Fact-checked by Grok 2 weeks ago

Cyclopropanation

Cyclopropanation is the chemical process of forming a cyclopropane ring, a three-membered carbocycle characterized by significant ring strain, typically achieved through the stereospecific addition of a carbene or metal carbenoid species to the double bond of an alkene.^[1] This reaction is a cornerstone of organic synthesis, enabling the construction of highly strained motifs that are prevalent in natural products such as terpenoids and alkaloids,^[2] as well as in pharmaceuticals including antibiotics like ciprofloxacin and antiviral agents.^[1]^[3] The unique reactivity of cyclopropanes, arising from their bond angles deviating markedly from the ideal tetrahedral geometry, makes them valuable intermediates for ring-opening transformations and the synthesis of more complex molecular architectures.^[4] The first synthesis of a cyclopropane derivative occurred in 1884 by William Henry Perkin in Adolf von Baeyer's laboratory, marking the beginning of interest in these strained systems despite early challenges in their preparation and stability.^[1] Over the subsequent decades, advancements in methodology have transformed cyclopropanation into a versatile tool, with the Simmons–Smith reaction—developed in 1958 using zinc and diiodomethane—emerging as a seminal non-catalytic method for methylene transfer to alkenes, prized for its mild conditions and stereospecificity, particularly in allylic alcohol substrates.^[5]^[6] Subsequent innovations include transition-metal-catalyzed decompositions of diazo compounds, such as copper- and rhodium-porphyrin systems, which facilitate enantioselective cyclopropanations with donor-acceptor carbenes for precise control over stereochemistry in drug synthesis. More recent developments encompass biocatalytic approaches using engineered heme proteins for sustainable, stereodivergent cyclopropanations,^[7] and photocatalytic methods with bismuth complexes for reductive variants under visible light.^[8] These strategies have been instrumental in total syntheses of bioactive compounds like saxagliptin, a DPP-4 inhibitor for diabetes treatment, and curacin A, a marine natural product with anticancer potential.^[6]

Fundamentals

Definition and Scope

Cyclopropanation is defined as the stereospecific addition of a carbene or carbenoid equivalent across a carbon-carbon double bond, resulting in the formation of a three-membered cyclopropane ring.^[9] This process typically involves singlet carbenes or their metal-associated analogs, which undergo a concerted [2+1] cycloaddition, preserving the geometric configuration of the alkene substrate.^[10] The reaction is distinct from other small-ring formations, such as epoxidation, which incorporates an oxygen atom into a three-membered heterocycle rather than an all-carbon carbocycle.^[11] The scope of cyclopropanation encompasses both intermolecular variants, where the carbene source and alkene are separate molecules, and intramolecular variants, in which a tethered carbene precursor adds to an internal double bond to form fused or bridged cyclopropane systems.^[12] These reactions are versatile in organic synthesis, enabling the construction of strained rings that serve as key motifs in natural products, pharmaceuticals, and materials, though they require careful control to manage the high reactivity of the intermediates.^[9] Historically, the foundation of cyclopropane chemistry was laid in 1881 when August Freund first synthesized cyclopropane by treating 1,3-dibromopropane with sodium metal, proposing its correct ring structure in the same report.^[13] Early developments in the late 19th century, including Sergei Reformatsky's 1887 discovery of the organozinc-mediated addition of α-halo esters to carbonyls, advanced the use of zinc carbenoids that later became central to alkene cyclopropanation methods.^[14] The general reaction can be represented as:

\ce{:CH2 + C=C ->[stereospecific] [cyclopropane](/page/Cyclopropane)}

where the stereochemistry of the alkene is retained in the product due to the syn addition mode.^[10]

Ring Strain and Reactivity

The cyclopropane ring features C-C-C bond angles of approximately 60°, significantly deviating from the ideal tetrahedral angle of 109.5° for sp³-hybridized carbon atoms. This compression forces the interorbital angles to exceed 104°, resulting in bent bonds with increased p-character in the C-C sigma bonds and correspondingly higher s-character (around 33%) in the C-H bonds. The bent geometry, often described as "banana-shaped" bonds, arises because the carbon orbitals cannot align parallel, leading to suboptimal overlap and weakened C-C bonds relative to typical alkanes. The total strain energy of cyclopropane is approximately 28 kcal/mol, primarily attributed to angle strain from the 49.5° deviation per bond angle, with a smaller torsional strain component due to the eclipsed conformation of the hydrogens. This strain energy is derived from comparisons of heats of formation and combustion with unstrained hydrocarbons like n-butane, highlighting the energetic penalty of forming the three-membered ring. Theoretical models, such as Walsh's molecular orbital diagram, illustrate how the symmetric overlap of hybrid orbitals in the plane of the ring contributes to this stability despite the distortion, with the highest occupied molecular orbital (HOMO) showing pi-like character that influences reactivity.^[15]^[16] Due to the strained bonding, cyclopropane exhibits heightened reactivity, particularly in ring-opening reactions. It undergoes facile cleavage with electrophiles, such as in acid-catalyzed additions where the bent bonds behave akin to double bonds, or with nucleophiles in donor-acceptor substituted variants that polarize the ring for selective opening. Homolytic cleavage is also prominent in radical processes, where the weak C-C bonds (bond dissociation energy ~65 kcal/mol) facilitate rearrangements like the vinylcyclopropane radical clock. Despite this, cyclopropane remains stable under inert conditions, such as in neutral hydrocarbon environments, without spontaneous decomposition.^[17]^[18] Spectroscopically, the ring strain manifests in the ¹H NMR spectrum as upfield chemical shifts for the methylene protons at 0.1-0.3 ppm, lower than typical alkane protons (0.9-1.8 ppm), due to the increased s-character in C-H bonds and the ring current effects from the strained geometry. This shielding is a diagnostic feature for cyclopropane moieties in larger molecules.

