Total synthesis of cyclopropane-containing natural products: recent progress (2016–2024)

Abstract

Cyclopropane, as the smallest all-carbon ring, is a ubiquitous functional group found in many complex natural products, such as terpenoids, alkaloids, steroids, and fatty acids. Natural products containing cyclopropane motifs have attracted burgeoning interest owing to their fascinating architectural features and versatile biological properties. In recent decades, a variety of methods for the construction of cyclopropane rings have emerged, which can be mainly classified into [2 + 1]-type cycloaddition and direct 1,3-cyclization. These methods have been extensively utilized by synthetic chemists in their pursuit of synthesizing cyclopropane-containing natural products. This review outlines recent progress in this research area, with a particular focus on the ingenious application of novel synthetic methodologies and tactics for assembling naturally occurring three-membered rings, aiming to complement the existing literature in this field.

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Neng Wang

Neng Wang received his BS degree from the West China School of Pharmacy, Sichuan University, in 2017. Then, he started his doctoral studies under the supervision of Professor Feng Gao and obtained his PhD from the School of Life Science and Engineering, Southwest Jiaotong University, in 2023. Currently, he is a postdoctoral researcher at the Shanghai Institute of Materia Medica, working in Professor Jian-Min Yue's laboratory. His research primarily focuses on the biomimetic semisynthesis of bioactive natural products.

Jin-Xin Zhao

Jin-Xin Zhao received his PhD in 2015 from the Shanghai Institute of Materia Medica, Chinese Academy of Sciences. In 2018, he completed his postdocs at the same institute, and joined the research group of Professor Jian-Min Yue as an assistant research fellow. After working as a 2-year (2019–2021) visiting investigator at the Scripps Research Institute, he returned to Yue's group, and worked as an associate professor, where he continues to work. His current research interests involve the discovery, total synthesis, and structural optimization of bioactive natural products.

Jian-Min Yue

Jian-Min Yue received his PhD in organic chemistry from Lanzhou University in 1990 and continued postdoctoral research at the Kunming Institute of Botany, Chinese Academy of Sciences (1991–1993) and the University of Bristol (1993–1994). He was an associate professor at the Kunming Institute of Botany (1994–1996), and then joined the staff of Unilever Research SIOC as a senior scientist and project manager until 1999. He then moved to the Shanghai Institute of Materia Medica and where he continues to work as a professor. His research interests include the discovery, synthesis, biosynthesis, and mechanisms of bioactive metabolites from natural resources and R&D of innovative drugs.

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10th anniversary statement

Organic Chemistry Frontiers serves as an excellent platform for the organic chemistry community to disseminate their findings and engage in meaningful discourse. My journey with this prestigious journal began with a comprehensive review of the chemical constituents of Trigonostemon plants in its very first issue. Since then, I have had the privilege of sharing pivotal research on the isolation and total synthesis of structurally intriguing and biologically significant natural products within its pages. Each submission experience was notably pleasant. Impressively, Organic Chemistry Frontiers has established itself as an authoritative journal in the field of organic chemistry after a decade of growth, exerting a significant influence globally. I am confident that the journal will continue to thrive and evolve positively in the future, and I would be delighted to continue to contribute my work to this esteemed journal.

1. Introduction

Cyclopropane, being the smallest carbocycle, constitutes a fundamental component in the basic structures of natural products (NPs). Since Ruzicka's first isolation of (+)-trans-chrysanthemic acid in 1924,¹ numerous secondary metabolites bearing a cyclopropane moiety have been found from various sources, including plants, fungi, and marine organisms.^2–4 Cyclopropane-containing NPs are mainly terpenoids, especially diterpenoids and sesquiterpenoids.^5,6 In this regard, cyclopropane acts as a key marker for the skeletal classification of these compounds, such as Euphorbia diterpenoids^7–9 and Chloranthus sesquiterpenoids.¹⁰ In addition, cyclopropanes also exist in many other NPs, such as alkaloids,^11–13 steroids,^14–16 and fatty acids.¹⁷ Notably, these NPs demonstrate a wide range of biological properties, including anticancer, enzyme inhibition, antiviral, antibacterial, and insecticidal activities.² For example, tigilanol tiglate (1),¹⁸ a tigliane diterpenoid isolated from Fontainea picrosperma, is undergoing clinical trials for the treatment of a broad range of cancers. Sarbracholide (2),¹⁹ a lindenane sesquiterpenoid dimer, exhibits unprecedented picomolar activity (EC₅₀ = 4.3 ± 0.3 pM) against chloroquine-resistant Plasmodium falciparum (Fig. 1). However, the limited accessibility of these compounds has hindered adequate exploration of their biological functions. To this end, developing efficient strategies for the rapid assembly of these cyclopropane-containing NPs has long been highly desirable in synthetic and medicinal chemistry.

Fig. 1 Representative NPs possessing cyclopropane moieties.

As the smallest cycloalkane, cyclopropane is exceptional among various carbocycles by virtue of its uncommon bonding characteristics (Fig. 2a).²⁰ The co-planarity of the three carbon atoms in the cyclopropane ring results in extreme ring strain (27.5 kcal mol⁻¹) owing to the imposed 60° bond angle and eclipsing C–H bonds. In essence, the relatively short C–C bonds in cyclopropanes, along with their enhanced p-character, resemble C□C double bonds, while the C–H bonds exhibit increased s-character and are shorter and stronger than those in typical alkanes.^21,22 Despite the unique synthetic challenges posed by ring strain, the preparation of variously substituted cyclopropanes has been well explored over the past decades,^23–26 such as the Simmons–Smith reaction,²⁷ metal-catalyzed decomposition of diazoalkanes^28,29 and Michael initiated ring closure (MIRC) reactions.³⁰

Fig. 2 (a) Comparison of ring strain energies and structural properties of various cycloalkanes. (b) General classification of strategies used to form cyclopropane.

