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Comprehensive Summary: Discovery of unprecedented donor‐acceptor patterns can essentially enrich the chemistry of donor‐acceptor cyclopropanes. We herein introduce a concept of vinylogous fluorine stabilizing effect, which guides rational design of a novel donor‐acceptor cyclopropane employing gem‐difluorovinyl group as the electron donor, namely dFVCP. Application of such dFVCPs in a [3+2] cycloaddition with aldehydes and a controlled ring‐opening polymerization by a Mg(OTf)2/DIPEA/C(sp3)‐H initiator system have been demonstrated, providing direct access to fluorine‐containing tetrahydrofurans and all‐carbon main‐chain polymers. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Discovery of unprecedented donor‐acceptor patterns can essentially enrich the chemistry of donor‐acceptor cyclopropanes. We herein introduce a concept of vinylogous fluorine stabilizing effect, which guides rational design of a novel donor‐acceptor cyclopropane employing gem‐difluorovinyl group as the electron donor, namely dFVCP. Application of such dFVCPs in a [3+2] cycloaddition with aldehydes and a controlled ring‐opening polymerization by a Mg(OTf)2/DIPEA/C(sp3)‐H initiator system have been demonstrated, providing direct access to fluorine‐containing tetrahydrofurans and all‐carbon main‐chain polymers. [ABSTRACT FROM AUTHOR]

C(sp3)‐rich heterocycles are privileged building blocks for pharmaceuticals and agrochemicals. Therefore, synthetic methods that provide access to novel saturated nitrogen‐containing heterocycles are in high demand. Herein, we report a general synthesis of 1‐azabicyclo[2.1.1]hexanes (1‐aza‐BCH) via a formal cycloaddition of azabicyclo[1.1.0]butanes (ABB) with styrenes under photochemical conditions. To overcome the challenging direct single electron reduction of ABBs, we designed a polar‐radical‐polar relay strategy that leverages a fast acid‐mediated ring‐opening of ABBs to form bromoazetidines, which undergo efficient debrominative radical formation to initiate the cycloaddition reaction. The reaction is applicable to a broad range of ABB‐ketones and we demonstrate the 1‐aza‐BCH products can be further functionalized to access larger saturated, conformationally rigid heterocycles. [ABSTRACT FROM AUTHOR]

Comprehensive Summary Conjugate addition and allylic substitution are two essential chemical transformations, and they could be competitive for substrates with multiple reactive sites. Herein, we report the diversified enantioselective synthesis of cyclobutenes via the functionalization of cyclobutenones. The conjugate addition of cyclobutenones with arylzinc halides provided enantioenriched cyclobutenes with all‐carbon quaternary centers. On the other hand, when cyclobutenones with gem‐dichloro groups were employed, a chemo‐ and enantioselective allylic substitution occurred. Further synthetic utility was demonstrated for synthesizing versatile cyclobutane derivatives, together with ring‐opening and expansion products. [ABSTRACT FROM AUTHOR]

The incorporation of cationic groups onto electron‐poor compounds is a viable strategy for achieving potent electron acceptors, as evidenced by reports of air‐stable radical forms of large aromatic diimides such as naphthalene and perylene diimides. These ions have also been observed to exhibit anion–π interaction tendencies of interest in molecular recognition applications. The benefits of phosphonium incorporation, however, have not yet been extended to the smallest benzene diimides. Here, we report that dibrominated pyromellitic diimide and mellophanic diimide both readily undergo substitution reactions with phosphine sources to yield bisphosphonium compounds. In the single crystalline form, these dications display anion‐π interactions and, in the case of mellophanic diimide, the stabilization of a bromide–water H−bonding ring pattern. The reaction of these dications with chemical reductants readily provides the singly and doubly reduced redox states, which were characterized by UV‐vis spectroscopy and found to exhibit intense absorptions extending into the near‐IR region. Taken together, this work demonstrates that phosphonium incorporation onto congested aromatic diimide scaffolds is synthetically viable and produces unusual electron‐poor compounds. [ABSTRACT FROM AUTHOR]

Bridged cyclobutanes and sulfur heterocycles are currently under intense investigation as building blocks for pharmaceutical drug design. Two formal cycloaddition modes involving bicyclobutanes (BCBs) and pyridinium 1,4‐zwitterionic thiolate derivatives were described to rapidly expand the chemical space of sulfur‐containing bridged cyclobutanes. By using Ni(ClO4)2 as the catalyst, an uncommon higher‐order (5+3) cycloaddition of BCBs with quinolinium 1,4‐zwitterionic thiolate was achieved with broad substrate scope under mild reaction conditions. Furthermore, the first Lewis acid‐catalyzed asymmetric polar (5+3) cycloaddition of BCB with pyridazinium 1,4‐zwitterionic thiolate was accomplished. In contrast, pyridinium 1,4‐zwitterionic thiolates undergo an Sc(OTf)3‐catalyzed formal (3+3) reaction with BCBs to generate thia‐norpinene products, which represent the initial instance of synthesizing 2‐thiabicyclo[3.1.1]heptanes (thia‐BCHeps) from BCBs. Moreover, we have successfully used this (3+3) protocol to rapidly prepare thia‐BCHeps‐substituted analogues of the bioactive molecule Pitofenone. Density functional theory (DFT) computations imply that kinetic factors govern the (5+3) cycloaddition reaction between BCB and quinolinium 1,4‐zwitterionic thiolate, whereas the (3+3) reaction involving pyridinium 1,4‐zwitterionic thiolates is under thermodynamic control. [ABSTRACT FROM AUTHOR]

