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. 2025 Oct 6;15(44):37125–37151. doi: 10.1039/d5ra04921k

A review on the sulfur ylide-mediated Corey–Chaykovsky reaction: a powerful approach to natural product synthesis

Ammara a, Asim Mansha a, Samreen Gul Khan a, Ameer Fawad Zahoor a,✉, Muhammad Jawwad Saif b, Bushra Parveen a, Muhammad Athar Saeed c, Aijaz Rasool Chaudhry d, Ahmad Irfan e, Muhammad Abbas f,✉
PMCID: PMC12499417  PMID: 41058672

Abstract

The Corey–Chaykovsky reaction is an efficient transformation in organic syntheses, which enables the construction of 3-membered cores via a sulfur ylide-mediated process. The reaction enables a simple yet versatile strategy to access cyclopropanes, epoxides and aziridines. The resulting cyclic frameworks are significantly valuable for the synthesis of several structurally complex compounds, including numerous natural products and their analogues. This review underscores the importance and utility of the Corey–Chaykovsky reaction towards the total synthesis of several classes of natural products reported since 2020.

The current review summarizes the recent applications of Corey–Chaykovsky reaction toward the total synthesis of several classes of natural products i.e., alkaloids, terpenoids, depsipeptides, polyketides and amino acids, etc.graphic file with name d5ra04921k-ga.jpg

1. Introduction

C–C bond-forming reactions are ubiquitously employed in organic transformations to carry out chain elongation and functionalization.1–3 In organic synthesis, the Corey–Chaykovsky reaction (CCR), introduced by Corey and Chaykovsky in 1960, is a significant carbon–carbon bond-forming reaction that deals with the efficacious synthesis of aziridine, cyclopropane and epoxide through the reaction of respective functionalized olefinic compounds with dimethylsulfonium methylide 1 or Corey's ylide (dimethylsulfoxonium methylide) 2 (Scheme 1). The functionalized olefinic compound may include imine, carbonyl, enones or thiocarbonyl.4–7

Scheme 1. General representation of the Corey–Chaykovsky reaction.

Scheme 1

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In the classic Corey–Chaykovsky reaction, the deprotonation of sulfoxonium and sulfonium halides generates ylides in the presence of a strong base, and the resulting ylides react with ketones/aldehydes and enones to yield oxirane and cyclopropyl-ketones, respectively. The typically used bases are NaH, tBuOK and BuLi, with THF, dioxane and DMF employed as solvents.1,8–14

Johnson and colleagues first documented the mechanism for the CCR using a carbonyl group and sulfonium ylide, which has received acceptance from the scientific community. Sulfonium ylide 5 nucleophilically attacks the electrophilic center of 6 to form a zwitterionic intermediate, A. The intermediate A yields a 3-membered ring 8, facilitated by an intramolecular SN2 reaction, where X is the nucleophile and sulfide is the leaving group (Fig. 1). For all other sulfide derivatives, the same mechanism may be employed. The sulfonium ylide, being more reactive, reacts with deactivated ketones, whereas the oxosulfonium ylide remains inert. Upon reaction via α–β unsaturated ketones, oxosulfonium selectively adds to the olefinic bond, whereas sulfonium ylide may generate oxirane or cyclopropane depending on the substituent (Fig. 1).15–17

Fig. 1. General mechanism for the Corey–Chaykovsky reaction.

Fig. 1

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Since the discovery of the Corey–Chaykovsky reaction, various research groups have employed several methodological modifications to carry out the facile synthesis of targeted molecules to address challenges such as the stereo-control, structural complexity and chemoselectivity of the reactions with α, β-unsaturated ketones. The recent methodological development of the Corey–Chaykovsky reaction includes the following: the fluoromethyl sulfonium reagent for the synthesis of fluorocyclopropane derivatives,18 Amberlyst-A26 (ref. 19) as the base for direct cyclopropanation, and a metal-free approach involving ILs20 as the catalyst and solvent. These innovations provide a valuable alternative to classical methods, enhancing the scope and versatility of the reaction.

Several heterocyclic scaffolds are of significant interest in medicinal and synthetic chemistry owing to their vast biological activities.22–24 The CCR proceeds via the introduction of sulfur ylide to electrophiles (enones, carbonyls, imines), serving as an essential tool in the formation of three-membered rings (cyclopropane, epoxide and aziridine) and a variety of different compounds.25,26 Owing to the easy handling and affordability of the reactants, the CCR is a robust technique for cyclopropane synthesis. It has gained prominence over the past decade due to the significant advancement of donor–acceptor cyclopropane chemistry.27–30 Cyclopropanes are ubiquitous moieties with versatile effects in agrochemicals and pharmaceuticals.31 Several biologically active natural products have also been found to include a cyclopropane ring in their structural frameworks.32–35

The Johnson–Corey–Chaykovsky epoxidation is a pioneering synthesis technique for a structurally versatile class of terminal oxiranes.36 The asymmetric version of CCR (via a chiral sulfide) has been developed over the past thirty years to complement alkene epoxidation.7,37–41 The retro-Corey–Chaykovsky epoxidation involves the efficient transformation of epoxides to ketones in a non-oxidative and mildly basic environment.42 The aza-Corey–Chaykovsky reaction was first reported by Aggarwal et al. as an efficacious carbenoid-addition approach to attain aziridines.43,44 The modification in traditional aza-CCR not only addresses the limitations in ketimine aziridination but also provides a practical route for the development of complex amino acid derivatives, reinforcing the versatility of Corey's original approach in modern synthetic strategies.45

The synthesis of natural products has always been a challenging and interesting subject for synthetic researchers.46–49 The CCR provides a simple yet versatile strategy to convert any ethylenic moiety and, further, to develop natural products and structurally complex compounds.50–52 E. J. Corey and his research group developed many new synthetic substances with intricate organic frameworks. They also carried out the total synthesis of significant natural compounds that encouraged the development of organic syntheses in recent years.53 The Corey–Chaykovsky reaction has been found to be involved in the generation of a variety of lactones,54 heterocyclic compounds,55 and functionalized furans56 as well as in the remolding of pyridium salts.57 The asymmetric CC cyclopropanation58 also finds its applications towards the synthesis of dihydofurans and several new classes of hydrofluorenones.59 In addition, asymmetrical intramolecular CC epoxidation has been reported to obtain vepdegestrant.60 Till now, various natural products and synthetic analogs of natural products (aza-cryptophycin)61 have been synthesized by incorporating the CCR as one of the significant steps, thereby highlighting its importance. Some of these bioactive natural products, such as (+)-varitriol 9,62 uovalicin 10,63 naphthotectone 11,64 2,3-methano-β-proline derivative 12 (ref. 65) and MF-310 13 (ref. 66) have been successfully synthesized by the CCR, whose structures are displayed in Fig. 2.

Fig. 2. Structures of natural products formed by employing the CCR as a key step.

Fig. 2

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Altogether, the chemically stable and economical sulfur ylide reagents, regio and stereoselectivity, wide substrate scope, mild conditions, good yields and metal-free approach demonstrate the noteworthiness of the CCR for synthesizing various natural products. To date, only two reviews have been published featuring the applications of the CC cyclopropanation67 and the methodological developments of the CCR, along with the total synthesis of natural products.60 The purpose of our review is to highlight the recent applications of the Corey–Chaykovsky reaction as a pivotal step to access the diverse range of natural products reported since 2020.

2. Literature review

2.1. Synthesis of alkaloid-based natural products

The structures of two novel marine-derived chiral alkaloids, i.e., marinoaziridine A and B, were isolated from the marine Gram-negative bacteria (Cytophagales order).68 Marinoaziridines not only possess the therapeutically interesting quinolin-2(1H)-one ring but also the aziridine rings69–71 featuring one stereocenter, allowing two enantiomers of each product. Both enantiomers are capable of exhibiting selective and distinct bioactivity.

In 2024, Buljan et al.72 reported the total synthesis of (±)-marinoaziridine B 19, which involved the Staudinger reaction and the Johnson–Corey–Chaykovsky epoxidation as key steps.73 Attempts to synthesize (±)-marinoaziridine A have not been successful so far, yielding only its (±)-N-methyl derivative 20. Bulijan and coworkers explored the synthetic pathway involving the reaction of aniline 14 with ethyl acetoacetate 15via microwave irradiation to furnish compound 16 in 68% yield, which in turn was subjected to the Knorr reaction, followed by Riley's oxidation74 to accomplish aldehyde 17 in 55% yield. Moving forward, the Corey–Chaykovsky reaction between aldehyde 17, sulfonium salt A (obtained by an AgBF4-mediated reaction between 2-iodopropane and dimethyl sulfide75) and the in situ base-generated sulfur ylide, utilizing t-BuLi as the base in tetrahydrofuran, produced (±)-marinoepoxide 18 (at −78 °C to −40 °C) in 14.6% yield.73 Consequently, the epoxide 18 was subjected to a multiple-step process to generate (±)-marinoaziridine B 19 in 80% yield, which was transformed into (±)-N-methyl marinoaziridine A 20 in 91% yield by utilizing MeI reagent and sodium hydride as the base (Scheme 2).

Scheme 2. Synthesis of (±)-marinoaziridine B 19.

Scheme 2

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Sarpagine alkaloids are members of the monoterpene indole alkaloid family, mainly isolated from plant families (Apocynaceae and Gelsemiaceae).76–80 Structurally, they are characterized by a cage-shaped core framework, involving indole-fused azabicyclo[2.2.2]octane and azabicyclo[3.3.1]nonane as substructures. Ajmaline, a notable analog of sarpagine alkaloid, is diagnostically used for Brugada syndrome.81 Koumine alkaloids, originating from sarpagine alkaloids,82,83 exhibit a wide range of analgesic, anti-tumor, immunomodulatory and anti-inflammatory properties.84,85 However, the putative bioactivities of sarpagine alkaloids are yet to be explored, presumably because of their scarce nature.

In 2021, Yang et al.86 strategically developed a unified total synthetic pathway for both Koumine and Sarpagine alkaloids, utilizing the Corey–Chaykovsky reaction as one of the key steps. Their strategy involved using l-tryptophan 21 (ref. 87) as a starting material for the construction of cage intermediate 22 in a multiple-step process, featuring allene and ketone groups. The assembly of a cage scaffold of intermediate 22 involves two structural transformations: (a) formation of the bicyclo[2.2.2]octane core via ketone α-allenylation and (b) construction of the bicyclo[3.3.1]nonane core through intramolecular oxidative cyclopropanol cyclization. Their strategy enabled the synthesis of a wide range of sarpagine alkaloids with different substituents after accessing the key precursor 22. The intermediate 22 was subjected to the Corey–Chaykovsky reaction in the presence of Me3SOI and sodium hydride in DMSO at room temperature for 6 hours to obtain epoxide 23 in 90% yield. Upon the treatment of epoxide 23 with MABR (methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide)), followed by partial allene hydrogenation, (+)-vellosimine 24 was afforded in good yield (>20 : 1 E/Z selectivities). Conversely, epoxide 23 was transformed into alcohol 25 (88%) by treating it with DIBAL-H, which was further converted into (+)-normacusine B 26 (>20 : 1 E/Z) by partial allene hydrogenation. However, the protection of the hydroxyl group and nitrogen atom of alcohol 25 as a borane-complexed silyl ether, the oxidation/hydrogenation of the allene moiety using Ma's protocol,88 and silyl group deprotection and borane removal led to the preparation of (−)-trinervine 27 in 40% yield. Next, the Corey–Chaykovsky reaction of intermediate 22 with Me3SI ylide, NaH in DMSO/THF (at 65 °C to 0 °C, then at rt, 6 h) afforded epoxide 28 in 92% yield, along with the addition of the –Me group on the indole nitrogen. Treating compound 28 with MABR produced compound 29 in 78% yield, which was further subjected to halogenation and partial hydrogenation to achieve (+)-Na-methyl-16-epipericyclivine 30 in 76% yield.89 Conversely, the reduction of 28 followed by partial hydrogenation afforded (+)-affinisine 31 in 65% yield (Scheme 3).

Scheme 3. Synthesis of sarpagine alkaloids.

Scheme 3

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Reserpine and its congener deserpidine are significant Rauwolfia alkaloids that were extracted in the 1950s.90–92 They have the potential to exhibit sedative and anti-hypertensive activities.93 Both molecules are composed of a yohimbine scaffold and a highly functionalized cyclohexane ring; thus, the construction of these molecules poses a significant synthetic challenge. The total synthesis of naturally occurring deserpidine has rarely been reported compared to the case with reserpine,94–99 and the only available asymmetric strategy involves the conversion of reserpines to deserpidine.99 Wu and co-workers99 accomplished the first asymmetric total synthesis of a stereoisomer of deserpidine in 2021 by employing a visible-light-induced radical cascade strategy100 involving the Corey–Chaykovsky reaction as a significant step. To synthesize the deserpidine with a complete corynanthe scaffold, they aimed to assemble the tetracyclic ring system through the inter/intramolecular radical cascade reaction, which proceeded by ring formation.

The synthetic endeavor towards the total synthesis of deserpidine was commenced with the preparation of pentacyclic compound 33 as a pair of inseparable diastereomers (6 : 1) in 50% yield via a multiple-step approach from the chiral aldehyde 32. For late-stage synthesis, the van Leusen reaction101 failed to transform the ketone into a nitrile, generating an intermediate in only 24% yield. Therefore, the Corey–Chaykovsky reaction was performed with compound 33 by utilizing Me3SI and tBuOK in the presence of a solvent at room temperature, which resulted in epoxide 34 (72%, confirmed by X-ray). Subsequently, the epoxide 34 underwent reductive ring opening to afford separable diastereomers 35a (65%) and 35b (23%). Isomers 35a and 35b were subjected to a multiple-step approach to accomplish 16,17,20-epi-deserpidine 36 (69%) and a lactone derivative 37 (50%) of (−)-deserpidine, respectively (Scheme 4).

Scheme 4. Synthesis 16,17,20-epi-deserpidine 36.

Scheme 4

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2.2. Synthesis of terpene-based natural products

2.2.1. Synthesis of sesquiterpenoid-based natural products

(R)-Curcuquinone 43 is a member of the bisabolene family of sesquiterpenes exhibiting anti-fungal and anti-microbial properties. In 2024, Bellido et al.102 documented the enantioselective formal synthetic route to (R)-curcuquinone 43 to illustrate the applicability of an improved methodology for the regioselective ring opening of oxetane utilizing Lewis superacid Al(C6F5)3. Their strategy featured the Ir-catalyzed asymmetric hydrogenation approach via the Ir-UbaPHOX ligand103 to induce chirality and a double Corey–Chaykovsky reaction to synthesize the key intermediates,104 which were pivotal for the synthesis of targeted natural products.

The seven-step total synthesis of chiral curcuquinone 43 began with the conversion of the acetophenone 38 to p-methoxyphenyl oxetane 39via a double Corey–Chaykovsky reaction employing trimethylsulfoxonium iodide and t-butoxide in the presence of t-BuOH at 70 °C for 2 days to afford the oxetane 39. Proceeding, the highly selective homoallylic alcohol 40 was achieved in 71% yield by the Al(C6F5)3-catalyzed regioselective ring opening of oxetane 39 in toluene. Subsequently, homoallylic alcohol 40 was treated with iodine, triphenylphosphine and imidazole through the Appel reaction, followed by sodium phenyl sulfinate substitution to generate homoallylic sulfone 41 in 52% yield. The Ir-catalyzed asymmetric hydrogenation of sulfone 41 gave the enantioselective compound 42 (91%, 96% ee). Then, the enantioselective product 42 was processed through a few steps to give (R)-curcuquinone 43 in 10% overall yield (Scheme 5).

