Cyclopropyl Research Articles

Organophotocatalyst Enabled Deoxycyclopropanation of Alcohols.

Cyclopropane fragments, which widely exist in marketed drugs and natural products, can confer special pharmacological properties to small-molecule drugs. Therefore, developing methods to construct cyclopropanes is of great significance. Nevertheless, the introduction of cyclopropane primarily relies on already-formed cyclopropyl groups, which significantly restricts the diversity of cyclopropane skeletons. Late-stage direct cyclopropanation is still a challenging task. Herein, a photo-induced intermolecular deoxycyclopropanation reaction that employs alcohols as substrates, and 1 mol.% of 2,3,5,6-tetrakis(carbazol-9-yl)-1,4-dicyanobenzene (4CzTPN)as organophotocatalyst is reported. This method proceeds with high transformation efficiency (up to 98% yield) and exhibits broad functional group tolerance, such as primary, secondary, and tertiary alcohols as well as various activated β-halogenated alkenes. This process is mild, easy to operate, and has low equipment requirements. The power of this technology is demonstrated by the late-stage functionalization of five marketed drugs and five natural products.

Photodegradation of ciprofloxacin and its interaction with Cu(II) in different water matrices: Insight into degradation pathways

Co-contamination of ciprofloxacin (CIP) and Cu(II) is common in marine aquaculture water. However, the transmission and transformation of these substances in natural water matrices are often overlooked. This study sought to assess the impact of Cu(II) on CIP degradation in distilled (DI) and simulated (SI) mariculture water, as well as to develop a relationship between Cu(II), CIP, and its degradation products. First, complexation assays and analog computations revealed that Cu (II) forms complexes by binding to the oxygen atoms of the carbonyl (C=O) and carboxyl (COOH) groups in the CIP molecule. Second, photodegradation experiments showed that Cu(II) significantly hindered the degradation effect of CIP in DI water, while Cu(II) did not significantly hinder the degradation of CIP in SI water. Furthermore, the effect of Cu(II) on the degradation mechanism of CIP was determined by combining quenching and EPR experiments, Materials Studio software calculations, and UPLC-MS results. It was demonstrated that Cu(II) enhanced the production of singlet oxygen (1O2), hydroxyl radicals (•OH), and superoxide radicals (•O2−) in DI water. In the presence of Cu(II), CIP undergoes hydroxylation and decarbonylation reactions, forming hydroxylated and nitroxylated products. Additionally, direct defluorination and cleavage of the piperazine ring occur, followed by complexation reactions with Cu(II). However, in SI water, the production of 1O2 depends on the indirect action of Cu(II) and the excited state transformation of organic matter. Experimental evidence has shown that CIP can create intermediate compounds that include O-O peroxide rings, with or without the presence of Cu(II). When Cu(II) is present, the cyclopropyl group of the CIP molecule is more prone to transformation and so degradation. Finally, the toxicity assessment results indicated that both Cu(II) and SI water increased the toxicity of the degradation products.

Silicon Analogues of Cyclopropyl Radical Derived from a Highly Stable Cyclic Disilene Compound Featuring a Si-Br Bond.

A halogen-substituted cyclic disilene compound, bromocyclotrisilene, Si3Br(Eind)3 (3a), bearing fused-ring bulky Eind (a: R1 = R2 = Et) groups, has been synthesized as an extraordinarily air-stable compound by the reduction of 1,2-dibromodisilene, (Eind)BrSi═SiBr(Eind) (2a), or tribromosilane, (Eind)SiBr3 (1a), with the Mg or Li metal. The X-ray diffraction analysis of 3a showed that the disilene moiety has an almost planar, but slightly trans-bent structure. Even though 3a is quite air-stable both in solutions and in the solid state, its Si-Br bond is reactive under reducing conditions. The further treatment of 3a with the Li metal leads to the formation of room-temperature thermally stable silicon homologues of the cyclopropyl radical, i.e., the cyclotrisilanyl radicals (6a) [6a(syn) and 6a(anti)], via intramolecular C-H bond activation in a transient silicon homologue of the cyclopropenyl radical, i.e., the cyclotrisilenyl radical, [Si3(Eind)3]• (5a). The formation mechanism of 6a from 5a is discussed based on the theoretical calculations. The unique structural and electronic properties of these Si3 three-membered ring species incorporating the Eind groups have been experimentally and theoretically investigated.