The advantages of these cyclopropanation methodologies have been deftly harnessed by synthetic chemists to enable the elegant assembly of various cyclopropane-containing NPs. In the past two decades, several reviews focusing on the total synthesis of cyclopropane-containing NPs have been published.^31–34 Complementary to those earlier reports, the purpose of this review is to highlight the strategic considerations for the construction of the cyclopropane moiety in recent total synthesis (2016–2024). It should also be emphasized that the organization of this review is based on the reaction type so that it is much easier to appreciate their versatility in synthesis (Fig. 2b). These methods can be broadly grouped into three categories, including (a) [2 + 1] cycloaddition, (b) intramolecular 1,3-cyclization, and (c) others, which can be further subdivided into different types according to the mechanisms and intermediates. Due to space limitations, only 1–3 examples of total synthesis are provided for each type. Moreover, specific reaction mechanisms for the construction of cyclopropane rings have been extensively reviewed elsewhere;^35–39 therefore, they will not be discussed in detail in this review.

2. [2 + 1] cycloaddition

[2 + 1] cycloaddition strategies, widely employed for constructing strained cyclopropane rings, encompass cycloaddition of carbene equivalents to olefins, coupling of 1,1-carbodianion and 1,2-carbodication equivalents, and coupling of 1,1-carbodication and 1,2-carbodianion equivalents. These methods allow for the formation of two C–C bonds in a single preparative step.⁴⁰ The frequently employed [2 + 1] cycloaddition strategies include Simmons–Smith cyclopropanation,^27,41 transition-metal-catalyzed decomposition of diazo compounds,^28,29 MIRC reactions,³⁰ and free carbene addition.^42,43 These protocols have proven useful in the intermolecular context, as demonstrated by recent applications in assembling three-membered carbocycles in various NPs.

2.1 Simmons–Smith cyclopropanation

The Simmons–Smith cyclopropanation reaction is one of the most well-known methods for the conversion of olefins into cyclopropanes,⁴⁴ commonly mediated by zinc carbenoids that are typically generated from an organozinc reagent and a diiodoalkane (Fig. 3).⁴⁵ The widespread popularity of this reaction stems from the broad substrate scope, the tolerance of various functional groups, and the stereospecificity with respect to the alkene geometry.

Fig. 3 Simmons–Smith cyclopropanation.

Ito's synthesis of (±)-naupliolide (2016). Naupliolide (3), isolated from the aerial parts of Nauplius graveolens subsp. oborus (Schousb) Wikl. in 2006 by Barrero et al., is a tetracyclic sesquiterpenoid that contains an α,β-unsaturated ketone on the eight-membered ring, fused with a γ-butyrolactone and a cyclopentane, on which a cyclopropane is also grafted.⁴⁶

In 2016, Ito and co-workers accomplished the first total synthesis of (±)-naupliolide (3),⁴⁷ through the utilization of key steps including Simmons–Smith cyclopropanation, radical cyclization, and ring-closing metathesis (RCM) reactions (Scheme 1). Initially, the starting material 4 underwent Dess–Martin oxidation, followed by a Horner–Wadsworth–Emmons reaction and reduction of the ester group, yielding a separable 1 : 1 mixture of alcohols cis-5a/trans-5b. Under the standard Simmons–Smith cyclopropanation conditions, the desired products cis-6a/trans-6b were obtained with excellent stereoselectivity, which was attributed to the strong directing effect of the adjacent dioxane.^48,49 After six-step functional group transformations, a remarkable SmI₂-initiated radical cascade reaction of aldehyde 7 generated the key 5/5/3 tricyclic intermediate 8, which was subsequently converted to terminal diene 9via an additional five-step sequence. Finally, the application of a second-generation Grubbs catalyst in an RCM reaction, followed by a Swern oxidation step, successfully delivered (±)-naupliolide (3) (18 LLS, 1.2% overall yield).

Scheme 1 Simmons–Smith cyclopropanation in the total synthesis of (±)-naupliolide (Ito, 2016).⁴⁷

2.2 Diazo-derived carbenoid addition

The transition metal-catalyzed diazo-derived carbenoid addition is another powerful method for converting alkenes into cyclopropanes in NP syntheses.⁵⁰ α-Diazocarbonyls are versatile synthons in this transformation, and can be easily prepared from readily accessible precursors.²⁸ The electrophilic metal carbenoids, generated in situ via the interaction of transition-metal catalysts with diazo compounds containing electron-withdrawing groups, are highly reactive species and are proposed as crucial intermediates in the cyclopropanation process (Fig. 4).^51,52 Highly effective and stereoselective syntheses of functionalized cyclopropanes have been achieved using catalysts based on copper, rhodium, and more recently, ruthenium.

Fig. 4 Transition-metal-catalyzed cyclopropanation by decomposition of diazo alkanes.

Shi/Cao's synthesis of (+)-cycloclavine (2019). Cycloclavine (11), an ergot alkaloid, was first isolated in 1969 from the seeds of the African morning glory (Ipomea hildebrandtii) by Hofmann and co-workers.⁵³ Despite having a compact size (MW = 238), cycloclavine possesses a pentacyclic core featuring a unique 3-azabicyclo[3.1.0]hexane motif. The sterically congested cyclopropane ring, along with three contiguous stereocenters, two of which are fully substituted and part of the cyclopropane ring, poses a significant synthetic challenge. In 2019, Shi, Cao, and co-workers disclosed a concise and efficient asymmetric formal synthesis of (+)-cycloclavine (11), featuring a Rh-catalyzed diazo-derived carbenoid cyclopropanation and an ester aminolysis cyclization (Scheme 2).⁵⁴ The synthesis started with the known five-step conversion of 4-bromoindole 12 into the known Ellman (S)-N-tert-butanesulfinyl imine 13, which reacted with vinylmagnesium bromide, giving a pair of separable diastereomers 14 and 15. Then, N-methylation of 14 followed by the Heck reaction afforded the 6-exo-trig cyclization product 16. At this point, terminal alkene 16 underwent a stereoselective Rh-catalyzed cyclopropanation with ethyl 2-diazopropanoate, delivering 17 as a single diastereomer. Then, another three-step manipulation involving an ester aminolysis cyclization smoothly produced lactam 18, completing the formal synthesis of (+)-cycloclavine (11) (13 LLS, 2.0% overall yield).⁵⁵

Scheme 2 Rh-catalyzed diazo-derived carbenoid cyclopropanation in the formal synthesis of (+)-cycloclavine (Shi/Cao, 2019).⁵⁴

Tu's synthesis of (+)-niduterpenoid B (2024). Niduterpenoid B (19), a naturally occurring ERα inhibitor isolated from Aspergillus nidulans, is a unique sesterterpenoid featuring five cyclopentane rings and one cyclopropane ring.⁵⁶ The intriguing 5/5/5/5/3/5-fused hexacyclic skeleton in combination with 13 contiguous stereocenters renders niduterpenoid B (19) a formidable synthetic challenge. Very recently, Tu's group reported the first total synthesis of this sesterterpenoid,⁵⁷ employing an intramolecular Rh-catalyzed [2 + 1] cycloaddition to forge the pentasubstituted cyclopropane ring (Scheme 3).