Capitalizing the inherent strain energy within molecules, strain‐release‐driven reactions have been widely employed in organic synthesis. Small cycloalkanes like cyclopropanes and cyclobutanes, with their moderate ring strain, typically require dense functionalization to induce bias or distal activation of (hetero) aromatic rings via single‐electron oxidation for relieving the tension. In this study, we present a pioneering direct activation of alkyl cyclopropanes/butanes through electrochemical oxidation. This approach not only showcases the potential for ring‐opening of cyclopropane/butane under electrochemical conditions but also streamlines the synthesis of diverse oxazolines and oxazines. The applicability of our method is exemplified by its broad substrate scopes. Notably, the products derived from cyclobutanes undergo a formal ring contraction to cyclopropanes, introducing an intriguing aspect to our discoveries. These discoveries mark a significant advancement in strain‐release‐driven skeletal rearrangement reactions of moderately strained rings, offering sustainable and efficient synthetic pathways for future endeavours. [ABSTRACT FROM AUTHOR]

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 % 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. [ABSTRACT FROM AUTHOR]

The present work reports synthesis, characterization and theoretical insights on novel hydroxymethyl‐bishomocubanone derivatives. Twelve new bishomocubanes (BHCs) were synthesized and fully characterized by various spectroscopic techniques and single crystal X‐ray analysis. The densities of the title compounds were in the range of 1.30–1.59 g/cm3. Density‐functional theory (DFT) based calculations at B3LYP/6‐311++G(d,p) level of theory were performed on ten selected BHC based cage compounds. Propulsive and ballistic properties of newly synthesized hydroxymethyl‐bishomocubanone derivatives in solid and liquid propulsion systems were calculated, and the results suggested that these compounds are superior to conventional fuel RP1 and binder HTPB. The detonation parameters revealed that these compounds are not explosive in nature and safe to use as solid propellants. Furthermore, kinetic and thermal stabilities of the title compounds were determined by HOMO‐LUMO energy gap, ESP maps, impact sensitivity (h50) and bond dissociation energies (BDEs) followed by thermogravimetric analysis (TGA) and differential thermal analysis (DTA). Three compounds, a dinitroazide (Isp,vac=310.98 s), a dinitrate (Isp,vac=309.51 s), and a dinitronitrate (Isp,vac=309.20s) were found to be excellent candidates for volume limited applications. [ABSTRACT FROM AUTHOR]

The intramolecular coupling of dichloro‐substituted helically fused anthracenes using the Yamamoto coupling yielded cyclized products with sterically congested molecular structures. The X‐ray analysis and DFT calculations showed that the aromatic framework adopted a nonplanar structure with a twisted conformation about the newly formed single bond, which acts as a chiral axis. Interestingly, the X‐ray structure obtained through the Hirshfeld atom refinement revealed short interatomic distances between the inner hydrogen atoms (1.648–1.692 Å), much shorter than the sum of their van der Waals radii. Owing to these unusually short contacts, the 1H NMR spectrum exhibited a significant deshielding (12.5 ppm) and a large nuclear Overhauser effect (44 %). Additionally, the IR spectrum displayed a high‐frequency shift of the C−H stretching vibration. These observations, along with the noncovalent interaction plot indicative of a characteristic steric environment, strongly support the presence of steric hindrance. Moreover, dynamic NMR measurement of the mesityl‐substituted derivative yielded a barrier to helical inversion of 84 kJ mol−1. The optical properties and crystal packing of the cyclized products are also reported. [ABSTRACT FROM AUTHOR]

The exploration of the complex chemical diversity of bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over the past two decades. Regiodivergent syntheses of thiabicyclo[4.1.1]octanes (S‐BCOs) and highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid‐catalyzed formal cycloaddition of bicyclobutanes (BCBs) and 3‐benzylideneindoline‐2‐thione derivatives have been established. The first hetero‐(4+3) cycloaddition of BCBs, catalyzed by Zn(OTf)2, was achieved with a broad substrate scope under mild conditions. In contrast, the less electrophilic BCB ester undergoes a Sc(OTf)3‐catalyzed [2π+2σ] reaction with 1,1,2‐trisubstituted alkenes, yielding BCHs with a spirocyclic quaternary carbon center. Control experiments and preliminary theoretical calculations suggest that the diastereoselective [2π+2σ] product formation may involve a concerted cycloaddition between a zwitterionic intermediate and E‐1,1,2‐trisubstituted alkenes. Additionally, the hetero‐(4+3) cycloaddition may involve a concerted nucleophilic ring‐opening mechanism. [ABSTRACT FROM AUTHOR]

Cyclic anthraquinodimethane (AQD) dimer with a highly constrained structure was synthesized by using the Au-templated method. X-ray diffraction analysis and UV-Vis spectroscopy revealed that the AQD skeleton adopts a deeply folded structure and exhibits red-shifted absorptions in the dimer compared to those in noncyclized monomeric AQD. Due to the rigid and constrained structure, both enantiomers of the cyclic AQD dimer with planar chirality can be isolated and show strong circular dichroism signals. It is demonstrated that the Au-templated method is a valuable way to access a highly constrained cyclic structure with AQD skeletons. [ABSTRACT FROM AUTHOR]