Study on The Current Status and Progress of Clinical Application of Ciprofol

Ciprofol, as a new type of short-acting intravenous anesthetic drug, belongs to the category of gamma-aminobutyric acid (GABA) receptor agonists. Its unique chemical structure, through the introduction of the cyclopropyl group in the isopropyl side chain of propofol, constructs a new type of chiral molecule, which significantly enhances the spatial effect, and improves the affinity for GABA receptors. Its pharmacological properties are characterized by high potency, rapid onset of action, rapid recovery, low accumulation, and minimal adverse reactions. Therefore, it has a wide range of applications in various endoscopic diagnostic and therapeutic operations, ICU sedation, and general anesthesia. In this paper, the related knowledge of ciprofol and the development of clinical application research are comprehensively sorted out and synthesized, to provide a solid theoretical basis for the rational application of ciprofol in clinical practice. At the same time, the future research direction of ciprofol will also be prospected to provide valuable references for research in related fields.

Study on the Mass Spectrometry Cleavage Pattern of Quinolone Antibiotics.

Quinolone antibiotics are extensively used clinically for human treatment and in agriculture. However, improper and excessive use can lead to the persistence of quinolone residues in animal tissues, potentially accumulating in the human body and posing health risks. Investigating the correlation between mass spectrometry cleavage patterns and molecular structural features enhances the analytical framework for detecting trace or unknown impurities in quinolones. To collect data, we employed triple quadrupole linear ion trap mass spectrometry in electrospray positive ion mode. Primary mass spectrometry scanning was utilized to confirm parent ions, while secondary mass spectrometry scanning enabled the observation of fragment ions. The cleavage characteristics and pathways of the compounds were inferred from accurate mass-to-charge ratios obtained from both primary and secondary mass spectrometry. Under soft ionization conditions, the compounds generally exhibited characteristic fragment ions of [M+H-H2O]+, [M+H-CO]+, and [M+H-H2O-CO]+. Additionally, subtle variations were observed in each compound due to differences in modifying groups. For instance, upon deacidification, the piperazine ring structure underwent breakage and rearrangement, yielding fragment ion peaks devoid of neutral molecules such as C2H5N, C3H7N, or C4H8N. Notably, compounds featuring a cyclopropyl substituent group at the N-1 position typically exhibited characteristic fragments resulting from the loss of the cyclopropyl radical (⋅C3H5). Moreover, substituents at the N-1 and C-8 positions, when linked to form a six-membered carbocyclic ring, were prone to cleavage, releasing the neutral C3H6 molecule. Quinolone antibiotics share structural similarities in their parent nuclei, leading to partially similar cleavage pathways. Nevertheless, distinct cleavage patterns emerge due to variations in functional groups. According to the difference of mass spectrometry cleavage patterns, it can provide an identification basis for the measured detection of antibiotics.

Anticancer activity of 4α-(cyclopropyl formylpiperazinyl)-4-deoxypodophyllotoxin and its mechanism of action