Scheme 3 Rh-catalyzed intramolecular diazo-derived carbenoid cyclopropanation in the total synthesis of (+)-niduterpenoid B (Tu, 2024).⁵⁷

They hypothesized that the fused 3/5 bicyclic skeleton (E/F rings) would be installed at a late stage and the tetraquinane (A–D rings) would be introduced via a tandem Nazarov cyclization and double ring expansions of 1,3-dicyclobutylidene acetone.⁵⁸ Their endeavor commenced with known cyclobutanone 20, which was elaborately transformed into dienone 21 on a decagram scale in 4 steps, involving the Horner–Wadsworth–Emmons (HWE) reaction, hydrolysis of methyl ester, β-ketone ester formation, and Knoevenagel condensation. After optimization of various reaction parameters, the desired tandem 4π electrocyclization/double ring expansions/elimination reaction was conducted to give the congested tetraquinane 22 in 41% yield by treatment with B(C₆F₅)₃, CSA and 4 Å molecular sieves. Based on a further five-step manipulation, 22 was converted to carboxylic acid 23. Treatment of freshly prepared diazoethane with acyl chloride, derived from acid 23 and oxalyl chloride, produced diazoketone 24 in 70% yield. Notably, the intramolecular [2 + 1] cycloaddition occurred smoothly in the presence of catalytic amounts of [Rh(OAc)₂]₂, affording the cyclopropanation product 25 in 83% yield as a single isomer. The high diastereoselectivity in cyclopropanation can be attributed to steric hindrance on the concave face of the C/D rings, which renders the convex face more accessible. This key transformation forges the strained 3/5 bicycle (E/F rings) angularly fused with ring D in one step. With 25 in hand, (+)-niduterpenoid B (19) was finally synthesized via an additional five-step sequence (17 LLS, 0.09% overall yield).

2.3 Free carbene addition

In the 1950s, Doering and Hoffmann reported that exposure of haloform 26 (X = Br and Cl) to cyclohexene 27 in the presence of t-BuOK delivered halogen-substituted norcarane 28 (Fig. 5).⁵⁹ This reaction provided evidence for the formation of dihalocarbene via the deprotonation of the haloform followed by loss of the halide ion from the trihalomethyl anion. Subsequent nucleophilic bismethylation with MeI gave the gem-dimethyl cyclopropane subunit. This two-step sequence is widely employed in the total synthesis of gem-dimethyl cyclopropane-containing NPs,⁶⁰ particularly, Euphorbia diterpenoids.

Fig. 5 Cyclopropanation through addition of free carbenes to olefins.

Li's synthesis of (+)-pedrolide (2024). Pedrolide (29), isolated in 2021 from Euphorbia pedroi by Ferreira and co-workers,⁶¹ is a noncytotoxic diterpenoid with P-glycoprotein-based multidrug-resistance reversal activity. Structurally, the highly oxygenated pedrolide features an unprecedented cage-like 5/5/6/6/3 hexacyclic core composed of a distinctive bridged bicyclo[2.2.1]heptane ring system. The integration of this complex ring system with 12 contiguous stereocenters presents a formidable challenge for this total synthesis.

Very recently, Li and co-workers described the elegant total synthesis of pedrolide (29) (Scheme 4),⁶² by employing dibromocarbene cycloaddition followed by bismethylation to forge the gem-dimethylcyclopropane ring moiety. The synthesis commenced with the preparation of tricycle 32 from cyclopentadiene 30 and 31 through a streamlined one-pot method involving an enantioselective ene reaction, Wittig reaction, and intramolecular Diels–Alder (IMDA) reaction. A further 8-step functional group manipulation was required to convert 32 into cyclohexene 33. At this point, however, despite testing several slightly modified substrates (e.g.I, II, and III) and employing different approaches (Wender's photolysis of cyclic diazene, MIRC reaction with sulfur ylide, and Baran's TFAA-promoted cascade rearrangement of β-hydroxy diketone) for cyclopropane ring formation, all attempts ultimately resulted in failure. Moving forward, sequential oxidation of 33 followed by enolization and silyl etherification afforded 34 in 51% yield. Fortunately, the dibromocyclopropanation of enol ether 34 proceeded with exclusive diastereoselectivity, and subsequent nucleophilic dimethylation using LiCuMe₂/MeI successfully assembled the requisite gem-dimethyl cyclopropane subunit in 35. This conversion provides a new approach for the efficient and diastereoselective construction of the highly oxygenated carane moiety that is usually found in numerous NPs of the tigliane type.⁶³ Finally, after peripheral functional group adjustment, (+)-pedrolide (29) was successfully obtained (17 LLS, 0.45% overall yield).

Scheme 4 Free carbene cyclopropanation in the total synthesis of (+)-pedrolide (Li, 2024).⁶²

2.4 MIRC cyclopropanation

Michael-initiated ring-closure (MIRC) cyclopropanation is a process that typically involves a domino reaction. This reaction sequence consists of two steps: a conjugate addition to an electrophilic alkene, and subsequently, an intramolecular ring closure of the generated carbanion (Fig. 6).^30,36 In these reactions, the leaving group can be located either on the alkene or the nucleophile itself. The frequently used reagents for MIRC reactions are heteroatom-derived ylides such as sulfur (Corey–Chaykovsky cyclopropanation)^64,65 and ammonium ylides.⁶⁶

Fig. 6 MIRC cyclopropanation reaction.