Cyclobutanes with a gem‐dimethyl group are common motifs in natural products. However, strategies for constructing enantioenriched gem‐dimethyl cyclobutanes are still underdeveloped. Herein, we report an enantioselective approach to synthesize a broad group of chiral 2,3‐disubstituted cyclobutanones through sequential 1,4‐conjugate addition/trapping/cross‐coupling of readily available cyclobutenones. The intermediate 2‐bromocyclobutanone provides a valuable synthetic handle for further coupling transformations. In addition, this strategy was successfully utilized to synthesize gem‐dimethyl cyclobutane‐containing natural products, including (+)‐β‐caryophyllene, (−)‐raikovenal, (−)‐1β,9αH‐5‐linoleoyloxy‐4,5‐secocaryophyllen‐4‐one, and (−)‐rumphellanones A−C. [ABSTRACT FROM AUTHOR]

Herein, we have synthesized multifunctionalized 2‐oxa‐3‐azabicyclo[3.1.1]heptanes, which are considered potential bioisosteres for meta‐substituted arenes, through Eu(OTf)3‐catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes with nitrones. This methodology represents the initial instance of fabricating bicyclo[3.1.1]heptanes adorned with multiple heteroatoms. The protocol exhibits both mild reaction conditions and a good tolerance for various functional groups. Computational density functional theory calculations support that the reaction mechanism likely involves a nucleophilic addition of nitrones to bicyclo[1.1.0]butanes, succeeded by an intramolecular cyclization. The synthetic utility of this novel protocol has been demonstrated in the concise synthesis of the analogue of Rupatadine. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Stereoselective synthesis of multi‐substituted cyclobutanes with different substituents is still a daunting challenge in organic synthesis. We report here a practical and facile approach to synthesizing all‐trans 2,3,4‐trisubstituted cyclobutanones from readily available dichlorocyclobutanones. The substitution reaction proceeds smoothly via oxyallyl cation intermediates under mild basic conditions. Further transformation to the synthesis of 1,2,3,4‐tetrasubstituted cyclobutanes was also explored. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Stereoselective synthesis of multi‐substituted cyclobutanes with different substituents is still a daunting challenge in organic synthesis. We report here a practical and facile approach to synthesizing all‐trans 2,3,4‐trisubstituted cyclobutanones from readily available dichlorocyclobutanones. The substitution reaction proceeds smoothly via oxyallyl cation intermediates under mild basic conditions. Further transformation to the synthesis of 1,2,3,4‐tetrasubstituted cyclobutanes was also explored. [ABSTRACT FROM AUTHOR]

We leveraged the recent increase in synthetic accessibility of SF5 Cl and Ar-SF4 Cl compounds to combine chemistry of the SF5 and SF4 Ar groups with strain-release functionalization. By effectively adding SF5 and SF4 Ar radicals across [1.1.1]propellane, we accessed structurally unique bicyclopentanes, bearing two distinct elements of bioisosterism. Upon evaluating these "hybrid isostere" motifs in the solid state, we measured exceptionally short transannular distances; in one case, the distance rivals the shortest nonbonding C⋅⋅⋅C contact reported to date. This prompted SC-XRD and DFT analyses that support the notion that a donor-acceptor interaction involving the "wing" C-C bonds is playing an important role in stabilization. Thus, these heretofore unknown structures expand the palette for highly coveted three-dimensional fluorinated building blocks and provide insight to a more general effect observed in bicyclopentanes.

Isoxeniolide A is a highly strained xenicane diterpenoid of marine origin. This natural product is representative for a subfamily of xenicanes incorporating an allylic hydroxy group in the nine‐membered ring; members of this xenicane subfamily so far have not been targeted by total synthesis. Herein, we describe the first asymmetric total synthesis of isoxeniolide A. Key to forming the challenging E‐configured cyclononene ring was a diastereoselective intramolecular Nozaki–Hiyama–Kishi reaction. Other important transformations include an enzymatic desymmetrization for absolute stereocontrol, a diastereoselective cuprate addition and the use of a bifunctional vinyl silane building block. Our strategy also permits access to the enantiomer of the natural product and holds potential to access a multitude of xenicane natural products and analogs for structure–activity relationship studies. [ABSTRACT FROM AUTHOR]

Bicyclo[1.1.1]pentane (BCP) derivatives have attracted significant recent interest in drug discovery as alkyne, tert‐butyl and arene bioisosteres, where their incorporation is frequently associated with increased compound solubility and metabolic stability. While strategies for functionalisation of the bridgehead (1,3) positions are extensively developed, platforms allowing divergent substitution at the bridge (2,4,5) positions remain limited. Recent reports have introduced 1‐electron strategies for arylation and incorporation of a small range of other substituents, but are limited in terms of scope, yields or practical complexity. Herein, we show the synthesis of diverse 1,2,3‐trifunctionalised BCPs through lithium‐halogen exchange of a readily accessible BCP bromide. When coupled with medicinally relevant product derivatisations, our developed 2‐electron "late stage" approach provides rapid and straightforward access to unprecedented BCP structural diversity (>20 hitherto‐unknown motifs reported). Additionally, we describe a method for the synthesis of enantioenriched "chiral‐at‐BCP" bicyclo[1.1.1]pentanes through a novel stereoselective bridgehead desymmetrisation. [ABSTRACT FROM AUTHOR]

