Ring Expansion Strategy Research Articles

Total Synthesis Analysis of Pseuboyenes D

In this work, we propose a total synthesis route for the antifungal agent Pseuboyenes D, a compound derived from Pseudallescheria boydii CS-793. Pseuboyenes D exhibits antifungal activity comparable to Amphotericin B while offering the advantage of a simpler structure, making it a promising candidate for clinical applications. The system became the focus of this analysis due to its regioselectivity, and after exploration, a [2+2] photocycloaddition and ring expansion strategy was adopted to construct the key bridged ring system. The route employs readily available substrates and mild reaction conditions, making it scalable and suitable for large-scale production. Computational analysis of the regioselectivity of the photocycloaddition revealed that the bridged adduct was thermodynamically favored over the fused system. The synthetic route was further diversified by incorporating functional group modifications using TMS derivatives, enhancing the potential for pharmacological applications. Overall, this work establishes an efficient and scalable synthetic pathway for Pseuboyenes D, paving the way for future applications in antifungal drug development.

Ring expansion strategy to access functionalized 2-oxazolines (microreview)

Ring expansion strategy to access functionalized 2-oxazolines (microreview)

Expanding the scope of the successive ring expansion strategy for macrocycle and medium-sized ring synthesis: unreactive and reactive lactams.

New methods are described that expand the scope of the Successive Ring Expansion (SuRE) with respect to synthetically challenging lactams. A protocol has been developed for use with 'unreactive' lactams, enabling SuRE reactions to be performed on subsrates that fail under previously established conditions. Ring expansion is also demonstarted on 'reactive' lactams derived from iminosugars for the first time. The new SuRE methods were used to prepare a diverse array of medium-sized and macrocyclic lactams and lactones, which were evaluted in an anti-bacterial assay against E. coli BW25113WT.

Synthesis of Curved Polycyclic Arenes Embedded with Oxepine and Thiepine Using Ring Expansion Strategy.

A tandem oxidative ring expansion of a six- to seven-membered ring was developed to construct a new class of negatively curved polycyclic arenes embedded with oxepine and thiepine, namely, dibenzo[b,f]phenanthro[9,10-d]oxepine (DBPO) and dibenzo[b,f]phenanthro[9,10-d]thiepine (DBPT), respectively. Mechanistic studies disclosed that an unexpected [4 + 2] cycloadduct formed between the alkene moiety of o-biphenyl-linked methylenexanthenes and o-chloranil serves as a radical cation or a dication equivalent that facilitates the FeCl3-mediated tandem ring expansion process.

Iron-Catalyzed Alkoxyl Radical-Induced C-C Bond Cleavage/gem-Difluoroalkylation Cascade.

An inexpensive iron-catalyzed alkoxyl radical-induced C-C bond cleavage/gem-difluoroalkylation cascade is presented. Regulated by the structure of alkoxyl radical precursors, fluorinated distal diketones were synthesized through a ring-opening strategy and difluoroalkylated medium-sized lactones and macrolactones were constructed via a ring-expansion strategy. Both protocols proceeded under mild and redox neutral conditions with a broad substrate scope and good functional group compatibility.

Facile Synthesis of Nitrogen‐Doped Nanographenes with Joined Nonhexagons via a Ring Expansion Strategy

AbstractSynthetic methodology is considered a holy grail in both organic chemistry and materials science. Over the past few decades, researchers have explored graphene‐type molecules (or nanographenes) through classic Scholl oxidative cyclodehydrogenation. Despite the successes achieved with various nanographenes, the development of new methods to synthesize these highly desired molecules lags behind. Herein, we developed a facile and effective method to produce a series of nanographenes bearing nitrogen (N)‐doped pentagon‐heptagon pairs in acceptable yields. Modification of the heptagonal ring endowed the resultant nanographenes with tunable physicochemical properties; for instance, M9 exhibited both aggregation‐caused quenching and aggregation‐induced emission behavior. Most strikingly, novel nanographenes containing N‐doped pentagon‐octagon pairs were also obtained using the same synthetic strategy, demonstrating the superior versatility and efficiency of the proposed ring expansion method.