Scheme 5. Synthesis of (R)-curcuquinone (R)-43.

Scheme 5

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Curcumene 49 belongs to the bisabolane family of sesquiterpenes,105,106 which displays a broad spectrum of bioactivities. They are widely recognized as traditional medicines107,108 and exhibit distinct enantiomeric properties. In particular, (S)-α-curcumene is used as an insecticide, whereas (R)-α-curcumene exhibits anti-tumor and anti-microbial properties.109,110 The stereogenic α-methyl aromatic moiety is the key feature of many natural products and pharmaceutical drugs. In 2023, Bellido et al.110 described the method for the asymmetrical total synthesis of (−)-curcumene 49, involving the synthesis of homoallylic sulfones, Ir-catalyzed asymmetric hydrogenation and Corey–Chaykovsky reaction as pivotal steps. The homoallylic alcohols served as precursors for the synthesis of the corresponding homoallylic sulfones. In the foremost step, oxetane 45 was synthesized from aryl methyl ketone 44via a double Corey–Chaykovsky reaction.111 The B(C6F5)3-catalyzed regioselective isomerization of oxetane 45 generated homoallylic alcohol 46 in excellent yield (91% yield),112 and the Appel reaction and nucleophilic substitution reaction yielded homoallylic sulfones. Subsequently, the iridium-catalyzed asymmetric hydrogenation of homoallylic sulfones was studied by utilizing a substrate and Ir-Ubaphox catalyst {[(4S,5S)-Cy2-Ubaphox]Ir(COD)} BArF (C1),113 to obtain γ-chiral sulfones. The reaction proceeded effectively at 1 bar H2, with 93% ee yield obtained at room temperature.114 By increasing pressure (15–50 bar), the enantioselectivity of the reaction reduced due to isomerization,115 whereas it increased by lowering the temperature to −20 °C up to 97% ee. The α-deprotonation of γ-chiral sulfones utilizing LDA/TMEDA, followed by alkylation with 2,2-dimethyloxirane,116 afforded 48 as a 2 : 1 mixture of diastereomers. The dehydration of 48 yielded an olefin under reflux conditions. In addition, the sulfone group was eliminated using a Pd-catalyzed methodology involving LiHBEt3 (superhydride) under mild conditions,117 thereby resulting in (R)-(−)-curcumene 49 in 72% yield (Scheme 6).

Scheme 6. Synthesis of (R)-(−)-curcumene 49.

Scheme 6

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Linariophyllenes A–C were isolated from Evolvulus linarioides, which belong to the caryophyllane-type sesquiterpenoid family. The biosynthetic modifications of β-caryophyllene or its oxide result in the generation of these natural products. Linariophyllenes A–C have been found to exhibit anti-inflammatory properties, particularly linariophyllene B.118 In 2023, Stakanovs et al.119 developed a semisynthetic approach to synthesize linariophyllenes A–C by harnessing easily accessible and cost-effective sesquiterpenoid starting materials.120–125 The total synthesis of linariophyllene C employed Corey–Chaykovsky epoxidation as one of the significant steps. The synthesis commenced with the stereo-selective Corey–Chaykovsky epoxidation of kobusone 50 utilizing trimethylsulfonium iodide with KOtBu as the base in DMF, at 0 °C to achieve diepoxide 51 in 91% yield and increased stereoselectivity. Subsequently, the ring opening of one of the epoxides of diepoxide 51 in the presence of CsOAc and 18-crown-6 at a high temperature produced the diol 52 as the main product in 62% yield and acetate 53 in 12% yield. The desired acetate 53 was also synthesized from diol 52 in 91% yield using a standard acetylation procedure (Scheme 7).

Scheme 7. Synthesis of linariophyllene C 53.

Scheme 7

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Isohirsut-4-ene 58 is a linear triquinane-based natural product characterized by tricyclic skeletons, which displays a wide range of biological properties. The synthesis of such triquinanes and their congeners could be noteworthy for pharmaceutical and biological research. Ikeda's group126 isolated isohirsut-4-ene and isohirsut-1-ene from engineered bacteria. In 2022, Liu et al.127 disclosed the first total synthesis of isohirsut-4-ene 58 with a 5/5/5 tricyclic core, confirming the proposed structure. Prior to this study, their structures had not been determined, and even Kutateladze128 and Tantillo129 had only predicted their relative configuration via computational NMR data. Liu and co-workers developed a new transannular strategy based on the [5 + 2 + 1] reaction130–132 for linear triquinanes (isohirsut-4-ene). The synthesis featured a [5 + 2 + 1] cycloaddition, the Corey–Chaykovsky reaction, and a transannular epoxide–alkene cyclization to construct the key framework of a natural product.

The six-step total synthesis of 58 began with the preparation of starting compound 54, i.e., ene-VCP (DEC tethered ene-vinylcyclopropane)133,134 in a single step. Then, the [5 + 2 + 1] reaction was carried out under optimized conditions to obtain a pure diastereomer of 5/8 bicyclic product 55 (64% yield). Compound 55 was then transformed into epoxide 56 (45% yield) via the Corey–Chaykovsky reaction under standard conditions (NaH, DMSO, trimethylsulfoxide iodide). A transannular epoxide–alkene cyclization of epoxide 56 utilizing the InCl3 catalyst afforded a 5/5/5-fused tricyclic product, followed by the LiAlH4-promoted reduction that resulted in a triol product 57 (71% yield). Compound 57 was converted into trifluoro-methanesulfonate ester, followed by the reduction of all three hydroxyl groups of esters via LAH, thereby furnishing the desired product, isohirsut-4-ene 58, in 32% overall yield. The NMR spectral results of synthetic compound 58 were determined to be consistent with the literature data. The strategy was further extended to synthesize other congeners of linear triquinanes (Scheme 8).135

Scheme 8. Synthesis of isohirsut-4-ene 58.

Scheme 8

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2.2.2. Synthesis of diterpenoid-based natural products

Hamigerans belong to the family of diterpenoids, displaying significant biological and structural activities. Cambie and his colleagues first isolated numerous hamigeran natural products from Hamigera tarangaensis.136–140 This family structurally exhibits tricyclic cores of two types, 6–6–5 and 6–7–5, featuring a polysubstituted and brominated aromatic ring. In vitro, hamigeran B exhibits potent inhibitory action against the replication of polio and herpes virus, and hamigeran G 7 shows inhibition against the growth of HL-60 (leukemia) cell line. Early research focused on the 6–6–5 tricyclic core of hamigeran A and B, which led to several efficient total syntheses. However, the challenge of synthesizing seven-membered rings resulted in fewer reports focusing on the synthesis of hamigerans with a 6–7–5 carbon core.

In 2016, Gao et al. revealed the first total synthesis of hamigeran G by employing (R)-piperitone, followed by the Suzuki and McMurry coupling to afford a key intermediate.141 Subsequently, in 2018, Stoltz and colleagues142 reported the total syntheses of hamigeran C and D through a Pd-catalyzed asymmetric decarboxylative allylation and other key steps. In 2020, Jiang et al.143 devised a synthetic strategy for the construction of a 6–7–5 three-cyclic carbon framework of hamigeran natural products. Their first attempt featuring 5-bromovanillin 144 as the starting material did not work out, as they were unsuccessful in reducing the tetrasubstituted double bond. In the second attempt, Jiang and his group envisioned the selective C–C bond cleavage of cyclopropane as a masked CH3 group. Their synthetic route commenced with the Corey–Chaykovsky cyclopropanation145 of symmetric tricyclic enone 59, utilizing the trimethylsulfoxonium iodide reagent with KOtBu base in DMSO at room temperature to afford tetracyclic compound 60 in 69% yield. Subsequently, compound 60 was transformed into vinyl triflate in 94% yield in the presence of Comin's reagent and LiHMDS in THF at −78 °C to 0 °C, followed by Suzuki coupling with 62 in DMF that resulted in diene 61 in 77% yield. Thereafter, the diene 48 underwent a sequence of steps to afford 63, which was subjected to hydrogenation conditions in a mixture of CH3COOH and ethanol or THF and triethylsilane in DCE to afford benzylic cation 64 initially due to the acidic conditions. Later, benzylic cation 64 was transformed into the desired product 65 in 40% yield via deprotonation. Although the saturation of the tetrasubstituted double bond of intermediate 65 and the selective cleavage of the C–C bond in cyclopropane 63 could not be achieved, the reported synthetic pathway led to the construction of a tricyclic carbon core (6–7–6) of hamigeran natural products (Scheme 9).

Scheme 9. Synthesis of compound 65.

Scheme 9

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In 1989, myrocins were first discovered in culture filtrates of the soil fungus Myrothecium verrucaria, which belongs to the family of anti-proliferative and antibiotic pimarane diterpenes.146,147 (+)-Myrocin C and (−)-myrocin B were the first isolated metabolites that showcased antibiotic effect towards Gram (+) bacteria, fungi and yeast.148,149 The structural analogs of metabolite 5–7 were isolated from cultures of marine and soil fungi, and they exhibited comparable antibiotic effects.150–153 In 1993, Danishefsky and Chu-Moyer unveiled the pivotal total synthesis of (±)-myrocin C.154,155 Later, Yamada and co-workers presented their research regarding myrocin C.156 Prompted by the hypothesis of Chu-Moyer–Danishefsky that myrocin C could crosslink DNA157 and following the Hoffmann et al.158,159 model, Tomanik and co-workers160 reported the synthesis of (−)-myrocin G recently. In 2020, Tomanik et al.161 documented the synthetic pathway for myrocin G, involving the Corey–Chaykovsky reaction as one of the key steps.

The total synthetic pathway of (−)-myrocin G includes the complex stereoselective fragment coupling–cyclization cascade of iodocyclopropane 68 and α-iodoenone 71. In the first step, the preparation of iodocyclopropane 68 began with the asymmetric Robinson annulation162 of the β-ketoester 66 with diethyl acrolein to afford an enone 67 (32%, 92% ee). Next, the enone 67 was subjected to dehydroiodination by the aid of I2 and pyridine, followed by the Corey–Chaykovsky cyclopropanation employing trimethylsulfoxonium iodide and NaH base, which furnished the enantioenriched iodocyclopropane 68 (d.r. = 2.3 : 1) in 68% yield. Secondly, the unsaturated ketone 69 underwent a six-step process to prepare the C-ring coupling fragment 70 in 19% overall yield. Subsequently, the cyclodehydration (tandem coupling) of 68 and 70 resulted in the desired diosphenol 71 in 38% yield. Lastly, the global deprotection of 71 employing TBAF delivered the (−)-myrocin G 72 in 64% yield (Scheme 10).

Scheme 10. Synthesis of (−)-myrocin G 72.

Scheme 10

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2.2.3. Synthesis of sesterterpenoid-based natural products

The ophiobolins are bioactive 5,8,5-fused sesterterpene-based natural products that are extracted from fungal pathogens (Aspergillus and Bipolaris genus).163–165 In particular, ophiobolin A 78 is highly cytotoxic against breast cancer (MCF-7), multidrug-resistant leukemia (MDR HL-60), glioblastoma multiforme (GBM) and thirty other cell lines. The 6-epi-ophiobolin A 78 epimer also exhibits cytotoxic activity, and a cell-line-specific relationship has been found between C6 stereochemistry and anti-cancer activity.

Regardless of the significance of ophiobolin in the synthetic community, only three ophiobolin syntheses were reported in the last 30 years before 2020.166,167 Thach et al.168 in 2020 introduced a 14-step pathway to (+)-78, utilizing a radical cascade approach. Their successful synthetic strategy expanded the synthesis of a number of key structural derivatives of ophiobolins. Thach's total synthesis commenced with the preparation of a geraniol-derived cyclopropyl iodide 73 (via Charette's protocol),169,170 which was transformed into a ring-opened lithiate and was coupled with the (−)-linalool-derived enone 74, resulting in an enolate intermediate. In the following step, the enolate was quenched with N-tert-butylbenzenesulfinimidoyl chloride (Mukaiyama's reagent), forming the corresponding enone 74 directly.171 The highly selective 1,4-reduction enabled by PhMe2SiCu–H and C-acylation with Cl3CCOCl, followed by radical cyclization via di-tert-butylbipyridine-ligated Cu, afforded the polycycle 75 in 55% yield on isolation. Compound 75 then underwent a sequence of reactions to ultimately yield the trans-addition product 76. Compound 76 was further treated via four steps involving a final approach to accomplish the total synthesis of 6-epi-ophiobolin A 78. The treatment of carbonyl C7 of 76 with Me3SI and n-BuLi at −20 °C for 10 min generated the Corey–Chaykovsky epoxide in the presence of THF, followed by tandem reductive epoxide opening, dehalogenation and silyl ether deprotection (TBAF), which produced the triol intermediate 77 (52% yield). Lastly, the Swern oxidation of intermediate 77 afforded the 6-epi-ophiobolin A 78 in 85% yield (Scheme 11).

Scheme 11. Synthesis of 6-epi-ophiobolin A 78.

Scheme 11

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2.2.4. Synthesis of apocarotenoid-based natural products

Strigolactones (SLs) (apocarotenoid compounds) are recognized as germination enhancers of root parasitic plants.172 They also show application potential as rhizosphere-signaling compounds for the AM (arbuscular mycorrhizal) symbiotic relationship.173,174 To date, about thirty strigolactones have been characterized from several plant root secretions.175

In 2020, Mori et al.176 successfully synthesized 18-OH-MeCLA 84 in eight steps, including the Corey–Chaykovsky as a pivotal step in the synthetic route. The synthesis began with the triflate ester 79, which was reduced with diisobutylaluminium hydride to give triflate alcohol, followed by the protection of the –OH group by a TBS [tert-butyl(dimethyl)silyl] group to obtain the resulting silyl-protected triflate 80. The Heck reaction of silyl-protected triflate with acrolein afforded TBSO-C12-aldehyde 81. The silylated aldehyde 81 was treated further to attain TBSO-C13-aldehyde 82via the Corey–Chaykovsky epoxidation upon reaction with dimethylsulfonium methylide and THF in DMSO, followed by MABR (methylaluminium bis(4-bromo-2,6-di-tert-butylphenoxide))-promoted epoxide rearrangement to afford aldehyde 83. The aldehyde in the multiple-step process afforded 18-OH-MeCLA 84 (Scheme 12).

Scheme 12. Synthesis of 18-OH-MeCLA 84.

Scheme 12

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2.3. Synthesis of polyketide-based natural products

Borolithochromes are rare natural products composed of unique spiroborate cores, featuring two benzo[gh]tetraphene ligands.177 These red pigments have been isolated from the remains of Solenopora jurassica178 (Jurassic putative red alga). From this family, a racemic mixture of borolithochromes A, D, and G was isolated, whereas borolithochrome F was attained as a single enantiomer. Furthermore, the benzo[gh]tetraphene scaffold is rarely found in natural products, barring clostrubins A and B, which exhibit potent anti-bacterial properties.179,180 Likewise, it was expected that the ligands in borolithochromes also exhibit bioactivities. Due to the limited availability of isolated borolithochromes, the information regarding their bioactivities and notable structures was scarce, motivating scientists to develop the total synthesis methods for these pigments.

