Recent progress of [5 + 2] cycloaddition reactions in natural product synthesis

Nan Wang† , Yu Bai† , Qingyi Zeng , Tao Zhang and Jun Deng *
State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Frontiers Science Center for New Organic Matter, Nankai University, Tianjin 300071, China. E-mail: dengjun@nankai.edu.cn

First published on 28th July 2025

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Nan Wang

Nan Wang was born in Hohhot, Inner Mongolia, P. R. of China. He received his bachelor's degree in Shandong First Medical University in 2021 and received his master's degree in 2024 under the supervision of Prof. Lingyi Kong and Prof. Jun Luo at China Pharmaceutical University. After graduation, he joined the research group of Prof. Jun Deng at Nankai University as a doctoral candidate. He has been working on the bioinspired total synthesis of natural products.

Yu Bai

Yu Bai was born in Gansu, China, in 2003. He enrolled in the College of Chemistry at Nankai University in 2022. Currently, he is conducting undergraduate research in Deng's group, focusing on the bioinspired total synthesis of natural products, with an emphasis on exploring innovative synthetic methodologies and their potential applications.

Qingyi Zeng

Qingyi Zeng was born in Xi'an, Shaanxi Province in 2004. She entered the College of Chemistry at Nankai University as a student in 2022. She joined Professor Jun Deng's group for undergraduate research training in 2024. Her present research endeavors center around the total synthesis of complex natural products.

Tao Zhang

Tao Zhang was Born in 2004 in Lvliang, Shanxi Province, China. He enrolled in the College of Chemistry at Nankai University in 2022. He is interested in the total synthesis of complex natural products and the development of novel synthetic methodologies with potential applications. Currently, he is conducting undergraduate research in Prof. Deng's group.

Jun Deng

Jun Deng received his BSc from Lanzhou University, and PhD from Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences (2014) with Professor Ang Li. After a short period of postdoctoral research in Professor Andrew Myers' lab at Harvard University (2014–2016), he was appointed a Pioneer “Hundred Talents Program” Researcher at Kunming Institute of Botany, Chinese Academy of Sciences in 2017. In December 2020, he moved to Nankai University where he is Professor in college of chemistry. He was received Thieme Journals Award (2020). His research focuses on natural product total synthesis and medicinal chemistry.

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1 Introduction

The intricate polycyclic frameworks of natural products are central to their diverse biological activities. Efficient cyclization reactions are therefore crucial for the total synthesis of these complex molecules, exemplified by landmark syntheses of natural products such as taxol¹ and cephalotane diterpenoids.² Cycloaddition reactions have become powerful tools for constructing diverse and complex natural product (NP) skeletons efficiently. Among them, the [4 + 2] cycloaddition—in particular, the classic Diels–Alder reaction—has long been a cornerstone of synthetic organic chemistry.^3,4 It facilitates the construction of six-membered rings and bridged bicyclo[2.2.2] ring systems under mild conditions with minimal side reactions, playing a pivotal role in numerous total syntheses of natural products.^5–7

In contrast, the [5 + 2] cycloaddition reaction offers a unique advantage by enabling the rapid construction of seven-membered rings and bridged bicyclo[3.2.1] ring systems through the simultaneous formation of two C–C bonds in a single step. Both [4 + 2] and [5 + 2] cycloadditions share several key advantages: they enable the one-step formation of complex bridged ring systems, facilitate the continuous construction of chiral centers, and preserve the stereoisomeric configuration of dienophiles. However, limited reaction conditions and competing side pathways have historically restricted the use of [5 + 2] cycloadditions in total synthesis of natural products compared to the [4 + 2] reaction (Fig. 1).

Despite these challenges, the synthetic utility of the [5 + 2] cycloaddition reaction has gained increasing attention from synthetic chemists, particularly given the widespread occurrence of seven-membered rings and bridged bicyclo[3.2.1] ring systems in natural products. Over the past decade, this reaction type has not only seen substantial methodological advancements but has also demonstrated critical applications in the total synthesis of complex natural products.

While the last comprehensive review on [5 + 2] cycloaddition reactions was published in 2013,⁸ offering valuable insights to researchers, no thorough and up-to-date review encompassing the remarkable achievements from 2013 to 2024 has been available. Although several mini-reviews have addressed specific aspects, a comprehensive and up-to-date overview remains lacking.⁹ In this review, we systematically highlight the significant progress in [5 + 2] cycloaddition reactions, focusing on three major advancements:

(1) Broadened substrate scope: the range has expanded from traditional oxidopyrylium ylides to include various of phenols and quinones.

(2) Enriched product diversity: the reaction's product scope has evolved from exclusively generating bridged bicyclo[3.2.1] ring systems to now producing diverse fused ring systems and bridged bicyclo[m.n.1] ring systems.