Reddy's synthesis of (−)-nardoaristolone B (2016). Nardoaristolone B (36), possessing an aristolane norsesquiterpenoid skeleton with an unusual 3/5/6 tricyclic ring system, was isolated from the underground parts of Nardostachys chinensis Batal.⁶⁷ In 2016, Reddy's group achieved the stereoselective synthesis of nardoaristolone B, relying on a stereoselective MIRC cyclopropanation (Scheme 5).⁶⁵ The synthesis commenced with the preparation of diene 37 from the commercially available (+)-(R)-pulegone over eight steps. Treatment of 37 with a second-generation Grubbs catalyst initiated an RCM reaction, leading to the generation of hydrindane derivative 38, which was then oxidized to dienone 39. Finally, treatment of 39 with isopropyldiphenylsulfonium tetrafluoroborate in the presence of t-BuLi effectively initiated a stereoselective MIRC cyclopropanation reaction, and the gem-dimethyl cyclopropyl group was successfully installed, resulting in the desired product (−)-nardoaristolone B (36) in 35% yield, and its isomer 40 in 13% yield (11 LLS, 3.0% overall yield).

Scheme 5 MIRC cyclopropanation in the total synthesis of (−)-nardoaristolone B (Reddy, 2016).⁶⁵

Vijaykumar's synthesis of (−)-phellilane L (2021). In 2004, Gaunt's group reported a general and practical intermolecular enantioselective organocatalytic cyclopropanation reaction via ammonium ylides.⁶⁸ Vijaykumar and co-workers realized the potential of this methodology to provide a concise synthetic route toward phellilane L (41),⁶⁶ a cyclopropane-containing sesquiterpenoid bearing four contiguous stereocenters (Scheme 6).⁶⁹ Initially, TiCl₄-catalyzed chiral auxiliary-controlled diastereoselective [4 + 2] cycloaddition of 42 with 43 provided cyclohexene 44 in 79% yield. Subsequently, compound 44 was converted to enone 45via a three-step synthetic sequence, including saponification, Weinreb amide formation, and Grignard addition. Following Gaunt's procedure, the enantioselective MIRC cyclopropanation of enone 45 with 2-bromo-N,O-dimethylacetamide 46 in the presence of the quinine ligand L1 and Cs₂CO₃ resulted in 48 in 86% yield. In this system, the α-bromo carbonyl compound 46 underwent an S_N2 displacement with the tertiary amine catalyst L1 to form a quaternary ammonium salt, which was followed by deprotonation with a mild base to give the ylide intermediate 47. Finally, diastereoselective methylation using methyl magnesium bromide accomplished the total synthesis of (−)-phellilane L (41) (6 LLS, 36.1% overall yield).

Scheme 6 MIRC cyclopropanation in the total synthesis of (−)-phellilane L (Vijaykumar, 2021).⁶⁶

2.5 1,n-Enyne cyclization

The transition-metal-catalyzed transformation of 1,n-enynes has played an important role in the preparation of diverse cyclic structures including cyclopropanes,^23,31 with Au catalysts being extensively utilized for catalyzing these cyclization reactions. Unlike traditional metal carbene chemistry, cyclopropanation of 1,n-enynes can proceed in either a concerted or stepwise manner, depending on the substrates and the type of Au species.⁷⁰

Yang's synthesis of (−)-pre-schisanartanin C (2020). Pre-schisanartanin C (49), a Schisandra triterpenoid isolated by Sun and colleagues in 2010 from the medicinal plant Schisandra propinqua var. propinqua, exhibits potent antitumor, anti-hepatitis, and anti-HIV properties.⁷¹ The salient structural feature includes a highly substituted bicyclo[6.1.0]nonane core, incorporating an all-carbon quaternary stereocenter at C13.

In 2020, Yang's group reported an enantioselective synthesis of (−)-pre-schisanartanin C (49) (Scheme 7).⁷² Key to the successful synthesis lies in a Au-catalyzed intramolecular cyclopropanation reaction of a 1,8-enyne containing an ester group at the propargylic position to forge the bicyclo[6.1.0]nonane motif. Their pursuit of (−)-pre-schisanartanin C (49) began with the synthesis of bicyclic fragment 52 from diene 50 and dienophile 51 in five steps, which was further elaborated to advanced 1,8-enyne 53 in additional 7 steps. At this point, treatment of enyne 53 with AuCl under strictly anhydrous conditions gave the desired product 55 in 35% yield, together with allenyl ester 56 (52%) as the major product. This cyclopropanation process involved a Au-mediated 1,2-shift of the propargyl ester to form a Au-stabilized vinyl carbenoid 54, which then underwent intramolecular cyclization to produce 55. Of note, protection of the C22-OH with a benzyl group resulted in a complicated mixture in the Au-catalyzed enyne cyclization due to a benzylic hydrogen shift to the vinyl gold carbene complexes generated in situ.⁷³ Alternatively, the use of ^pFBn as a protecting group effectively prevented this type of oxidation. Different conditions were explored to facilitate the conversion of 53 into 55, including variations in solvents, catalysts, substrate concentrations, and the application of heat, radiation, or ultrasound. However, the reaction was complicated by substrate or product decomposition and the formation of unidentifiable side products. Fortunately, 56 could be slowly converted to 55 under the same conditions via intermediate 54.⁷⁴ After the diastereoselective construction of the bicyclo[6.1.0]nonane core in 55, (−)-pre-schisanartanin C (49) was synthesized in 11 additional steps (24 LLS, 1.3% overall yield).

Scheme 7 1,n-Enyne cyclization in the total synthesis of (−)-pre-schisanartanin C (Yang, 2020).⁷²

3. Intramolecular 1,3-cyclization

1,3-Cyclization reactions refer to the formation of cyclopropane rings through the creation of a C–C bond in the fleeting precursors such as 1,3-zwitterions, homoallylic radicals, and homoallylic cation species.^75–77 Intramolecular direct 1,3-ring-closure strategies provide an efficient route to assemble polysubstituted cyclopropanes that are embedded in complex carbon backbones, despite the entropic disadvantages of these processes. Such approaches, mainly involving radical cyclization, cyclization via homoallylic elimination and intramolecular nucleophilic cyclization, can be performed in a highly regio- or stereoselective fashion, and have gained widespread use in the total syntheses of cyclopropane-containing NPs.