In 2024, Kirita et al.181 carried out the first total syntheses of borolithochromes A, D and G involving the Diels–Alder reaction for tricyclic intermediates, intramolecular Corey–Chaykovsky reaction to construct pentacyclic ligand and spiroborate formation as one of the significant steps. Firstly, the synthetic route for borolithochrome G 94 involved the Diels–Alder reaction. The desired diene 86 and dienophile naphthoquinone 88 were prepared individually via a multiple-step approach using benzoic acid derivative 85 and isopropyl methyl ketone 87 as starting materials, respectively. Then, treating diene 86 and naphthoquinone 88via the Diels–Alder reaction resulted in the formation of an anthraquinone 89 mixture (5 : 1) in 76% yield. In the next step, the mixture produced the sulfonium ion 90 on treating it with iodomethane. The sodium hydride was added at r.t. to the solution of sulfonium ion 90 in dry THF to facilitate the intramolecular Corey–Chaykovsky epoxidation, which afforded the pentacyclic epoxide 91 in 75% yield. The crude mixture 91 was rearranged under acidic conditions to give phenol 92 in 90% yield. Ultimately, the phenol 92 (ref. 182) was subjected to multiple steps, resulting in the targeted natural product, borolithochrome G 94, in 86% yield (Scheme 13).183

Scheme 13. Synthesis of borolithochrome G 94.

Scheme 13

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The spiroborate of borolithochrome D (99) also consists of ligands of borolithochrome A and D. Thus, the synthesis of a heterocomplex was achieved by the stepwise substitution of ligands in borate, which involved the boron : aromatic (1 : 1) ligand complex intermediate. The synthesis involved the coupling of ligands 93 (obtained via Corey–Chaykovsky reaction) and 96. Initially, the monomer complex 97 was prepared by treating ligand 93 with trimethyl borate in the presence of N,N-dimethylethanolamine. Then, the ligand 96 was complexed with 97 to form a mixed complex, which was further subjected to O-demethylation using AlCl3 to afford the borolithochrome D 99 in 75% yield (Scheme 14).

Scheme 14. Synthesis of borolithochrome D 99.

Scheme 14

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In 2024, Kirita et al.184 first reported the method for the total syntheses of optically pure borolithochromes I1 (105) and I2 (106) involving the Diels–Alder reaction, Corey–Chaykovsky reaction and boron complexation as key steps. The synthetic route began with the synthesis of a common pentacyclic ligand. Firstly, the naphthoquinone 101 was prepared from (S)-2-methylbutanol 100via TEMPO oxidation185 in six steps. Subsequently, the naphthoquinone 101 and diene 86 were subjected to the Diels–Alder reaction under basic conditions to give the product in 62% yield, followed by S-methylation to give sulfonium ion 102. NaH was added to the sulfonium ion 102 in dry THF at r.t. to facilitate the intramolecular Corey–Chaykovsky epoxidation,186 which gave the pentacyclic epoxide 103 in 75% yield. The epoxide 103 then underwent rearrangement187 and gave the product in 98% yield, followed by C-selective O-demethylation with LiCl in DMF, which resulted in the pentacyclic ligand 104 in 70% yield.188,189

Moving forward, the monomethyl ether 104 was treated with B(OMe)3 in potassium carbonate to give the product in 96% yield, followed by O-demethylation via LiI in DMF to produce the mixture of borolithochromes I1 (105) and I2 (106) in 98% yield.182 Ultimately, the diastereomeric mixture was separated by HPLC via CHIRALPAK IC to give optically pure borolithochrome I1 105 and I2 106 (Scheme 15).

Scheme 15. Synthesis of borolithochrome I1 105 and I2 106.

Scheme 15

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2.4. Synthesis of cyclic depsipeptide-based natural products

Arenastatin A is a cytotoxic cyclic depsipeptide, first isolated from Dysidea arenaria Okinawan marine sponge in 1994.182 Total synthesis and NMR analyses have been employed to determine its structure.190,191 Depsipeptides are members of the cryptophycin family that display potent cytotoxic behavior.192 Cryptophycin-52, a powerful analog, was discovered by extensive medicinal research. The cytotoxicity of arenastatin A and its related analogs is influenced by the stereochemistry of the compounds. The 7,8-epoxide moiety is crucial in the compounds, as its (7S,8S) epimer is inactive. Previously, this moiety was achieved either via m-CPBA/dioxirane oxidation or cyclization of bromohydrin, which resulted in isomeric mixture that required separation and relatively long synthetic routes, respectively. However, Aggarwal et al.193 devised an efficacious technique to construct a stereoselective epoxide (>99 : 1 d.r.) moiety via CCR using the chiral sulfonium salt.

In 2024, Mihara et al.194 proposed an optimized synthetic route for the total synthesis of arenastatin A 117 and analogs of segments B, including the construction of the 7,8-epoxide moiety using the Corey–Chaykovsky reaction. The synthetic route began with the assembly of the four segments A–D. Firstly, (R)-O-methyltyrosine 107 was transformed into an acrylamide (77%) using C3H3ClO and NEt3 in DCM. The acrylamide went through cross-metathesis with segment A, employing Grubbs II catalyst on reflux, producing segment AC 109 (95%). On the other hand, Fmoc-β-alanine 111 (segment D) was coupled with l-leucic acid 110 using SOCl2 and acyl chloride (segment B) to give the segment BD 112. Then, the assembly of two segments following the Yamaguchi esterification technique resulted in the cyclization of precursor 113, which, on Fmoc removal with piperidine195 and macrocyclization, led to macrolactam 114 (84%). Lastly, the PMB was subjected to cleavage via TFA, followed by the Dess–Martin oxidation to afford the aldehyde 116. The treatment of aldehyde 116 with a chiral sulfonium salt via the Corey–Chaykovsky epoxidation using phosphazene P2–Et in DCM at −78 °C produced arenastatin A 117 in 81% yield, with complete stereoselectivity (Scheme 16).

Scheme 16. Synthesis of arenastatin A 117.

Scheme 16

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2.5. Synthesis of styryl-lactone-based natural products

5,6-Dihydro-2H-pyran-2-one, 3,6-dihydro-2H-pyran (DHP) and tetrahydropyran (THP) are six-membered oxygen heterocycles, which are ubiquitous core units of a variety of natural products. R-(+)-Goniothalamin 129, a 5,6-dihydro-2H-pyran-2-one derivative, exhibits cytotoxic properties. In 2022, Kumar et al.196 reported a transition-metal-free approach to generate 3,6-dihydro-2H-pyran derivatives via a modified Corey–Chaykovsky reaction. It involved the synthesis of the desired epoxy cyclopropane from corresponding enones.

The two-step synthesis of racemic goniothalamin 129, an anti-tumor agent, commenced with a styryl-substituted α,β-unsaturated aldehyde 127, which was subjected to an extended Corey–Chaykovsky reaction using the sulfoxonium ylide and sodium hydroxide in DMSO to afford 128 at room temperature. Following this, compound 128 underwent oxidation to yield 129 (5,6-dihydro-2H-pyran-2-one) in the presence of PDC and sodium acetate in DCM (Scheme 17).

Scheme 17. Synthesis of rac-goniothalamin 129.

Scheme 17

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2.6. Synthesis of amino acid-based natural products

(2S)-Aminoadipic acid (AA), a homologue of (S)-glutamate, is a broad-spectrum endogenous agonist of mGluR. Madsen and co-workers197 reported (S)-AA as a potent selective agonist for mGlu2. In 2024, Staudt et al.198 documented their strategy to synthesize conformationally restricted hybrid structures of (S)-AA analogs. The synthetic route of these analogs featured a Corey–Chaykovsky reaction as one of the crucial steps.

The synthesis of (S)-AA analog 134 was initiated by the strategic protection of (S)-aspartate 130 to achieve Weinreb-amide, which was subjected to selective reduction to yield the desired aldehyde 131 in 92% yield. The Horner–Wadsworth–Emmons reaction of aldehyde 131 resulted in the E-isomer of unsaturated ester, followed by the double Boc-protection of the amine with DMAP to yield 132. The in situ Corey–Chaykovsky reaction of 132 was carried out employing (CH3)3SOI and sodium hydride to afford a 1 : 1 mixture of 133 in DMSO at 80 °C in 18% yield. Ultimately, the global deprotection of 133 in 6 M HCl on reflux resulted in the desired (S)-AA analog 134 with a 1 : 1 mixture of diastereomers (Scheme 18).

Scheme 18. Synthesis of (S)-AA analog 134.

Scheme 18

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The synthesis of the 5-methyl analog 138 began with the olefination of commercially available aldehyde 135, utilizing triethyl 2-phosphonopropionate and NaH, in the presence of THF to furnish the single stereoisomer of compound 136 in 73% yield. Subsequently, the Corey–Chaykovsky reaction of 136 was carried out to accomplish a 4 : 1 diastereomeric mixture of the 5-methyl-cyclopropane analog 137 in 51% yield employing TMSOI, sodium hydride and DMSO at 80 °C. Lastly, the global deprotection of analog 137 in 6 M HCl under reflux, followed by Jones-oxidation, afforded the desired analog 138 in 16% yield (4 : 1 d.r.) (Scheme 19).

Scheme 19. Synthesis of the 5-methyl analog 138.

Scheme 19

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2.7. Synthesis of hybrid natural products

2.7.1. Monoterpene indole alkaloids

In 2019, Zhang and colleagues199 first isolated (−)-hunterine A 144 from Hunteria zeylanica, which belongs to the terpenoid indole alkaloid class with a characteristic 6/7/6/6/5 pentacyclic framework featuring an exotic 7-membered 2,3,4,5 tetrahydro-1H-azepine bridge scaffold.200–202 The sparse amount of available alkaloid optimistically described the bioefficacy of (−)-hunterine A, which exhibited cytotoxicity against HepG2.199 Zhang et al. reported a feasible biogenetic route for the synthesis of 144 using tuboxenine as the starting material.

In 2024, Zsigulics et al.203 pursued the bioinspired total synthesis of (−)-hunterine A (144) by addressing the selectivity challenges via the aspidosperma core unit. The total synthesis was achieved through an interim template technique carried out without a direct group, featuring the ring-opening cascade and the Corey–Chaykovsky reaction as critical steps to construct the epoxide intermediate. The bioinspired synthesis began with the modified Stork's tricyclic ketone 139, which was subjected to selective hydrolysis and decarboxylation under acidic conditions, followed by Fischer indolization that produced indolenine 140 in 48% yield (2 steps). Then, the Boc-protection of indolenine 140 after deprotonation with LDA at −78 °C gave the product in 87% yield. Next, the partial reduction of the ester moiety in 2 steps (reduction via DIBAL-H in toluene at −78 °C with 99% yield, followed by oxidation via DMP in DCM) resulted in the key aldehyde intermediate 141. Subsequently, the Corey–Chaykovsky reaction204,205 was used to achieve the desired epoxide configuration by treating key intermediate 141 with Me3+SI− and sodium hydride in DMSO at 25 °C, followed by the addition of 141 in DMSO at 15–25 °C, resulting in C20(R)-142 (d.r. = 1 : 2) in 44% yield (2 steps). Then, the C20(R)-142 diastereomeric mixture was treated with aq. H2SO4 under biphasic conditions (DCM/water), inducing a sequence of cascade transformations, including protecting-group removal/hydration/epoxide ring opening as well as ring-expansion reactions, thereby ultimately resulting in (−)-hunterine A 144 alongside isomer 145. Meanwhile, the key intermediate 141 was treated with trifluoroacetic acid in DCM to furnish aldehyde 143. Thus, the isomeric product 145 was obtained as a single diastereomer by the C1 homologation of aldehyde 143 under cryogenic conditions using nucleophilic carbenoid, followed by exposure to acidic/hydrolytic conditions (Scheme 20).

Scheme 20. Synthesis of (−)-hunterine A 144.

Scheme 20

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2.7.2. Synthesis of sesquiterpene-lactone-based natural products

Hypocretenolides are naturally occurring sesquiterpenoids, first reported by Bohlmann et al. in 1982 from Hypochaeris cretensis.206 A number of natural hypocretenolides with variable glycosylation or oxidation states have also been isolated. Hypocretenolides feature an α-methylene-γ-lactone core exhibiting a distinct bridged 5/7/6 ring system. Prior research confirmed that these natural products are active against cancer metastasis207,208 as they depicted low IC50 values against multiple tumor cell lines and suppressed the activation of NF-κB.209,210 Regardless of the potential efficacy of hypocretenolides, further evaluation had been hindered due to their limited quantity; moreover, no total synthesis of hypocretenolides had been reported, impeding structure–activity relationship (SAR) studies and the development of potential derivatives.

To circumvent this limitation, Chen et al.211 in 2024 devised an efficient approach for the first collective total synthesis of four hypocretenolides, involving the Corey–Chaykovsky reaction as a key step to introduce the cyclopropane moiety. The synthesis was initiated with the economical feedstock (S)-carvone 146, which underwent the Corey–Chaykovsky reaction with Me3SOI and sodium hydride in DMSO at 50 °C to afford cyclopropane ring 147 in 96% yield. The cyclopropane-endowed compound 147 was treated over a number of steps to afford the allylic chlorinated product 148. The alkene lithium obtained from compound 149 mounted a nucleophilic attack on compound 148, followed by TBAI-induced alkylation and desilylation to afford an alcohol 150 in 30% yield. Then, DMP oxidation of 150 gave aldehyde in 80% yield, followed by oxime intermediate formation with NH2OH·HCl. The intermediate was subjected to intramolecular 1,3-dipolar cycloaddition, which gave the isoxazoline product 151 in 75% yield with the desired 5/6/7 ring system. In the next step, the isoxazoline ring was subjected to Fe/AcOH reduction, which gave the desired dienone 152 in 87% yield. The dienone 152 was treated over several steps to furnish hypocretenolide 153 (Scheme 21).

Scheme 21. Synthesis of hypocretenolide 153.

Scheme 21

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Damascenolide™ [4-(4-methylpent-3-en-1-yl)furan-2(5H)-one] is isolated from Rosa damascena (damask rose),212 with a characteristic citrus-like odor that imparts blooming and natural aroma character to artificial rose. Miyazawa et al. explored the SOR (structure–odor relationships) of a total of 24 analogs of damascenolide™ and studied their syntheses for developing more aroma compounds.213,214 Their previous research on the analogs of damascenolide™ revealed that slight structural changes significantly influenced the odor.

In 2021, Miyazawa et al.215 synthesized 10 analogs of damascenolide™ and performed odor evaluation; the analogs were divided into 3 groups (dimethylated, cyclopropanated and other analogs). Group 2, featuring cyclopropanated analogs, was selected because previous evaluation showed that cyclopropanation alters the odor of various odor-active compounds. Initially, Miyazawa et al. attempted to synthesize cyclopropanate damascenolide™ but failed. However, the Corey–Chaykovsky cyclopropanation was successfully used to synthesize cyclopropane 156. The synthetic intermediate of damascenolide™ 154 was subjected to the Corey–Chaykovsky reaction using trimethylsulfoxonium iodide and KOtBu in DMSO at room temperature to yield compound 155. The EE group of compound 155 was removed using aqueous HCl in THF, followed by one-pot lactonization to afford compound 156 in 18% yield (2 steps) (Scheme 22).