(3) Strategic synthetic applications: the [5 + 2] cycloaddition has been strategically applied to the efficient synthesis of a broad array of complex natural products.

To provide a clear and logical structure, we classify the examples of [5 + 2] cycloaddition reactions into three categories based on substrate types: oxidopyrylium ylide [5 + 2] cycloaddition, oxidative dearomatization-induced (ODI) [5 + 2] cycloaddition, and quinone [5 + 2] cycloaddition. By organizing the content in this manner, we aim to offer a comprehensive and insightful overview of the advancements and applications of [5 + 2] cycloaddition reactions in the total synthesis of natural products, fostering further research and development in this dynamic field (Fig. 2).

2 Oxidopyrylium ylide [5 + 2] cycloaddition in natural product synthesis

Since its discovery in 1977,¹⁰ the oxidopyrylium ylide [5 + 2] cycloaddition has become one of the most frequently utilized variants of the [5 + 2] cycloaddition, primarily due to the ready availability of its starting materials. Over the years, significant advancements have been achieved by numerous talented chemists, firmly establishing the type I [5 + 2] cycloaddition as a powerful tool for constructing fused bicyclic systems. Notable examples include Sammes' synthesis of valeranone¹¹ and Wender's synthesis of phorbol,¹² which demonstrated the efficiency and versatility of this reaction in complex molecule synthesis.

In the past decade, Li pioneered the type II [5 + 2] cycloaddition,¹³ applying it strategically in the synthesis of a range of structurally complex natural products—a significant milestone in the field. His work not only broadened the substrate scope and improved reaction conditions but also demonstrated the method's potential in assembling polycyclic frameworks efficiently.

In this section, we present a selection of noteworthy examples of complex natural product syntheses accomplished via the type II [5 + 2] cycloaddition. Additionally, to provide a comprehensive perspective, we compare these syntheses with alternative strategies employed for the same targets, highlighting the advantages and limitations of the type II [5 + 2] cycloaddition. This comparative analysis aims to underscore the unique benefits of this approach in the context of natural product synthesis and its evolving role in the field of synthetic organic chemistry (Scheme 1)

2.1 Synthesis of (−)-colchicine

Colchicine (16), a natural alkaloid, is renowned for its potent antimitotic properties and has been explored for its therapeutic potential in treating various conditions, including acute gout, familial Mediterranean fever, and chronic myelocytic leukemia.¹⁴ Its distinctive 6-7-7-membered ring system, combined with the stereocenter at C-7 and an R-configured stereogenic axis defined by the pivot bond connecting the A and C rings, presents a significant challenge to synthetic chemists. In 2017, Chuang-Chuang Li's team unveiled a streamlined, enantioselective, and scalable synthesis of (−)-colchicine (16).¹⁵

The synthesis commenced with an elegant transition-metal-catalyzed C–H bond functionalization of 10, followed by a series of carefully orchestrated transfomations, including selective hydrogenation, the Seyferth–Gilbert homologation, and 1, 2-addition with an organolithium reagent, leading to the formation of ketone 11. The subsequent condensation of ketone 11 with the Ellman auxiliary, followed by DIBAL-H reduction of the resulting tert-butane-sulfinyl (t-BS) ketimine, produced 12 (R = t-BS) with remarkable diastereoselectivity. Treating 12 with HCl and methanol in a one-pot procedure yielded the acetylated amine 13 in 78% yield.

The synthesis's centerpiece involved the oxidative rearrangement of 13 using meta-chloroperoxybenzoic acid (m-CPBA), followed by acetylation of the anomeric hydroxyl group and an intramolecular [5 + 2] cycloaddition of acetoxypyranone 14, all carried out under carefully optimized one-pot conditions. This key transformation efficiently constructed the tricyclic 6/7/7 skeleton of colchicine, achieving a 52% yield on 1.0 g scale, as confirmed by X-ray crystallography. From compound 15, the enantioselective synthesis of colchicine was completed in four well-planned steps, resulting in a 9.2% overall yield with >99% enantiomeric excess (ee) (Scheme 2).

Li's synthesis of (−)-colchicine (16) demonstrated that the [5 + 2] cycloaddition is a powerful method for constructing a complex core, including a 7-membered ring, in a single step, while preserving the configurations of the other components. Furthermore, the bicyclo[3.2.1] structure formed by the [5 + 2] cycloaddition appears to easily transform into an aromatic structure, which could be beneficial for synthesizing related natural products.