Synthetic Methods

Carbenoid Additions to Alkenes

Carbenoids are organometallic species, such as iodomethylzinc iodide (ICH₂ZnI), that function as methylene (:CH₂) equivalents in cyclopropanation reactions by delivering the carbene unit to alkenes in a controlled manner.^[19] These reagents avoid the hazards of free carbenes while maintaining reactivity for forming the three-membered ring. The Simmons–Smith reaction represents a seminal non-catalyzed carbenoid method for intermolecular cyclopropanation, developed in 1958.^[5] In this procedure, an alkene is treated with diiodomethane (CH₂I₂) and a zinc-copper couple (typically a 10:90 Cu:Zn alloy) in an inert solvent like diethyl ether, generating the carbenoid in situ at room temperature. The reaction proceeds via a concerted mechanism, inserting the methylene group across the double bond to yield the cyclopropane product and zinc(II) iodide as byproduct. The general equation is:

\text{alkene} + \text{CH}_2\text{I}_2 + \text{Zn/Cu} \rightarrow \text{cyclopropane} + \text{ZnI}_2

Early examples demonstrated its efficacy with simple alkenes, highlighting the method's utility for unfunctionalized substrates.^[5] Free carbenes for cyclopropanation can also be generated through thermal or photolytic decomposition of diazomethane (CH₂N₂), which extrudes nitrogen gas to form singlet methylene (:CH₂).^[20] The decomposition is represented as:

\text{CH}_2\text{N}_2 \xrightarrow{\Delta \text{ or } h\nu} :\text{CH}_2 + \text{N}_2

This approach, first utilized for cyclopropane synthesis in the late 19th century, adds the electrophilic carbene to the alkene in a stereospecific syn manner, preserving the alkene's geometry in the product.^[20] However, diazomethane poses significant risks due to its toxicity, mutagenicity, and potential for explosive decomposition, necessitating careful handling in dilute solutions or under controlled conditions.^[20] Both carbenoid and free carbene additions exhibit scope best suited to electron-rich alkenes, such as allyl ethers or enol ethers, where the nucleophilic π-system facilitates electrophilic attack.^[19] In substituted cases, regioselectivity favors addition to the more electron-rich double bond or the less hindered face, though electron-deficient alkenes like acrylates react sluggishly or require modified conditions.^[19] Limitations include poor compatibility with sensitive functional groups and challenges in achieving high yields with sterically hindered substrates. Later metal-catalyzed enhancements have expanded applicability to broader alkene classes.^[19]

Ylide-Based Cyclopropanation

Ylide-based cyclopropanation involves the reaction of carbanionic ylides, typically derived from phosphorus or sulfur, with electron-deficient alkenes such as α,β-unsaturated carbonyl compounds, providing a mild alternative to carbenoid methods for constructing cyclopropane rings.^[21] This approach was pioneered in the early 1960s, with Elias James Corey and Michael Chaykovsky introducing sulfur ylides for the synthesis of epoxides and cyclopropanes in 1962, marking a significant advancement in selective ring formation under non-acidic conditions.^[22]^[23] Phosphorus ylides, building on Wittig olefination chemistry, were subsequently applied to similar transformations around 1965. The mechanism proceeds via nucleophilic 1,4-addition (Michael addition) of the ylide to the β-carbon of the electron-deficient alkene, generating a zwitterionic betaine intermediate with a negatively charged α-carbon and a positively charged heteroatom (P or S).^[21] This is followed by intramolecular proton transfer from the ylide-derived methylene group to the α-position, positioning the carbanion for displacement of the phosphine or sulfide leaving group, thereby closing the three-membered ring.^[21] For example, triphenylphosphorane methylide (\ce{Ph3P=CH2}) or dimethylsulfonium methylide (\ce{(CH3)2S=CH2}) reacts with Michael acceptors like chalcones in this stepwise manner.^[23] The Corey-Chaykovsky reaction exemplifies sulfur ylide-mediated cyclopropanation, employing dimethylsulfoxonium methylide—generated in situ from trimethylsulfoxonium iodide and a base—for the conversion of α,β-unsaturated carbonyls to donor-acceptor cyclopropanes.^[22] This reagent offers superior stability and reduced propensity for side reactions compared to the dimethylsulfonium methylide variant, which exhibits higher reactivity but generates more byproducts like Michael addition adducts.^[22]^[23] A representative transformation is depicted below:

\ce{R-CH=CH-C(O)R' + (CH3)2S(O)=CH2 ->[base] R-CH-CH2-C(O)R' + (CH3)2S(O)}

(with the cyclopropane ring formed between the original alkene carbons and the ylide methylene).^[22] Phosphorus ylides, such as non-stabilized \ce{Ph3P=CH2}, follow an analogous pathway but typically require activated substrates to favor cyclopropanation over standard Wittig olefination, yielding cyclopropyl carbonyl compounds with good efficiency. These reactions often proceed in protic solvents to facilitate proton transfer in the betaine intermediate.^[21] Key advantages of ylide-based methods include excellent functional group tolerance, as the nucleophilic nature avoids interference from sensitive moieties like alcohols or amines, and preferential reactivity with electron-poor alkenes over simple ones.^[21] Stereochemically, these transformations frequently afford trans-cyclopropanes as major products due to the betaine geometry and ring closure dynamics, enabling access to enantioenriched variants with chiral auxiliaries.^[21]