Scheme 22. Synthesis of the analog of damascenolide™ 156.

Scheme 22

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3. Miscellaneous

Classical lignans, specifically caryltetralin, arylnaphthalene and dihydronaphthalene, are bioactive natural products.216 The utilization of their synthetic derivatives as pharmaceutical agents prompted research efforts into their synthetic strategies. The variety of existing methods for preparing natural complexes often fall short in interrogating the SAR (structure–activity relationship). Therefore, modern techniques emphasize diversity and modularity. Alfonzo and co-workers reported a unified method that utilized THFs (tetrahydrofurans) as key scaffolds to synthesize various CLs and their subtypes.217

In 2020, Alfonzo et al.218 reported that a modular one-pot method enabling the efficacious synthesis of arylnaphthalene and dihydronaphthalene natural products can be carried out with simply accessible precursors (epoxides and dipolarophiles) covering multiple oxidation states, e.g., pycnanthulignene C. These are also known to exhibit anti-microbial action against a range of drug-resistant microbes.219 The total synthesis of pycnanthulignene C 162 involved the Corey–Chaykovsky reaction and photoredox-catalyzed [3 + 2] cycloaddition as key steps. Firstly, sulfonium ylide A was prepared by treating the benzyl alcohol 157 with tetrahydrothiophene 158 and HBF4·OEt2, then with NaH in the MeCN solvent at 0–23 °C. The ylide A was subjected to a one-pot Corey–Chaykovsky reaction with aldehyde 159 to afford epoxide 160 in 98% yield (d.r. = 5 : 1). Following this, the epoxide mixture in CHCl3 (chloroform) employing DTAC underwent [3 + 2] cycloaddition, after which the addition of HFIP and HCl at 10 °C without changing the solvent furnished the dihydronaphthalene 162 in 95% yield (r.r. > 20 : 1). Finally, the reduction via LiAlH4 and the hydrogenation of 162 in EtOAc (ethyl acetate) afforded pycnanthulignene C 163 in 88% overall yield, over four steps (Scheme 23).

Scheme 23. Synthesis of pycnanthulignene C 162.

Scheme 23

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Liparacid A 170,220 a rare natural product, was isolated from the rhizoma of Liparis nakaharai in 2007, and it has relevance in Chinese folk medicine as an anti-tumor agent. In 2020, Song et al. reported the first total synthesis of liparacid A 170, featuring CuI-catalyzed etherification and Corey–Chaykovsky epoxidation as key reactions.221 The synthetic route commenced with the CuI-catalyzed etherification222 of 4-bromosalicylaldehyde 164 to furnish a product in 88% yield, and a subsequent Lindlar reduction223 gave compound 166 in 97% yield. Following this, compound 166 was subjected to the Corey–Chaykovsky reaction224 employing dimethyl sulfide and NaOH in tBuOH/H2O (9 : 1) solvent to synthesize epoxide 168 (2 steps) in 80% yield. In the next step, the new cascade technique was applied to epoxide 168, which resulted in the ketone 169 with the desired 2H-chromene framework in 45% yield. Ultimately, the three-step sequence, including the Luche reduction225 of ketone 169 (96% yield), formylation (79% yield), and Kraus–Pinnick oxidation (87% yield), produced the liparacid A 170 in 87% yield (Scheme 24).

Scheme 24. Synthesis of liparacid A 170.

Scheme 24

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4. Conclusion

To summarize, this review presents a detailed overview of the applications of the Corey–Chaykovsky reaction in the total syntheses of various natural products and their analogs. The Corey–Chaykovsky reaction provides an efficient stereoselective route to access cyclopropanes as well as other heterocycles, such as epoxides and aziridines, in high yields under mild conditions. In recent years, this reaction has been consistently proven as a key transformational tool in the toolkit of synthetic organic chemistry, particularly for the synthesis of complex natural products. This review underscores the synthetic utility and stereoselectivity of CC methodology in the synthesis of a diverse range of natural products, including alkaloids, terpenoids, depsipeptides, polyketides and amino acids. We anticipate that the continued methodological advances in CCR will consolidate it as a reliable and robust technique towards the total synthesis of natural products.

Conflicts of interest

The authors declare no conflicts of interest.

Acknowledgments

Authors are thankful to the facilities provided by Government College University Faisalabad, Pakistan. A. Irfan extends his appreciation to the Deanship of Research and Graduate Studies at King Khalid University for funding this work through the Large Groups Research Project under grant number (RGP2/172/45). Authors are thankful to the Deanship of Graduate Studies and Scientific Research at the University of Bisha for supporting this work through the Fast-Track Research Support Program.