3.1 MHAT based radical cyclopropanation

The metal-hydride hydrogen atom transfer (MHAT) reaction plays an important role in C–H, C–C, and C–X bond-forming reactions.⁷⁸ In 2014, Baran and co-workers reported a practical transformation that allowed the direct coupling of inert olefins with electron-deficient olefins in both intra- and intermolecular settings utilizing an iron catalyst and an inexpensive silane (Fig. 7).^79,80 This reaction involves an Fe-catalyzed transformation of substituted olefins into the nucleophilic radical via hydrogen atom transfer (HAT) and a subsequent Giese conjugate addition to electron-deficient olefins, generating hindered bicyclic systems, vicinal quaternary centers, and even cyclopropanes. This transformation enables the facile exploration of underdeveloped chemical space and provides an alternative to other established retrosynthetic C–C bond disconnections.

Fig. 7 Radical-mediated 1,3-cyclization to cyclopropane via MHAT.

Dai's synthesis of (−)-peyssonnoside A (2022). In 2022, Dai's group reported the elegant application of this method to construct cyclopropane in NPs, ultimately facilitating a concise 13-step total synthesis (Scheme 8) of (−)-peyssonnoside A (57),⁸¹ a sulfated diterpenoid glycoside featuring a highly substituted and sterically encumbered cyclopropane ring, isolated from the marine red alga Peyssonnelia sp.⁸²

Scheme 8 MHAT-based radical cyclopropanation in the total synthesis of (−)-peyssonnoside A (Dai, 2022).⁸¹

Their efforts began with a Cu-catalyzed enantioselective conjugate addition/enolate alkylation reaction, delivering ketone 59 in 61% yield. A four-step operation was implemented to transform 59 into 60 involving palladium-catalyzed regioselective syn-hydro-arylation, enantioselective hydrogenation, vinyl triflate formation, and demethylation processes. Then, compound 60 underwent dearomative cyclization, catalyzed by [Pd(cinnamyl)Cl]₂/RuPhos, giving rise to tricyclic product 61. Inspired by the plausible biosynthetic pathway of peyssonnoside A, they envisioned a HAT-initiated intramolecular radical cyclization of 61 to form the pentasubstituted cyclopropane. Pleasingly, upon treatment of 61 with Fe(acac)₃ and PhSiH₃ in EtOH, the desired cyclopropane product 62 was obtained with good conversion. This work exemplified the first application of MHAT in constructing rigid cyclopropanes in the total synthesis of NPs, highlighting the practicality of Baran's iron-catalyzed methodology for C–C bond formation. Moving forward, 62 underwent a requisite six-step functional group manipulation, delivering the target (−)-peyssonnoside A (54) (13 LLS, 3.3% overall yield).

Carreira's synthesis of (+)-pedrolide (2023). Carreira's group also employed this method with great success in their total synthesis of pedrolide (29) (Scheme 9).⁸³ Key to the success lies in the use of an Fe-catalyzed radical cyclization that provides a novel approach for the synthesis of a densely functionalized carane, as well as an intramolecular cyclopentadiene-Diels–Alder cycloaddition to achieve the bicyclo[2.2.1]heptane ring system. The synthesis was initiated with the preparation of the highly substituted carane 66. Commercially available phenol 63 was converted to the known enone 64 in two steps. Subsequently, a four-step reaction sequence including Rubottom oxidation, diastereoselective isopropenyl Grignard addition, ketal deprotection, and diol protection afforded the cyclization precursor 65. The following trials based on Baran's well-established conditions (Fe(acac)₃, PhSiH₃, and EtOH) resulted in intramolecular Giese addition, yielding the desired cyclopropyl ketone 66 in excellent yield (98%). Of note, this HAT-promoted cyclopropanation delivered the fully functionalized carane fragment of pedrolide in an efficient manner. Subsequent installation of a side-chain at C8 followed by the introduction of the norbornadiene moiety at C9 furnished alcohol 67. Then, a three-step sequence including chemo-selective removal of the silyl ether, oxidation/lactonization, and elimination of the hydroxy group led to enoate 68. Next, a tetrazine-promoted complex Diels–Alder reaction cascade of 68 smoothly produced the cage-like bicyclo[2.2.1]heptane 69. Epoxidation of 69 using m-CPBA followed by Me₂CuLi-mediated regioselective epoxide opening delivered the desired methylated product 70 as a single regioisomer, thus allowing the Dess–Martin oxidation, silyl deprotection, and acylation of alcohols to complete the total synthesis of (+)-pedrolide (29) (20 LLS, 0.12% overall yield).

Scheme 9 MHAT-based radical cyclopropanation in the total synthesis of (+)-pedrolide (Carreira, 2023).⁸³

Fan's synthesis of (−)-trachinol (2022). The ent-kauranes and ent-trachylobanes are biosynthetically related families of diterpenoid NPs. Structurally, ent-trachylobane diterpenoids are distinguished by the additional C12–C16 bond, leading to the formation of a rigid cyclopropane embedded within a [3.2.1.0^2,7]-tricyclic system. Recently, Fan and co-workers disclosed a unified strategy by exploiting late-stage skeletal diversification of ent-kaurane and ent-trachylobane scaffolds to achieve the synthesis of nine C8-ethano-bridged diterpenoids, including trachinol (71), an ent-trachylobane diterpenoid (Scheme 10).⁸⁴ The task commenced with the preparation of aldehyde 74 and bromide 75 from known chiral cyclohexenone 72 and γ-cyclogeraniol 73. Then, the two monoterpene-like fragments were merged via a lithium-mediated Barbier allylation reaction to furnish alcohol 76. Sequential oxidation of 76 using IBX and Dess–Martin periodinane gave ene-enone 77 in 91% yield. Subsequently, the key MHAT cyclization of 77 was investigated. Upon treatment with Fe(acac)₃, PhSiH₃, Na₂HPO₄·12H₂O, and EtOH/(CH₂OH)₂, surprisingly, ent-trachylobane 80 was directly obtained in 49% yield with >20 : 1 dr. This Fe-mediated HAT reaction involved a classical coupling of the inert Δ¹⁰⁽²⁰⁾ olefin with the electron-deficient Δ⁹⁽¹¹⁾ olefin to form ent-kaurane 78 followed by a radical cyclopropanation of the Δ¹⁶⁽¹⁷⁾ olefin with the keto group⁸⁵via radical 79 to produce ent-trachylobane 80. This hypothesis was confirmed by the fact that exposing 78 to identical conditions also led to 80 with similar reactivity (72% yield). Notably, this MHAT reaction opens a way from the tetracyclic ent-kaurane core to the pentacyclic ent-trachylobane core. With 80 in hand, Barton–McCombie deoxygenation of C12-OH followed by Meerwein–Pondorf–Verley reduction of the C7-keto motif successfully delivered (−)-trachinol (71) (10 LLS, 3.3% overall yield).