Facile Synthesis of Nitrogen-Doped Nanographenes with Joined Nonhexagons via a Ring Expansion Strategy.

Synthetic methodology is considered a holy grail in both organic chemistry and materials science. Over the past few decades, researchers have explored graphene-type molecules (or nanographenes) through classic Scholl oxidative cyclodehydrogenation. Despite the successes achieved with various nanographenes, the development of new methods to synthesize these highly desired molecules lags behind. Herein, we developed a facile and effective method to produce a series of nanographenes bearing nitrogen (N)-doped pentagon-heptagon pairs in acceptable yields. Modification of the heptagonal ring endowed the resultant nanographenes with tunable physicochemical properties; for instance, M9 exhibited both aggregation-caused quenching and aggregation-induced emission behavior. Most strikingly, novel nanographenes containing N-doped pentagon-octagon pairs were also obtained using the same synthetic strategy, demonstrating the superior versatility and efficiency of the proposed ring expansion method.

Scaffold Remodelling of Diazaspirotricycles Enables Synthesis of Diverse sp3 -Rich Compounds With Distinct Phenotypic Effects.

A 'top down' scaffold remodelling approach to library synthesis was applied to spirotricyclic ureas prepared by a complexity-generating oxidative dearomatisation. Eighteen structurally-distinct, sp3 -rich scaffolds were accessed from the parent tricycle through ring addition, cleavage and expansion strategies. Biological screening of a small compound library based on these scaffolds using the cell-painting assay demonstrated distinctive phenotypic responses engendered by different library members, illustrating the functional as well as structural diversity of the compounds.

Ring Expansion Strategies for the Synthesis of Medium Sized Ring and Macrocyclic Sulfonamides

AbstractTwo new ring expansion strategies are reported for the synthesis of medium sized ring and macrocyclic sulfonamides. Both methods can be performed without using classical protecting groups, with the key ring expansion step initiated by nitro reduction and amine conjugate addition respectively. Each method can be used to make diversely functionalised cyclic sulfonamides in good to excellent yields, in a range of ring sizes. The ring size dependency of the synthetic reactions is in good agreement with the outcomes modelled by Density Functional Theory calculations.

Ring Expansion Strategies for the Synthesis of Medium Sized Ring and Macrocyclic Sulfonamides.

Two new ring expansion strategies are reported for the synthesis of medium sized ring and macrocyclic sulfonamides. Both methods can be performed without using classical protecting groups, with the key ring expansion step initiated by nitro reduction and amine conjugate addition respectively. Each method can be used to make diversely functionalised cyclic sulfonamides in good to excellent yields, in a range of ring sizes. The ring size dependency of the synthetic reactions is in good agreement with the outcomes modelled by Density Functional Theory calculations.

CuBr-mediated synthesis of 1,4-naphthoquinones via ring expansion of 2-aryl-1,3-indandiones.

A CuBr-mediated direct insertion of alkenes into unstrained ring 2-aryl-1,3-indandiones is reported, which provides a one-carbon ring expansion strategy for the synthesis of 1,4-naphthoquinones. Entirely differing from the existing reports, the alkenes herein behave as C1 units to participate in annulation reactions. This transformation provides a facile route to access a class of highly functionalized 1,4-naphthoquinones with good yields, good functional-group tolerance and high atom-economy. Further research on the application of this reaction is currently underway in our laboratory.

Double Ring Expansion Strategy for Fused 3-Benzazepines: Alternative Synthesis of the Dolby-Weinreb Enamine.

A double ring expansion strategy for constructing fused 3-benzazepines is described. The oxidative ring expansion of spiroamine compounds with N-chlorosuccinimide and subsequent ring expansion of the resulting ketiminium ion intermediates with trimethylsilyldiazomethane afforded fused 3-benzazepines in a one-pot operation. Importantly, the Dolby-Weinreb enamine, which is a key synthetic intermediate for harringtonine alkaloids, cephalotaxines, can be accessed from commercial materials in only two steps using our developed method.