Intramolecular Cyclizations

Intramolecular cyclizations represent a key strategy in cyclopropanation for constructing fused or bridged ring systems, where a carbenoid, radical, or equivalent species generated within a single molecule adds to an embedded alkene, often yielding strained bicyclic motifs like bicyclo[3.1.0]hexanes. These approaches exploit the connectivity of a tether to enforce regioselectivity and stereocontrol, making them valuable for synthesizing polycyclic frameworks in natural product analogs. Unlike intermolecular variants, intramolecular methods minimize side reactions and enable precise control over ring fusion geometry.^[24] A foundational method involves the dehalogenation of allylic gem-dihalides with zinc or magnesium to form intramolecular carbenoids that cyclize onto a pendant alkene. In this process, substrates bearing an allylic gem-dihalide moiety, such as CH₂=CH-(CH₂)ₙ-CHX₂ (where X = halogen and n ≈ 2 for optimal ring size), undergo reductive activation to generate an organozinc carbenoid, which adds across the alkene in a stereospecific manner, affording cyclopropyl derivatives fused to the chain. This zinc-copper couple-mediated reaction, first demonstrated in the 1960s, proceeds via a concerted or semi-concerted pathway, preserving alkene geometry and providing access to cis-fused systems.^[24]^[25] Focusing on cyclization precursors like homoallylic halides, these compounds serve as versatile starting points for intramolecular processes, particularly in setups mimicking the inverse divinylcyclopropane rearrangement. Dehalogenation of homoallylic halides (e.g., with zinc) generates allylic organometallics that can cyclize to divinylcyclopropane intermediates, which rearrange under thermal conditions to form the target cyclopropane-embedded structures. This strategy is effective for building [3.1.0] frameworks, with the halide position dictating the regiochemistry of closure.^[24] Radical-mediated intramolecular cyclizations offer an alternative, utilizing tributyltin hydride (Bu₃SnH) and azobisisobutyronitrile (AIBN) to initiate 3-exo-trig additions of carbon radicals to alkenes. The process begins with halogen abstraction from a halide precursor (often α to a stabilizing group), forming a carbon radical that adds intramolecularly to the alkene, followed by hydrogen abstraction from Bu₃SnH to close the cyclopropane. This method tolerates functional groups and has been applied in iterative syntheses, such as ring expansions leading to rotaxane precursors, where the radical step efficiently forms the three-membered ring. These cyclizations excel in 5-exo-trig modes, reliably producing bicyclo[3.1.0] systems with the cyclopropane fused cis to the five-membered ring, driven by favorable transition state geometry. Stereocontrol is achieved via the tether's rigidity or substituents, often yielding diastereoselectivities >20:1 through directed addition. In natural product synthesis, such methods have enabled the construction of strained polycycles, as seen in analogs of platensimycin and other bioactive terpenoids, where intramolecular carbenoid or radical closure installs the core [3.1.0] motif with high fidelity.^[24]

\begin{align*} &\ce{CH2=CH-(CH2)_n-CHX2} \\ &\quad \xrightarrow{\ce{Zn or Mg}} \\ &\ce{cyclopropyl derivative} \end{align*}

^[25]

Miscellaneous Routes

Samarium diiodide (SmI₂) serves as an effective alternative to zinc in Simmons-Smith-type cyclopropanation reactions, enabling stereospecific addition of methylene units to alkenes via organosamarium carbenoids. This method proceeds through a radical or single-electron transfer mechanism, where SmI₂ reduces gem-dihalides or allylic halides to generate the active species, followed by [2+1] cycloaddition with high chemo- and stereoselectivity, often preserving the alkene's geometry. For instance, treatment of (E)- or (Z)-stilbene with CH₂I₂ and SmI₂ yields the corresponding trans- or cis-1,2-diphenylcyclopropane in excellent yields and diastereoselectivities exceeding 95:5.^[26] Photochemical routes provide niche access to cyclopropanes through light-induced generation of reactive intermediates, bypassing traditional thermal activations. UV irradiation of dibromomalonates in the presence of alkenes triggers catalyst-free dehalogenation and carbene formation, leading to [2+1] cycloaddition products with moderate to good yields (up to 80%) for electron-rich alkenes like styrenes. Similarly, UV-promoted cycloadditions involving allenes and alkenes can form vinylcyclopropanes via diradical intermediates, though these often require sensitizers and yield mixtures due to competing [2+2] pathways. Electrochemical methods generate carbenoids anodically from gem-dihalides, offering controlled, metal-free alternatives for cyclopropanation. In the presence of copper-phenanthroline catalysts, anodic oxidation of dibromomalonates with styrene proceeds via a redox chain involving Cu(I)/Cu(II) cycles and radical addition, selectively affording cyclopropanes in 50-70% yields while suppressing polymerization side products. Recent flow electroreductive variants using nickel catalysis and gem-dichloroalkanes achieve scalable synthesis with >90% yields for unactivated alkenes, highlighting the approach's compatibility with continuous processing.^[27] Hydrogenation of cyclopropenes represents a straightforward saturation route to cyclopropanes, typically employing Pd/C or Pt catalysts under mild conditions to deliver cis diastereomers quantitatively. This method complements [2+1] strategies by leveraging the inherent strain of cyclopropenes for selective double-bond reduction without ring opening. Synthetic mimics of biocatalytic heme enzymes, such as iron porphyrin complexes, enable non-enzymatic cyclopropanation by coordinating carbene precursors and facilitating stereoselective transfer to alkenes. These porphyrin catalysts, inspired by cytochrome P450 active sites, promote [2+1] additions with ethyl diazoacetate to styrenes in up to 90% ee and 80% yields, mimicking enzymatic selectivity without protein scaffolds. Despite their versatility, these miscellaneous routes often suffer from lower yields (typically 40-70%) compared to standard carbenoid additions and are confined to niche applications, such as incorporating sensitive functionalities in complex natural product syntheses where compatibility with orthogonal groups is paramount.^[26]

Catalyzed Processes

Metal-Catalyzed Diazo Methods

Metal-catalyzed diazo methods represent a cornerstone of cyclopropanation chemistry, enabling the efficient transfer of carbene units from diazo compounds to alkenes under mild conditions with high catalytic turnover. These processes typically employ transition metals such as copper, rhodium, and ruthenium to decompose diazoalkanes, generating metallocarbene intermediates that undergo stereospecific [2+1] cycloaddition with unsaturated substrates, extruding nitrogen gas as the sole byproduct. This approach has become a preferred route for synthesizing functionalized cyclopropanes due to its broad substrate compatibility and scalability, particularly with donor-acceptor diazo compounds like ethyl diazoacetate (EDA, EtO₂CCHN₂). The mechanistic pathway common to these methods involves initial coordination of the diazo compound to the metal center, followed by heterolytic cleavage of the C-N bond and loss of N₂ to afford a three-coordinate metallocarbene species. This electrophilic intermediate then engages the alkene π-bond in a concerted, stereospecific manner, yielding the cyclopropane product and regenerating the catalyst. For copper catalysis, computational and experimental studies support a Cu(I)/Cu(III) redox cycle, where the Cu(I) species forms the carbene, followed by oxidative addition to the alkene to generate a Cu(III) intermediate that undergoes reductive elimination to form the cyclopropane and regenerate the catalyst.^[28] Rhodium and ruthenium variants similarly proceed via metallocarbene formation, though with distinct electronic properties influencing reactivity; rhodium carbenes exhibit higher electrophilicity, favoring addition to electron-rich alkenes. The overall transformation can be represented as:

\ce{R^1R^2C=N2 + cat. ->[loss of N2] [M]=CR^1R^2 ->[alkene] cyclopropane + cat.}

where [M]=CR¹R² denotes the metallocarbene. These mechanisms ensure syn addition and retention of alkene geometry in the product, with yields often exceeding 90% for simple substrates like styrene and EDA. Copper catalysis, pioneered in the 1960s, initially drew from the Arndt-Eistert homologation protocol but evolved into a versatile tool for intermolecular cyclopropanation using Cu(I) or Cu(II) salts, such as CuCl or Cu(acac)₂. These catalysts excel with donor-acceptor carbenes like EDA, promoting selective addition to a wide range of alkenes, including those bearing electron-withdrawing groups, to afford donor-acceptor cyclopropanes in high trans selectivity. Early developments highlighted the role of Cu in stabilizing carbenoid intermediates, enabling reactions at room temperature with low catalyst loadings (1-5 mol%). The method's scope extends to functionalized systems, though regioselectivity in conjugated dienes favors 1,2-addition over 1,4-pathways due to the carbene's localized reactivity.^[29] Rhodium carboxylate catalysts, particularly dirhodium(II) paddlewheel complexes like Rh₂(OAc)₄, emerged in the 1970s and offer superior activity and turnover numbers (up to 10⁴), making them ideal for challenging substrates. Developed through contributions from researchers like Doyle, these catalysts facilitate rapid decomposition of diazo compounds, achieving complete conversions in minutes with minimal side products. Dirhodium(II) systems are particularly effective for EDA-derived carbenes, delivering cyclopropanes with excellent diastereoselectivity (trans:cis > 20:1) and basic control over absolute configuration via achiral ligands. In dienes, they exhibit high regioselectivity for terminal addition, enabling sequential functionalizations in natural product synthesis. Ruthenium catalysts, such as Ru(II) complexes, complement these by providing milder conditions for sensitive alkenes, though with slightly lower turnover compared to rhodium.^[30] Since the 1960s, advancements in these methods have focused on catalyst optimization for efficiency and selectivity, with Doyle's systematic studies establishing dirhodium carboxylates as benchmarks for high-impact applications. Recent developments (as of 2025) include iron-porphyrin catalysts for eco-friendly cyclopropanations and advanced chiral rhodium systems for multifunctional diazo compounds, expanding scope to bioactive molecule synthesis.^[31] These techniques have transformed cyclopropanation from a stoichiometric process into a catalytic powerhouse, influencing synthetic strategies across organic chemistry.

Asymmetric Variants

Asymmetric cyclopropanation refers to the enantioselective formation of cyclopropanes from alkenes and carbene precursors, typically using chiral metal catalysts to achieve high levels of stereocontrol. Pioneering work in the 1980s by Andreas Pfaltz introduced chiral semicorrin ligands for copper-catalyzed reactions, enabling enantioselectivities up to 97% ee in the addition of diazoacetates to olefins.^[32] Concurrently, David A. Evans and Eric N. Jacobsen developed C2-symmetric bis(oxazoline) (box) ligands, which form highly effective complexes with copper(I) or copper(II) for enantioselective cyclopropanation. These advances established metal-carbene pathways as versatile tools for synthesizing enantioenriched cyclopropanes, with selectivities often exceeding 95% ee for trans products from electron-rich alkenes like styrenes.^[28] Copper-bis(oxazoline) complexes have become a cornerstone for asymmetric cyclopropanation, particularly with ethyl diazoacetate (EDA) as the carbene source. For instance, the reaction of styrene with EDA in the presence of a chiral Cu(I)-box catalyst derived from (S,S)-t-butyl box affords the trans-cyclopropane product in up to 99% ee and >99:1 trans/cis ratio.^[33] The mechanism involves coordination of the alkene to the copper-carbene intermediate, where the chiral ligand enforces facial selectivity, favoring si-face attack for (R,R)-configuration in many cases. Pfaltz's semicorrin ligands, early precursors to box systems, similarly deliver high enantioselectivity (up to 94% ee) for styrene derivatives, highlighting the role of nitrogen-based chelation in stabilizing the active species. These Cu-based systems extend to substituted styrenes and dienes, maintaining >90% ee while tolerating functional groups like esters. Rhodium-based chiral catalysts, particularly dirhodium(II) complexes with carboxylate ligands, excel in handling donor-acceptor carbenes for applications in natural product synthesis. Dirhodium(II) tetrakis(prolinate) derivatives, such as Rh2(S-DOSP)4 developed by Huw M. L. Davies, catalyze the cyclopropanation of styrenes with aryldiazoacetates to yield trans-cyclopropanes in 92–99% ee, enabling tandem processes like sequential cyclopropanation-Michael additions for complex scaffolds.^[34] Chiral carboxylates inspired by Pfaltz's designs, including proline-based ligands, provide tunable axial chirality in the dirhodium paddlewheel, directing enantioselectivity through steric differentiation in the metal-carbene binding. These Rh catalysts are particularly effective for electron-deficient alkenes, achieving >95% ee in intermolecular additions. The scope of asymmetric variants includes directed cyclopropanation of allylic alcohols, where the hydroxyl group coordinates to the metal center, enhancing diastereoselectivity. With Cu-box catalysts, (E)-allylic alcohols undergo cyclopropanation with EDA to form syn-diastereomers in up to 96% ee and >20:1 dr, facilitating synthesis of cyclopropane-containing pharmaceuticals. Tandem reactions, such as those using dirhodium prolinates, integrate cyclopropanation with subsequent rearrangements, as demonstrated in the total synthesis of dictyopterenes where >90% ee is preserved across steps.^[35] \ce{PhCH=CH2 + N2CH2CO2Et ->[chiral Cu-box][cat.] (1R,2R)-PhCH-CH-CH2CO2Et} (with >99% ee for trans product)^[28]