2.2 Synthesis of cyclocitrinol

In 2000, Gräfe and co-workers reported the first isolation of cyclocitrinol (27), a novel fungal metabolite isolated from Terrestrial P. citrinum, characterized by its distinctive C-25 skeleton.¹⁶ Cyclocitrinol (27) features a sterically compact 7/7/6/5 tetracyclic skeleton and an unusual bicyclo[4.4.1] undecene A/B ring system, along with a strained bridgehead (anti-Bredt) double bond at C-1 to C-10, eight stereocenters, including two quaternary centers. The intricate structure and potential medicinal value of cyclocitrinol (27) have made it a coveted objective that synthetic chemists ardently strive to conquer. In 2007, Schmalz and colleagues reported an efficient method to access the bicyclo[4.4.1] A/B ring, via a SmI₂-mediated cyclopropane fragmentation.¹⁷ In 2014, Leighton and colleagues unveiled a sophisticated tandem Ireland–Claisen/Cope rearrangement sequence to achieve the core ring system of cyclocitrinol (23) (Scheme 3).¹⁸

Gui's team developed a streamlined and scalable method for synthesizing cyclocitrinol (27) from readily accessible and cost-effective pregnenolone via a biomimetic cascade rearrangement in 2018.¹⁹ After modifying pregnenolone (24) through six sequential steps, they obtained compound 25 as a single diastereomer on gram scale. Oxidation of 25 with meta-chloroperbenzoic acid (m-CPBA) produced a diastereomeric mixture of sulfoxides which were then heated with O-methylquinine in toluene at 130 °C to induce syn-elimination. Under optimized conditions, 26 was synthesized with a notable 54% yield over formation and fragmentation of a cyclopropane intermediate, particularly on the gram scale. Finally, they completed the synthesis in two additional steps, as shown in Scheme 3, demonstrating the remarkable efficiency of the biomimetic cascade rearrangement.

Although Gui's biomimetic synthesis was impressive, Li's group achieved the first asymmetric total synthesis of cyclocitrinol (27) in 2018.²⁰ 28 was synthesized after a 7-step linear sequence, then 29 was obtained as a single product on a gram scale underwent an Achmatowicz reaction. Subsequently, Li selected acetic anhydride (Ac₂O), 2, 2, 6, 6-tetramethylpiperidine (TMP) and dimethylaminopyridine (DMAP) as the acetylation conditions, resulting in the formation of the key intermediate 30 (Scheme 3).

The type II intramolecular [5 + 2] cycloaddition was then performed using TMP as a base under heating conditions in a sealed tube, affording the tetracyclic core 32 as a single diastereomer in 68% overall yield (1.9 g scale from 28, following a single column chromatography step).²¹ The presence of the CH₂OAc group at the allylic position of the dienophile alkene was pivotal for achieving high diastereoselectivity.²² The successful formation of compound 32 underscored the robustness of the methodology. After nine additional linear steps the target product was obtained. Thus, the first asymmetric total synthesis of cyclocitrinol (27) was accomplished, with a modest overall yield of 1.0% from commercially available starting materials. This synthesis also provided unequivocal confirmation of the structure and absolute configuration of naturally occurring cyclocitrinol (30).

Both synthesis achievements were outstanding. Li's group successfully completed the first total synthesis of cyclocitrinol using the [5 + 2] strategy, while Gui's biomimetic strategy provided an efficient route, yielding higher results and demonstrating an impressive cascade rearrangement catalyzed by organic bases. Although stereoselectivity in both strategies was achieved by controlling the substrates, the substrates for the [5 + 2] strategy were prepared from simple, commercially available molecules. Considering this, it appears that the substrate scope of Li's [5 + 2] strategy is broader than that of Gui's cascade rearrangement.

2.3 Synthesis of cerorubenic acid-III

Cerorubenic acid-III (44), first isolated by Naya and colleagues in 1983 from the secretions of the scale insect Ceroplastes rubens Maskell, is presumed to play an important role in insect communication based on the preliminary evaluation of its biological activity.²³ This compound features a sterically compact 6/3/7/6 tetracyclic skeleton and seven stereocenters, encompassing a notable all-carbon quaternary stereocenter within a cyclopropane moiety, which poses considerable challenges to synthetic chemists.

In 1998, Paquette and co-workers developed a masterful synthetic approach to cerorubenic acid-III methyl ester (37),²⁴ employing an intricate sequence of intramolecular oxidative coupling, an anionic oxy-Cope rearrangement, and a Diels–Alder cycloaddition to elegantly construct its unique ring system. However, synthesis of cerorubenic acid-III (44) from its ester remained elusive (Scheme 4).