A Consecutive Ring-Expansion Strategy towards the Macrocyclic Core of the Solomonamide Natural Products

AbstractA synthetic strategy based on the application of three consecutive ring-expansion reactions has been used in the synthesis of analogues of the macrocyclic core of the solomonamide natural products. Starting from a simple, readily available tetrahydrocarbazole, oxidative ring expansion is followed by two further 3- and 4-atom ring-expansion reactions, enabling the insertion of amino acid and hydroxy acid derived linear fragments into 15- to 17-membered-ring-enlarged macrocyclic products.

The Dowd-Beckwith Reaction: History, Strategies, and Synthetic Potential.

Ring-expansion strategies are valuable synthetic tools that take benefit of existing ring structures and evade the unfavorable enthalpic-and entropic effects that arise with end-to-end cyclizations. One potentially important class of such reactions is the Dowd-Beckwith reaction, the ring-expansion of ketones via alkoxy radicals. The exciting advancement in this research area is starting to show its potential, as demonstrated by applying this methodology in strategy-level bond formation to synthesize complex natural products. This Review aims to provide the first comprehensive survey of the development of the Dowd-Beckwith reaction spanning three decades from the initial report to the present day, thus providing the readers with great detail about the contributions of this reaction to organic synthesis. We hope that this review will further disclose the salient features of the Dowd-Beckwith reaction for synthetic applications and encourage the development of new, more advanced applications.

Rhodium-Catalyzed (4+1) Cycloaddition between Benzocyclobutenones and Styrene-Type Alkenes.

Herein, we describe a unique one-carbon ring-expansion strategy to access multi-substituted 2-indanones from benzocyclobutenones and styrene-type olefins. The use of a cationic "ligandless" rhodium catalyst was the key for both high reactivity and selectivity towards the (4+1) product. Broad functional group tolerance, a good substrate scope, and scalability have been demonstrated. Computation studies reveal that the origin of the (4+1) selectivity is due to a facile β-H elimination pathway that reduces the overall barrier of the turnover-limiting C-C reductive elimination step.

Rhodium-Catalyzed Ring Expansion of Azetidines via Domino Conjugate Addition/N-Directed α-C(sp3)–H Activation

A facile synthetic method for 4-aryl-4,5-dihydropyrrole-3-carboxylates is developed, with a rhodium-catalyzed ring expansion strategy from readily available 2-(azetidin-3-ylidene) acetates and aryl boronic acids. Mechanistic investigations suggest a novel domino "conjugate addition/N-directed α-C(sp3)-H activation" process. The asymmetric catalytic synthesis of the 4-aryl-4,5-dihydropyrrole-3-carboxylate is realized by using QuinoxP* (91-97% ee). The synthetic utility of this protocol is demonstrated by the synthesis of 3,4-disubstituted or 2,3,4-trisubstituted pyrrolidines with excellent diastereoselectivities.

Discovery of Novel Triazolothiadiazines as Fungicidal Leads Targeting Pyruvate Kinase

Pyruvate kinase (PK) was discovered as a potent new target for novel fungicide development. A series of novel triazolothiadiazine derivatives were rationally designed and synthesized by a ring expansion strategy and computer-aided pesticide design using the 3D structure of Rhizoctonia solani PK (RsPK) obtained by homology modeling as a receptor and our previously discovered lead YZK-C22 as a ligand. The in vitro bioassay results indicated that compounds 4g, 6h, 6m, 6n, 6o, and 6p exhibited good activity against R. solani with the EC50 values falling between 10.99 and 72.76 μM. Especially, 6m showed similar potency to YZK-C22 (10.99 vs 11.97 μM of the EC50 value, respectively). The in vivo bioassay results suggested that 6m against R. solani at a concentration of 200 μg/mL displayed a numerically higher inhibition than YZK-C22 (70 vs 60%, respectively). A field experiment validated that 6m at an application rate of 120 g ai/ha showed comparable efficacy against R. solani to thifluzamide at an application rate of 80 g ai/ha (77.80 vs 84.5%, respectively). Enzymatic inhibition suggested that the potency of 6m was about twofold lower than that of YZK-C22 (67.30 vs 32.64 μM of IC50, respectively). Fluorescence quenching studies validated that RsPK was quenched by both 6m and YZK-C22, implying that they both might act at the same target site of PK. A possible binding conformation of 6m in the RsPK active site was depicted by molecular docking. Our studies suggest that 6m could be a fungicidal lead targeting PK.