Scheme 10 MHAT-based radical cyclopropanation in the total synthesis of (−)-trachinol (Fan, 2022).⁸⁴

3.2 Homoallylic cyclization

Direct cyclization of olefins bearing a homoallylic leaving group is an effective method for preparing cyclopropanes (Fig. 8). The resulting cyclopropyl carbinyl cation intermediate could undergo β-elimination or be trapped by a suitable nucleophile.⁷⁵

Fig. 8 Homoallylic cyclization for cyclopropane formation.

Lou's synthesis of (−)-ent-trachylobane-3β-ol (2020). In 2020, Lou and co-workers successfully accomplished the total synthesis of ent-trachylobane-3β-ol (81) by employing a bioinspired cationic cyclopropanation method as the pivotal step (Scheme 11),⁸⁶ which provided a strong chemical correlation between ent-kauranes and ent-trachylobanes. The synthesis commenced with the preparation of bicyclic bromine 83 through a four-step sequence from known enyne 82. Treatment of 83 with enol ether 84 generated coupling products 85 and epi-85 as a 3 : 2 diastereomer mixture. The subsequent de Mayo reaction of 85 under photoirradiation delivered tetracyclic intermediates 86′ and 87′, which were converted into ent-kaurene-type 86 and ent-phyllocladene-type 87 after an acidic work-up, respectively. Subsequent Wittig methenylation of 86 furnished terminal alkene 88 in excellent yield. Using 0.6 equivalents of 1 N HCl (aq), the desired cyclopropyl ketone 90 was successfully obtained through acid-promoted cyclopropanation. Alcohol 89 was considered the key intermediate for this process via the cationic cyclization process. Finally, keto removal and debenzylation resulted in the target (−)-ent-trachylobane-3β-ol (81) (15 LLS, 0.77% overall yield).

Scheme 11 Homoallylic cyclization in the total synthesis of (−)-ent-trachylobane-3β-ol (Lou, 2020).⁸⁶

Renata's synthesis of (−)-mitrephorone A (2020). In 2020, Renata and co-workers reported the divergent synthesis of complex ent-kaurane, ent-atisane, and ent-trachylobane diterpenoids through a hybrid oxidative approach that combines chemical transformations with enzymatic oxidations.⁸⁷ In this elegant work, they offered an alternative chemical correlation between ent-atisanes and ent-trachylobanes. The cyclopropane moiety in the ent-trachylobane diterpenoids, e.g. mitrephorone A (91), was formed via a crucial BF₃·Et₂O-mediated cationic cyclization (Scheme 12). The synthesis of mitrephorone A commenced with isosteviol (92), an ent-beyerane diterpenoid available in one step from stevioside ($0.65 per g). Site-selective hydroxylation of isosteviol with PtmO5-RhFRed occurred exclusively at its C12 position, affording 93 on a multigram scale. Exposure of 93 to TfOH initiated the formal Wagner–Meerwein rearrangement, delivering 94 that contains the requisite ent-atisane [2.2.2] C- and D-ring bicycle. Upon reducing the carbonyl group with L-selectride, exposure of alcohol 95 to BF₃·Et₂O and Et₃SiH enabled the formation of a new C–C bond between C13 and C16 via a nonclassical cationic cyclization, resulting in the desired cyclopropane product 96. Finally, (−)-mitrephorone A (91) was obtained through a five-step functional group operation (9 LLS, 13.3% overall yield).

Scheme 12 Homoallylic cyclization in the total synthesis of (−)-mitrephorone A (Renata, 2020).⁸⁷

Dong's synthesis of (±)-phainanoid A (2021). Phainanoid A (97), a highly modified dammarane-type triterpenoid bearing the unique benzofuranone-based 4,5-spirocycle, [4.3.1]propellane, and 5,5-oxaspirolactone moieties, was isolated from Phyllanthus hainanensis by our group in 2015.⁸⁸ Driven by the fascinating chemical structure, potent immunosuppressive activity, and hampered accessibility of phainanoid A, Dong's lab achieved the first total synthesis of phainanoid A starting from the known allyl alcohol 98 (Scheme 13).⁸⁹ The advanced vinyl triflate 100 could be obtained through bidirectional fragment assembly from tricycle 99. Next, to construct the requisite [4.3.1]propellane framework, a challenging tandem reaction involving a reductive Heck cyclization and a homoallylic cyclization was implemented. Crucially, numerous attempts highlighted the indispensable role of excess LiBr in facilitating the Ni(cod)₂-mediated Heck reaction. Specifically, the excess bromide anion may promote the reactivity of Ni(0), while the excess lithium cation could swap Ni(II) from the enolate intermediate. Smooth progression of the Et₃N-promoted homoallylic elimination of 101 led to the formation of the vinylcyclopropane moiety. Remarkably, this cascade reaction efficiently forged two rings and three contiguous stereocenters in a single step, building the core structure of the phainanoid NPs. Finally, the resulting 102 was further elaborated to the target product (±)-phainanoid A (97) in two additional steps (29 LLS, 0.012% overall yield).

Scheme 13 Homoallylic cyclization in the total synthesis of (±)-phainanoid A (Dong, 2021).⁸⁹

3.3 Intramolecular nucleophilic substitution

Generally, under basic conditions, substrates bearing an electron-withdrawing group and a γ-position leaving group can undergo an intramolecular S_N2 reaction to form cyclopropane (Fig. 9). The electron-withdrawing groups are usually carbonyl groups, and the leaving groups include epoxides, OMs,^90,91 OTs, X,^92,93 and others.

Fig. 9 Construction of cyclopropane via intramolecular nucleophilic substitution.

