Ring Scaffolds Research Articles

Zinc-Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes.

The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp3)-rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza-BCHs) by an enantioselective zinc-catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2-acyl imidazole group and a diverse array of alkynyl- and aryl-substituted imines. The target aza-BCHs, which consist of α-chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94% yield and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring-opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid-catalyzed cycloadditions of BCBs.

Zinc‐Catalyzed Enantioselective Formal (3+2) Cycloadditions of Bicyclobutanes with Imines: Catalytic Asymmetric Synthesis of Azabicyclo[2.1.1]hexanes

The cycloaddition reaction involving bicyclo[1.1.0]butanes (BCBs) offers a versatile and efficient synthetic platform for producing C(sp3)‐rich rigid bridged ring scaffolds, which act as phenyl bioisosteres. However, there is a scarcity of catalytic asymmetric cycloadditions of BCBs to fulfill the need for enantioenriched saturated bicycles in drug design and development. In this study, an efficient synthesis of valuable azabicyclo[2.1.1]hexanes (aza‐BCHs) by an enantioselective zinc‐catalyzed (3+2) cycloadditions of BCBs with imines is reported. The reaction proceeds effectively with a novel type of BCB that incorporates a 2‐acyl imidazole group and a diverse array of alkynyl‐ and aryl‐substituted imines. The target aza‐BCHs, which consist of α‐chiral amine fragments and two quaternary carbon centers, are efficiently synthesized with up to 94% yield and 96.5:3.5 er under mild conditions. Experimental and computational studies reveal that the reaction follows a concerted nucleophilic ring‐opening mechanism of BCBs with imines. This mechanism is distinct from previous studies on Lewis acid‐catalyzed cycloadditions of BCBs.

The Tribological Properties of Novel Sulfoximine Derivatives as Lubricant Additives.

Introducing an additive is a practical approach to improve the lubrication performance of base oil in the field of tribology. Herein, a series of sulfoximine derivatives was synthesized and incorporated into base oil A51 as additives. The tribological properties of these lubricants were evaluated at both room and high temperatures, and the result demonstrated that they displayed excellent friction reduction and wear resistance in the friction process under both test conditions. Moreover, the chemical composition of the worn scar surface was inspected using EDS, XPS and TOF-SIMS to explore the lubricating mechanism. It is reasonable to conclude that the synergistic interaction between the aromatic ring scaffolds and elements like N, F, and S facilitated the adsorption of lubricant on the steel block surfaces and forming a tribofilm during the friction process. This tribofilm has a dominant impact on the system's lubrication performance. This research provides novel oil-soluble lubricant additives, offering a facile approach to formulating high-quality lubricants.

Asymmetric Construction of Bis‐Spirocyclic Pyrazolones Bearing Vicinal Quaternary Carbon Centers

AbstractA catalytic asymmetric (3+2) cyclization of pyrazolone‐based MBH adducts with alkylidenyl isoxazolones was presented by using DMAP‐derived chiral catalyst, affording bis‐spirocyclic pyrazolones bearing vicinal all‐carbon quaternary stereocenters within an imbedded cyclopentene ring scaffold in good yields with excellent stereoselectivities under mild conditions.

Catalytic Ring Expanding Difluorination: An Enantioselective Platform to Access β,β-Difluorinated Carbocycles.

Cyclic β,β-difluoro-carbonyl compounds have a venerable history as drug discovery leads, but limitations in the synthesis arsenal continue to impede chemical space exploration. This challenge is particularly acute in the arena of fluorinated medium rings where installing the difluoromethylene unit subtly alters the ring conformation by expanding the internal angle (∠C-CF2-C>∠C-CH2-C): this provides a handle to modulate physicochemistry (e.g. pKa). To reconcile this disparity, a highly modular ring expansion has been devised that leverages simple α,β-unsaturated esters and amides, and processes them to one-carbon homologated rings with concomitant geminal difluorination (6 to 10 membered rings, up to 95 % yield). This process is a rare example of the formal difluorination of an internal alkene and is enabled by sequential I(III)-enabled O-activation. Validation of enantioselective catalysis in the generation of unprecedented medium ring scaffolds is reported (up to 93 : 7 e.r.) together with X-ray structural analyses and product derivatization.

