to N-Arylamides as Potential Antibacterial and Anticancer Agents.

We present, for the first time, an efficient ligand-free iron-copper catalyzed cross-coupling reaction involving a variety of aryl, heteroaryl halides (including chlorides, bromides, and iodides), and alkyl bromides with diverse aryl and aliphatic primary amides, conducted under solvent-minimized conditions. This economically competitive protocol successfully yielded the corresponding cross-coupling products, N-arylamides and N-alkylamides, in good to excellent yields with broad substrate scope (65 examples) and tolerance to several sensitive functionalities (including heterocycles). No conventional work-up is required for this protocol, and the developed method is applicable for gram-scale synthesis. Notably, the catalyst is inexpensive, environmentally friendly, and can be reused at least four times with minimal loss of catalytic activity. A series of experiments, including X-ray photoelectron spectroscopy (XPS), UV spectroscopy, cyclic voltammetry (CV), electron paramagnetic resonance (EPR), and X-ray diffraction (XRD) were conducted to identify the oxidation state of active catalytic species and radical clock experiment was performed using a radical probe to investigate the reaction mechanism. Furthermore, we evaluated the antibacterial and anticancer properties of selected synthesized products (3 ii, 3 xii, and 3 xxxx) in-vitro. The results indicated that the prepared compounds exhibited promising antibacterial and anticancer activities (MTT and Molecular Docking).

Exploring Fluorinase Substrate Tolerance at C-2 of SAM.

The fluorinase enzyme (EC 2.5.1.63) utilises fluoride ion and S-adenosyl-L-methionine (SAM) as substrates for conversion to 5'-fluoro-5'-deoxy-adenosine (5'-FDA) and L-methionine (L-Met). The enzyme has a very strict substrate specificity, however it has been shown to tolerate acetylenes and NH2 replacements for H at C-2 of the adenine ring of SAM. This substrate tolerance is explored further here with -NHR, -N3, -OR and -SR substituents attached to C-2. New activities are demonstrated, for example with NH-methyl, NH-propyl,NH-butyl and O-butyl substrates at C-2, however azide and thioethers were not tolerated. Outcomes are supported by in silico analysis, revealing favourable H-bonding interactions involving NH and O substituents at the adenine C-2 position with N278 and the backbone amide of A279 at the active site respectively. The study informs on the selectivity of the fluorinase as a tool for radiolabelling candidate ligands with fluorine-18 for positron emission tomography programmes.

Rational Assembly of Three-component Coordination Polymers as Heterogeneous Catalysts for CO2 Cycloaddition and Cyanosilylation Reactions.

Four new coordination polymers based on 5-(((1H-imidazol-2-yl)methyl)amino) isophthalic acid (H3L) and auxiliary ligands (1,10-phenanthroline, 2,2'-bipyridine, and 4,4'-bipyridine), namely, {[Zn(HL)(phen)(H2O)] ⋅ 2H2O}n (CP 1), {[Ni(HL)(phen)(H2O)]}n (CP 2), {[Ni(HL)(2,2'-bpy)(H2O)] ⋅ 2H2O}n (CP 3) and {[Cd(HL)(4,4'-bpy)0.5(H2O)] ⋅ 2H2O}n (CP 4) were rationally assembled. Furthermore, these four CPs were screened as heterogeneous catalysts for CO2 cycloaddition and cyanosilylation reactions under mild conditions. The catalytic experiments showed that CP 1 had the better catalytic performance, excellent substrate tolerance and recyclability for the above two reactions. It is speculated that the excellent activity of CP 1 may be due to the open Lewis base site and the Lewis acidic characteristics of the zinc (II) center. After five cycles, the catalytic activities of CP 1 did not significantly decrease, and the structures remained unchanged. Therefore, the CP 1 was considered efficient and stable heterogeneous catalysts for above the two reactions.

Asymmetric Formal [5 + 2] Annulation of 3-Hydroxyquinolinones and Vinylethylene Carbonates through Pd/Cu Tandem Catalysis.

The asymmetric [5 + 2] cycloaddition of VECs remains to be comparatively rare. Herein, we reported an enantioselective formal [5 + 2] annulation of 3-hydroxyquinolinones and vinylethylene carbonates (VECs) through Pd- and Cu-catalyzed tandem allylation/asymmetric [1,3]-rearrangement/hemiketalization sequences. The strategy exhibits good substrate tolerance, affording a wide range of tricyclic quinolinones bearing two adjacent quaternary stereocenters in moderate to good yields with excellent enantioselectivities.

Oxydiazomethylation of Alkenes via Photoredox Catalysis.

α-Diazoesters belong to significantly important carbenoid precursors in synthetic chemistry. Diazomethylation-based difunctionalization of alkenes is highly valuable but remain nontrivial. Herein, we reported a general and modular approach for the direct 1,2-oxydiazomethylation of alkenes through visible-light photoredox catalysis. This process exploits photocatalyzed strategy to convert alkenes to γ-formyloxyl-α-diazoesters using α-diazo iodonium salts as carbyne precursors, featuring wide substrate tolerance and broad late-stage diversifications. Mechanistic studies suggest that the formation of γ-carbocation-tethered α-diazoesters plays a crucial role in trapping DMF and H2O to allow for this transformation.

A Novel 2-Methylimidazole Promoted Oxyacyloxylation of α-Hydroxy Ketones and Anhydrides: An Easy Access to α-Acyloxy Ketones

An efficient and operationally simple method for the synthesis of α-acyloxy ketones through the readily available 2-methylimidazole-promoted reaction of α-hydroxy ketones and anhydrides is developed. In the reaction, the anhydrides act as both a substrate and a solvent. The new method features good substrate tolerance, mild reaction conditions, readily accessible starting materials, and excellent yields, providing facile and green access to the targets. Importantly, the reaction also avoids the use of reagents with pungent odors, such as pyridine, in traditional esterification, which may promote the development of organocatalysis using nitrogen-containing heterocyclic compounds as catalysts.

Reductive Coupling of N-Heteroarenes and 1,2-Dicarbonyls for Direct Access to γ-Amino Acids, Esters, and Ketones Using a Heterogeneous Single-Atom Iridium Catalyst.

Despite their significant importance, the challenges in direct and diverse synthesis of N-heterocyclic γ-amino acids/esters/ketones hamper exploration of their applications. Herein, by developing a multifunctional heterogeneous iridium single-atom catalyst composed of silica-confined iridium species and a boron-doped ZrO2 support (Ir-SAs@B-ZrO2/SiO2), we describe its utility in establishing a new reductive coupling reaction of N-heteroarenes and 1,2-dicarbonyls for selective and diverse construction of the as-described compounds in a straightforward manner. The striking features, including good substrate and functionality tolerance, high step and atom economy, exceptional catalyst reusability, and diversified product post-transformations, highlight the practicality of the developed chemistry. Mechanistic studies reveal that the synergy between the active Ir sites and acidic support favors a chemoselective reduction of the more inert N-heteroarenes and affords requisite enamine intermediates. In this work, the concept on precise transformation of reductive intermediates will open a door to further develop useful tandem reactions by rational catalyst design.

Development of a Divergent Synthesis Strategy for 5-Sulfonyl-Substituted Uracil Derivatives.

An efficient, diversity-orientated synthesis of 5-sulfone-substituted uracils was established. The use of protecting groups to synthesize sulfones from N-heterocycles was avoided. Various heterocycles were synthesized for the first time from favorable, easily accessible starting materials. Diversity-orientated syntheses are important for the medicinal chemistry of virostatics and chemotherapeutics. This approach provides a broad substrate tolerance and excellent yields of up to 98%.