In 2019, Li's group further demonstrated the robustness of oxidopyrylium ylide [5 + 2] cycloaddition strategy in their asymmetric total synthesis of cerorubenic acid-III (44).²⁵ The [5 + 2] substrate 39 was synthesized from compound 38 via oxidation with VO(acac)₂ and TBHP, followed by a one-pot acetylation of the anomeric hydroxyl group.²⁶ The type II [5 + 2] cycloaddition of 39 was then carried out using TMP as a base under heating in a sealed tube, producing the tetracyclic compound 40 as a single diastereomer with a 72% yield on 1.5 g scale. This product was found to be both kinetically and thermodynamically favorable, as confirmed by density functional theory (DFT) calculations. Aldehyde 41 was synthesized from 40 in four steps. With 41 in hand, the expected transannular cyclization was successfully achieved using an optimized t-BuOK/t-BuOH system, which likely proceeding via a cationic mechanism, to afford compound 42. Finally, alkene metathesis was applied to install carboxylic acid groups onto the side chains, thus completing the first asymmetric total synthesis of cerorubenic acid-III (44).

It is remarkable that Paquette's group achieved the synthesis of the core structure of cerorubenic acid-III through a concise and efficient approach, particularly by constructing the skeleton from substrates containing a fragile cyclopropane moiety. Although their attempt to deprotect the methyl ester was unsuccessful, the bold synthetic route they pursued remains inspiring. In contrast, Li's work not only represented the first total synthesis of cerorubenic acid-III utilizing a [5 + 2] cycloaddition strategy, but also revealed the synthetic potential of the resulting bicyclo[3.2.1] core. Notably, this intermediate enabled a sequence involving oxidation state adjustment at C-5 and construction of the cyclopropane fragment, ultimately culminating in the successful total synthesis of cerorubenic acid-III.

2.4 Synthesis of (−)-vinigrol

The star molecule (−)-vinigrol (49), a novel diterpenoid natural product, was first isolated from the fungus Virgaria nigra F-5408 by the Hashimoto team in 1987.²⁷ Structurally, (−)-vinigrol (49) is distinguished by its unique tricyclic framework, featuring a cis-[4.4.0] fused ring system and an eight-membered bridge ring, closely resembling the 6/8-bridged ring system found in the renowned natural product taxol. Over the years, many organic chemists have attempted to construct this challenging ring system—along with the eight contiguous stereocenters—using different strategies.^28–30

In 2009, Baran's group achieved a landmark in the first total synthesis of (±)-vinigrol (49).³¹ The [2.2.2]-bridged ring compound 46 was obtained via a smooth endo-selective Diels–Alder reaction and a Stille coupling. Conversion of 46 to the tetracyclic compound 47 was accomplished through an intramolecular Diels–Alder reaction under in situ heating conditions. Compound 48, the core of vinigrol was obtained from 47 via Grob fragmentation and subsequent reactions. Finally, 48 was transformed into (±)-vinigrol (49) within three-step reaction (Scheme 5).

In 2013, Njardarson and coworkers accomplished a comprehensive 38-step total synthesis of (±)-vinigrol (49).³² After acquiring the well-designed precursor 50 through a sequence of simple transformations, a strategic oxidative dearomatization process was employed, which eventually led to a high-yield Diels–Alder reaction to produce the cycloadduct 51. This was followed by a palladium-catalyzed cyclization cascade, which constructing the carbocyclic core of vinigrol. Subsequently, a 27-step-pathway successfully led the conversion of 52 to (±)-vinigrol (49).

The two total synthesis of (±)-vinigrol (49) showcased many incredible ideas. Baran's synthesis involved an elegant combination of proximity-induced intramolecular Diels–Alder cycloaddition and subtle Grob fragmentation. Njardarson's work cleverly utilized Heck cyclization cascade to construct the skeleton of (±)-vinigrol (49). Although the two works were both adopted intramolecular Diels–Alder reaction to construct the complex 6/6/8 tricyclic ring system, the reactions only employed in the early stage of building the core skeleton. Additionally, adjustments of oxidation state and functional group were also posing many significant obstacles to two chemistries.

In 2019, Luo's group overcame the challenge of achieving the first asymmetric total synthesis of (−)-vinigrol (49) (Scheme 6).³³ Ketone 54, featuring a ten-membered ring, was synthesized by an oxy-Cope rearrangement of compound 53. After seven steps, the key precursor 55 was subjected to a transannular inverse electron demand Diels–Alder reaction, which eliminated one molecule of carbon dioxide in situ. This was followed by a series of strategic hydroxylations on the unsaturated hexacyclic ring, ultimately completing the first asymmetric total synthesis of (−)-vinigrol (49).

In the same year, Li and colleagues achieved a notable enantioselective total synthesis of (−)-vinigrol (49) using a [5 + 2] cycloaddition strategy developed in their lab (Scheme 6).³⁴ Starting from commercially available chiral pool materials, compound 58 was synthesized through a five-step process involving functional group manipulations, followed by etherification with a trifluoroethoxy group, creating a stable precursor for the oxidopyrylium ylide 59.