Catalytic Ring Expanding Difluorination: An Enantioselective Platform to Access β,β‐Difluorinated Carbocycles

AbstractCyclic β,β‐difluoro‐carbonyl compounds have a venerable history as drug discovery leads, but limitations in the synthesis arsenal continue to impede chemical space exploration. This challenge is particularly acute in the arena of fluorinated medium rings where installing the difluoromethylene unit subtly alters the ring conformation by expanding the internal angle (∠C−CF2−C>∠C−CH2−C): this provides a handle to modulate physicochemistry (e.g. pKa). To reconcile this disparity, a highly modular ring expansion has been devised that leverages simple α,β‐unsaturated esters and amides, and processes them to one‐carbon homologated rings with concomitant geminal difluorination (6 to 10 membered rings, up to 95 % yield). This process is a rare example of the formal difluorination of an internal alkene and is enabled by sequential I(III)‐enabled O‐activation. Validation of enantioselective catalysis in the generation of unprecedented medium ring scaffolds is reported (up to 93 : 7 e.r.) together with X‐ray structural analyses and product derivatization.

Effects of additional ring-fusion site on dual reactivity based dynamic covalent chemistry

Tautomers are widespread in organic chemistry, and their unique reactivity allows diverse transformations. In this work, the incorporation of nearby amide ring-fusion site offered a versatile platform for controlling dual reactivity based dynamic covalent chemistry (DCC) of aldehyde ring-chain tautomers. A suite of 2-formylbenzosulfonamide derived tautomers were prepared, and the intramolecular ring-chain equilibrium and intermolecular dynamic covalent reactions along the underlying mechanistic foundation were investigated. By regulating the substituent electronic effect and solvent effect, ring-chain tautomerization equilibrium was readily regulated in solution. The adjacent amide NH participates in intramolecular hydrogen bonding, as revealed by crystal analysis. Furthermore, the addition of acid and the change of solvent allowed turning on/off the intramolecular cyclization from the amide group to create fused ring scaffolds. Finally, the reversible covalent reactions with amine nucleophile reagents maintained the intermolecular reactivity successfully. The molecular and pathway diversity reported herein sets the scene for future design and applications.

Enzymatic Assembly of Diverse Lactone Structures: An Intramolecular C-H Functionalization Strategy.

Lactones are cyclic esters with extensive applications in materials science, medicinal chemistry, and the food and perfume industries. Nature's strategy for the synthesis of many lactones found in natural products always relies on a single type of retrosynthetic strategy, a C-O bond disconnection. Here, we describe a set of laboratory-engineered enzymes that use a new-to-nature C-C bond-forming strategy to assemble diverse lactone structures. These engineered "carbene transferases" catalyze intramolecular carbene insertions into benzylic or allylic C-H bonds, which allow for the synthesis of lactones with different ring sizes and ring scaffolds from simple starting materials. Starting from a serine-ligated cytochrome P450 variant previously engineered for other carbene-transfer activities, directed evolution generated a variant P411-LAS-5247, which exhibits a high activity for constructing a five-membered ε-lactone, lactam, and cyclic ketone products (up to 5600 total turnovers (TTN) and >99% enantiomeric excess (ee)). Further engineering led to variants P411-LAS-5249 and P411-LAS-5264, which deliver six-membered δ-lactones and seven-membered ε-lactones, respectively, overcoming the thermodynamically unfavorable ring strain associated with these products compared to the γ-lactones. This new carbene-transfer activity was further extended to the synthesis of complex lactone scaffolds based on fused, bridged, and spiro rings. The enzymatic platform developed here complements natural biosynthetic strategies for lactone assembly and expands the structural diversity of lactones accessible through C-H functionalization.