Biosynthesis and Natural Occurrence

Enzymatic Pathways

Enzymatic cyclopropanation primarily occurs in bacteria through specialized S-adenosylmethionine (SAM)-dependent enzymes that modify unsaturated lipids by forming cyclopropane rings, enhancing membrane stability under environmental stress. In bacteria such as Escherichia coli, cyclopropane fatty acid synthase (CFAS, also known as CPA) catalyzes the conversion of cis double bonds in phospholipid-bound unsaturated fatty acids to cyclopropane fatty acids (CFAs) during stationary phase or osmotic stress. Similarly, in mycobacteria like Mycobacterium tuberculosis, a family of cyclopropane mycolic acid synthases (CMAS), including enzymes such as PcaA, CmaA1, and CmaA2, introduce cyclopropane rings into the alkene portions of mycolic acids, which are key components of the cell wall.^[36] These enzymes belong to the SAM-dependent methyltransferase superfamily but operate via a unique carbocation-based mechanism rather than standard methylation. The catalytic mechanism involves the nucleophilic attack of the alkene on the activated methylene group of SAM, leading to transfer of a :CH₂ unit and formation of a carbocation intermediate at one of the alkene carbons; a conserved glutamate residue then abstracts a proton from the adjacent methylene group (effectively from the alkane chain), closing the three-membered ring and yielding S-adenosylhomocysteine (SAH) as a byproduct.^[37] This process can be represented as:

\text{unsaturated lipid chain} + \text{SAM} \rightarrow \text{cyclopropane-lipid} + \text{SAH}

Structural studies of E. coli CFAS reveal a dimeric enzyme with a deep active site pocket that accommodates the phospholipid substrate, positioning the double bond near the SAM binding site for efficient methylene transfer.^[38] In mycobacterial CMAS, the enzymes exhibit site-specificity, with distinct members targeting proximal or distal positions in the mycolic acid chain, influencing cell wall permeability and virulence.^[39] These reactions exclusively produce cis-cyclopropane stereochemistry, which modulates membrane fluidity by increasing packing density without altering chain length, thereby protecting against oxidative damage and maintaining homeostasis. The discovery of these enzymatic pathways dates to the 1960s, when cyclopropane-containing fatty acids were first identified in bacterial lipids, with E. coli CFAS purified and characterized shortly thereafter. Gene cloning efforts in the 1990s identified the cfa gene in E. coli, while genomic sequencing of M. tuberculosis post-2000 revealed the CMAS gene cluster (e.g., mmaA operon), enabling functional studies that linked these enzymes to stress adaptation and pathogenesis.^[40]^[41]

Role in Natural Products

Cyclopropane rings represent a rare structural motif in natural products, first identified in the 1920s with the isolation of (+)-chrysanthemic acid from pyrethrum flowers (Tanacetum cinerariifolium), a key component of the insecticidal pyrethrins.^[42] This discovery marked the beginning of recognizing cyclopropanes as biologically significant, despite their inherent ring strain of approximately 27 kcal/mol, which limits their prevalence but underscores their conservation in specialized biosynthetic pathways for adaptive advantages.^[43] In plants, cyclopropanes often appear in terpenoids, such as the bicyclo[3.1.0]hexane system in α-thujone, a monoterpene ketone found in sage (Salvia officinalis), contributing to the plant's essential oil profile.^[44] Notable examples include chrysanthemic acid in pyrethroids, where the cyclopropane dicarboxylic acid esterifies with monoterpenoid alcohols to form pyrethrins, serving as potent defense toxins against insect herbivores by disrupting sodium channel function and causing paralysis.^[45]^[46] In vibsane diterpenes from Viburnum species, the divinylcyclopropane moiety integrates into complex macrocyclic frameworks, as seen in vibsanin derivatives, potentially aiding plant defense through neurotrophic or cytotoxic effects.^[47] Fungal natural products, such as the illudins from Omphalotus species, feature a strained cyclopropane in sesquiterpenoids, exhibiting antitumor activity that may function in microbial competition or defense.^[48] In bacteria, cyclopropane fatty acids (CFAs) modify membrane lipids, introducing rigid kinks that enhance bilayer stability and regulate fluidity under stress, such as during stationary phase or acid exposure, thereby acting as adaptive membrane modifiers.^[49] Evolutionarily, the motif's scarcity reflects the energetic cost of synthesis via carbocation or radical mechanisms, yet it persists in conserved pathways—like those involving S-adenosylmethionine-dependent cyclopropanases—where the ring's unique steric and electronic properties confer selective biological roles, from toxicity to structural rigidity.^[50]

Applications

In Organic Synthesis

Cyclopropanation serves as a versatile tool in organic synthesis by introducing strained three-membered rings that can undergo subsequent transformations, such as ring expansion reactions, to construct larger carbocycles. For instance, cyclopropanes generated via diazoester addition to α-silyloxyacroleins can participate in a Lewis acid-catalyzed semi-pinacol rearrangement, expanding the ring to form cyclobutanones with high enantioselectivity (up to 98% ee) and diastereoselectivity (>20:1 dr). This approach leverages the strain relief of the cyclopropane to drive the migration of substituents, enabling the synthesis of quaternary centers essential for complex molecular architectures. Recent applications include the 2023 synthesis of complex glycolates via hydrogen-borrowing catalysis for α-cyclopropanation of ketones, expanding access to strained motifs in natural product analogs.^[51] In total synthesis, cyclopropanation has been pivotal in constructing key frameworks for bioactive molecules, including prostaglandin analogs. The Corey-Chaykovsky reaction, employing dimethylsulfonium methylide, facilitates the cyclopropanation of α,β-unsaturated esters to install the cyclopropane moiety in inhibitors of m-prostaglandin E synthase-1, such as MK-7285, providing a strained unit that enhances binding affinity. Similarly, sequential cyclopropanations contribute to polycyclic ladderane structures; oligo-cyclopropane precursors can rearrange to ladderanes, mimicking biosynthetic pathways and enabling the assembly of fused cyclobutane arrays in model natural product scaffolds. Tandem processes further amplify the utility of cyclopropanation by combining it with pericyclic rearrangements. A notable example is the rhodium(II)-catalyzed cyclopropanation of vinyldiazomethanes with pyrroles, followed by a Cope rearrangement, which efficiently constructs the tropane core of (±)-ferruginine and (±)-anhydroecgonine methyl ester in a stereocontrolled manner.^[52] This sequence exploits the divinylcyclopropane intermediate to form seven-membered rings, demonstrating rapid complexity buildup. The stereochemical precision of cyclopropanation is particularly valuable, as it retains the geometry of the starting alkene, allowing control over multiple stereocenters in the product. Concerted carbene addition ensures that cis-alkene substituents remain cis in the cyclopropane, facilitating the synthesis of stereodefined polycycles. In modern alkaloid total syntheses since the 1990s, this feature has been harnessed; for example, a stereoselective cyclopropanation enables the core assembly of the ergot alkaloid cycloclavine, while an intramolecular variant constructs the strained ring in rauvomine B, both achieving high diastereocontrol.