Peng's synthesis of (±)-shizukaols A and E (2018). Lindenane sesquiterpenoids, possessing a special 3/5/6 linear tricyclic skeleton, are the characteristic metabolites of the Chloranthaceae family, and exhibit a wide spectrum of bioactivities.^94,95 Most of them exist as dimers and biosynthetically originate from different monomers by various C–C bond connections, such as the intermolecular Diels–Alder reaction and Michael addition.¹⁰ In 2018, Peng's group completed the total synthesis of two lindenane sesquiterpenoid dimers, shizukaols A (103) and E (104), from commercially available Wieland–Miescher ketone (105) (Scheme 14).⁹¹ After a series of functional group transformations, the key cyclization precursor 106 was obtained. Upon treatment of enone 106 with KHMDS,⁹⁶ the desired cyclopropane product 107 with the desired stereochemistry was exclusively achieved in 90% yield via an S_N2-type intramolecular nucleophilic substitution. The common intermediate 107 was then transferred to monomers 108, 109, and 110 in 14, 11, and 16 steps, respectively, which underwent the biomimetic Diels–Alder reactions to give the [4 + 2]-type dimers 111 and 112 smoothly. Finally, after several steps of functional group adjustment, (±)-shizukaols A (103) and E (104) were successfully obtained (28 LLS, 0.11% overall yield for 103; 32 LLS, 0.17% overall yield for 104).

Scheme 14 Intramolecular nucleophilic substitution in the total synthesis of (±)-shizukaols A and E (Peng, 2018).⁹¹

4. Others

4.1 Intramolecular Diels–Alder (IMDA) reaction

The [4 + 2] Diels–Alder cycloaddition has been widely used for the synthesis of six-membered scaffolds. In the case of the intramolecular Diels–Alder (IMDA) reaction, an additional ring is formed, providing significant opportunities for the construction of complex polycyclic systems.⁹⁷ In 2003, Trauner et al. reported the intramolecular Diels–Alder reaction of 5-vinyl-1,3-cyclohexadienes, leading to the formation of substituted tricyclo[3.2.1.0^2,7]oct-3-enes in one step (Fig. 10).⁹⁸ In this process, a cyclopropane is generated as an appendage, and this transformation has recently been successfully applied in the total synthesis of NPs bearing a tricyclo[3.2.1.0^2,7]oct-3-ene core.^99–103

Fig. 10 Intramolecular Diels–Alder reaction for cyclopropane formation.

Qin's synthesis of (±)-vilmoraconitine (2023). In 2008, a rearranged aconitine-type C₁₉-diterpenoid alkaloid, vilmoraconitine (113), was isolated by Tan et al. from Aconitum vilmorinianum.¹⁰⁴ Compared to the conventional aconitines, a salient feature of vilmoraconitine is the additional C8–C10 bond, resulting in an unprecedented heptacyclic backbone with a pentasubstituted cyclopropane ring. In 2023, Qin's group disclosed the first total synthesis of this intriguing NP, utilizing an IMDA cycloaddition to construct the congested cyclopropane ring (Scheme 15).¹⁰³

Scheme 15 IMDA reaction in the total synthesis of (±)-vilmoraconitine (Qin, 2023).¹⁰³

The synthesis began with the preparation of bridged tricyclic intermediate 116 from aldehyde 114 and phenol 115 in 11 steps. Subjecting 116 to the slightly modified Kwon's conditions¹⁰⁵ precisely delivered aldehyde 117 in 77% yield. Then, the TFA-promoted intramolecular Mannich reaction of 117 proceeded efficiently to afford the azatetracyclic product 118, which was transformed into the pentacyclic product 119via a deft three-step operation, involving the stereoselective installation of two side chains at C10 and an intramolecular aldol reaction, which resulted in the construction of the C/G rings bearing a highly substituted cyclopropane moiety. Based on a further five-step functional group manipulation, 119 was elaborated to α,β-unsaturated cyanide 120. However, upon direct enol-silane formation from 120, the expected IMDA reaction failed at different elevated temperatures. The authors attributed the decomposition of the substrate to the presence of tertiary amines. Thus, the less reactive amide 121 was generated using I₂ and NaHCO₃. Encouragingly, subjecting 121 to a one-pot enol silane formation/IMDA process delivered the desired cyclopropane 123 in 75% yield via the enol silane 122. This approach thereby allowed access to the intact vilmoraconitine skeleton. Ultimately, (±)-vilmoraconitine (113) was produced through a sequence of four additional reactions (28 LLS, 0.96% overall yield).

Magauer's synthesis of (−)-mitrephorones A and B (2019). In 2019, Magauer and colleagues reported another ingenious example of the IMDA reaction to construct the tricyclo[3.2.1.0^2,7]oct-3-ene moiety in mitrephorones A (91) and B (124) (Scheme 16).¹⁰⁰ This transformation process not only established the chemical correlation between ent-pimaranes and ent-trachylobanes, but also offered an alternative approach to synthesize the trachylobane core, distinct from the methods developed by Lou and Renata (Schemes 11 and 12).

Scheme 16 IMDA reaction in the total synthesis of (−)-mitrephorones A and B (Magauer, 2019).¹⁰⁰

Magauer's total synthesis started with the known compound 125, which could be prepared on a multigram scale with a good overall yield. Subjecting 125 to dihydroxylation conditions produced 126, which was converted to tricyclic enone 127 by employing a two-step Robinson annulation protocol. Next, a six-step procedure enabled the transformation of 127 into 5-vinyl-1,3-cyclohexadiene 128. Subsequent heating at 170 °C triggered a clean IMDA reaction to afford cyclopropane 129 in excellent yield (98%), completing the construction of the intact ent-trachylobane skeleton. Then, a five-step functional group operation was performed on 129, providing the desired product (−)-mitrephorone B (124) (16 LLS, 4.6% overall yield). Finally, an elegant oxetane formation was achieved via C–H oxidation under the White–Chen catalyst system, yielding (−)-mitrephorone A (91) (17 LLS, 2.8% overall yield), which corroborated the hypothesized biogenetic relationship between mitrephorones B and A.