Visualizing the Hierarchical Evolution of Aryl-Metal Bonding in Organometallic Nanostructures on Ag(111).

On-surface dehalogenative coupling reactions are promising for constructing nanostructures with diverse properties and functionalities. Extensive efforts have been devoted to single aryl-halogen (C-X) substituents and substitutions at various functionalization sites (typically including meta- and para-substitutions) to generate aryl-aryl single bonds. Moreover, multiple C-X substituents at the ortho-site and the peri- and bay-regions have been applied to create a variety of ring scaffolds. However, for multiple C-X substituents, the hierarchy of aryl-metal bond formation and dissociation remains elusive. Herein, by combining scanning tunneling microscopy imaging and density functional theory calculations, we have visualized and demonstrated the hierarchical evolution of aryl-metal bonding in organometallic intermediates involved in a dehalogenative coupling reaction on Ag(111), using a molecular precursor with both para-substitution and potential bay-region substitution. Our results elucidate how metal atoms are progressively embedded into and removed from organometallic intermediates, enhancing the understanding of on-surface dehalogenative coupling reactions for the controlled construction of the desired nanostructures.

Sequential [3+2] and [4+4] Annulation of Diynone and o‐Hydroxyaryl Azomethine Ylide: Construction of Dihydropyrrole Fused Eight‐Membered Ring Scaffold

AbstractWe developed a cascade reaction of diynone and o‐hydroxy aromatic aldimine under mild conditions. This protocol is proposed to proceed through sequential [3+2]/[4+4] cycloaddition and proton transfer processes, thus providing an efficient way for the synthesis of a variety of dihydropyrrole fused eight‐membered ring scaffolds.

Cu(ii)-mediated direct intramolecular cyclopropanation of distal olefinic acetate: access to cyclopropane-fused γ-lactones.

Cyclopropane-fused ring scaffolds represent one of the most appealing structural motifs in organic chemistry due to their wide presence in bioactive molecules and versatility in organic synthesis. These skeletons are typically prepared from olefinic diazo compounds via transition-metal catalysed intramolecular carbenoid insertion, which suffers from prefunctionalization of starting materials and limited substrate scope. Herein, we disclose a practical copper-mediated direct intramolecular cyclopropanation of distal olefinic acetate to synthesize cyclopropane-fused γ-lactones and lactams. This cascade reaction is postulated to proceed through a hydrogen atom transfer event induced radical cyclization and copper-mediated cyclopropanation sequence. The protocol features high atom- and step-economy, excellent diastereoselectivity, broad tolerance of functional groups, and operational simplicity.

Deconstructive Synthesis of Bridged and Fused Rings via Transition-Metal-Catalyzed "Cut-and-Sew" Reactions of Benzocyclobutenones and Cyclobutanones.

ConspectusBridged and fused rings are commonly found in biologically important molecules. Current tactics to construct these ring systems are primarily based on stepwise ring formation (i.e., making one ring first followed by making another) and cycloaddition reactions (e.g., Diels–Alder reaction). To seek a complementary and perhaps more unified ring-forming approach, a deconstructive strategy based on C–C bond activation of cyclic ketones has been conceived. The named “cut-and-sew” reaction uses cyclic ketones with a tethered unsaturated moiety as substrates, which involves oxidative addition of a transition metal into the ketone C–C bond followed by intramolecular insertion of the unsaturated unit. This strategy has proved successful to access diverse ring scaffolds that are nontrivial to construct otherwise.This Account offers a concise summary of our laboratory’s systematic efforts in developing transition metal-catalyzed cut-and-sew reactions for the synthesis of bridged and fused rings over the past 10 years. In particular, we will focus on the reactions using readily available benzocyclobutenones and cyclobutanones. To date, the scope of the cut-and-sew reactions has been greatly expanded. First, diverse unsaturated moieties can serve as suitable coupling partners, such as alkenyl, alkynyl, allenyl, carbonyl, and iminyl groups. Second, a variety of reaction modes have been uncovered. In this account, (4 + 2), (4 + 2 – 1), and (4 + 1) cycloadditions that lead to a range of bridged or fused scaffolds will be summarized. Third, enantioselective transformations have been realized to efficiently construct chiral scaffolds, which are enabled by two strategies: enantio-determining migratory insertion and desymmetrization of cyclobutanones. Fourth, the synthetic applications have been demonstrated in streamlined total syntheses of a number of complex natural products. Compared to conventional synthetic logics, the cut-and-sew reaction allows the development of new bond-disconnecting strategies. Thus, the syntheses of (−)-cycloclavine, (−)-thebainone A, penicibilaenes, and the proposed cycloinumakiol are discussed in more detail.In addition to the narrative of the development of the cut-and-sew chemistry, this Account also aims to provide core guiding foundations and inspirations toward broader deconstructive synthetic applications through C–C bond cleavage. It is anticipated that more classes of cyclic compounds could serve as the substrates beyond benzocyclobutenones and cyclobutanones, and more diverse unsaturated moieties could be coupled. It can also be envisaged that more innovative utilization of this cut-and-sew strategy in complex organic syntheses will be revealed in the near future.