Podophyllotoxin (PPT) is a naturally occurring lignan extracted from the rhizomes of the Podophyllum plant. It exhibits toxicity towards a broad spectrum of cancer cells and can induce cell death by inhibiting the polymerization of microtubule proteins. In our pursuit of more potent anticancer drug candidates, 4α-(cyclopropyl formylpiperazinyl)-4-deoxypodophyllotoxin (GHGT-17) was successfully synthesized by introducing a piperazine group, formyl group, and cyclopropyl group at the C-4 position of PPT. The activity of GHGT-17 against various types of cancer cells was evaluated using the MTT assay. It exhibited significant potency against lung cancer cells, with IC50 values of 0.080 ± 0.020 μM (A549) and 0.086 ± 0.004 μM (H460), without obvious toxicity towards lung epithelial cells 16HBE (IC50 > 100 μM). Further investigations demonstrated that GHGT-17 induced morphological changes in A549 and H460 cells, inhibited proliferation in a time- and dose-dependent manner. Furthermore, GHGT-17 inhibited the formation of cell colonies in a dose-dependent manner. It was found to inhibit cell migration, arrest the cell cycle in the G2/M phase, induce nuclear wrinkling, decrease mitochondrial membrane potential, and inhibit microtubule protein polymerization. These effects ultimately contribute to the induction of endogenous apoptosis. In silico studies, ADMET analysis revealed that GHGT-17 exhibited a satisfactory bioavailability with good water solubility, easy absorption, and well-proportioned distribution in the body. Molecular docking was performed to predict the binding mode and interactions of GHGT-17 with tubulin protein (1SA0). Additionally, GHGT-17 was submitted to molecular dynamics simulation and RMSD, RMSF, Rg, hydrogen bonding was analyzed. The complex showed a rather low binding free energy (−36.37 kJ mol−1) and thus exhibited a superior binding affinity towards to tubulin protein. In summary, the combined results indicated that GHGT-17 exhibits promise as a prospective potential novel drug candidate worthy of further investigation for its potential application in lung cancer therapy.

Immunomodulatory Effects of Fluoroquinolones in Community-Acquired Pneumonia-Associated Acute Respiratory Distress Syndrome.

Community-acquired pneumonia is reported as one of the infectious diseases that leads to the development of acute respiratory distress syndrome. The innate immune system is the first line of defence against microbial invasion; however, its dysregulation during infection, resulting in an increased pathogen load, stimulates the over-secretion of chemokines and pro-inflammatory cytokines. This phenomenon causes damage to the epithelial-endothelial barrier of the pulmonary alveoli and the leakage of the intravascular protein into the alveolar lumen. Fluoroquinolones are synthetic antimicrobial agents with immunomodulatory properties that can inhibit bacterial proliferation as well as exhibit anti-inflammatory activities. It has been demonstrated that the structure of fluoroquinolones, particularly those with a cyclopropyl group, exerts immunomodulatory effects. Its capability to inhibit phosphodiesterase activity leads to the accumulation of intracellular cAMP, which subsequently enhances PKA activity, resulting in the inhibition of transcriptional factor NF-κB and the activation of CREB. Another mechanism reported is the inhibition of TLR and ERK signalling pathways. Although the sequence of events has not been completely understood, significant progress has been made in comprehending the specific mechanisms underlying the immunomodulatory effects of fluoroquinolones. Here, we review the indirect immunomodulatory effects of FQs as an alternative to empirical therapy in patients diagnosed with community-acquired pneumonia.

Effects of solution chemistry on dielectric barrier atmospheric non-thermal plasma for operative degradation of antiretroviral drug nevirapine

The global prevalence of human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) has been an environmental menace. Tons of drug wastes from antiretroviral therapy are released into the environment annually. We, for the first time, employed the novel dielectric barrier atmospheric non-thermal plasma (DBANP) discharge, to mitigate the inadvertent pollution arising from the antiretroviral therapy. A 40-min treatment of nevirapine achieved >94 % (0.075 min−1) removal efficiency at discharge power of 63.5 W and plasma working gas of atmospheric air. Chemical probes confirmed •OH, ONOO− and eaq− as the dominant reactive species whilst further revealing the reaction acceleration role of NaNO3 and CCl4 which are known reaction terminators. The commonly coexisting inorganic anions potentiated nevirapine removal with over 98 % efficiency, achieving the highest rate constant of 0.148 min−1 in this study. Moreover, the initial solution pH (1.5–11.1) was no limiting factor either. The insensitivity of the DBANP discharge to actual water matrices was an eminent inference of its potential applicability in practical conditions. With reference to data obtained from the liquid chromatography-mass spectrometer analysis, nevirapine degradation pathway was proposed. A nucleophilic attack by ONOO− at the cyclopropyl group and •OH attack at the carbonyl carbon of the amide group, respectively, initiated nevirapine degradation process. It is anticipated that the findings herein, will provide new insights into antiretroviral drug waste management in environmental waters using the innovative and green non-thermal plasma process.