By treating compound 58 with hydroquinidine, the team successfully initiated a type II [5 + 2] cycloaddition reaction, generating tricyclic compound 60, which contains a 6/8/7 bridged ring system. Hydrogenation of the terminal alkene with Wilkinson catalyst, followed by an in situ hydroboration/oxidation sequence delivered diol compound 61. One of the most unexpected and elegant steps of this synthesis was the IBX-mediated rearrangement of compound 61, followed by quenching with NaHCO₃/Na₂S₂O₃ in a one-pot process, yielding product 62 in an impressive 72% isolated yield. The mechanism, likely analogous to a benzilic acid rearrangement, involved ring contraction and decarboxylation (Scheme 6). Compound 62 was then converted into (−)-vinigrol (49) in five additional steps. In total, Li's team completed a concise, asymmetric 15-step total synthesis of (−)-vinigrol (49), notably without the use of any protecting groups—highlighting the efficiency and elegance of their strategy.

Both two synthetic routes are highly impressive and effective. Luo's approach, featuring an oxy-Cope rearrangement and a transannular inverse electron-demand Diels–Alder reaction, demonstrates an innovative understanding of molecular framework reorganization and cross-ring reactions. This strategy reflects a remarkable ability to manipulate molecular architecture. In contrast, Li's [5 + 2] strategy provides a powerful and modular method to build the core of (−)-vinigrol (49) from simple, commercially available precursors. This synthesis marks the first application of a type II [5 + 2] cycloaddition in the total synthesis of a natural product bearing an eight-membered bridged ring. The work highlights the unique advantage of this strategy in assembling complex intermediates. Moreover, the strategic use of oxidation states within the bicyclo[3.2.1] core further emphasizes the synthetic value of the [5 + 2] approach in constructing (−)-vinigrol (49).

2.5 Synthesis of (±)-daphgraciline

Daphgraciline (74), a yuzurine-type Daphniphyllum alkaloid, was first isolated from the bark of Daphniphyllum gracile Gage by Yamamura and co-workers in 1980.³⁵ It was later obtained from the fruit of Daphniphyllum macropodum Miq. by Hao and colleagues in 2008.³⁶ It features a compact 6/7/5/5/6 pentacyclic skeleton, characteristic of this subfamily, and multiple stereocenters, including two adjacent quaternary carbon centers, as well as two tetrasubstituted double bonds and a hemiketal moiety. Due to its high structural complexity, the total synthesis of any member of the yuzurine-type subfamily had remained unachieved since 1974, until Li's group accomplished the first total synthesis of (±)-daphgraciline (74) in 2022.³⁷

The synthesis began with a three-step preparation of key intermediate 63 from commercially available starting materials. Compound 63 underwent an Achmatowicz reaction upon treatment with m-CPBA, followed by one-pot acetylation, a strategy often employed to facilitate the rearrangement. This was followed by an intramolecular type II [5 + 2] cycloaddition of compound 64 under mild conditions with dihydroquinidine (DHQD) at 55 °C, affording compound 65 as a single diastereomer in 75% yield. This step represents the first successful synthesis of an azabicyclo[4.3.1] ring system via the type II [5 + 2] cycloaddition. Next, a diastereoselective 1,2-addition to compound 65 set the stage for a smooth intramolecular Diels–Alder reaction, leading to compound 68 as a mixture of C-15 diastereomers. Dihydroxylation with K₂OsO₄, followed by IBX oxidation, furnished diketone 69, and subsequent KOH treatment facilitated epimerization at C-15. The transformation of 69 into the desired ring-contracted product 62 was achieved via a benzilic acid-type rearrangement. After four additional transformations, treatment of 71 with Li(0) in EtNH₂ was identified as optimal for cleaving the oxa-bridge, followed by methyl group installation. The resulting etherified diol intermediate was then subjected to KHMDS and Ts-imidazole (Ts-Im) in two consecutive steps to furnish the anticipated epoxide 72. Subsequent addition of acrylonitrile and Cp₂TiCl₂ to a suspension of Zn(0) effected a reductive epoxide coupling, delivering spirolactone 73.³⁸ Compound 73 then underwent seven further steps, ultimately completing the first total synthesis of (±)-daphgraciline (74) (Scheme 7).

Although there have been many significant achievements in the total synthesis of Daphniphyllum alkaloids, Li's synthesis of (±)-daphgraciline (74) using the [5 + 2] strategy remains particularly notable. This work demonstrated that the [5 + 2] cycloaddition could proceed efficiently on an unstable tertiary amine, and that the conversion potential of the carbonyl and oxygen bridge within the bicyclo[3.2.1] core can be effectively harnessed to complete the synthesis.