Industrial and Medicinal Uses

Cyclopropane moieties are integral to several pharmaceuticals, enhancing their biological activity and pharmacokinetic properties. A prominent example is cilastatin, a renal dehydropeptidase inhibitor containing a 2,2-dimethylcyclopropyl group, which is co-administered with the beta-lactam antibiotic imipenem to prevent its enzymatic degradation in the kidneys and broaden its spectrum against bacterial infections such as those caused by Pseudomonas aeruginosa.^[53] This combination has been a cornerstone in treating serious infections, including intra-abdominal and skin infections, since its approval in the 1980s.^[54] In antiviral applications, cyclopropane-containing compounds have shown promise as neuraminidase inhibitors and nucleoside analogs. For instance, methylenecyclopropane nucleoside derivatives, such as cyclopropavir, exhibit potent activity against human cytomegalovirus (HCMV) and other herpesviruses by inhibiting viral DNA polymerase, with EC50 values in the low micromolar range and low cytotoxicity.^[55] These analogs mimic natural nucleosides but incorporate the strained cyclopropane ring to improve metabolic stability and antiviral potency, offering alternatives to oseltamivir in cases of resistance.^[56] Agrochemicals, particularly pyrethroid insecticides, rely heavily on cyclopropanation for their core structure. Permethrin, a widely used synthetic pyrethroid for insect control in agriculture and public health, is derived from chrysanthemic acid, where the cyclopropane ring is installed via the Simmons-Smith reaction using diiodomethane and zinc-copper couple on the corresponding alkene precursor.^[57] This method ensures stereocontrol, yielding the trans-configured cyclopropane essential for the insecticide's neurotoxic action on insect sodium channels, with permethrin achieving over 90% mortality against pests like mosquitoes at low concentrations.^[58] In materials science, cyclopropanation enables the synthesis of advanced polymers for nanomaterials. Divinylcyclopropanes undergo thermal Cope rearrangement to form cycloheptadiene units, which can be incorporated into ladder polymers with rigid, conjugated backbones exhibiting high thermal stability and optoelectronic properties suitable for carbon nanotube composites or conductive films.^[59] These structures provide enhanced mechanical strength and charge transport, with applications in flexible electronics where the cyclopropane acts as a strained linker for precise nanostructure control.^[60] Industrial-scale cyclopropanation leverages rhodium- and copper-catalyzed diazo transfer methods for efficient, high-turnover production. In pyrethroid manufacturing, rhodium(II) carboxylate catalysts facilitate ton-scale synthesis of chrysanthemic acid derivatives from diazoacetates and alkenes, achieving yields above 85% with catalyst loadings below 0.1 mol%, significantly reducing costs compared to traditional Simmons-Smith processes that require stoichiometric zinc.^[61] Economic advantages include lower metal waste and scalability, with global pyrethroid production exceeding 10,000 tons annually, driven by demand in crop protection and vector control.^[62] Recent developments in the 2010s include patents for cyclopropane-embedded organic semiconductors in light-emitting diodes (LEDs). For example, cyclopropane-bridged polycyclic aromatic compounds were patented as dopants in OLEDs to improve electron mobility and color purity, enabling devices with external quantum efficiencies over 20% in blue-emitting layers.^[63] These innovations address stability issues in organic electronics, with cyclopropane rings providing steric protection and tunable conjugation for commercial phosphorescent OLED displays.^[64]