Activity-Based Protein Profiling Identifies Protein Disulfide-Isomerases as Target Proteins of the Volatile Salinilactones.

The salinilactones, volatile marine natural products secreted from Salinispora arenicola, feature a unique [3.1.0]-lactone ring system and cytotoxic activities through a hitherto unknown mechanism. To find their molecular target, an activity-based protein profiling with a salinilactone-derived probe is applied that disclosed the protein disulfide-isomerases (PDIs) as the dominant mammalian targets of salinilactones, and thioredoxin (TRX1) as secondary target. The inhibition of protein disulfide-isomerase A1 (PDIA1) and TRX1 is confirmed by biochemical assays with recombinant proteins, showing that (1S,5R)-salinilactone B is more potent than its (1R,5S)-configured enantiomer. The salinilactones bound covalently to C53 and C397, the catalytically active cysteines of the isoform PDIA1 according to tandem mass spectrometry. Reactions with a model substrate demonstrated that the cyclopropyl group is opened by an attack of the thiol at C6. Fluorophore labeling experiments showed the cell permeability of a salinilactone-BODIPY (dipyrrometheneboron difluoride) conjugate and its co-localization with PDIs in the endoplasmic reticulum. The study is one of the first to pinpoint a molecular target for a volatile microbial natural product, and it demonstrates that salinilactones can achieve high selectivity despite their small size and intrinsic reactivity.

Structural, Biochemical, and Bioinformatic Basis for Identifying Radical SAM Cyclopropyl Synthases.

The importance of radical S-adenosyl-l-methionine (RS) enzymes in the maturation of ribosomally synthesized and post-translationally modified peptides (RiPPs) continues to expand, specifically for the RS-SPASM subfamily. We recently discovered an RS-SPASM enzyme that installs a carbon-carbon bond between the geminal methyls of valine residues, resulting in the formation of cyclopropylglycine (CPG). Here, we sought to define the family of cyclopropyl (CP) synthases because of the importance of cyclopropane scaffolds in pharmaceutical development. Using RadicalSAM.org, we bioinformatically expanded the family of CP synthases and assigned unique peptide sequences to each subclade. We identified a unique RiPP biosynthetic pathway that encodes a precursor peptide, TigB, with a repeating TIGSVS motif. Using LCMS and NMR techniques, we show that the RS enzyme associated with the pathway, TigE, catalyzes the formation of a methyl-CPG from the conserved isoleucine residing in the repeating motif of TigB. Furthermore, we obtained a crystal structure of TigE, which reveals an unusual tyrosyl ligation to the auxiliary I [4Fe-4S] cluster, provided by a glycine-tyrosine-tryptophan motif unique to all CP synthases. Further, we show that this unique tyrosyl ligation is absolutely required for TigE activity. Together, our results provide insight into how CP synthases perform this unique reaction.

Incorporating reduced axis system embedding into ab initio tunnelling-rotation Hamiltonians with curvilinear vibrational Møller–Plesset perturbation theory

Large-amplitude vibrational motion influences the rovibrational structure of molecules that tunnel between multiple wells. Reaction path (RP) Hamiltonians, and curvilinear coordinates more generally, are useful for modelling pure vibrational motion in these systems and provide a practical framework for calculating accurate ab initio anharmonic vibrational energies and tunnelling splittings with perturbation theory. These computational tools also offer the means to address rotation-vibration coupling associated with large-amplitude motion in rotating molecules. In this paper, we incorporate the reduced axis system (RAS) frame embedding with RP Hamiltonians and second-order vibrational Møller-Plesset perturbation theory (VMP2). Because the RP-RAS Hamiltonian eliminates rotation-vibration momentum coupling everywhere along a one-dimensional reaction path, it is well suited for rovibrational VMP2 methods, the convergence of which relies critically on approximate vibration-vibration and vibration-rotation separability. The accuracy of this combined RP-RAS-VMP2 scheme is demonstrated by comparisons with numerically exact variational calculations and VMP2 parameters based on traditional Eckart embeddings for reduced-dimension models of torsional tunnelling in hydrogen peroxide and inversion tunnelling in cyclopropyl radical. The favourable computational scaling of VMP2 makes it a promising strategy for calculating accurate tunnelling-rotation parameters for medium-sized and larger molecules in full dimensionality.