Cycloparaphenylenes (CPPs) are the smallest possible armchair carbon nanotubes, the properties of which strongly depend on their ring size. They can be further tuned by either peripheral functionalization or by replacing phenylene rings for other aromatic units. Here we show how four novel donor–acceptor chromophores were obtained by incorporating fluorenone or 2‐(9H‐fluoren‐9‐ylidene)malononitrile into the loops of two differently sized CPPs. Synthetically, we managed to perform late‐stage functionalization of the fluorenone‐based rings by high‐yielding Knoevenagel condensations. The structures were confirmed by X‐ray crystallographic analyses, which revealed that replacing a phenylene for a fused‐ring‐system acceptor introduces additional strain. The donor–acceptor characters of the CPPs were supported by absorption and fluorescence spectroscopic studies, electrochemical studies (displaying the CPPs as multi‐redox systems undergoing reversible or quasi‐reversible redox events), as well as by computations. The oligophenylene parts were found to comprise the electron donor units of the macrocycles and the fluorenone parts the acceptor units. [ABSTRACT FROM AUTHOR]

Homocubane, a highly strained cage hydrocarbon, contains two very different positions for the introduction of a nitrogen atom into the skeleton, e. g. a position 1 exchange results in a tertiary amine whereas position 9 yields a secondary amine. Herein reported is the synthesis of 9‐azahomocubane along with associated structural characterization, physical property analysis and chemical reactivity. Not only is 9‐azahomocubane readily synthesized, and found to be stable as predicted, the basicity of the secondary amine was observed to be significantly lower than the structurally related azabicyclo[2.2.1]heptane, although similar to 1‐azahomocubane. [ABSTRACT FROM AUTHOR]

Bicyclo[2.1.1]hexanes (BCHs) are becoming ever more important in drug design and development as bridged scaffolds that provide underexplored chemical space, but are difficult to access. Here a silver‐catalyzed dearomative [2π+2σ] cycloaddition strategy for the synthesis of indoline fused BCHs from N‐unprotected indoles and bicyclobutane precursors is described. The strain‐release dearomative cycloaddition operates under mild conditions, tolerating a wide range of functional groups. It is capable of forming BCHs with up to four contiguous quaternary carbon centers, achieving yields of up to 99 %. In addition, a scale‐up experiment and the synthetic transformations of the cycloadducts further highlighted the synthetic utility. [ABSTRACT FROM AUTHOR]

A carbon–carbon (C–C) single bond longer than 1.7 Å shows unique bond flexibility, even though a C–C single bond is typically rigid and robust. We report here that the bond length of flexible C–C single bonds surrounded by bulky alkyl groups in novel hexaphenylethane-type hydrocarbons might be affected by weak noncovalent interactions, such as London dispersion. Thanks to London dispersion, an ultralong and flexible C–C single bond exhibits an obvious bond contraction. X-ray analyses and Raman spectroscopy provided direct information regarding the bond length and strength, whereas density functional theory calculations explained the bond contraction driven by London dispersion. The change in bond length of an extremely elongated flexible C–C bond would be a good probe for quantifying weak interactions that are usually difficult to detect. [ABSTRACT FROM AUTHOR]

The synthesis of structurally complex and highly strained natural products provides unique challenges and unexpected opportunities for the development of new reactions and strategies. Herein, the synthesis of (+)-[5]-ladderanoic acid is reported. En route to the target, unusual and unexpected strain release driven transformations were uncovered. This occurrence required a drastic revision of the synthetic design that ultimately led to the development of a novel stepwise cyclobutane assembly by an allylboration/Zweifel olefination sequence.

The use of metalated (aza)bicyclo[1.1.0]butanes in synthesis is currently experiencing a renaissance, as evidenced by the numerous reports in the last 5 years that have relied on such intermediates to undergo unique transformations or generate novel fragments. Since their discovery, these species have been demonstrated to participate in a wide range of reactions with carbon and heteroatom electrophiles, as well as metal complexes, to facilitate the rapid diversification of (aza)bicyclo[1.1.0]butane-containing compounds. Key to this is the relative acidity of the bridgehead C--H bonds which promotes facile deprotonation and subsequent functionalization of an unsubstituted position on the carbon framework via the intermediacy of a metalated (aza)bicyclo[1.1.0]butane. Additionally, the late-stage incorporation of deuterium atoms in strained fragments has led to the elucidation of numerous reaction mechanisms that involve strained bicycles. The continued investigation into the inimitable reactivity of metalated bicycles will cement their importance within the field of organometallic chemistry. [ABSTRACT FROM AUTHOR]