3 ODI-[5 + 2] cycloaddition in natural product synthesis

It is well established that phenols can be converted into reactive dienes through oxidative dearomatization, enabling intramolecular [4 + 2] cycloaddition reactions.³⁹ This strategy has been extensively applied in the synthesis of various natural products containing the bicyclo[2.2.2]octane scaffold. In contrast, phenols can also undergo [5 + 2] cycloaddition, followed by a pinacol rearrangement, to generate bridged bicyclo[3.2.1] octane subunits (Scheme 8).

This transformation was first reported by Pettus in 2011, in their biomimetic synthesis of α-pipitzol (84) starting from curcuphenol (81) (Scheme 9).⁴⁰ The key steps in this synthesis involve the oxidative dearomatization of curcuphenol (73), followed by an intramolecular [5 + 2] cycloaddition that constructs the distinctive [3.2.1] octane framework. The benzylic stereocenter plays a crucial role in controlling the formation of the initial two stereocenters, while the cascade terminates with the selective incorporation of acetic acid as a nucleophile, establishing the third stereocenter. This approach offers a concise route to access polycyclic complex terpenoids and has inspired further exploration of oxidative dearomatization-induced (ODI) reactions in related syntheses.

Building on a systematic study of this reaction, Ding's group developed a solvent-dependent ODI-[5 + 2] cascade reaction to synthesize complex ring systems (Scheme 8).⁴¹ This advancement transformed what was previously a case-specific reaction into a more general and versatile strategy. Notably, they discovered that the [5 + 2] cycloaddition product could spontaneously undergo a pinacol-type 1, 2-acyl migration, enabling the formation of bridged bicyclo[3.2.1] octane subunits in a one-pot procedure. Furthermore, Ding's group strategically applied this ODI-[5 + 2] methodology to the synthesis of various complex diterpenoids, demonstrating the significant potential of the [5 + 2] cycloaddition reaction in natural product synthesis.

3.1 Synthesis of pseurata C

As a representative class of diterpenoids, the ent-kaurenoid,⁴² have long captivated organic chemists due to their unique bicyclo[3.2.1] octane skeleton and the remarkable bioactivities,^43–45 including anti-inflammatory, antibacterial, antifungal, and insect regulatory properties.⁴⁶ In 2017, Ma and colleagues developed a convergent and efficient route to a series of ent-kaurane diterpenoids,⁴⁷ focusing on the Hoppe's homo-aldol reaction to forge the C-5–C-6 bond and an unprecedented BF₃·OEt₂-mediated intramolecular Mukaiyama–Michael-type reaction to construct the fully decorated B ring. This strategy enabled the first total syntheses of two highly oxidized ent-kaurane diterpenoids, lungshengenin D (92) and 1α, 6α-diacetoxy-ent-kaura-9(11), 16-dien-12, 15-dione (93). The challenging [3.2.1] bicyclic core was pre-installed through a Pd-catalyzed cycloalkenylation (Scheme 10).

Around the same time, Ding and colleagues introduced a novel strategy to establish this highly oxygenated [3.2.1] ring system via an oxidative dearomatization-induced (ODI) diastereoselective [5 + 2] cycloaddition, successfully achieving the first synthesis of pharicin A (99), pharicinin B (100), 7-O-acetylpseurata C (101) and pseurata C (102) simultaneously.⁴⁸

The synthesis began with the preparation of the vinyl-phenols 94a and 94b. Under specific oxidative conditions, intermediate 95, formed via dearomatization, underwent an intramolecular [5 + 2] cycloaddition reaction to produce the tetracyclic intermediate 96. A subsequent pinacol-type 1, 2-acyl migration then completed the construction of the bicyclo[3.2.1] octane framework, achieving the target molecules with a 70% yield. Further oxidation state adjustments facilitated a retro-aldol/aldol reaction, which provided the inversion of the hydroxyl group at C-14, followed by a stereoselective reduction to yield the diol 98. An unprecedented singlet oxygen ene reaction was then carried out smoothly, and the resulting hydroperoxide was dehydrated in a one-pot process to produce the anticipated pharicin A (99). Finally, saponification of pharicin A (99) furnished pharicinin B (100), while a parallel procedure involving regioselective oxidation of pharicin A (99), followed by deacylation, led to the first syntheses of 7-O-acetylpseurata C (101) and pseurata C (102) (Scheme 10).

This ODI [5 + 2] cascade reaction efficiently constructs multiple rings and quaternary carbon centers in a single step, highlighting both the effectiveness and elegance of this synthetic strategy. It streamlines the assembly of ent-kaurenoid diterpenoid in a systematic manner, and provides valuable intermediates for divergent synthesis.