Enantio- and Diastereodivergent Cyclopropanation of Allenes by Directed Evolution of an Iridium-Containing Cytochrome.

Alkylidene cyclopropanes (ACPs) are valuable synthetic intermediates because of their constrained structure and opportunities for further diversification. Although routes to ACPs are known, preparations of ACPs with control of both the configuration of the cyclopropyl (R vs S) group and the geometry of the alkene (E vs Z) are unknown. We describe enzymatic cyclopropanation of allenes with ethyl diazoacetate (EDA) catalyzed by an iridium-containing cytochrome (Ir(Me)-CYP119) that controls both stereochemical elements. Two mutants of Ir(Me)-CYP119 identified by 6-codon (6c, VILAFG) saturation mutagenesis catalyze the formation of (E)-ACPs with -93% to >99% ee and >99:1 E/Z ratio with just three rounds of 96 mutants. By four additional rounds of mutagenesis, an enzyme variant was identified that forms (Z)-ACPs with up to 94% ee and a 28:72 E/Z ratio. Computational studies show that the orientation of the carbene unit dictated by the mutated positions accounts for the stereoselectivity.

Combining total synthesis and genetic engineering to probe dihydropyran formation in ambruticin biosynthesis.

The ambruticins are a family of potent antifungal polyketide derived natural products isolated from the myxobacterium Sorangium cellulosum. Their unusual structures include a trisubstituted cyclopropyl group and two oxygen heterocycles, a tetrahydropyran (THP) and dihydropyran (DHP). Herein we report a flexible modular approach for the total synthesis of ambruticins which is used to prepare ambruticins F and S as well as in the first total synthesis of 20,21-dihydroambruticin F. The flexible strategy unites 3 fragments via Julia-Kocienski olefinations and provides important standards for investigation of dihydropyran formation in ambruticin biosynthesis. Cultures of wild-type S. cellulosum So ce10 produce mainly ambruticin S and the VS series of metabolites. An efficient electroporation method enabled gene knockout experiments which revealed that the ΔambP-S mutant of S. cellulosum accumulated the bisTHP polyketide 20,21-dihydroambruticin F. In contrast, the ΔambN-S mutant gave ambruticin F with the 20,21-alkene as the major metabolite confirming that AmbP and AmbO (a Rieske enzyme and flavin-dependent monooxygenase respectively) are implicated in 20,21-alkene formation. The results of feeding studies to a Sorangium strain containing only ambP and ambO are in accord with formation of the 20,21-alkene occurring prior to generation of the C3 to C7 dihydroxylated tetrahydropyran in ambruticin biosynthesis.

Vitamin B12‐Photocatalyzed Cyclopropanation of Electron‐Deficient Alkenes Using Dichloromethane as the Methylene Source**

AbstractThe cyclopropyl group is of great importance in medicinal chemistry, as it can be leveraged to influence a range of pharmaceutical properties in drug molecules. This report describes a Vitamin B12‐photocatalyzed approach for the cyclopropanation of electron‐deficient alkenes using dichloromethane (CH2Cl2) as the methylene source. The reaction proceeds in good to excellent yields under mild conditions, has excellent functional group compatibility, and is highly chemoselective. The scope could also be extended to the preparation of D2‐cyclopropyl and methyl‐substituted cyclopropyl adducts starting from CD2Cl2 and 1,1‐dichloroethane, respectively.