Applying a Bioisosteric Replacement Strategy in the Discovery and Optimization of Mesoionic Pyrido[1,2-a]pyrimidinone Insecticides: A Review.

Mesoionic pyrido[1,2-a]pyrimidinones are a unique class of heterocyclic compounds. Compounds from this class with a n-propyl group substituted at the 1 position of the mesoionic core were discovered with interesting insecticidal activity in our screen. In this overview, we showcase how a bioisosteric replacement strategy was applied during the discovery and optimization of this class of compounds. Through exploring various substituents at the 1 position, evaluating a variety of mesoionic bicyclic ring scaffolds, and examining substituents on the phenyl group at the 3 position of the mesoionic core as well as substituents on the mesoionic ring skeleton, many compounds were discovered with excellent hopper activity or potent activity against a wide range of Lepidoptera. Ultimately, dicloromezotiaz was identified for commercial development to control a broad spectrum of lepidopteran pests.

Selective, Transition Metal-free 1,2-Diboration of Alkyl Halides, Tosylates, and Alcohols.

Defunctionalization of readily available feedstocks to provide alkenes for the synthesis of multifunctional molecules represents an extremely useful process in organic synthesis. Herein, we describe a transition metal‐free, simple and efficient strategy to access alkyl 1,2‐bis(boronate esters) via regio‐ and diastereoselective diboration of secondary and tertiary alkyl halides (Br, Cl, I), tosylates, and alcohols. Control experiments demonstrated that the key to this high reactivity and selectivity is the addition of a combination of potassium iodide and N,N‐dimethylacetamide (DMA). The practicality and industrial potential of this transformation are demonstrated by its operational simplicity, wide functional group tolerance, and the late‐stage modification of complex molecules. From a drug discovery perspective, this synthetic method offers control of the position of diversification and diastereoselectivity in complex ring scaffolds, which would be especially useful in a lead optimization program.

Photoredox synthesis of 6- and 7-membered ring scaffolds via N-centered radicals.

N-Containing heterocycles are important scaffolds due to their ubiquitous presence in bioactive compounds. Their synthesis has been considered as an important research field. In this work we report the access to 6- and 7-membered rings via a photoinduced strategy. To our knowledge, this work represents the first exemple of photo-induced 7-endo-trig cyclization with N-centered radicals.

Stereoselective construction of novel biaryl bridged seven-membered ring scaffolds via intramolecular [3 + 2] cycloaddition reactions

A novel approach to biaryl bridged seven-membered carbocyclic scaffolds was developed by means of an intramolecular [3 + 2] cycloaddition process of in situ formed azomethine ylides from 2-cinnamoyl-2'-formyl biphenyl and diethyl aminomalonate hydrochloride. A range of biaryl bridged carbocyclic motifs with five-membered pyrrole ring bearing three steregenic centers was achieved with good to excellent yields (up to 98%) along with excellent diastereoselectivities (up to >20:1 dr).