Data availability

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

References

  1. Mayr H. Kempf B. Ofial A. R. π-Nucleophilicity in carbon–carbon bond-forming reactions. Acc. Chem. Res. 2003;36:66–77. doi: 10.1021/ar020094c. [DOI] [PubMed] [Google Scholar]
  2. Mushtaq A. Zahoor A. F. Ahmad M. N. Khan S. G. Akhter N. Nazeer U. Mansha A. Ahmad H. Chaudhry A. R. Irfan A. Accessing the synthesis of natural products and their analogues enabled by the Barbier reaction: a review. RSC Adv. 2024;14:33536–33567. doi: 10.1039/d4ra05646a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Akhtar R. Zahoor A. F. Irfan M. Bokhari T. H. ul Haq A. Recent green synthetic approaches toward Ullmann reaction: A review. Chem. Pap. 2022;76:7275–7293. [Google Scholar]
  4. Corey E. J. Chaykovsky M. Dimethyloxosulfonium methylide ((CH3)2SOCH2) and dimethylsulfonium methylide ((CH3)2SCH2). Formation and application to organic synthesis. J. Am. Chem. Soc. 1965;87:1353–1364. [Google Scholar]
  5. Corey E. J. Chaykovsky M. Methylsulfinylcarbanion. J. Am. Chem. Soc. 1962;84:866–867. [Google Scholar]
  6. Thompson S. K. Heathcock C. H. Total synthesis of some marasmane and lactarane sesquiterpenes. J. Org. Chem. 1992;57:5979–5989. [Google Scholar]
  7. Li A. H. Dai L. X. Aggarwal V. K. Asymmetric ylide reactions: epoxidation, cyclopropanation, aziridination, olefination, and rearrangement. Chem. Rev. 1997;97:2341–2372. doi: 10.1021/cr960411r. [DOI] [PubMed] [Google Scholar]
  8. Merz A. Märkl G. Phase-transfer-catalyzed Production of Sulfur Ylides in an Aqueous System. Angew. Chem., Int. Ed. Engl. 1973;12:845–846. [Google Scholar]
  9. Ciaccio A. Drahus A. L. Meis R. M. Tingle C. T. Smrtka M. Geneste R. Instant methylide modification of the Corey–Chaykovsky epoxide synthesis. Synth. Commun. 2003;33:2135–2143. [Google Scholar]
  10. Ciaccio J. A. Aman C. E. Instant methylide, modification of the Corey–Chaykovsky epoxide synthesis. Synth. Commun. 2006;36:1333–1341. [Google Scholar]
  11. Liu L. Tian R. Liu S. Chen X. Guo L. Che Y. Pestaloficiols A–E, bioactive cyclopropane derivatives from the plant endophytic fungus Pestalotiopsis fici. Bioinorg. Med. Chem. 2008;16:6021–6026. doi: 10.1016/j.bmc.2008.04.052. [DOI] [PubMed] [Google Scholar]
  12. Watanabe M. Hirokawa T. Kobayashi T. Yoshida A. Ito Y. Yamada S. Orimoto N. Yamasaki Y. Arisawa M. Shuto S. Investigation of the bioactive conformation of histamine H3 receptor antagonists by the cyclopropylic strain-based conformational restriction strategy. J. Med. Chem. 2010;53:3585–3593. doi: 10.1021/jm901848b. [DOI] [PubMed] [Google Scholar]
  13. Zhang H. K. Yu L. F. Eaton J. B. Whiteaker P. Onajole O. K. Hanania T. Brunner D. Lukas R. J. Kozikowski A. P. Chemistry, pharmacology, and behavioral studies identify chiral cyclopropanes as selective α4β2-nicotinic acetylcholine receptor partial agonists exhibiting an antidepressant profile. Part II. J. Med. Chem. 2013;56:5495–5504. doi: 10.1021/jm400510u. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Qiao J. X. Cheney D. L. Alexander R. S. Smallwood A. M. King S. R. He K. Rendina A. R. Luettgen J. M. Knabb R. M. Wexler R. R. Lam P. Y. S. Achieving structural diversity using the perpendicular conformation of alpha-substituted phenylcyclopropanes to mimic the bioactive conformation of ortho-substituted biphenyl P4 moieties: Discovery of novel, highly potent inhibitors of Factor Xa. Bioorg. Med. Chem. Lett. 2008;18:4118–4123. doi: 10.1016/j.bmcl.2008.05.095. [DOI] [PubMed] [Google Scholar]
  15. Johnson A. W. LaCount R. B. 9-Dimethylsulfonium fluorenylide. Chem. Ind. 1958:1440–1441. [Google Scholar]
  16. Johnson C. R. Utilization of sulfoximines and derivatives as reagents for organic synthesis. Acc. Chem. Res. 1973;6:341–347. [Google Scholar]
  17. Johnson C. R. Schroeck C. W. Chemistry of sulfoxides and related compounds. XLV. Asymmetric syntheses using optically active oxosulfonium alkylides. J. Am. Chem. Soc. 1973;95:7418–7423. [Google Scholar]
  18. Kazia A. Melngaile R. Mishnev A. Veliks J. Johnson–Corey–Chaykovsky fluorocyclopropanation of double activated alkenes: scope and limitations. Org. Biomol. Chem. 2020;18:1384–1388. doi: 10.1039/c9ob02712b. [DOI] [PubMed] [Google Scholar]
  19. Shaikh M. A. Ubale A. S. Gnanaprakasam B. Amberlyst-A26-Mediated Corey–Chaykovsky Cyclopropanation of 9-Alkylidene-9 H-fluorene under Continuous Process. J. Org. Chem. 2024;89:2283–2293. doi: 10.1021/acs.joc.3c02260. [DOI] [PubMed] [Google Scholar]
  20. Malunavar S. S. Sutar S. M. Prabhala P. Savanur H. M. Kalkhambkar R. G. Aridoss G. Laali K. K. Facile synthesis of libraries of functionalized cyclopropanes and oxiranes using ionic liquids–A new approach to the classical Corey-Chaykovsky reaction. Tetrahedron Lett. 2021;81:153339. [Google Scholar]
  21. Irfan A. Faiz S. Rasul A. Zafar R. Zahoor A. F. Kotwica-Mojzych K. Mojzych M. Exploring M. the synergistic anticancer potential of benzofuran–oxadiazoles and triazoles: Improved ultrasound-and microwave-assisted synthesis, molecular docking, hemolytic, thrombolytic and anticancer evaluation of furan-based molecules. Molecules. 2022;27:1023. doi: 10.3390/molecules27031023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Irfan A. Faisal S. Zahoor A. F. Noreen R. Al-Hussain S. A. Tuzun B. Javaid R. Elhenawy A. A. Zaki M. E. A. Ahmad S. Abdellattif M. H. In silico development of novel benzofuran-1, 3, 4-oxadiazoles as lead inhibitors of M. tuberculosis polyketide synthase 13. Pharmaceuticals. 2023;16:829. doi: 10.3390/ph16060829. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Irfan A. Faisal S. Ahmad S. Al-Hussain S. A. Javed S. Zahoor A. F. Parveen B. Zaki M. E. Structure-based virtual screening of furan-1, 3, 4-oxadiazole tethered N-phenylacetamide derivatives as novel class of hTYR and hTYRP1 inhibitors. Pharmaceuticals. 2023;16:344. doi: 10.3390/ph16030344. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Caiuby C. A. D. Furniel L. G. Burtoloso A. C. B. Asymmetric transformations from sulfoxonium ylides. Chem. Sci. 2022;13:1192–1209. doi: 10.1039/d1sc05708a. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Bisag G. D. Ruggieri S. Fochi M. Bernardi L. Sulfoxonium ylides: simple compounds with chameleonic reactivity. Org. Biomol. Chem. 2020;18:8793–8809. doi: 10.1039/d0ob01822h. [DOI] [PubMed] [Google Scholar]
  26. Schneider T. F. Kaschel J. Werz D. B. A new golden age for donor–acceptor cyclopropanes. Angew. Chem., Int. Ed. 2014;53:5504–5523. doi: 10.1002/anie.201309886. [DOI] [PubMed] [Google Scholar]
  27. Ghosh K. Das S. Recent advances in ring-opening of donor acceptor cyclopropanes using C-nucleophiles. Org. Biomol. Chem. 2021;19:965–982. doi: 10.1039/d0ob02437f. [DOI] [PubMed] [Google Scholar]
  28. Xia Y. Liu X. Feng X. Asymmetric catalytic reactions of donor–acceptor cyclopropanes. Angew. Chem., Int. Ed. 2021;60:9192–9204. doi: 10.1002/anie.202006736. [DOI] [PubMed] [Google Scholar]
  29. Pirenne V. Muriel B. Waser J. Catalytic enantioselective ring-opening reac- tions of cyclopropanes. Chem. Rev. 2021;121:227–263. doi: 10.1021/acs.chemrev.0c00109. [DOI] [PubMed] [Google Scholar]
  30. Nazeer U. Mushtaq A. Zahoor A. F. Hafeez F. Shahzadi I. Akhtar R. Cloke–Wilson rearrangement: a unique gateway to access five-membered heterocycles. RSC Adv. 2023;13:35695–35732. doi: 10.1039/d3ra07410b. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Talele T. T. The ‘Cyclopropyl Fragment is a Versatile Player that Frequently Appears in Preclinical/Clinical Drug Molecules. J. Med. Chem. 2016;59:8712–8756. doi: 10.1021/acs.jmedchem.6b00472. [DOI] [PubMed] [Google Scholar]
  32. Gupta A. K. Bharadwaj M. Kumar A. Mehrotra R. Spiro-oxindoles as a Promising Class of Small Molecule Inhibitors of p53−MDM2 Interaction Useful in Targeted Cancer Therapy. Top. Curr. Chem. 2017;375:3. doi: 10.1007/s41061-016-0089-0. [DOI] [PubMed] [Google Scholar]
  33. Shi W. Jiang Z. He H. Xiao F. Lin F. Sun Y. Hou L. Shen L. Han L. Zeng M. Lai K. Gu Z. Chen X. Zhao T. Guo L. Yang C. Li J. Chen S. Discovery of 3,3′-Spiro[Azetidine]-2-oxoindoline Derivatives as Fusion Inhibitors for Treatment of RSV Infection. ACS Med. Chem. Lett. 2018;9:94–97. doi: 10.1021/acsmedchemlett.7b00418. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sansinenea E. Ortiz A. The Chemistry of Cyclopropanes and New Insight in Organocatalyzed Asymmetric Cyclopropanation. Eur. J. Org Chem. 2022;2022:e202200210. [Google Scholar]
  35. Li J. J., in Name Reactions in Heterocyclic Chemistry, John Wiley & Sons, Inc., Hoboken, NJ, 2005, pp. 2–14 [Google Scholar]
  36. Johnson A. W. Lacount R. B. The Chemistry of Ylids. VI. Dimethylsulfonium Fluorenylide-A Synthesis of Epoxides. J. Am. Chem. Soc. 1961;83:417. [Google Scholar]
  37. Dai L. X. Hou X. L. Zhou Y. G. Stereoselective Synthesis of Three-membered Ring Compounds via Ylide Routes. Pure Appl. Chem. 1999;71:369. [Google Scholar]
  38. Aggarwal V. K. Winn C. L. Catalytic, Asymmetric Sulfur Ylide-Mediated Epoxidation of Carbonyl Compounds: Scope, Selectivity, and Applications in Synthesis. Acc. Chem. Res. 2004;37:611. doi: 10.1021/ar030045f. [DOI] [PubMed] [Google Scholar]
  39. McGarrigle E. M. Myers E. L. Illa O. Shaw M. A. Riches S. L. Aggarwal V. K. Chalcogenides as Organo-catalysts. Chem. Rev. 2007;107:5841. doi: 10.1021/cr068402y. [DOI] [PubMed] [Google Scholar]
  40. Briere J. F. and Metzner P., Organosulfur Chemistry in Asymmetric Synthesis, Wiley-VCH, Weinheim, Germany, 2008, vol. 37, p. 321 [Google Scholar]
  41. Li S. Li P. Xu J. Retro-Corey-Chaykovsky Epoxidation: Converting Geminal Disubstituted Epoxides to Ketones. Helv. Chim. Acta. 2019;102:e1900164. [Google Scholar]
  42. Aggarwal V. K. Thompson A. Jones R. V. Standen M. C. Novel catalytic and asymmetric process for aziridination mediated by sulfur ylides. J. Org. Chem. 1996;61:8368–8369. [Google Scholar]
  43. Aggarwal V. K. Alonso E. Fang G. Ferrara M. Hynd G. Porcelloni M. Application of chiral sulfides to catalytic asymmetric aziridination and cyclopropanation with in situ generation of the diazo compound. Angew. Chem., Int. Ed. 2001;40:1433–1436. doi: 10.1002/1521-3773(20010417)40:8<1433::AID-ANIE1433>3.0.CO;2-E. [DOI] [PubMed] [Google Scholar]
  44. Marsini M. A. Reeves J. T. Desrosiers J. N. Herbage M. A. Savoie J. Li Z. Fandrick K. R. Sader C. A. McKibben B. Gao D. A. Cui J. Gonella N. C. Lee H. Wei X. Roschangar F. Lu B. Z. Senanayake C. H. Diastereoselective synthesis of α-quaternary aziridine-2-carboxylates via Aza-Corey–Chaykovsky aziridination of N-tert-butanesulfinyl ketimino esters. Org. Lett. 2015;17:5614–5617. doi: 10.1021/acs.orglett.5b02838. [DOI] [PubMed] [Google Scholar]
  45. Mushtaq A. Zahoor A. F. Bilal M. Hussain S. M. Irfan M. Akhtar R. Irfan A. Kotwica-Mojzych K. Mojzych M. Sharpless asymmetric dihydroxylation: an impressive gadget for the synthesis of natural products: a review. Molecules. 2023;28:2722. doi: 10.3390/molecules28062722. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Munawar S. Zahoor A. F. Hussain S. M. Ahmad S. Mansha A. Parveen B. Ali K. G. Irfan A. Steglich esterification: A versatile synthetic approach toward the synthesis of natural products, their analogues/derivatives. Heliyon. 2024;10 doi: 10.1016/j.heliyon.2023.e23416. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Munir R. Zahoor A. F. Anjum M. N. Mansha A. Irfan A. Chaudhry A. R. Irfan A. Kotwica-Mojzych K. Glowacka M. Mojzych M. Yamaguchi esterification: a key step toward the synthesis of natural products and their analogs—a review. Front. Chem. 2024;12:1477764. doi: 10.3389/fchem.2024.1477764. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Tabassum S. Zahoor A. F. Ahmad S. Noreen R. Khan S. G. Ahmad H. Cross-coupling reactions towards the synthesis of natural products. Mol. Diversity. 2022;26:647–689. doi: 10.1007/s11030-021-10195-6. [DOI] [PubMed] [Google Scholar]
  49. Corey E. J. Arai Y. Mioskowski C. Total synthesis of (.+-.)-5, 6-oxido-7, 9-trans, 11, 14-cis-eicosapentaenoic acid, a possible precursor of SRSA. J. Am. Chem. Soc. 1979;101:6748. [Google Scholar]
  50. Farnum D. G. Veysoglu T. Cardt A. M. Duhl-Emswiler B. Pancoast T. A. Reitz T. J. CardE R. T. A stereospecific synthesis of (+)-disparlure, sex attractant of the gypsy moth. Tetrahedron Lett. 1977;18:4009. [Google Scholar]
  51. Rosenberger M. Neukom C. Total synthesis of (5S, 6R, 7E, 9E, 11Z, 14Z)-5-hydroxy-6-[(2R)-2-amino-2-(carboxyethyl) thio]-7, 9, 11, 14-eicosatetraenoic acid, a potent SRS-A. J. Am. Chem. Soc. 1980;102:5425. [Google Scholar]
  52. Heravi M. M. Asadi S. Nazari N. Malekzadeh Lashkariani B. Developments of Corey-Chaykovsky in organic reactions and total synthesis of natural products. Curr. Org. Synth. 2016;13:308–333. [Google Scholar]
  53. Corey E. J. Chaykovsky M. Dimethyloxosulfonium Methylide ((CH3)2SOCH2) and Dimethylsulfonium Methylide ((CH3)2SCH2). Formation and Application to Organic Synthesis. J. Am. Chem. Soc. 1965;87:1353–1364. [Google Scholar]
  54. Fadeev A. A. Makarov A. S. Ivanova O. A. Uchuskin M. G. Trushkov I. V. Extended Corey–Chaykovsky reactions: transformation of 2-hydroxychalcones to benzannulated 2, 8-dioxabicyclo [3.2. 1] octanes and 2, 3-dihydrobenzofurans. Org. Chem. Front. 2022;9:737–744. [Google Scholar]
  55. Shcherbakov R. O. Myasnikov D. A. Trushkov I. V. Uchuskin M. G. Extended Version of the Corey–Chaykovsky Reaction: Synthesis of 2, 4-Substituted Furans by the Treatment of β-Dialkylamino Chalcones with Dimethylsulfonium Methylide. J. Org. Chem. 2023;88:8227–8235. doi: 10.1021/acs.joc.3c00203. [DOI] [PubMed] [Google Scholar]