References

[1]
Introduction: Cyclopropanes and Related Rings | Chemical Reviews
Tremendous advances have been made in the stereoselective synthesis of cyclopropane derivatives in the past 20 years. This becomes evident in the contributions ...
[2]
Use of cyclopropanes and their derivatives in organic synthesis
Anti-selective Cyclopropanation of Nonconjugated Alkenes with Diverse Pronucleophiles via Directed Nucleopalladation.
[3]
https://scitechdaily.com/a-new-easier-and-safer-way-to-synthesize-medicines/
[4]
Simmons–Smith Cyclopropanation: A Multifaceted Synthetic ... - NIH
Simmons–Smith cyclopropanation is a widely used reaction in organic synthesis for stereospecific conversion of alkenes into cyclopropane.
[5]
Reductive Cyclopropanation through Bismuth Photocatalysis
Aug 5, 2024 · We present here a catalytic method based on a low-valent Bi complex capable of cyclopropanation of double bonds under blue LED irradiation.
[6]
11.3.5 Cyclopropanation of Alkenes - Chemistry LibreTexts
Jun 5, 2019 · One common method of cyclopropane synthesis is the reaction of carbenes with the double bond in alkenes or cycloalkenes.
[7]
Cyclopropanation of Alkenes - Master Organic Chemistry
Oct 18, 2023 · Cyclopropanes are the smallest cycloalkane rings. Due to the fact that their internal angles (60°) are considerably smaller than the ideal ...
[8]
https://pubs.acs.org/doi/10.1021/jacs.4c07262
[9]
Asymmetric Inter- and Intramolecular Cyclopropanation of Alkenes ...
Extensive investigations of asymmetric intermolecular cyclopropanation of terminal alkenes with diazoacetates catalyzed by ruthenium porphyrin
[10]
Cyclopropane - American Chemical Society
Sep 17, 2012 · It was discovered by A. Freund in 1881; the same year he proposed the correct structure and synthesized it by treating 1,3-dibromopropane with ...Missing: August | Show results with:August
[11]
The Reformatsky reaction | Organozinc Reagents - Oxford Academic
Oct 31, 2023 · The insertion of metallic zinc into a.-haloesters is the historically first and still most widely used form of this process, to which this ...
[12]
Strain Energy of Small Ring Hydrocarbons. Influence of C−H Bond ...
The generally accepted value for the ring strain energy of cyclopropane is derived from its ΔHf = 12.7 kcal/mol and half of that for cyclohexane (ΔHf = −14.8 ...Missing: cyclopropane kcal/ mol
[13]
Comment on “The Concept of Protobranching and Its Many ...
Feb 15, 2010 · In any organic chemistry textbook it is stated that the strain energy of cyclopropane is 27.5 kcal/mol. Recently, Schleyer et al. (1) argued ...
[14]
Intramolecular donor–acceptor cyclopropane ring-opening cyclizations
Nov 21, 2013 · In the literature, many examples of these polarized cyclopropanes' reactivity with nucleophiles, electrophiles, and radicals are prevalent.
[15]
Ab initio calculations on the ring opening of cyclopropane radical ...
Ab initio calculations on the ring opening of cyclopropane radical cation. Trimethylene radical cation is not a stable intermediate.<|control11|><|separator|>
[16]
https://pubs.acs.org/doi/full/10.1021/jp908894q
[17]
https://pubs.rsc.org/en/content/articlelanding/2014/cs/c3cs60238a
[18]
Asymmetric Ylide Reactions: Epoxidation, Cyclopropanation, Aziridination, Olefination, and Rearrangement†
### Summary of Cyclopropanation Using Sulfur and Phosphorus Ylides
[19]
Dimethylsulfoxonium Methylide | Journal of the American Chemical ...
Extended Version of the Corey–Chaykovsky Reaction: Synthesis of 2,4-Substituted Furans by the Treatment of β-Dialkylamino Chalcones with Dimethylsulfonium ...Missing: original | Show results with:original<|control11|><|separator|>
[20]
Dimethylsulfonium Methylide, a Reagent for Selective Oxirane ...
Dimethylsulfonium Methylide, a Reagent for Selective Oxirane Synthesis from Aldehydes and Ketones ... Journal of the American Chemical Society. Cite this: J.
[21]
https://pubs.acs.org/doi/10.1021/cr960411r
[22]
https://pubs.acs.org/doi/10.1021/ja00864a040
[23]
https://pubs.acs.org/doi/10.1021/ja00878a046
[24]
Correlations between catalytic reactions of diazo compounds and ...
Correlations between catalytic reactions of diazo compounds and stoichiometric reactions of transition-metal carbenes with alkenes. Mechanism of the ...
[25]
Copper(I) catalysis in cyclopropanations with diazo compounds ...
An in-depth computational study of alkene cyclopropanation catalyzed by Fe(porphyrin)(OCH3) complexes. The environmental effects on the energy barriers.
[26]
Catalyzed Cyclopropanation of Diazooxindoles and Alkenes
Dec 13, 2012 · The metal-catalyzed cyclopropanation between diazo compounds and alkenes is a powerful strategy for the synthesis of cyclopropane derivatives.
[27]
Chiral Copper‐Semicorrin Complexes as Enantioselective Catalysts ...
Optical yields of up to 97% ee characterize the cyclopropanation of olefins with diazoacetates in the presence of the semicorrin complex CuL2 (R = CMe2OH).Missing: Cu | Show results with:Cu
[28]
C2-Symmetric Chiral Bis(Oxazoline) Ligands in Asymmetric Catalysis
The cyclopropanation of styrene was performed with a complex derived from box 2 and Cu(I) as the catalyst, since the results obtained using either Cu(II) or ...
[29]
Bis(oxazolines) as chiral ligands in metal-catalyzed asymmetric ...
Highly Enantioselective Copper- and Iron-Catalyzed Intramolecular Cyclopropanation of Indoles. Journal of the American Chemical Society 2017, 139 (23) ...
[30]
Asymmetric Cyclopropanations by Rhodium(II) N-(Arylsulfonyl ...
This study showed that the asymmetric cyclopropanation can be carried out with a variety of diazovinylacetate derivatives and is not limited to the 4-phenyl-2- ...
[31]
Catalytic Asymmetric Cyclopropanation of Allylic Alcohols with ...
Alkyl-substituted allylic alcohols gave modest yields and enantiomeric ratios (up to 87:13) but these compare favorably with those observed with other ...Results and Discussion · Supporting Information Available · References
[32]
A common mechanism for the biosynthesis of methoxy and ... - PNAS
Using the gene for the enzyme that introduces the distal cyclopropane (cma1) as a probe, we have cloned and sequenced a cluster of genes coding for four highly ...
[33]
Insights into E. coli Cyclopropane Fatty Acid Synthase (CFAS ...
Apr 25, 2024 · According to the currently accepted cyclopropanation mechanism, CFAS enzymes catalyse the cyclopropanation of phospholipids via a carbocation ...Abstract · Introduction · Results and Discussion · Conclusion