A set of four planar‐chiral sila[1]ferrocenophanes equipped with a benzyl group in the α‐position, either on one or both Cp rings, and substituted on the bridging silicon atom, either by methyl or phenyl groups, were prepared. While NMR, UV/Vis, and DSC measurements did not show anything uncommon, single crystal X‐ray analyses revealed unexpectedly large variations of the dihedral angles between both Cp rings (α tilt angle). While DFT calculations predicted α between 19.6 and 20.8°, measured values were found between 16.6(2) and 21.45(14)°. However, experimentally determined conformers differ significantly from those calculated for the gas phase. For the sila[1]ferrocenophane with the largest mismatch between the experimental and predicted α angle, it was shown that the orientation of benzyl groups have a significant influence on the ring‐tilted structure. Packing of molecules in the crystal lattice forces benzyl groups into unusual orientations, resulting in a significantly reduced α angle through steric repulsions. [ABSTRACT FROM AUTHOR]

Embedding seven‐membered rings into polycyclic aromatic molecules is attractive as they can exert an influence on molecular conformation that ultimately changes the solubility and π‐electronics. The considerations in designing and synthesizing a highly strained azatriseptane framework are discussed herein. We employ a twofold macrocyclization strategy to form the [7,7,7]‐system and through scoping various strategies identify that the Friedel–Crafts approach is the key. In addition to the successes presented here, the synthetic limitations we have identified highlight the key challenges in forming triseptane frameworks and pave the way for second‐generation analogues that may have various applications in optical and electronic organic materials. [ABSTRACT FROM AUTHOR]

From an (R)‐(+)‐pulegone‐derived building block that incorporates the stereo‐defined tertiary carbon bearing a methyl group, as found in the targeted sesquiterpenoid, a four‐step synthesis of (−)‐4‐epi‐presilphiperfolan‐8‐α‐ol was achieved. The key processes involved are a ring‐closing metathesis leading to a bridged alkene‐tethered ketone and its subsequent FeIII‐mediated metal‐hydride atom transfer (MHAT) transannular cyclization. This synthetic method, implying an irreversible addition of a carbon‐centered radical upon a ketone by means of a hydrogen atom transfer upon the alkoxy radical intermediate, was also applied in the synthesis of trans‐fused hydrindanols structurally related to botrydial compounds. [ABSTRACT FROM AUTHOR]

This publication promotes the increased necessity for strain management in topochemical reactions with an enlarged structural extension of the molecular products formed, i. e., when going from small molecule dimerizations, through linear polymerizations to the formation of 2D polymers. Further, it promotes to combine the trap model for photon absorption with concrete molecular scale consequences of this absorption on topochemical transformations and briefly discusses the expected consequences topological dimensionality of the forming (macro)molecular products has on trap location. The time appears ripe for going in this direction because local information concerning structural changes within single crystals is now accessible by the 3D‐ΔPDF method. This method greatly facilitates the analysis of diffuse X‐ray scattering providing access to concrete values of pair distribution functions and, thus, factual information on which and how distances change near a reaction site. Although only based on a first case where distance changes could be quantified in a lateral polymerization, the thoughts put forward may ignite more research towards a full understanding of all the action that occurs when a photochemically triggered topochemical reaction takes place. The 3D‐ΔPDF method is so attractive for this purpose because it provides otherwise inaccessible local information in pair correlation functions rather than average structure information, which is used through the ubiquitous Bragg scattering. [ABSTRACT FROM AUTHOR]

Cyclobutenones provide a straightforward four‐carbon ring platform for further structural elaborations in that every carbon atom of the ring could be potentially functionalized. We report here a nickel catalyzed enantioconvergent Negishi coupling of 4‐iodocyclobutenones with an array of aryl or alkenyl zinc reagents to access enantioenriched 4‐substituted cyclobutenones, from which a modular approach to the synthesis of 1,2,3,4‐tetrasubstituted cyclobutanes was demonstrated. [ABSTRACT FROM AUTHOR]

The development of preparative methods for the synthesis of four‐membered carbocycles is gaining increasing importance due to the widespread utility of cyclic compounds in medicinal chemistry. Herein, we report the development of a new methodology for the production of spirocyclic epoxides and aziridines containing a cyclobutane motif. In a two‐step one‐pot process, a bicyclo[1.1.0]butyl sulfoxide is lithiated and added to a ketone, aldehyde or imine, and the resulting intermediate is cross‐coupled with an aryl triflate through C−C σ‐bond alkoxy‐ or aminopalladation with concomitant epoxide or aziridine formation. After careful optimization, a remarkably efficient reaction was conceived that tolerated a broad variety of both aromatic and aliphatic substrates. Lastly, through several high yielding ring‐opening reactions, we demonstrated the excellent applicability of the products as modular building blocks for the introduction of three‐dimensional structures into target molecules. [ABSTRACT FROM AUTHOR]

Sulfonylated aromatics are commonplace motifs in drugs and agrochemicals. However, methods for the direct synthesis of sulfonylated non‐classical arene bioisosteres, which could improve the physicochemical properties of drug and agrochemical candidates, are limited. Here we report a solution to this challenge: a one‐pot halosulfonylation of [1.1.1]propellane, [3.1.1]propellane and bicyclo[1.1.0]butanes that proceeds under practical, scalable and mild conditions. The sulfonyl halides used in this chemistry feature aryl, heteroaryl and alkyl substituents, and are conveniently generated in situ from readily available sulfinate salts and halogen atom sources. This methodology enables the synthesis of an array of pharmaceutically and agrochemically relevant halogen/sulfonyl‐substituted bioisosteres and cyclobutanes, on up to multidecagram scale. [ABSTRACT FROM AUTHOR]