  56. Singh B. Ansari A. J. Malik N. Ramasastry S. S. V. An interrupted Corey–Chaykovsky reaction of designed azaarenium salts: synthesis of complex polycyclic spiro-and fused cyclopropanoids. Chem. Sci. 2023;14:6963–6969. doi: 10.1039/d3sc01578e. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Zhou Y. Li N. Cai W. Huang Y. Asymmetric Sequential Corey–Chaykovsky Cyclopropanation/Cloke–Wilson Rearrangement for the Synthesis of 2, 3-Dihydrofurans. Org. Lett. 2021;23:8755–8760. doi: 10.1021/acs.orglett.1c03225. [DOI] [PubMed] [Google Scholar]
  58. Maurya J. P. Ramasastry S. S. V. Interrupted Corey–Chaykovsky Reaction of Tethered Bis-Enones to Access 2, 3-Epoxy-hexahydrofluoren-9-ones. Org. Lett. 2024;26:4571–4575. doi: 10.1021/acs.orglett.4c01550. [DOI] [PubMed] [Google Scholar]
  59. Bernhardson D. J. Lara-Boykin S. McWilliams J. C. Nieves-Quinones Y. Sharninghausen L. S. Singer R. A. Girvin Z. C. Asymmetric Synthesis of the cis-1, 2-Diaryltetralin Vepdegestrant Core via an Enantioselective Intramolecular Corey-Chaykovsky Epoxidation. Org. Process Res. Dev. 2024;28:4420–4430. [Google Scholar]
  60. Bendelac A. Benedetti F. Doublet-Decabras V. Lokovi R. Decalogne F. Bigot A. Fit-for-Purpose Synthesis of an Aza-Cryptophycin Analogue as the Payload for an Antibody–Drug Conjugate. Org. Process Res. Dev. 2022;26:2145–2154. [Google Scholar]
  61. Vamshikrishna K. Srihari P. Total synthesis of (+)-varitriol and (+)-6′-epi-varitriol. Tetrahedron. 2012;68:1540–1546. [Google Scholar]
  62. Yadav J. S. Pamu S. Bhunia D. C. Pabbaraja S. Formal total synthesis of ovalcin by carbohydrate approach. Synlett. 2007;2007(06):0992–0994. [Google Scholar]
  63. Guerrero-Vásquez G. A. Andrade C. K. Z. Molinillo J. M. Macías F. A. Practical First Total Synthesis of the Potent Phytotoxic (±)-Naphthotectone, Isolated from Tectona grandis. Eur. J. Org Chem. 2013;2013:6175–6180. [Google Scholar]
  64. Adamovskyi M. I. Artamonov O. S. Tymtsunik A. V. Grygorenko O. O. The synthesis of a 2-azabicyclo [3.1. 0] hexane by rearrangement of a spirocyclic epoxide. Tetrahedron Lett. 2014;55:5970–5972. [Google Scholar]
  65. Molinaro C. Gauvreau D. Hughes G. Lau S. Lauzon S. Angelaud R. O'Shea P. D. Janey J. Palucki M. Hoerrner S. R. Raab C. E. Sidler R. R. Belley M. Han Y. Remote Electronic Control in the Regioselective Reduction of Succinimides: A Practical, Scalable Synthesis of EP4 Antagonist MF-310. J. Org. Chem. 2009;74:6863–6866. doi: 10.1021/jo901267x. [DOI] [PubMed] [Google Scholar]
  66. Beutner G. L. George D. T. Opportunities for the application and advancement of the Corey–Chaykovsky cyclopropanation. Org. Process Res. Dev. 2022;27:10–41. [Google Scholar]
  67. Choi E. J. Nam S. J. Paul L. Beatty D. Kauffman C. A. Jensen P. R. Fenical W. Previously uncultured marine bacteria linked to novel alkaloid production. Chem. Biol. 2015;22:1270–1279. doi: 10.1016/j.chembiol.2015.07.014. [DOI] [PubMed] [Google Scholar]
  68. Sweeney J. B. Aziridines: Epoxides’ ugly cousins. Chem. Soc. Rev. 2002;31:247–258. doi: 10.1039/b006015l. [DOI] [PubMed] [Google Scholar]
  69. Mandal S. Bhuyan S. Jana S. Hossain J. Chhetri K. Roy B. G. Efficient visible light mediated synthesis of quinolin 2(1H)-ones from quinoline N-oxides. Green Chem. 2021;23:5049–5055. [Google Scholar]
  70. Simonetti S. O. Larghi E. L. Kaufman T. S. The 3,4-dioxygenated 5-hydroxy-4-aryl-quinolin-2(1H)-one alkaloids. Results of 20 years of research, uncovering a new family of natural products. Nat. Prod. Rep. 2016;33:1425–1446. doi: 10.1039/c6np00064a. [DOI] [PubMed] [Google Scholar]
  71. Buljan A. Stepanić V. Čikoš A. Babić Brčić S. Bojanić K. Roje M. Total Synthesis and Biological Profiling of Putative (±)-Marinoaziridine B and (±)-N-Methyl Marinoaziridine A. Mar. Drugs. 2024;22:310. doi: 10.3390/md22070310. [DOI] [PMC free article] [PubMed] [Google Scholar]
  72. Buljan A. Roje M. Application of green chiral chromatography in enantioseparation of newly synthesized racemic marinoepox ides. Mar. Drugs. 2022;20:530. doi: 10.3390/md20080530. [DOI] [PMC free article] [PubMed] [Google Scholar]
  73. Baraldi P. G. Budriesi R. Cacciari B. Chiarini A. Garuti L. Giovanninetti G. Leoni A. Roberti M. Synthesis and calcium antagonist activity of dialkyl 1,4-dihydro-2,6-dimethyl-4-(nitrogenous heteroaryl)-3,5-pyridine dicarboxylates. Collect. Czech. Chem. Commun. 1992;57:169–178. [Google Scholar]
  74. Durst T., Ben R. N. and Roy M. N., e-EROS Encyclopedia of Reagents for Organic Synthesis, Wiley, New York, NY, USA, 2013, pp. 1–3 [Google Scholar]
  75. Lounasmaa M., Hanhinen P. and Westersund M., The Alkaloids: Chemistry and Biology, ed. G. A. Cordell, Academic Press, San Diego, 1999, vol. 52, pp. 103–195 [Google Scholar]
  76. Nam joshi O. A. and Cook J. M., The Alkaloids: Chemistry and Biology, ed. H.-J. Knçlker, Academic Press, San Diego, 2016, vol. 76, pp. 63–169 [Google Scholar]
  77. Lewis S. E. Alkorta I. Elguero J. Recent advances in the chemistry of macroline, sarpagine and ajmaline-related indole alkaloids. Tetrahedron. 2006;62:8655–8681. [Google Scholar]
  78. Rahman M. T. Tiruveedhula V. V. P. B. Cook J. M. Synthesis of bisindole alkaloids from the Apocynaceae which contain a macroline or sarpagine unit: a review. Molecules. 2016;21:1525. doi: 10.3390/molecules21111525. [DOI] [PMC free article] [PubMed] [Google Scholar]
  79. Rolf S. Bruns H. J. Wichter T. Kirchhof P. Ribbing M. Wasmer K. Paul M. Breithardt G. Haverkamp W. Eckardt L. The ajmaline challenge in Brugada syndrome: diagnostic impact, safety, and recommended protocol. Eur. Heart J. 2003;24:1104–1112. doi: 10.1016/s0195-668x(03)00195-7. [DOI] [PubMed] [Google Scholar]
  80. Namjoshi O. A. Cook J. M. Sarpagine and related alkaloids. Alkaloids. 2016;76:63–169. doi: 10.1016/bs.alkal.2015.08.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  81. Edwankar C. R. Edwankar R. V. Namjoshi O. A. Liao X. Cook J. M. Stereospecific approach to the synthesis of ring-A oxygenated sarpagine indole alkaloids. Total synthesis of the dimeric indole alkaloid P-(+)-dispegatrine and six other monomeric indole alkaloids. J. Org. Chem. 2013;78:6471–6487. doi: 10.1021/jo400469t. [DOI] [PMC free article] [PubMed] [Google Scholar]
  82. Ponglux D. Wongseripipatana S. Subhadhirasakul S. Takayama H. Yokota M. Ogata K. Phisalaphong C. Aimi N. Sakai S. Studies on the indole alkaloids of Gelsem1um elegans (thailand): Structure elucidation and proposal of biogenetic route. Tetrahedron. 1988;44:5075–5094. [Google Scholar]
  83. Rujjanawate C. Kanjanapothi D. Panthong A. Pharmacological effect and toxicity of alkaloids from Gelsemium elegans Benth. J. Ethnopharmacol. 2003;89:91–95. doi: 10.1016/s0378-8741(03)00267-8. [DOI] [PubMed] [Google Scholar]
  84. Dutt V. Thakur S. Dhar V. J. Sharma A. Diazo Insertion based Strategy for the Formation of Hexahydrocyclohepta [b] indoles. Pharmacogn. Rev. 2010;4:185–194. doi: 10.4103/0973-7847.70916. [DOI] [PMC free article] [PubMed] [Google Scholar]
  85. Jin G. L. Su Y. P. Liu M. Xu Y. Yang J. Liao K. J. Yu C. X. Medicinal plants of the genus Gelsemium (Gelsemiaceae, Gentianales)-A review of their phytochemistry, pharmacology, toxicology and traditional use. J. Ethnopharmacol. 2014;152:33–52. doi: 10.1016/j.jep.2014.01.003. [DOI] [PubMed] [Google Scholar]
  86. Yang Z. Tan Q. Jiang Y. Yang J. Su X. Qiao Z. Zhou W. He L. Qiu H. Zhang M. Asymmetric total synthesis of sarpagine and koumine alkaloids. Angew. Chem. 2021;133:13215–13221. doi: 10.1002/anie.202102416. [DOI] [PubMed] [Google Scholar]
  87. Singh P. Samanta K. Das S. K. Panda G. Amino acid chirons: a tool for asymmetric synthesis of heterocycles. Org. Biomol. Chem. 2014;12:6297–6339. doi: 10.1039/c4ob00943f. [DOI] [PubMed] [Google Scholar]
  88. Yuan W. Ma S. Ligand Controlled Highly Selective Copper-Catalyzed Borylcuprations of Allenes with Bis (pinacolato) diboron. Adv. Synth. Catal. 2012;354:1867–1872. [Google Scholar]
  89. Müller J. M. Schlittler E. Bein H. J. Reserpin, der sedative Wirkstoff aus Rauwolfia serpentina Benth. Experientia. 1952;8:338. doi: 10.1007/BF02174406. [DOI] [PubMed] [Google Scholar]
  90. Schlittler E. Ulshafer P. R. Pandow M. L. Hunt R. M. Dorfman L. Rauwolfia alkaloids, XVI. Deserpidine, a new alkaloid from Rauwolfia canescens. Experientia. 1955;11:64–65. doi: 10.1007/BF02179028. [DOI] [PubMed] [Google Scholar]
  91. Strawbridge R. Javed R. R. Cave J. Jauhar S. Young A. H. The effects of reserpine on depression: A systematic review. J. Psychopharmacol. 2023;37:248–260. doi: 10.1177/02698811221115762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  92. Woodson R. E., Younken H. W., Schlitter E. and Schneider J. A., Rauwolfia: Botany, Pharmacognosy, Chemistry and Pharmacology, Little, Brown and Co., Boston, 1957 [Google Scholar]
  93. Szántay C. Blaskó G. Honty K. Baitz-Gács E. Tamás J. Tőke L. Synthesis of reserpine-type alkaloids, III. Synthesis of rac-deserpidine and a rac-raunescine epimer. Liebigs Ann. Chem. 1983;8:1292–1309. [Google Scholar]
  94. Sakai S. Ogawa M. Chemical Transformation of Reserpine to Deserpidine. Heterocycles. 1978;10:67–71. [Google Scholar]
  95. Miyata O. Hirata Y. Naito T. Ninomiya I. A formal total synthesis of (±)-deserpidine. Heterocycles. 1984;22:1041–1044. [Google Scholar]
  96. Wu P. Zhou Q. Liu X. Y. Xue F. Qin Y. Synthetic studies towards (–)-deserpidine: Total synthesis of the stereoisomer and derivative of (–)-deserpidine. Chin. Chem. Lett. 2021;32:401–404. [Google Scholar]
  97. Mariano P. S. Baxter E. W. Labaree D. Ammon H. L. Formal total synthesis of deserpidine demonstrating a versatile amino-Claisen rearrangement/Wenkert cyclization strategy for the preparation of functionalized yohimbane ring systems. J. Am. Chem. Soc. 1990;112:7682–7692. [Google Scholar]
  98. Varchi G. Battaglia A. Samorì C. Baldelli E. Danieli B. Fontana G. Bombardelli E. Synthesis of deserpidine from reserpine. J. Nat. Prod. 2005;68:1629–1631. doi: 10.1021/np050179x. [DOI] [PubMed] [Google Scholar]
  99. Wu P. Zhou Q. Liu X. Y. Xue F. Qin Y. Synthetic studies towards (–)-deserpidine: Total synthesis of the stereoisomer and derivative of (–)-deserpidine. Chin. Chem. Lett. 2021;32:401–404. [Google Scholar]
  100. Oldenziel O. H. van Leusen D. VanLeusen A. M. Chemistry of sulfonylmethyl isocyanides. 13. A general one-step synthesis of nitriles from ketones using tosylmethyl isocyanide. Introduction of a one-carbon unit. J. Org. Chem. 1977;42:3114–3118. [Google Scholar]
  101. Fuganti C. Serra S. Baker's yeast-mediated enantioselective synthesis of the bisabolane sesquiterpenes (+)-curcuphenol, (+)-xanthorrhizol, (−)-curcuquinone and (+)-curcuhydroquinone. J. Chem. Soc., Perkin Trans. 2000;1:3758–3764. [Google Scholar]
  102. Bellido M. Riego-Mejías C. Sciortino G. Verdaguer X. Lledós A. Riera A. Regioselective Ring-Opening of Oxetanes Catalyzed by Lewis Superacid Al (C6F5)3. Adv. Synth. Catal. 2024;366:925–933. [Google Scholar]
  103. Menges F. Pfaltz A. Threonine-derived phosphinite-oxazoline ligands for the Ir-catalyzed enantioselective hydrogenation. Adv. Synth. Catal. 2002;344:40–44. [Google Scholar]
  104. Okuma K. Tanaka Y. Kaji S. Ohta H. Reaction of dimethyloxosulfonium methylide with epoxides. Preparation of oxetanes. J. Org. Chem. 1983;48:5133–5134. [Google Scholar]
  105. Honwad V. K. Rao A. S. Terpenoids-LXIX: Absolute Configuration of (−) α-Curcumene. Tetrahedron. 1965;21:2593–2604. [Google Scholar]
  106. da Silva G. S. Pozzatti P. Rigatti F. Hörner R. Alves S. H. Mallmann C. A. Heinzmann B. M. Antimicrobial evaluation of sesquiterpene α-curcumene and its synergism with imipenem. J. Microbiol., Biotechnol. Food Sci. 2015;4:434–436. [Google Scholar]
  107. Utkina N. K. Makarchenko A. E. Shchelokova O. V. Virovaya M. V. Antioxidant Activity of Phenolic Metabolites from Marine Sponges. Chem. Nat. Compd. 2004;40:373–377. [Google Scholar]
  108. Santos da Silva G. N. Pozzatti P. Rigatti F. Hörner R. Alves S. H. Mallmann C. A. Heinzmann B. M. Antimicrobial Evaluation of Sesquiterpene α-Curcumene and Its Synergism with Imipenem. J. Microbiol., Biotechnol. Food Sci. 2015;4:434–436. [Google Scholar]
  109. Itokawa H. Hirayama F. Funakoshi K. Takeya K. Studies on the Antitumor Bisabolane Sesquiterpenoids Isolated from Curcuma Xanthorrhiza. Chem. Pharm. Bull. 1985;33:3488–3492. doi: 10.1248/cpb.33.3488. [DOI] [PubMed] [Google Scholar]
  110. Bellido M. Riego-Mejías C. Diaz-Moreno A. Verdaguer X. Riera A. Enantioselective Ir-catalyzed hydrogenation of terminal homoallyl Sulfones: total synthesis of (−)-curcumene. Org. Lett. 2023;25:1453–1457. doi: 10.1021/acs.orglett.3c00181. [DOI] [PMC free article] [PubMed] [Google Scholar]
  111. Okuma K. Tanaka Y. Kaji S. Ohta H. Reaction of dimethyloxosulfonium methylide with epoxides. Preparation of oxetanes. J. Org. Chem. 1983;48:5133–5134. [Google Scholar]
  112. Cabre A. Rafael S. Sciortino G. Ujaque G. Verdaguer X. Lledos A. Riera A. Catalytic Regioselective Isomerization of 2,2 Disubstituted Oxetanes to Homoallylic Alcohols. Angew. Chem., Int. Ed. 2020;59:7521–7527. doi: 10.1002/anie.201915772. [DOI] [PubMed] [Google Scholar]
  113. Pfaltz A. Blankenstein J. Hilgraf R. Hörmann E. McIntyre S. Menges F. Schönleber M. Smidt S. P. Wustenberg B. Zimmermann N. Iridium-Catalyzed Enantioselective Hydrogenation of Olefins. Adv. Synth. Catal. 2003;345:33–43. [Google Scholar]
  114. Peters B. K. Zhou T. Rujirawanich J. Cadu A. Singh T. Rabten W. Kerdphon S. Andersson P. G. An Enantioselective Approach to the Preparation of Chiral Sulfones by Ir-Catalyzed Asymmetric Hydrogenation. J. Am. Chem. Soc. 2014;136:16557–16562. doi: 10.1021/ja5079877. [DOI] [PubMed] [Google Scholar]
  115. Mazuela J. Norrby P. O. Andersson P. G. Pámies O. Diéguez M. Pyranoside Phosphite-Oxazoline Ligands for the Highly Versatile and Enantioselective Ir-Catalyzed Hydrogenation of Minimally Functionalized Olefins. A Combined Theoretical and Experimental Study. J. Am. Chem. Soc. 2011;133:13634–13645. doi: 10.1021/ja204948k. [DOI] [PubMed] [Google Scholar]