[34]
Structural and Functional Analysis of E. coli Cyclopropane Fatty Acid ...
Jul 26, 2018 · Hari et al. report the crystal structure of E. coli cyclopropane fatty acid synthase, which converts alkenes found in unsaturated fatty acids into cyclopropyl ...Missing: SAM radical
[35]
Crystal Structures of Mycolic Acid Cyclopropane Synthases from ...
There are at least three mycolic acid cyclopropane synthases (PcaA, CmaA1, and CmaA2) that are responsible for these site-specific modifications of mycolic ...Experimental Procedures · Structure Determination And... · Results And Discussion
[36]
Cyclopropenoid Fatty Acids - an overview | ScienceDirect Topics
Cyclopropane fatty acid (CFA) synthase was discovered in 1963 by Zalkin et al.28 The enzyme from E. coli has since been extensively studied by Cronan and co ...
[37]
Escherichia coli cyclopropane fatty acid synthase - Courtois - 2004
Dec 6, 2004 · (1963) The path of hydrogen in the formation of cyclopropane fatty acids. Biochem. Biophys. Acta 70, 583–585.DOI: 10.1016/0006-3002(63)90794 ...Missing: 1960s | Show results with:1960s
[38]
The Molecular Genetics of Mycolic Acid Biosynthesis - ASM Journals
The mmaA2 gene of Mycobacterium tuberculosis encodes the distal cyclopropane synthase of the alpha-mycolic acid. J Biol Chem 278:7844–7849. View · PubMed.Mycolic Acid Structures · Mycolic Acid Biological... · Mycolic Acid Biosynthesis
[39]
Anti-inflammatory cyclopropanes and benzofurans from mangrove ...
Jul 10, 2025 · Since the first natural cyclopropane, (+)-chrysanthemic acid, was isolated from pyrethrum flowers in the 1920s, some metabolites have been ...
[40]
[PDF] Cyclopropane-‐Containing Natural Products | EPFL
If more labile, Energy source (~27 kcal·∙mol-‐1 cyclic strain):. – High-‐Energy intermediate in metabolism;. – Storage molecule to release energy-‐rich ...
[41]
Thujone - an overview | ScienceDirect Topics
Thujone is the main constituent of essential oils derived from plants such as sage ... cyclopropane ring of the sabinyl cation (12). α-Thujene (48) and ...
[42]
https://www.sciencedirect.com/science/article/abs/pii/S0031942225002341
[43]
Defense of pyrethrum flowers: repelling herbivores and recruiting ...
May 14, 2019 · Plant immunity to insect herbivores. ... Pyrethrins protect pyrethrum leaves against attack by western flower thrips, Frankliniella occidentalis.
[44]
Discovery of the Caged-Vibsane Norditerpenoids with ...
Aug 16, 2023 · Vibsane-type diterpenes (VibDs) have been regarded as a type of unusual diterpene that occurs exclusively in only six species of the genus Viburnum (Adoxaceae) ...
[45]
Fungal natural products—the mushroom perspective - Frontiers
The illudins from Lampteromyces and Omphalotus species (Omphalotaceae) are sesquiterpenes featuring an unusual cyclopropane ring and are currently developed ...Missing: coriolide | Show results with:coriolide
[46]
How Do Cyclopropane Fatty Acids Protect the Cell Membrane of ...
Feb 23, 2023 · It has been observed that the cyclopropane rings provide more rigid kinks in the lipid acyl chain compared to the double bonds and therefore ...
[47]
Biosynthesis of cyclopropane in natural products - RSC Publishing
Dec 3, 2021 · Here, the scientific literature from the last two decades relating to cyclopropane biosynthesis is summarized, and the enzymatic cyclopropanations, according ...Missing: coriolide fungi
[48]
https://www.frontiersin.org/journals/microbiology/articles/10.3389/fmicb.2015.00127/full
[49]
Cilastatin: Uses, Interactions, Mechanism of Action | DrugBank Online
Cilastatin is indicated, in combination with imipenem with or without relebactam, for the treatment of bacterial infections.
[50]
Imipenem/cilastatin therapy of serious infections: a U.S. multicenter ...
Imipenem/cilastatin, which combines a broad-spectrum antibiotic derived from thienamycin with a specific enzyme inhibitor, was administered in dosages of 1 to ...
[51]
Synthesis and Antiviral Activities of Methylenecyclopropane Analogs ...
The most active compound of this class is cyclopropavir (CPV), which exhibits good antiviral activity against human cytomegalovirus (HCMV), Epstein-Barr virus, ...
[52]
Antiviral Cyclopropane Acids from Deep-Sea-Derived Fungus ... - NIH
To date, thousands of natural products bearing cyclopropane moieties have been discovered in archaea, bacteria, fungi, and higher plants [2]. Most of them have ...Missing: coriolide | Show results with:coriolide
[53]
Synthesis and insecticidal activity of new pyrethroids | Request PDF
This reaction has been successfully used for the synthesis of chrysanthemic acid from diester derived from natural tartaric acid. ... Asymmetric Simmons-Smith ...<|separator|>
[54]
5 Chemistry of Plant Protection
1 Synthesis of Pyrethroid Acids. 1.1 Synthesis of Chrysanthemic Acid. The synthesis of chrysanthemic acid 1 as mixture of stereoisomers, as racemate of pure.
[55]
Recent applications of the divinylcyclopropane–cycloheptadiene ...
This review summarizes the application of the divinylcyclopropane–cycloheptadiene rearrangement in synthetic organic chemistry.
[56]
[PDF] Porphyrin-based [3]- and [4]rotaxanes
Dec 14, 2012 · For example, they described ladder-shaped assemblies obtained ... polymer and materials science. Angew. Chem. Int. Ed. 2007, 46, 1018 ...Missing: divinylcyclopropanes | Show results with:divinylcyclopropanes
[57]
[PDF] Recent developments in asymmetric cyclopropanation Tetrahedron
Apr 25, 2008 · Asymmetric intramolecular cyclopropanation of allylic diazoacetates catalysed by Rh2[(5R)-MEPY]4. Another class of chiral dirhodium(II) ...
[58]
[PDF] Pyrethroid insecticides. Chapter I. Synthesis, structure, biochemistry ...
Feb 11, 2021 · Chrysanthemic acid (2a) not only (i) allows the synthesis of a large variety of biologically active pyrethroids on esterification, but also (ii) ...
[59]
Organic semiconducting material and electronic component
The invention relates to an organic semiconducting material, comprising at least one matrix material and at least one doping material, wherein the doping ...
[60]
[PDF] (12) United States Patent - Googleapis.com
2010, 132236 A1 11, 2010. WO. WO 2011 131185 A1 * 10 ... Organic Light-Emitting Diodes.” Applied Physics ... (cyclopropane-1,2,3-triylidene)tris(2-(p ...