Mono‐alkene‐inserted [n]cycloparaphenylenes 1 [(ene)‐[n]CPP] with n=6, 8, and 10, mono‐ortho‐phenylene‐inserted [6]CPP 2, and di‐alkene‐insertved [n]CPP 3 [(ene)2‐[n]CPP] with n=4, 6, and 8 were synthesized by fusing CPP precursors and alkene or ortho‐ phenylene groups through coupling reactions. Single‐crystal X‐ray diffraction analyses reveal that the strips formed by the π‐surfaces of 1 and 2 exhibited a Möbius topology in the solid state. While the Möbius topology in the parent 1 and 2 in solution was lost due to the free rotation of the paraphenylene unit even at low temperatures, ene‐[6]CPP 4 with eight 1‐pyrrolyl groups preserved the Möbius topology even in solution. Despite a twist, 1 has in‐plane conjugation and possesses a unique size dependence of the electronic properties: namely, the opposite size dependency of the HOMO–LUMO energy relative to conventional π‐conjugated molecules. [ABSTRACT FROM AUTHOR]

Despite the favorable properties that azetidine rings can engender on drug‐compounds, methods for the diversity‐oriented synthesis of azetidine‐based structures are significantly underdeveloped. Herein, we report the successful realization of a multicomponent [1,2]‐Brook rearrangement/strain‐release‐driven anion relay sequence and its application to the modular synthesis of substituted azetidines. The rapidity of the reaction, as confirmed by in situ infra‐red spectroscopy, leverages the strain‐release ring‐opening of azabicyclo[1.1.0]butane to drive the equilibrium of the Brook rearrangement. The three electrophilic coupling partners, added sequentially to azabicyclo[1.1.0]butyl‐lithium, could be individually varied to access a diverse compound library. The utility of this methodology was demonstrated in a 4‐step synthesis of the EP2 receptor antagonist PF‐04418948. [ABSTRACT FROM AUTHOR]

Quantum mechanical tunneling has long been recognized as an important phenomenon when considering transformations dominated by a lightweight hydrogen atom. Tunneling of heavier atoms like carbon, initially dismissed as negligible, has seen a quickly increasing number of computationally predicted and/or experimentally confirmed examples over the last decade, thus highlighting its importance for a wide variety of reactions. However, no common structural motif has been pointed out within these seemingly unconnected examples, strongly limiting the predictability of the impact of heavy‐atom tunneling on a given reaction. This Concept article will provide this perspective and showcase how the recognition of the formation and cleavage of three‐membered rings as common motif can inform the prediction of and research into heavy‐atom tunneling reactions. [ABSTRACT FROM AUTHOR]

We have designed and synthesized photochromic tetrathienyl corannulene compounds, 1,2,7,8‐tetrakis(2‐methyl‐5‐phenylthiophen‐3‐yl)corannulene (1) and 1,2,7,8‐tetrakis(2,4‐dimethyl‐5‐phenylthiophen‐3‐yl)corannulene (2), by fusing two units of photochromic terarylene with a curved aromatic corannulene with a promising antenna effect. Compound 1 exhibited highly sensitive photoreactivity, with a large molar absorption coefficient of 8.2×104 M−1 cm−1 and practically photon‐quantitative photocyclization. On the other hand, a terarylene derivative with a planar aromatic phenanthrene, 9,10‐bis(2,4‐dimethyl‐5‐phenylthiophen‐3‐yl)phenanthrene (4) showed no photoreactivity. The reason for such a difference was attributed to the predominance of the photoreactive atropisomers amplified by energy migration, and the shortened distance between reactive carbons induced by the curved structure. [ABSTRACT FROM AUTHOR]

[1.1][n]Paracyclophanes ([1.1][n]PCPs) (3) with n = 2, 3, and 4, which consist of two [n]paraphenylene units connected by methylene bridges, were synthesized using short synthetic pathways with good overall yields. Single-crystal X-ray diffraction analyses reveal that the paraphenylene unit in 3 is bent, resulting in an elliptic core structure of 3. The facing bridgehead carbons of the paraphenylene units are separated by a distance much shorter than the sum of the van der Waals radii of sp2-carbon atoms. UV-vis absorption spectra, fluorescence spectra, electrochemical measurements, and theoretical calculations were used to demonstrate the presence of through-space (TS) conjugation in 3. Furthermore, host-guest complex formation between 3D (n = 3) and tetracyanoquinodimethane in the solid state was revealed., (© 2024 Wiley‐VCH GmbH.)