3.2 Synthesis of (−)-rhodomollanol A

Grayanane diterpenoids, a large family of natural products derived from Ericaceae plants, are characterized by distinctive 5/7/6/5 tetracyclic carbon frameworks and exhibit a wide range of biological activities.^49,50

In 2019, Newhouse and colleagues reported the first total synthesis of principinol D (109), a rearranged kaurane diterpenoid, using a convergent fragment coupling approach.⁵¹ This approach features a Ni-catalyzed α-vinylation reaction to form the bicyclo[3.2.1] octane fragment, a diastereoselective SmI₂-mediated ketone reduction, and a selective ester reduction in the presence of ketones. By dividing the complex molecule into two modifiable fragments—each readily adjustable at an early stage—the convergent strategy enabled the synthesis of structurally diverse analogs of this natural product family (Scheme 11).

In 2017, Yao and colleagues isolated and elucidated the structure of a novel grayanane diterpenoid, rhodomollanol A (118), from the leaves of Rhododendron molle.⁵² This molecule features a unique 3/5/7/5/5/5 hexacyclic carbon skeleton, including a rare 7-oxabicyclo[4.2. 1]nonane core. After three years of intensive research, Ding and colleagues achieved the first asymmetric synthesis of (−)-rhodomollanol A (118), utilizing a pivotal ODI [5 + 2] cycloaddition approach (Scheme 11).⁵³

The synthesis commenced with the 1, 2-addition of an organolithium to aldehyde 110, previously reported in the group's earlier work. This was followed by a well-designed ODI [5 + 2] cascade, which constructed the characteristic [3.2.1] skeleton 114. A THP protection group was employed to secure the desired major product. A skeletal rearrangement, combined with multiple oxidation state adjustments, led to the formation of the α-alcohol 115. The successful photo-Nazarov cyclization of 115—optimized after extensive investigation—furnished the desired 5/7/5/5/5 skeleton. Final refinements of the oxidation statement and the stereochemistry culminated in the first total synthesis of (−)-rhodomollanol A (118).

This synthetic work demonstrates the versatility of the [3.2.1] fused ring system, constructed via ODI-[5 + 2] cyclization, in the synthesis of complex terpene frameworks. Through a series of creative transformations, this strategy allows access to diverse terpenoid skeletons. The use of cascade reactions in this approach provides both synthetic efficiency and structural diversity, offering a concise and systematic strategy for the synthesis of ent-kaurane diterpenoid family members.

3.3 Synthesis of (−)-epoxyshikoccin

Another typical class of ent-kaurane diterpenoids, the 8, 9-seco-ent-kaurane diterpenoids, are biosynthetically formed via a retro-Aldol reaction, which results in the cleavage of the C-8, C-9 bond and loss of H₂O, leading to the formation of either a C-8, C-14 or C-7, C-8 double bond. These compounds possess a unique condensed cyclohexyl bicyclo[7.2.1] dodecane framework and exhibit potent biological activities, making them attractive yet challenging synthetic targets.

In 1996, Paquette and colleagues reported the first total synthesis of cytotoxic 8, 9-seco-kaurene diterpenoids, including (−)-O-methylshikoccin (122) and (+)-O-methylepoxyshikoccin (123).^54,55 The synthesis commenced with the construction of the oxygenated bicyclo[7.2.1] dodecene subunit via a Knoevenagel condensation followed by an oxy-Cope rearrangement, which was then elaborated through selective functional group modifications to access the final products (Scheme 12).

In 2021, Ding and colleagues reported the asymmetric total synthesis of five 8, 9-seco-ent-kauranoid natural products starting from compound 124, utilizing an electrochemical ODI-[5 + 2] cascade reaction.⁵⁶ However, initial attempts to perform the standard PIFA/HFIP-mediated ODI-[5 + 2] cascade reaction were unsuccessful due to the acid sensitivity of the benzyl alcohol in compound 124, which decomposed rapidly. After optimization, the target product 127 was obtained under condition a in the presence of K₄P₂O_7, although the yield was insufficient for further transformations.

Building on the work of Yamamura and Nishiyama,⁵⁷ the authors explored the ODI-[5 + 2] cascade reaction under electrochemical condition b, successfully constructing the desired bicyclo[3.2.1] octenones 127. Stereoselective acetal formation was achieved to control stereochemistry at C-14, leveraging the chelating effect of the C-7 hydroxyl group with LiHMDS, followed by Jones oxidation. To introduce the hydroxyl group at C-9, a sequence of transformations was developed, including global reduction, Schenck olefination, and selenylation, leading to the formation of enone 128. This intermediate was designed for a [2,3]-sigmatropic rearrangement. Subsequent hydrogenation, methylation, and epoxidation enabled the successful synthesis of (−)-O-methylshikoccin (122) and (+)-O-methylepoxyshikoccin (123).