4.2 Gas extrusion

Echavarren's synthesis of (−)-lundurines A–C (2016). Gas extrusion reactions (e.g. Ramberg–Backlund reaction, dinitrogen extrusion, etc.) have primarily been employed as key strategies for inducing ring contraction in organic synthesis,¹⁰⁶ resulting in the formation of smaller, more strained ring systems, particularly, cyclopropane. These reactions typically involve the loss of small gaseous molecules, such as N₂ ^107–110 and CO₂.¹¹¹

The dihydroindole alkaloids, lundurines A–C (130–132), are distinguished by the presence of a cyclopropyl moiety embedded within the hexacyclic ring system. In 2016, Echavarren and co-workers accomplished the concise total syntheses of these three lundurine family members, relying on the N₂ extrusion approach to forge the key cyclopropane moiety (Scheme 17).¹¹² The project commenced with the preparation of alkyne 136 in two steps from oxoester 133 and 5-methoxytryptamine 134, setting the stage for the key Au(I)-catalyzed hydroarylation. This transformation was efficiently achieved with perfect 8-endo selectivity in the presence of 5 mol% AuCl to furnish cyclization product 137, which was subsequently converted to 138via a four-step sequence involving N-methoxycarbonylation, sequential oxidation, and tosyl hydrazone formation. With hydrazone 138 in hand, their next task was the crucial intramolecular cyclopropanation. However, initial efforts to synthesize 140 under various transition-metal catalyzed conditions were unsuccessful, instead resulting in the double-bond-migrated product 140′ in low yields through the N₂ extrusion of pyrazoline intermediate 139. Encouragingly, treating hydrazone 138 with BF₃·Et₂O successfully produced 140 in satisfactory yields. Subsequent experiments revealed that 140′ exhibited superior reactivity compared to 140. Fortunately, 140 could be converted into 140′via a homodienyl retro-ene/ene rearrangement. With an open approach to unexpected results, the authors not only discovered a novel transformation but also importantly, harnessed this transformation to streamline the synthesis. This achievement serves as a reminder to the synthetic chemistry community of the potential value in serendipitous discoveries and encourages a proactive approach for exploring and capitalizing on such unexpected results. Finally, advanced 140′ was transformed into (−)-lundurines A–C (130–132) via further reduction or oxidation operation (13 LLS, 3.0% overall yield for 130; 14 LLS, 3.0% overall yield for 131; 12 LLS, 6.6% overall yield for 132).

Scheme 17 N₂ extrusion in the total synthesis of (−)-lundurines A–C (Echavarren, 2016).¹¹²

4.3 Oxa-di-π-methane rearrangement

Wu's synthesis of (−)-cucurbalsaminones B and C (2024). The oxa-di-π-methane rearrangement of β,γ-unsaturated ketones, involving a formal 1,2-acyl migration and three-membered ring formation was first reported by Tenney in 1966.¹¹³ Subsequent studies by numerous researchers have underscored its significance as a highly valuable reaction in organic synthesis, especially for the efficient construction of complex polycyclic structures in one reaction step.^114,115 Very recently, the bioinspired synthesis of cucurbalsaminones B (141) and C (142) reported by Wu's group stands as an elegant example of the application of this rearrangement (Scheme 18).¹¹⁶ Their synthesis began with the preparation of epoxy 144, which could be obtained from commercially available lanosterol (143) in four steps. The subsequent BF₃·Et₂O-promoted tandem epoxide ring-opening/Wagner–Meerwein rearrangement of 144 was conducted to afford cucurbitane 145. Then, the photorearrangement precursor 146 could be obtained in 83% yield over two steps through hydrolysis of C3 acetate followed by oxidation with PCC. After extensive screenings, pleasingly, the desired oxa-di-π-methane rearrangement of β,γ-unsaturated ketone 146 proceeded smoothly to deliver cyclopropane product 147 in an impressive 73% yield under 390 nm irradiation with thioxanthen-9-one as the photocatalyst. Significantly, recognizing sunlight's capacity to mediate this transformation led to a revised biosynthetic proposal for cucurbalsaminones. Specifically, a non-enzymatic photoinduced oxa-di-π-methane rearrangement was suggested as the mechanism for forging the 5/6/3-fused ring system of cucurbalsaminones, instead of the previously proposed ionic pathway. These findings exemplify the potential of biomimetic synthesis in elucidating biosynthetic pathways. With the intact pentacyclic carbon skeleton secured, 147 was converted to (−)-cucurbalsaminones B (141) and C (142) in six additional steps (14 LLS, 0.51% overall yield for 141; 14 LLS, 0.86% overall yield for 142).

Scheme 18 Oxa-di-π-methane rearrangement in the total synthesis of (−)-cucurbalsaminones B and C (Wu, 2024).¹¹⁶

5. Conclusions

In this review, we have summarized different strategies and methods for accessing structurally diverse cyclopropane-containing NPs. The syntheses presented were selected to demonstrate the practicability of well-explored cyclopropanation methods, as well as potentially generalizable lessons from each synthesis. Generally, peripheral cyclopropane moieties can be readily constructed via intermolecular [2 + 1] cycloaddition of alkenes, such as the Simmons–Smith reaction and diazo-derived carbenoid addition. Additionally, intramolecular cyclization strategies offer greater possibility and creativity for accessing densely substituted cyclopropanes embedded within the core of structurally complicated skeletons. Overall, with a deeper understanding of cyclopropane chemistry, we believe that the continuous development of novel synthetic methodologies and strategies will undoubtedly drive future breakthroughs in the synthesis of structurally complex and biologically important cyclopropane-containing NPs.

Author contributions

Neng Wang and Jin-Xin Zhao: conceptualization, investigation, visualization, writing the original draft, and funding acquisition. Jian-Min Yue: funding acquisition, supervision, and review & editing.

Data availability

No primary research results, software or code have been included and no new data were generated or analysed as part of this review.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

The financial support from the National Key Research and Development Program of China (no. 2023YFE0206100), the National Natural Science Foundation of China (no. 82404459), the Youth Innovation Promotion Association of the Chinese Academy of Sciences (CAS) (no. 2022282), and the Shanghai Institute of Materia Medica of CAS (no. SIMM0120231001 and SIMM0120231002) is gratefully acknowledged.

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Footnote

† Contributed equally.

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