In artificial small‐molecule machines, molecular motors can be used to perform work on coupled systems by applying a mechanical load—such as strain—that allows for energy transduction. Here, we report how ring strain influences the rotation of a rotary molecular motor. Bridging the two halves of the motor with alkyl tethers of varying sizes yields macrocycles that constrain the motor's movement. Increasing the ring size by two methylene increments increases the mobility of the motor stepwise and allows for fine‐tuning of strain in the system. Small macrocycles (8–14 methylene units) only undergo a photochemical E/Z isomerization. Larger macrocycles (16–22 methylene units) can perform a full rotational cycle, but thermal helix inversion is strongly dependent on the ring size. This study provides systematic and quantitative insight into the behavior of molecular motors under a mechanical load, paving the way for the development of complex coupled nanomachinery. [ABSTRACT FROM AUTHOR]

Comprehensive Summary: Cyclobutane derivatives have been recognized as useful structural motifs in organic synthesis and drug design. With the revival of photochemistry, the enantioselective synthesis of cyclobutane derivatives using [2 + 2]‐cycloadditions has garnered numerous attentions. On the other hand, enantioselective functionalization of preformed four‐membered carbocycles is emerging as an important complementary approach to access chiral cyclobutane derivatives with versatile structural patterns. Herein, we summarize recent advances in this field from 2012. To avoid undesired C—C bond cleavage driven by strain‐releasing, it is crucial to choose compatible methods for enantioselective functionalization and meanwhile preserving intact four‐membered ring skeleton. Guided by calculated hydrogenation enthalpies, which are used to evaluate the strain energy of indicated C—C bond, a clear picture of the developed methodologies on functionalization of four‐membered carbocycles combining the strain energy and enhanced reactivity is presented. [ABSTRACT FROM AUTHOR]

The introduction of linear alkoxy chains into bianthrone promoted the aggregation of the minor twisted conformer and made it compete with the major folded conformer in the solid‐state. Rapid evaporation approach to the methoxy‐ and n‐butoxy‐substituted derivatives provided powder mixtures of folded and twisted conformers as metastable solids. Upon heating the powders, different lengths of alkyl chains converged to different conformers via solid‐state isomerization reaction with an apparent color change. Monitoring by FT‐IR spectroscopy and powder XRD ensured that these isomerization reactions involve only conformational isomerization without pyrolysis. In addition, single crystal X‐ray structure analysis revealed that twisted conformers with longer alkyl chains are stabilized in the solid‐state by the synergistic effect of their inter‐chain hydrophobic interactions and π‐π stacking interactions. [ABSTRACT FROM AUTHOR]

Although 1,2σ5λ5-oxaphosphetanes have been known for a long time, the "low-coordinate" 1,2σ3λ3-oxaphosphetanes have only been known since their first synthesis in 2018 via decomplexation. Apart from ligation of this P-heterocycle to gold(I)chloride and the oxidation using ortho-chloranil, nothing on their chemistry has been reported so far. Herein, we describe the synthesis of new 1,2σ3λ3-oxaphosphetane complexes (3a–e) and free derivatives (4a–e), as well as reactions of 4a with chalcogens and/or chalcogen transfer reagents, which yielded the P-chalcogenides (14–16a; Ch = O, S, Se). We also report on the theoretical results of the reaction pathways of C-phenyl-substituted 1,2 σ3λ3-oxaphosphetanes and ring strain energies of 1,2σ4λ5-oxaphosphetane P-chalcogenides. [ABSTRACT FROM AUTHOR]

The recent discovery of calix[3]pyrrole, a porphyrinogen‐like tripyrrolic macrocycle, has provided an unprecedented strain‐induced ring expansion reaction into calix[6]pyrrole. Here, we synthesized calix[n]furan[3‐n]pyrrole (n=1∼3) macrocycles to investigate the reaction scope and mechanism of the ring expansion. Single crystal X‐ray analysis and theoretical calculations revealed that macrocyclic ring strain increases as the number of inner NH sites increases. While calix[1]furan[2]pyrrole exhibited almost quantitative conversion into calix[2]furan[4]pyrrole within 5 minutes, less‐strained calix[2]furan[1]pyrrole and calix[3]furan were inert. However, N‐methylation of calix[2]furan[1]pyrrole induced a ring‐expansion reaction that enabled the isolation of a linear reaction intermediate. The mechanism analysis revealed that the ring expansion consists of regioselective ring cleavage and subsequent cyclodimerization. This reaction was further utilized for synthesis of calix[6]‐type macrocycles. [ABSTRACT FROM AUTHOR]

In the current study, a series of stabilized bis‐acetylene incorporated 4‐hydroxybenzaldehyde based macrocycles using the alkyne‐homocoupling approach were synthesized in moderate yields. A total of six newly stiff macrocycles were synthesized in a stepwise manner starting from 4‐hydroxybenzaldehyde. In the first step, base mediated propargylation was performed followed by copper mediated terminal alkyne homocoupling. The alkyne homocoupled substrate having carbonyl at both the terminals is cyclized in the final step via double imine formation reactions using substituted diamines as linker. All the newly synthesized rigid framework of the macrocycles were optimized at B3LYP/6‐31G (d,p) level of theory. Nonlinear optical behaviors of the synthesized macrocycles were explored by the DFT calculations where high values of first‐order hyperpolarizability and dipole moment were examined. In the reported study, a good agreement between experimental and theoretical parameters was observed that may play a significant contribution for the NLO applications. [ABSTRACT FROM AUTHOR]