  116. Serra S. Preparation and Use of Enantioenriched 2-Aryl Propylsulfonylbenzene Derivatives as Valuable Building Blocks for the Enantioselective Synthesis of Bisabolane Sesquiterpenes. Tetrahedron: Asymmetry. 2014;25:1561–1572. [Google Scholar]
  117. Hutchins R. O. Learn K. Regio- and Stereoselective Reductive Replacement of Allylic Oxygen, Sulfur, and Selenium Functional Groups by Hydride via Catalytic Activation by Palladium (0) Complexes. J. Org. Chem. 1982;47:4380–4382. [Google Scholar]
  118. Stakanovs G. Blazevica A. Belyakov S. Rasina D. Jirgensons A. Semisynthesis of Linariophyllenes A–C and Rumphellolide H, Structure Revisions and Proposed Biosynthesis Pathways. J. Nat. Prod. 2023;86:2368–2378. doi: 10.1021/acs.jnatprod.3c00574. [DOI] [PubMed] [Google Scholar]
  119. Stakanovs G. Mishnev A. Rasina D. Jirgensons A. J. A concise bioinspired semisynthesis of rumphellaones A–C and their C-8 epimers from β-caryophyllene. J. Nat. Prod. 2020;83:2004–2009. doi: 10.1021/acs.jnatprod.0c00403. [DOI] [PubMed] [Google Scholar]
  120. Stakanovs G. Belyakov S. Jirgensons A. Rasina D. Convergent biomimetic semisynthesis of disesquiterpenoid rumphellolide. Org. Biomol. Chem. 2022;20:2455–2461. doi: 10.1039/d2ob00238h. [DOI] [PubMed] [Google Scholar]
  121. Maliori A. Athanasiadou T. Psomiadou V. Bagkavou G. G. Stathakis C. I. Syntheses of ent-Aquilanol A and ent-Aquilanol B via Retro-Cycloisomerization of (−)-Caryophyllene Oxide. Access to Medium-Sized Oxygenated Carbocyclic Scaffolds. Org. Lett. 2022;24:6242–6246. doi: 10.1021/acs.orglett.2c02216. [DOI] [PubMed] [Google Scholar]
  122. Syntrivanis L. D. Némethová I. Schmid D. Levi S. Prescimone A. Bissegger F. Major D. T. Tiefenbacher K. J. Four-step access to the sesquiterpene natural product presilphiperfolan-1β-ol and unnatural derivatives via supramolecular catalysis. J. Am. Chem. Soc. 2020;142:5894–5900. doi: 10.1021/jacs.0c01464. [DOI] [PubMed] [Google Scholar]
  123. Bemis C. Y. Ungarean C. N. Shved A. S. Jamieson C. S. Hwang T. Lee K. S. Houk K. N. Sarlah D. J. Total synthesis and computational investigations of sesquiterpene-tropolones ameliorate stereochemical inconsistencies and resolve an ambiguous biosynthetic relationship. J. Am. Chem. Soc. 2021;143:6006–6017. doi: 10.1021/jacs.1c02150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  124. Parker W. Raphael R. A. Roberts J. S. Neoclovene a novel rearrangement product of caryophyllene. Tetrahedron Lett. 1965;6:2313–2316. [Google Scholar]
  125. Nigam I. C. Levi L. Essential Oils and Their Constituents. XXVI. 1 Rearrangement of Caryophyllene Oxide during Gas Chromatography. J. Org. Chem. 1965;30:653–654. doi: 10.1021/jo01013a509. [DOI] [PubMed] [Google Scholar]
  126. Yamada Y. Arima S. Nagamitsu T. Johmoto K. Uekusa H. Eguchi T. Shin-ya K. Cane D. E. Ikeda H. Novel terpenes generated by heterologous expression of bacterial terpene synthase genes in an engineered Streptomyces host. J. Antibiot. 2015;68:385–394. doi: 10.1038/ja.2014.171. [DOI] [PMC free article] [PubMed] [Google Scholar]
  127. Liu J. Zhou Y. Yu Z. X. Six-Step Total Synthesis of Isohirsut-4-ene through [5+ 2+ 1] Cycloaddition and Transannular Epoxide–Alkene Cyclization. Org. Lett. 2022;24:1444–1447. doi: 10.1021/acs.orglett.1c04383. [DOI] [PubMed] [Google Scholar]
  128. Kutateladze A. G. Kuznetsov D. M. Triquinanes and Related Sesquiterpenes Revisited Computationally: Structure Corrections of Hirsutanols B and D, Hirsutenol E, Cucumin B, Antrodins C−E, Chondroterpenes A and H, Chondrosterins C and E, Dichrocephone A, and Pethybrene. J. Org. Chem. 2017;82:10795–10802. doi: 10.1021/acs.joc.7b02018. [DOI] [PubMed] [Google Scholar]
  129. Nguyen N. Tantillo D. J. Using quantum chemical computations of NMR chemical shifts to assign relative configurations of terpenes from an engineered Streptomyces host. J. Antibiot. 2016;69:534. doi: 10.1038/ja.2016.51. [DOI] [PubMed] [Google Scholar]
  130. Wang Y. Wang J. Su J. Huang F. Jiao L. Liang Y. Yang D. Zhang S. Wender P. A. Yu Z. X. A Computationally Designed Rh(I)-Catalyzed Two-Component [5 + 2+1] Cycloaddition of Ene-vinylcyclopropanes and CO for the Synthesis of Cyclooctenones. J. Am. Chem. Soc. 2007;129:10060–10061. doi: 10.1021/ja072505w. [DOI] [PubMed] [Google Scholar]
  131. Wang Y. Yu Z. X. Rhodium-Catalyzed [5 + 2 + 1] Cycloaddition of Ene-Vinylcyclopropanes and CO: Reaction Design, Development, Application in Natural Product Synthesis, and Inspiration for Developing New Reactions for Synthesis of Eight Membered Carbocycles. Acc. Chem. Res. 2015;48:2288–2296. doi: 10.1021/acs.accounts.5b00037. [DOI] [PubMed] [Google Scholar]
  132. Wang Y. Liao W. Wang Y. Jiao L. Yu Z. X. Mechanism and Stereochemistry of Rhodium-Catalyzed [5+2+1] Cycloaddition of Ene-Vinylcyclopropanes and Carbon Monoxide Revealed by Visual Kinetic Analysis and Quantum Chemical Calculations. J. Am. Chem. Soc. 2022;144:2624–2636. doi: 10.1021/jacs.1c11030. [DOI] [PubMed] [Google Scholar]
  133. Wender P. A. Williams T. J. [(arene)Rh(cod)]+ Complexes as Catalysts for [5 + 2] Cycloaddition Reactions. Angew. Chem., Int. Ed. 2002;41:4550–4553. doi: 10.1002/1521-3773(20021202)41:23<4550::AID-ANIE4550>3.0.CO;2-D. [DOI] [PubMed] [Google Scholar]
  134. Wender P. A. Love J. A. Williams T. J. Rhodium-Catalyzed [5 + 2] Cycloaddition Reactions in Water. Synlett. 2003;2003:1295–1298. [Google Scholar]
  135. Liu J. Zhou Y. Zhu J. Yu Z. X. Synthesizing Molecules with Linear Tricyclic 5/5/5 and 6/5/5 Skeletons via [5 + 2 + 1]/Ene Strategy. Org. Lett. 2021;23:7566–7570. doi: 10.1021/acs.orglett.1c02766. [DOI] [PubMed] [Google Scholar]
  136. Wellington K. D. Cambie R. C. Rutledge P. S. Bergquist P. R. J. Chemistry of Sponges. 19. Novel Bioactive Metabolites from Hamigera tarangaensis. J. Nat. Prod. 2000;63:79–85. doi: 10.1021/np9903494. [DOI] [PubMed] [Google Scholar]
  137. Cambie R. C. Rickard C. E. F. Rutledge P. S. Wellington K. D. K. D. Hamigerin A and a hamigerin D decomposition product. Acta Crystallogr., Sect. C: Cryst. Struct. Commun. 2001;57:958–960. doi: 10.1107/s0108270101007442. [DOI] [PubMed] [Google Scholar]
  138. Dattelbaum J. D. Singh A. J. Field J. J. Miller J. H. Northcote P. T. J. The nitrogenous hamigerans: Unusual amino acid-derivatized aromatic diterpenoid metabolites from the New Zealand marine sponge Hamigera tarangaensis. Org. Chem. 2015;80:304–312. doi: 10.1021/jo502370b. [DOI] [PubMed] [Google Scholar]
  139. Singh A. J. Dattelbaum J. D. Field J. J. Smart Z. Woolly E. F. Barber J. M. Heathcott R. Miller J. H. Northcote P. T. structurally diverse hamigerans from the New Zealand marine sponge Hamigera tarangaensis: NMR-directed isolation, structure elucidation and antifungal activity. Org. Biomol. Chem. 2013;11:8041–8051. doi: 10.1039/c3ob41305e. [DOI] [PubMed] [Google Scholar]
  140. Woolly E. F. Singh A. J. Russell E. R. Miller J. H. Northcote P. T. J. Hamigerans R and S: nitrogenous diterpenoids from the New Zealand marine sponge Hamigera tarangaensis. J. Nat. Prod. 2018;81:387–393. doi: 10.1021/acs.jnatprod.7b00960. [DOI] [PubMed] [Google Scholar]
  141. Li X. Xue D. Wang C. Gao S. Total Synthesis of the Hamigerans. Angew. Chem. 2016;128:10096–10100. doi: 10.1002/anie.201604070. [DOI] [PubMed] [Google Scholar]
  142. Duquette D. C. Jensen T. Stoltz B. M. Progress towards the total synthesis of hamigerans C and D: a direct approach to an elaborated 6-7-5 carbocyclic core. J. Antibiot. 2018;71:263–267. doi: 10.1038/ja.2017.96. [DOI] [PMC free article] [PubMed] [Google Scholar]
  143. Jiang B. Dai M. Synthetic Studies toward the Hamigerans with a 6–7–5 Tricyclic Core. Org. Lett. 2020;22:4176–4179. doi: 10.1021/acs.orglett.0c01253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  144. Borger C. Schmidt A. W. Knolker H. H. First Total Synthesis of Murrastifoline B and an Improved Route to Murrastifoline F. Synlett. 2014;25:1381–1384. [Google Scholar]
  145. Hao W. Harenberg J. H. Wu X. MacMillan S. N. Lin S. Diastereo-and enantioselective formal [3+ 2] cycloaddition of cyclopropyl ketones and alkenes via Ti-catalyzed radical redox relay. J. Am. Chem. Soc. 2018;140:3514–3517. doi: 10.1021/jacs.7b13710. [DOI] [PubMed] [Google Scholar]
  146. Hsu Y. H. Hirota A. Shima S. Nakagawa M. Nozaki H. Tada T. Nakayama M. Structure of Myrocin C, a New Diterpene Antibiotic Produced by a Strain of Myrothecium Sp. Agric. Biol. Chem. 1987;51:3455–3457. [Google Scholar]
  147. Nakagawa M. Hsu Y. H. Hirota A. Shima S. Nakayama M. Myrocin C. a New Diterpene Antitumor Antibiotic from Myrothecium Verrucaria. I. Taxonomy of the Producing Strain, Fermentation, Isolation and Biological Properties. J. Antibiot. 1989;42:218–222. doi: 10.7164/antibiotics.42.218. [DOI] [PubMed] [Google Scholar]
  148. Hsu Y. H. Nakagawa M. Hirota A. Shima S. Nakayama M. Structure of Myrocin B, a New Diterpene Antibiotic Produced by Myrothecium Verrucaria. Agric. Biol. Chem. 1988;52:1305–1307. [Google Scholar]
  149. Lehr N. A. Meffert A. Antelo L. Sterner O. Anke H. Weber R. W. S. Antiamoebins, Myrocin B and the Basis of Antifungal Antibiosis in the Coprophilous Fungus Stilbella Erythrocephala (Syn. S. Fimetaria) FEMS Microbiol. Ecol. 2006;55:105–112. doi: 10.1111/j.1574-6941.2005.00007.x. [DOI] [PubMed] [Google Scholar]
  150. Tsukada M. Fukai M. Miki K. Shiraishi T. Suzuki T. Nishio K. Sugita T. Ishino M. Kinoshita K. Takahashi K. Shiro M. Koyama K. Chemical Constituents of a Marine Fungus, Arthrinium Sacchari. J. Nat. Prod. 2011;74:1645–1649. doi: 10.1021/np200108h. [DOI] [PubMed] [Google Scholar]
  151. Klemke C. Kehraus S. Wright A. D. Konig G. M. New Secondary Metabolites from the Marine Endophytic Fungus Apiospora Montagnei. J. Nat. Prod. 2004;67:1058–1063. doi: 10.1021/np034061x. [DOI] [PubMed] [Google Scholar]
  152. Ebada S. S. Schulz B. Wray V. Totzke F. Kubbutat M. H. G. Muller W. E. G. Hamacher A. Kassack M. U. Lin W. Proksch P. Arthrinins A− D: Novel Diterpenoids and Further Constituents from the Sponge Derived Fungus Arthrinium Sp. Bioorg. Med. Chem. 2011;19:4644–4651. doi: 10.1016/j.bmc.2011.06.013. [DOI] [PubMed] [Google Scholar]
  153. Wei W. Gao J. Shen Y. Chu Y. L. Xu Q. Tan R. X. Immunosuppressive Diterpenes from Phomopsis sp. S12. Eur. J. Org Chem. 2014;2014:5728–5734. [Google Scholar]
  154. Chu-Moyer M. Y. Danishefsky S. J. A Remarkable Cyclopropanation: The Total Synthesis of Myrocin C. J. Am. Chem. Soc. 1992;114:8333–8334. [Google Scholar]
  155. Chu-Moyer M. Y. Danishefsky S. J. Schulte G. K. Total Synthesis of (±)-Myrocin C. J. Am. Chem. Soc. 1994;116:11213–11218. [Google Scholar]
  156. Simmons H. E. Smith R. D. A New Synthesis of Cyclopropanes from Olefins. J. Am. Chem. Soc. 1958;80:5323–5324. [Google Scholar]
  157. Chu-Moyer M. Y. Danishefsky S. J. On the Mode of Action of Myrocin C: Evidence for a CC-1065 Connection. Tetrahedron Lett. 1993;34:3025–3028. [Google Scholar]
  158. Zander N. Langschwager W. Hoffmann H. M. R. The Enol Lactone Approach to Protected Hydroxy γ-Lactones (5 Hydroxy-dihydro-furan-2-ones) Synth. Commun. 1996;26:4577–4590. [Google Scholar]
  159. Langschwager W. Hoffmann H. M. R. Ring-Chain Tautomerism Provides a Route to 7a-hydroxy-3a-methyl-2,7-dioxo perhydrobenzofuran. Synthesis of the Hydroxy γ-Lactone Substruc ture of Myrocin and Other Bioactive Natural Products. Liebigs Ann. 1995;1995:797–802. [Google Scholar]
  160. Economou C. Tomanik M. Herzon S. B. Synthesis of Myrocin G, the Putative Active Form of the Myrocin Antitumor Antibiotics. J. Am. Chem. Soc. 2018;140:16058–16061. doi: 10.1021/jacs.8b10891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  161. Tomanik M. Economou C. Frischling M. C. Xue M. Marks V. A. Mercado B. Q. Herzon S. B. Development of a convergent enantioselective synthetic route to (−)-myrocin G. J. Org. Chem. 2020;85:8952–8989. doi: 10.1021/acs.joc.0c00891. [DOI] [PMC free article] [PubMed] [Google Scholar]
  162. Xu C. Zhang L. Luo S. Asymmetric Enamine Catalysis with β-Ketoesters by Chiral Primary Amine: Divergent Stereocontrol Modes. J. Org. Chem. 2014;79:11517–11526. doi: 10.1021/jo502152w. [DOI] [PubMed] [Google Scholar]
  163. Au T. K. Chick W. S. H. Leung P. C. The biology of ophiobolins. Life Sci. 2000;67:733–742. doi: 10.1016/s0024-3205(00)00668-8. [DOI] [PubMed] [Google Scholar]
  164. Rowley M. Tsukamoto M. Kishi Y. Total synthesis of (+)-ophiobolin C. J. Am. Chem. Soc. 1989;111:2735. [Google Scholar]
  165. Tsuna K. Noguchi N. Nakada M. Convergent total synthesis of (+)-ophiobolin A. Angew. Chem., Int. Ed. 2011;50:9452–9455. doi: 10.1002/anie.201104447. [DOI] [PubMed] [Google Scholar]
  166. Tsuna K. Noguchi N. Nakada M. Enantioselective Total Synthesis of (+)-Ophiobolin A. Chem.–Eur. J. 2013;19:5476–5486. doi: 10.1002/chem.201204119. [DOI] [PubMed] [Google Scholar]
  167. Brill Z. G. Grover H. K. Maimone T. J. Enantioselective synthesis of an ophiobolin sesterterpene via a programmed radical cascade. Science. 2016;352:1078–1082. doi: 10.1126/science.aaf6742. [DOI] [PMC free article] [PubMed] [Google Scholar]
  168. Thach D. Q. Brill Z. G. Grover H. K. Esguerra K. V. Thompson J. K. Maimone T. J. Total synthesis of (+)-6-epi-ophiobolin A. Angew. Chem., Int. Ed. 2020;59:1532–1536. doi: 10.1002/anie.201913150. [DOI] [PMC free article] [PubMed] [Google Scholar]
  169. Charette A. B. Juteau H. Lebel H. Molinaro C. Enantioselective cyclopropanation of allylic alcohols with dioxaborolane ligands: scope and synthetic applications. J. Am. Chem. Soc. 1998;120:11943–11952. [Google Scholar]
  170. Charette A. B. Naud J. Regioselective opening of substituted (cyclopropylmethyl) lithiums derived from cyclopropylmethyl iodides. Tetrahedron Lett. 1998;39:7259–7262. [Google Scholar]
  171. Mukaiyama T. Matsuo J. I. Kitagawa H. A new and one-pot synthesis of α, β-unsaturated ketones by dehydrogenation of various ketones with N-tert-butyl phenylsulfinimidoyl chloride. Chem. Lett. 2000;29:1250–1251. [Google Scholar]