Vitamin B12 -Photocatalyzed Cyclopropanation of Electron-Deficient Alkenes Using Dichloromethane as the Methylene Source.

The cyclopropyl group is of great importance in medicinal chemistry, as it can be leveraged to influence a range of pharmaceutical properties in drug molecules. This report describes a Vitamin B12 -photocatalyzed approach for the cyclopropanation of electron-deficient alkenes using dichloromethane (CH2 Cl2 ) as the methylene source. The reaction proceeds in good to excellent yields under mild conditions, has excellent functional group compatibility, and is highly chemoselective. The scope could also be extended to the preparation of D2 -cyclopropyl and methyl-substituted cyclopropyl adducts starting from CD2 Cl2 and 1,1-dichloroethane, respectively.

Activation of peroxymonosulfate for ciprofloxacin degradation by a novel oxygen-deficient CoTiO3/TiO2NTs/Ti composite catalytic membrane:Electron transfer pathway and underlying mechanism

The technique of activating peroxymonosulfate (PMS) by enriching oxygen vacancies (Vo) in heterogeneous catalysts has gained extensive attentions in the removal of emerging contaminants, e.g., antibiotics from wastewater. In this study, a Vo-CoTiO3/TiO2NTs/Ti (Vo-CTNs) catalytic membrane with rich oxygen vacancies was prepared and employed for the activation of PMS in degrading ciprofloxacin (CIP) in a continuous flow reactor. The averaged degradation efficiency of CIP in the Vo-CTNs/PMS system could reach 97.3 %, significantly higher than that in the CoTiO3/TiO2NTs/Ti (CTNs) system (91.1 %). Quenching experiments and electron paramagnetic resonance analysis collectively confirmed the presence of •OH, SO4•−, O2•− and 1O2 during the CIP degradation process. The results of the electrochemical experiments demonstrated that in the presence of oxygen vacancies, the mutual conversion between Co2+ and Co3+ was facilitated, resulting in a lower transfer resistance. At an initial CIP concentration of 10 mg/L and a membrane flux of 600 LMH, the degradation efficiency and mineralization rate of CIP could reach 95.2 % and 51.1 % after 12 h of operation, respectively. Meanwhile, limited leaching of cobalt ions (52 μg/L) from the catalytic membrane was observed during treatment. Theoretical calculations revealed that Vo engineering can modulate the surface electronic states, thereby enhancing binding energy and electron transfer for PMS activation. The degradation of CIP is mainly achieved through the ring opening reactions in the piperazine, quinolone, and cyclopropyl groups attacked by reactive oxygen species. In this work, we built cobalt-based composite nanomaterials to promote effective electron transfer and minimize leaching of cobalt ions, and providing a new method for activating PMS in a continuous flow system by enriching the oxygen vacancies in the catalytic membrane. This method has potentials to be applied in treating wastewater containing antibiotics such as CIP.

Radical and Cationic Pathways in C(sp3)-H Bond Oxygenation by Dioxiranes of Bicyclic and Spirocyclic Hydrocarbons Bearing Cyclopropane Moieties.

A product and DFT computational study on the reactions of 3-ethyl-3-(trifluoromethyl)dioxirane (ETFDO) with bicyclic and spirocyclic hydrocarbons bearing cyclopropyl groups was carried out. With bicyclo[n.1.0]alkanes (n = 3-6), diastereoselective formation of the alcohol product derived from C2-H bond hydroxylation was observed, accompanied by smaller amounts of products derived from oxygenation at other sites. With 1-methylbicyclo[4.1.0]heptane, rearranged products were also observed in addition to the unrearranged products deriving from oxygenation at the most activated C2-H and C5-H bonds. With spiro[2.5]octane and 6-tert-butylspiro[2.5]octane, reaction with ETFDO occurred predominantly or exclusively at the axial C4-H to give unrearranged oxygenation products, accompanied by smaller amounts of rearranged bicyclo[4.2.0]octan-1-ols. The good to outstanding site-selectivities and diastereoselectivities are paralleled by the calculated activation free energies for the corresponding reaction pathways. Computations show that the σ* orbitals of the bicyclo[n.1.0]alkane cis or trans C2-H bonds and spiro[2.5]octanes axial C4-H bond hyperconjugatively interact with the Walsh orbitals of the cyclopropane ring, activating these bonds toward HAT to ETFDO. The detection of rearranged oxygenation products in the oxidation of 1-methylbicyclo[4.1.0]heptane, spiro[2.5]octane, and 6-tert-butylspiro[2.5]octane provides unambiguous evidence for the involvement of cationic intermediates in these reactions, representing the first examples on the operation of ET pathways in dioxirane-mediated C(sp3)-H bond oxygenations. Computations support these findings, showing that formation of cationic intermediates is associated with specific stabilizing hyperconjugative interactions between the incipient carbon radical and the cyclopropane C-C bonding orbitals that trigger ET to the incipient dioxirane derived 1,1,1-trifluoro-2-hydroxy-2-butoxyl radical.