Lewis-Acid-Catalyzed Tandem Cyclization by Ring Expansion of Tertiary Cycloalkanols with Propargyl Alcohols.

A new method for the efficient synthesis of hexahydro-1H-fluorene and octahydrobenzo[a]azulene derivatives through a ring-expansion strategy is reported. With an appropriate combination of thulium(III) trifluoromethanesulfonate and 13X molecular sieves, a range of unsaturated polycyclic compounds were obtained in good yields. Mechanism studies reveal that the reaction is more likely to undergo Meyer-Schuster rearrangement, ring expansion, and Friedel-Crafts-type pathways, which provide a conceptually different strategy for the ring opening of tertiary cycloalkanols.

Discovery of glyantrypine-family alkaloids as novel antiviral and antiphytopathogenic-fungus agents.

Plant diseases caused by viruses and fungi have caused great losses to crop quality and yield. The discovery of novel and efficient antiviral and antiphytopathogenic-fungus agents is urgently needed. It is the most important pesticide innovation strategy to find active compounds from natural products. Here, glyantrypine-family alkaloids were taken as the parent structures and a series of their derivatives were designed through molecular splicing, ring expansion, and ring contraction strategies, and synthesized. The anti-tobacco mosaic virus (TMV) activities and antifungal activities of these alkaloids were systematically investigated for the first time. The antiviral activities of compounds 7bb, 7bc, 11c, 18b, 18d, 28d, and 28e are equivalent to or better than that of ribavirin (inhibitory rates 39%, 37%, and 40% at 500 μg mL-1 for inactivation, curative, and protection activity in vivo, respectively). Compounds 18d and 28d with good antiviral activities were selected for antiviral mode of action studies, which indicated that these alkaloids could achieve good antiviral effects by inhibiting TMV particle extension during assembly. These compounds also exhibited broad-spectrum fungicidal activities. Glyantrypine-family alkaloids and their derivatives were synthesized and evaluated for anti-TMV and fungicidal activities for the first time. Compounds 18d and 28d with excellent antiviral activities and compound 7bc with remarkable fungicidal activity emerged as novel lead compounds. This study lays a foundation for the application of glyantrypine alkaloids in plant protection.

Some novel hybrid quinazoline-based heterocycles as potent cytotoxic agents.

Background and purpose:In this study, some new cytotoxic hybrid structures were synthesized by combining pyrazolinone and imidazolinone rings with quinazoline pharmacophores.Experimental approach:The benzoxazinone, pyrazolo-quinazoline fused ring, and imidazolinone anchored quinazoline derivatives were synthesized by simple ring-opening, ring expansion, and ring closure strategies from oxazolones. The molecular docking studies of the final derivatives were accomplished on the epidermal growth factor receptor enzyme. The cytotoxic effect of the final compounds on the MCF-7 cell line was evaluated by MTT assay.Findings/Results:The docking results confirmed the optimized electrostatic, H-bonding, and hydrophobic interactions of structures with the key residues of the active site (ΔGbin< -9Kcal/mol). The derivatives have been obtained in good yield and purity, and their structures were confirmed by different methods (FT-IR, 1H-NMR, 13C-NMR, and CHNS analysis). The IC50s of all final derivatives against the MCF-7 cell line were lower than 10 μM, and between all, the IXa from pyrazolo-quinazolinone class (IC50: 6.43 μM) with chlorine substitute was the most potent. Furthermore, all derivatives showed negligible cytotoxicity on HUVEC normal cell line which would be a great achievement for a novel cytotoxic agent.Conclusion and implications:Based on the obtained results, pyrazolo[1,5-c] quinazolin-2-one series were more cytotoxic than imidazolinone methyl quinazoline-4(3H)-ones against MCF-7 cells. Chlorine substitute in the para position of the aromatic ring improved the cytotoxicity effect in both classes. It could be related to the polarizability of a chlorine atom and making better intermolecular interactions. Further pre-clinical evaluations are required for the promising synthesized cytotoxic compounds.