Phenothiazines Modified with the Pyridine Ring as Promising Anticancer Agents

Azaphenothiazines are the largest and most perspective group of modified phenothiazines, and they exhibit variety of biological activities. The review sums up the current knowledge on the anticancer activity of isomeric pyridobenzothiazines and dipyridothiazines, which are modified azaphenothiazines with one and two pyridine rings, respectively, against 10 types of cancer cell lines. Some 10-substituted dipyridothiazines and even 10-unsubstituted parent compounds, such as 10H-1,9-diazaphenothiazine and 10H-3,6-diazaphenothiazine, exhibited very potent action with the IC50 values less than 1 µg/mL and 1 µM against selected cancer cell lines. The strength of the anticancer action depends both on the tricyclic ring scaffolds and the substituents at the thiazine nitrogen atom. The review discusses the kind of the substituents, nature of tricyclic ring scaffolds with the location of the azine nitrogen atoms, the types of the cancer cell lines, and the mechanism of action.

Hydantoin-bridged medium ring scaffolds by migratory insertion of urea-tethered nitrile anions into aromatic C-N bonds.

Bicyclic or tricyclic nitrogen-containing heterocyclic scaffolds were constructed rapidly by intramolecular nucleophilic aromatic substitution of metallated nitriles tethered by a urea linkage to a series of electronically unactivated heterocyclic precursors. The substitution reaction constitutes a ring expansion, enabled by the conformationally constrained tether between the nitrile and the heterocycle. Attack of the metallated urea leaving group on the nitrile generates a hydantoin that bridges the polycyclic products. X-ray crystallography reveals ring-dependant strain within the hydantoin.

New Series of Potent Allosteric Inhibitors of Deoxyhypusine Synthase

Deoxyhypusine synthase (DHPS) is the primary enzyme responsible for the hypusine modification and, thereby, activation of the eukaryotic translation initiation factor 5A (eIF5A), which is key in regulating the protein translation processes associated with tumor proliferation. Although DHPS inhibitors could be a promising therapeutic option for treating cancer, only a few studies reported druglike compounds with this inhibition property. Thus, in this work, we designed and synthesized a new chemical series possessing fused ring scaffolds designed from high-throughput screening hit compounds, discovering a 5,6-dihydrothieno[2,3-c]pyridine derivative (26d) with potent inhibitory activity; furthermore, the X-ray crystallographic analysis of the DHPS complex with 26d demonstrated a distinct allosteric binding mode compared to a previously reported inhibitor. These findings could be significantly useful in the functional analysis of conformational changes in DHPS as well as the structure-based design of allosteric inhibitors.

Dissecting the Cellular Control of Septin Organization in a Global Cereal Killer

Rice blast disease, caused by the fungus Magnaporthe oryzae, destroys enough rice each year to feed 60 million people, and is a major threat to global food security. To establish disease, M. oryzae forms a specialized infection structure called an appressorium, which it uses to physically break into rice leaves. Essential for this process is the timely assembly of a septin ring structure at the base of the appressorium. Septins are a conserved family of GTP‐binding proteins, forming hetero‐oligomeric rods and filaments that are organized into higher‐order structures at the cell cortex. The M. oryzae septin ring scaffolds the formation of a donut‐shaped filamentous actin network, needed for the emergence of a polarized penetration structure from the base of the appressorium. Importantly, relatively little is understood about how higher‐order septin structures form in the right place and at the right time in appressoria to drive infection. We are using a proximity‐dependent proteomics to identify novel proteins involved in septin organization, and are functionally characterizing these using reverse genetics, and cell biological approach. We genetically tagged the septin protein Cdc11/Sep5 with TurboID, and identified a host of putatively proximal and interacting proteins. Here, we validate a number of these, and investigate their broader role in fungal biology. The outcomes of this research will provide fundamental new insight into the cellular control of septin organization in a global cereal killer.