C(sp3)–H Functionalization Enabled by Hydrogen Atom Transfer with Tertiary Cyclopropyl Radicals

C(sp3)–H Functionalization Enabled by Hydrogen Atom Transfer with Tertiary Cyclopropyl Radicals

Rh-Catalyzed [4 + 1] Reaction of Cyclopropyl-Capped Dienes (but not Common Dienes) and Carbon Monoxide: Reaction Development and Mechanistic Study.

Transition-metal-catalyzed [4 + 1] reaction of dienes and carbon monoxide (CO) is the most straightforward and easily envisioned cyclization for the synthesis of five-membered carbocycles, which are ubiquitously found in natural products and functional molecules. Unfortunately, no test of this reaction was reported, and consequently, chemists do not know whether such kind of reaction works or not. Herein, we report that the [4 + 1] reaction of common dienes and CO cannot work, at least under the catalysis of [Rh(cod)Cl]2. However, using cyclopropyl-capped dienes (also named allylidenecyclopropanes) as substrates, the corresponding [4 + 1] reaction with CO proceeds smoothly in the presence of [Rh(cod)Cl]2. This [4 + 1] reaction, with a broad scope, provides efficient access to five-membered carbocyclic compounds of spiro[2.4]hept-6-en-4-ones. The [4 + 1] cycloadducts can be further transformed into other molecules by using the unique chemistry of cyclopropyl groups present in these molecules. The mechanism of this [4 + 1] reaction has been investigated by quantum chemical calculations, uncovering that cyclopropyl-capped dienes are strained dienes and the oxidative cyclization step in the [4 + 1] catalytic cycle can release this (angular) strain both kinetically and thermodynamically. The strain release in this step then propagates to all followed CO coordination/CO insertion/reductive elimination steps in the [4 + 1] catalytic cycle, helping the realization of this cycloaddition reaction. In contrast, common dienes (including cyclobutyl-capped dienes) do not have such advantages and their [4 + 1] reaction suffers from energy penalty in all steps involved in the [4 + 1] catalytic cycle. The reactivity of ene-allenes for the [4 + 1] reaction with CO is also discussed.

Fe-Catalyzed Regioselective C(sp3)–H-Abstraction by Tertiary Cyclopropyl Radicals

Tertiary carbon radicals are usually more stable than secondary carbon radicals, and the hydrogen atom transfer (HAT) from secondary C(sp3)–H bonds to tertiary carbon radicals is normally considered to be a thermodynamically disfavored pathway. Herein, we disclose an unusual protocol involving a C(sp3)–H functionalization enabled by a tertiary cyclopropyl radical and proceeding through hydrogen abstraction from a variety of secondary and tertiary aliphatic C(sp3)–H bonds. The reaction can furnish valuable, densely functionalized cyclopropane derivatives. Sufficient mechanistic experiments and density functional theory (DFT) calculations have provided theoretical insights into the chemo- and regioselectivity in this underexplored HAT protocol. The method features broad functional group compatibility and high product diversity and offers a new prospect for radical C(sp3)–H functionalization.