The identification of spiro N‐heterocycles as scaffolds that display structural novelty, three‐dimensionality, beneficial physicochemical properties, and enable the controlled spatial disposition of substituents has led to a surge of interest in utilizing these compounds in drug discovery programs. Herein, we report the strain‐release‐driven Friedel–Crafts spirocyclization of azabicyclo[1.1.0]butane‐tethered (hetero)aryls for the synthesis of a unique library of azetidine spiro‐tetralins. The reaction was discovered to proceed through an unexpected interrupted Friedel–Crafts mechanism, generating a highly complex azabicyclo[2.1.1]hexane scaffold. This dearomatized intermediate, formed exclusively as a single diastereomer, can be subsequently converted to the Friedel–Crafts product upon electrophilic activation of the tertiary amine, or trapped as a Diels–Alder adduct in one‐pot. The rapid assembly of molecular complexity demonstrated in these reactions highlights the potential of the strain‐release‐driven spirocyclization strategy to be utilized in the synthesis of medicinally relevant scaffolds. [ABSTRACT FROM AUTHOR]

This Correspondence argues against the use of the adjectives "symmetrical" and "asymmetric" in the recent publication entitled "Fluorenylidene‐Cyclopentadithiophene Based Asymmetric Bistricyclic Aromatic Ene Compounds: Synthesis and Substituents Effects", by Beibei Xiao, Yongrui Yang, Shengnan Chen, Ye Zou, Xing Chen, Kanglei Liu, Nan Wang, Yali Qiao, and Xiaodong Yin (Chem. Eur. J., 2023, 29, e202301055).[1] [ABSTRACT FROM AUTHOR]

Cyclopropanes embedded in a polycyclic bridged architecture are a versatile structural motif, but such complex frameworks often impose substantial synthetic challenges. Herein we introduce a new approach for the expedient access to such spring‐loaded strained systems via an exceptionally mild intermolecular convergent process between the readily available isobenzopyryliums and vinyl boronic acids. Different from the typical conventional approaches, our protocol does not involve the highly active carbenoid intermediates or strong conditions in order to overcome the disfavored kinetic and thermodynamic problems. Instead, the key cyclopropane ring was formed between the well‐positioned nucleophile and electrophile in the adduct from the regioselective [4+2] cycloaddition. Thus, this unusual process also represents a new reactivity of the versatile isobenzopyryliums. The choice of a Brønsted acid catalyst with proper acidity is crucial to the high efficiency and selectivity for this multiple bond‐forming process. The strained products are precursors to other useful synthetic building blocks. [ABSTRACT FROM AUTHOR]

Main observation and conclusion: An efficient method for the activation of C‐terminal 4‐mecaptoproline‐ or penicillamine‐containing peptide hydrazides in ligation reactions is reported herein. The corresponding peptide hydrazides can be readily prepared using solid‐phase peptide synthesis, and subsequently activated by acetylacetone (acac) without exogenous thiol additives. Strained peptidyl thiolactones could be the possible reactive intermediates that drastically accelerate the reaction rates at the sterically demanding proline and valine sites. This developed protocol allows for sequential peptide ligations in a one‐pot manner, and expedites the assembly of mucin 1 (MUC‐1) variable number tandem repeat (VNTR) trimers in various glycosylated forms. [ABSTRACT FROM AUTHOR]

Main observation and conclusion: An efficient method for the activation of C‐terminal 4‐mecaptoproline‐ or penicillamine‐containing peptide hydrazides in ligation reactions is reported herein. The corresponding peptide hydrazides can be readily prepared using solid‐phase peptide synthesis, and subsequently activated by acetylacetone (acac) without exogenous thiol additives. Strained peptidyl thiolactones could be the possible reactive intermediates that drastically accelerate the reaction rates at the sterically demanding proline and valine sites. This developed protocol allows for sequential peptide ligations in a one‐pot manner, and expedites the assembly of mucin 1 (MUC‐1) variable number tandem repeat (VNTR) trimers in various glycosylated forms. [ABSTRACT FROM AUTHOR]

Herein, we report the precise synthesis of a 3D highly strained all‐phenylene bismacrocycle, termed conjoined (1,4)[10]cycloparaphenylenophane (SCPP[10]). This structure consists of a twisted benzene ring which is bridged twice by phenylene units anchored in two para‐positions. The conjoined structure of SCPP[10] was confirmed in real space at the atomic scale by scanning tunneling microscopy. Theoretical calculations indicate that this bismacrocycle has a very high strain energy of 110.59 kcal mol−1 and the largest interphenylene torsion angle of 46.07° caused by multiple repulsive interactions. Furthermore, a 1:2 host–guest complex of SCPP[10] and [6,6]‐phenyl‐C61‐butyric acid methyl ester was investigated, which represents the first peanut‐shaped 1:2 host–guest complex based on bismacrocycles. [ABSTRACT FROM AUTHOR]

1,6‐Anhydrosugars provide a valuable source of building blocks for the synthesis of a wide range of compounds of interest, from natural products to medicines. The unique reactivity of these functionalized, homochiral synthons is controlled by the 1,6‐anhydro bridge which locks the conformation of the pyranose ring, provides a dual protection of two hydroxyl groups, and either protects or activates the anomeric position. The concomitant release of the primary hydroxyl group at C‐6 during the ring‐opening step limits protecting group manipulations and enables the design of highly convergent synthetic strategies. In recent years, many examples of stereocontrolled ring‐opening of 1,6‐anhydrosugars by a diversity of nucleophiles, including hetero‐ and C‐nucleophiles, have been reported. The purpose of this review is to present an overview of the recent advances, applications and challenges associated with this process. [ABSTRACT FROM AUTHOR]