  172. Cook C. E. Whichard L. P. Turner B. Wall M. E. Egley G. H. Germination of witchweed (Striga lutea Lour.): Isolation and properties of a potent stimulant. Science. 1966;154:1189–1190. doi: 10.1126/science.154.3753.1189. [DOI] [PubMed] [Google Scholar]
  173. Akiyama K. Matsuzaki K. Hayashi H. Plant sesquiterpenes induce hyphal branching in arbuscular mycorrhizal fungi. Nature. 2005;435:824–827. doi: 10.1038/nature03608. [DOI] [PubMed] [Google Scholar]
  174. Besserer A. Puech-Pagès V. Kiefer P. Gomez-Roldan V. Jauneau A. Roy S. Portais J. C. Roux C. Bécard G. Séjalon-Delmas N. Strigolactones stimulate ar buscular mycorrhizal fungi by activating mitochondria. PLoS Biol. 2006;4:e226. doi: 10.1371/journal.pbio.0040226. [DOI] [PMC free article] [PubMed] [Google Scholar]
  175. Yoneyama K. Xie X. Yoneyama K. Kisugi T. Nomura T. Nakatani Y. Akiyama K. McErlean C. S. P. Which are the major players, canonical or non-canonical strigolactones. J. Exp. Bot. 2018;69:2231–2239. doi: 10.1093/jxb/ery090. [DOI] [PubMed] [Google Scholar]
  176. Mori N. Sado A. Xie X. Yoneyama K. Asami K. Seto Y. Nomura T. Yamaguchi S. Yoneyama K. Akiyama K. Chemical identification of 18-hydroxycarlactonoic acid as an LjMAX1 product and in planta conversion of its methyl ester to canonical and non-canonical strigolactones in Lotus japonicus. Phytochemistry. 2020;174:112349. doi: 10.1016/j.phytochem.2020.112349. [DOI] [PubMed] [Google Scholar]
  177. Wolkenstein K. Sun H. Falk H. Griesinger C. Structure and absolute configuration of Jurassic polyketide-derived spiroborate pigments obtained from microgram quantities. J. Am. Chem. Soc. 2015;137:13460–13463. doi: 10.1021/jacs.5b08191. [DOI] [PubMed] [Google Scholar]
  178. Wolkenstein K. Gross J. H. Falk H. Boron-containing organic pigments from a Jurassic red alga. Proc. Natl. Acad. Sci. U. S. A. 2010;107:19374–19378. doi: 10.1073/pnas.1007973107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  179. Shabuer G. Ishida K. Pidot S. J. Roth M. Dahse H. M. Hertweck C. Plant pathogenic anaerobic bacteria use aromatic polyketides to access aerobic territory. Science. 2015;350:670–674. doi: 10.1126/science.aac9990. [DOI] [PubMed] [Google Scholar]
  180. Pidot S. Ishida K. Cyrulies M. Hertweck C. Discovery of clostrubin, an exceptional polyphenolic polyketide antibiotic from a strictly anaerobic bacterium. Angew. Chem., Int. Ed. 2014;126:7990–7993. doi: 10.1002/anie.201402632. [DOI] [PubMed] [Google Scholar]
  181. Kirita K. Matsumoto H. Endo G. Hosokawa S. Total Syntheses of Borolithochromes A, D and G. Angew. Chem., Int. Ed. 2024;63:e202400586. doi: 10.1002/anie.202400586. [DOI] [PubMed] [Google Scholar]
  182. Kobayashi M. Aoki S. Ohyabu N. Kurosu M. Wang W. Kitagawa I. Arenastatin A, a potent cytotoxic depsipeptide from the Okinawan marine sponge Dysidea arenaria. Tetrahedron Lett. 1994;35:7969–7972. [Google Scholar]
  183. Rao S. N. MoreO'Ferrall R. A. Kelly S. C. Boyd D. R. Agarwall R. Acid-catalyzed aromatizations of arene oxides and arene hydrates: are arene oxides homoaromatic? J. Am. Chem. Soc. 1993;115:5458–5465. [Google Scholar]
  184. Kirita K. Matsumoto H. Endo G. Inoue K. Hosokawa S. Total syntheses of borolithochromes H1, H2, I1, and I2. Biosci., Biotechnol., Biochem. 2024;88:1144–1154. doi: 10.1093/bbb/zbae104. [DOI] [PubMed] [Google Scholar]
  185. Anelli P. L. Biffi C. Montanari F. Quici S. Fast and selective oxidation of primary alcohols to aldehydes or to carboxylic acids and of secondary alcohols to ketones mediated by oxoammonium salts under two-phase conditions. J. Org. Chem. 1987;52:2559–2562. [Google Scholar]
  186. Lupattelli P. D'Auria M. Blasio N. D. Lenti F. A novel approach to combretastatins: from trans-epoxide to CA-4 and its dioxolane derivative. Eur. J. Org Chem. 2009;2009:141–145. [Google Scholar]
  187. Rao S. N. More O'Ferrall R. A. Kelly S. C. Boyd D. R. Agarwal R. Acid-catalyzed aromatizations of arene oxides and arene hydrates: are arene oxides homoaromatic? J. Am. Chem. Soc. 1993;115:5458–5465. [Google Scholar]
  188. Bernard A. M. Ghiani M. R. Piras P. P. Rivoldini A. Dealkylation of activated alkyl aryl ethers using lithium chloride in dimethylformamide. Synthesis. 1989;1989:287–79. [Google Scholar]
  189. Harrison I. T. Cleavage of alkyl aryl ethers with lithium iodide. J. Chem. Soc. Chem. Commun. 1969;11:616a. [Google Scholar]
  190. Kobayashi M. Kurosu M. Ohyabu N. Wang W. Fujii S. Kitagawa I. The absolute stereostructure of arenastatin A, a potent cytotoxic depsipeptide from the Okinawan Marine sponge Dysidea arenaria. Chem. Pharm. Bull. 1994;42:2196–2198. [Google Scholar]
  191. Kobayashi M. Kurosu M. Wang W. Kitagawa I. A total synthesis of arenastatin A, an extremely potent cytotoxic depsipeptide, from the Okinawan marine sponge Dysidea arenaria. Chem. Pharm. Bull. 1994;42:2394–2396. [Google Scholar]
  192. Trimurtulu G. Ohtani I. Patterson G. M. L. Moore R. E. Corbett T. H. Valeriote F. A. Demchik L. Total Structures of Cryptophycins, Potent Antitumor Depsipeptides from the Blue-Green Alga Nostoc sp. Strain GSV 224. J. Am. Chem. Soc. 1994;116:4729–4737. [Google Scholar]
  193. Aggarwal V. K. Charmant J. Dudin L. Porcelloni M. Richardson J. Effect of sulfide structure on enantioselectivity in catalytic asymmetric epoxidation of aldehydes: Mechanistic insights and implications. Proc. Natl. Acad. Sci. U. S. A. 2004;101:5467–5471. doi: 10.1073/pnas.0307559101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  194. Mihara Y. Kadoya H. Kakihana S. Kotoku N. Concise and Stereospecific Total Synthesis of Arenastatin A and Its Segment B Analogs. Molecules. 2024;29:4058. doi: 10.3390/molecules29174058. [DOI] [PMC free article] [PubMed] [Google Scholar]
  195. Hoard D. W. Moher E. D. Martinelli M. J. Norman B. H. Synthesis of Cryptophycin 52 Using the Shi Epoxidation. Org. Lett. 2002;4:1813–1815. doi: 10.1021/ol025933+. [DOI] [PubMed] [Google Scholar]
  196. Kumar P. Kaur N. Kumar R. Banerjee P. α, β-Unsaturated Carbonyls for One-Pot Transition-Metal-Free Access to 3, 6-Dihydro-2 H-pyrans. J. Org. Chem. 2022;87:7167–7178. doi: 10.1021/acs.joc.2c00379. [DOI] [PubMed] [Google Scholar]
  197. Guldbrandt M. Johansen T. N. Frydenvang K. Brauner-Osborne H. Stensbol T. B. Nielsen B. Karla R. Santi F. Krogsgaard-Larsen P. Madsen U. Glutamate receptor ligands: synthesis, stereochemistry, and enantiopharmacology of methylated 2- aminoadipic acid analogs. Chirality. 2002;14:351–363. doi: 10.1002/chir.10104. [DOI] [PubMed] [Google Scholar]
  198. Staudt M. Liu N. Malhaire F. Doroudian Y. Prézeau L. Renard E. Hasanpour Z. Pin J.-P. Bunch L. Synthesis and pharmacological characterization of conformationally restricted 2-amino-Adipic acid analogs and carboxycyclopropyl glycines as selective metabotropic glutamate 2 receptor agonists. Eur. J. Med. Chem. 2024;266:116157. doi: 10.1016/j.ejmech.2024.116157. [DOI] [PubMed] [Google Scholar]
  199. Zhang J. Liu Z. W. Ao Y. L. Hu L. J. Wei C. J. Zhang Q. H. Yuan M. F. Wang Y. Zhang Q. W. Ye W. C. Zhang X. Q. Hunterines A–C, three unusual monoterpenoid indole alkaloids from Hunteria zeylanica. J. Org. Chem. 2019;84:14892–14897. doi: 10.1021/acs.joc.9b01835. [DOI] [PubMed] [Google Scholar]
  200. Zhang Y. Ding X. Shao S. Guo L. L. Zhao Q. Hao X. J. He H. P. Melocochines A and B, two alkaloids from the fruits of Melodinus cochinchinensis. Org. Lett. 2019;21:9272–9275. doi: 10.1021/acs.orglett.9b03785. [DOI] [PubMed] [Google Scholar]
  201. Kitajima M. Nakazawa M. Wu Y. Kogure N. Zhang R. P. Takayama H. Kopsiyunnanines L and M, Strychnos-related monoterpenoid indole alkaloids from Yunnan Kopsia arborea. Tetrahedron. 2016;72:6692–6696. [Google Scholar]
  202. Chiaroni A. Randriambola L. Riche C. Husson H. P. Structure of goniomine, an alkaloid of a new type biogenetically related to indole alkaloids. X-ray analysis of dihydrogoniomine. J. Am. Chem. Soc. 1980;102:5920–5921. [Google Scholar]
  203. Zsigulics B. Angyal P. Mészáros B. B. Daru J. Varga S. Soós T. Bioinspired Synthesis of (−)-Hunterine A: Deciphering the Key Step in the Biogenetic Pathway. Chem.–Eur. J. 2025;31:e202404501. doi: 10.1002/chem.202404501. [DOI] [PubMed] [Google Scholar]
  204. Kürti L. and Czakó B., Strategic Applications of Named Reactions in Organic Synthesis: Background and Detailed Mechanisms, Elsevier, 2005, pp. 102–103 [Google Scholar]
  205. Saito T. Suzuki T. Takeuchi K. Matsumoto T. Suzuki K. Implication and improvement of stereoselective methylenation of a chiral aldehyde related to total synthesis of the furaquinocins. Tetrahedron Lett. 1997;38:3755–3758. [Google Scholar]
  206. Bohlmann F. Singh P. A guaian-5, 12-olide from Hypochoeris cretensis. Phytochemistry. 1982;21:2119–2120. [Google Scholar]
  207. Huang S. Pettaway C. A. Uehara H. Bucana C. D. Fidler I. J. Blockade of NF-κB activity in human prostate cancer cells is associated with suppression of angiogenesis, invasion, and metastasis. Oncogene. 2001;20:4188–4197. doi: 10.1038/sj.onc.1204535. [DOI] [PubMed] [Google Scholar]
  208. Mirzaei S. Saghari S. Bassiri F. Raesi R. Zarrabi A. Hushmandi K. Sethi G. Tergaonkar V. NF-κB as a regulator of cancer metastasis and therapy response: A focus on epithelial–mesenchymal transition. J. Cell. Physiol. 2022;237:2770–2795. doi: 10.1002/jcp.30759. [DOI] [PubMed] [Google Scholar]
  209. Zidorn C. Stuppner H. Tiefenthaler M. Konwalinka G. Cytotoxic activities of Hypocretenolides from Leontodon h ispidus. J. Nat. Prod. 1999;62:984–987. doi: 10.1021/np990058v. [DOI] [PubMed] [Google Scholar]
  210. Zidorn C. Dirsch V. M. Rüngeler P. Sosa S. Loggia R. D. Merfort I. Pahl H. L. Vollmar A. M. Stuppner H. Anti-inflammatory activities of hypocretenolides from Leontodon hispidus. Planta Med. 1999;65:704–708. doi: 10.1055/s-1999-14046. [DOI] [PubMed] [Google Scholar]
  211. Chen B. Zhang X. Yang Y. Xu D. Wu Q. Wang S. Bao S. Zhang X. Ding Y. Wang L. Chen Y. Hypocretenolides: collective total syntheses and activities toward metastatic colon cancer. Chem. Sci. 2024;15:6397–6401. doi: 10.1039/d4sc01469c. [DOI] [PMC free article] [PubMed] [Google Scholar]
  212. de Faria M. L. Magalhaes R. D. A. Silva F. C. Matias L. G. D. O. Ceschi M. A. Brocksom U. Brocksom T. J. Enantiodivergent syntheses of cycloheptenone intermediates for guaiane sesquiterpenes. Tetrahedron: Asymmetry. 2000;11:4093–4103. [Google Scholar]
  213. Ohashi T. Miyazawa Y. Ishizaki S. Kurobayashi Y. Saito T. Identification of odor-active trace compounds in blooming flower of damask rose (Rosa damascena) J. Agric. Food Chem. 2019;67:7410–7415. doi: 10.1021/acs.jafc.9b03391. [DOI] [PubMed] [Google Scholar]
  214. Miyazawa Y. Kawaguchi K. Katsuta R. Nukada T. Ishigami K. Analog synthesis of DAMASCENOLIDE™, an important aroma component of roses, and their odor properties. Biosci., Biotechnol., Biochem. 2020;84:1560–1569. doi: 10.1080/09168451.2020.1753498. [DOI] [PubMed] [Google Scholar]
  215. Miyazawa Y. Kawaguchi K. Katsuta R. Nukada T. Ishigami K. Studies on analogs of DAMASCENOLIDETM: Part 3. Synthesis and odor evaluation of dimethylated, cyclopropanated, and other analogs of DAMASCENOLIDE™. Biosci., Biotechnol., Biochem. 2021;85:756–764. doi: 10.1093/bbb/zbaa103. [DOI] [PubMed] [Google Scholar]
  216. Teponno R. B. Kusaria S. Spiteller M. Recent Advances in Research on Lignans and Neolignans. Nat. Prod. Rep. 2016;33:1044–1092. doi: 10.1039/c6np00021e. [DOI] [PubMed] [Google Scholar]
  217. Alfonzo E. Beeler A. B. A Sterically Encumbered Photoredox Catalyst Enables the Unified Synthesis of the Classical Lignan Family of Natural Products. Chem. Sci. 2019;10:7746–7754. doi: 10.1039/c9sc02682g. [DOI] [PMC free article] [PubMed] [Google Scholar]
  218. Alfonzo E. Millimaci A. M. Beeler A. B. Photoredox Generated Carbonyl Ylides Enable a Modular Approach to Aryltetralin, Dihydronaphthalene, and Arylnaphthalene Lignans. Org. Lett. 2020;22:6489–6493. doi: 10.1021/acs.orglett.0c02286. [DOI] [PubMed] [Google Scholar]
  219. Nono E. C. N. Mkounga P. Kuete V. Marat K. Hultin P. G. Nkengfack A. E. Pycnanthulignenes A−D, Antimicrobial Cyclolignene Derivatives from the Roots of Pycnanthus Angolensis. J. Nat. Prod. 2010;73:213–216. doi: 10.1021/np9007393. [DOI] [PubMed] [Google Scholar]
  220. Kuo W. L. Huang Y. L. Shen C. C. Shieh B. J. Chen C. C. Prenylated Benzoic Acids and Phenanthrenes from Liparis nakaharai. J. Chin. Chem. Soc. 2007;54:1359–1362. [Google Scholar]
  221. Song L. Su Q. Lin X. Du Z. Xu H. Ouyang M. A. Yao H. Tong R. Cascade R. Claisen and Meinwald Rearrangement for One-Pot Divergent Synthesis of Benzofurans and 2 H-Chromenes. Org. Lett. 2020;22:3004–3009. doi: 10.1021/acs.orglett.0c00770. [DOI] [PubMed] [Google Scholar]
  222. Bell D. Davies M. R. Geen G. R. Mann I. S. Copper(I) Iodide: A Catalyst for the Improved Synthesis of Aryl Propargyl Ethers. Synthesis. 1995:707–712. [Google Scholar]
  223. Wang X. Lu N. Yang Q. Gong D. Lin C. Zhang S. Xi M. Gao Y. Wei L. Guo Q. You Q. Studies on chemical modification and biology of a natural product, gambogic acid (III): Determination of the essential pharmacophore for biological activity. Eur. J. Med. Chem. 2011;46:1280–1290. doi: 10.1016/j.ejmech.2011.01.051. [DOI] [PubMed] [Google Scholar]
  224. Parisotto S. Deagostino A. Synthesis of High Functionalized Allyl Alcohols from Vinyl Oxiranes and N-Tosylhydrazones via a Tsuji-Trost-Like ′′Palladium-Iodide′′ Catalyzed Coupling. Org. Lett. 2018;20:6891–6895. doi: 10.1021/acs.orglett.8b03026. [DOI] [PubMed] [Google Scholar]
  225. Gemal A. L. Luche J. L. Lanthanoids in organic synthesis. 6. Reduction of α-enones by sodium borohydride in the presence of lanthanoid chlorides: synthetic and mechanistic aspects. J. Am. Chem. Soc. 1981;103:5454–5459. [Google Scholar]

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