This synthesis broadens both the substrate scope and reaction conditions of the ODI-[5 + 2] cascade, demonstrating its compatibility with acid-sensitive ethylphenols under mild electrochemical conditions. The methodology facilitates the construction of diversely functionalized bicyclo[3.2.1] skeletons, providing greater synthetic flexibility and enabling efficient access to complex natural products (Scheme 12).

3.4 Synthesis of rhodojaponin III

In 2022, Luo's group reported the enantioselective total syntheses of three grayanane diterpenoids, including (−)-grayanotoxin III (134).⁵⁸ In their work, the authors employed a convergent synthetic strategy, meticulously assembling two distinct fragments through a diastereoselective Mukaiyama aldol reaction, followed by Sakurai reaction to obtain the major isomer 133. After installation of the vinyl group, a pivotal 7-endo-trig Prins cyclization was performed, which was instrumental in forging the intricate 5/7/6/5 tetracyclic skeleton (Scheme 13).

Also in 2022, Yang and colleagues unveiled the first total synthesis of mollanol A (138),⁵⁹ a distinguished natural product notable for its unique C-nor-D-homograyanane carbon skeleton and an intriguing 5, 8-epoxide functional group. Their strategy relied on a Stille coupling to assemble the seven-membered ring, forming compound 136 using the triflate 137 as a key intermediate (Scheme 13).

In 2024, Jia and colleagues reported the biomimetic total synthesis of six diterpenoid compounds derived from gray algae,⁶⁰ each exhibiting three distinct carbon skeletons. Their synthetic approach employed a nickel-catalyzed α-alkenylation reaction to construct a bicyclo[3.2.1]octane core, while an intramolecular Pauson–Khand reaction was utilized to assemble a 7/5 bicyclic system (Scheme 13).

In 2023, Ding's group introduced a divergent synthetic approach for the total synthesis of nine grayanane diterpenoids.⁶¹ This innovative route commenced with a modified electrochemical ODI-[5 + 2] cycloaddition/pinacol rearrangement cascade reaction to construct the bicyclo[3.2.1] octane skeleton of intermediate 142 from the enol 143. This transformation enabled the rapid assembly of the C/D ring system, followed by a well-designed photosantonin rearrangement to construct the 5/7 bicyclic A/B ring system, and a Grob fragmentation/carbonyl-ene cascade to access four additional subtypes of grayanane skeletons. To facilitate epimerization at C-1, 147 was transformed into a pair of epimers, 150 and 151 through a Grob fragmentation/carbonyl-ene cascade reaction. Reduction using LiBEt₃H, followed by further manipulations, led to the synthesis of principinol D (109), rhodojaponin III (152), and GTX-XV (153), respectively. To elucidate the intricate transformation mechanism from 147 to 150 and 151, density functional theory (DFT) calculations were employed to produce a persuasive illustration. This computational insight clarified the role of 1, 5-seco-GTX-Δ^1,10-ene intermediate, offering guidance for controlling the Grob fragmentation/carbonyl-ene cascade reaction under predetermined conditions and ultimately enabling the synthesis of leucothol B (149) and other derivatives.

This work represents a significant advancement in the total synthesis of grayanane diterpenoids, introducing a novel divergent synthetic strategy that enables access to nine compounds—both previously known and newly reported variants. Moreover, it demonstrates how oxidation states introduced by the [5 + 2] cycloaddition can be strategically leveraged in the synthesis of these complex natural products.

3.5 Synthesis of (−)-retigeranic acid A

(−)-Retigeranic acid A (158), a sesterterpene first identified as a mixture alongside retigeranic acid B from Lobaria retigera lichens in the Western Himalayas in 1965, was established by Sheshadri's group as a structurally distinctive member of the sesterterpene family.^62,63 This compound is characterized by an intricate trans-hydrindane-fused angular triquinane architecture, with a pentacyclic framework bearing eight stereogenic centers.

In 2023, Chen and colleagues reported the asymmetric total synthesis of (−)-retigeranic acid A (158).⁶⁴ The pivotal steps included an NHK coupling to connect the two preassembled fragments, followed by a late-stage Fe-mediated hydrogen atom transfer (HAT) that rapidly forged the core structure. Their strategy overcame significant challenges associated with the swift construction of the congested angular triquinane core and precise incorporation of stereochemistry (Scheme 14).

In the same year, Ding and colleagues disclosed a second asymmetric total synthesis of (−)-retigeranic acid A (158).⁶⁵ This endeavor commenced with the synthesis of compound 160 via a series of transformations. A sophisticated ODI-[5 + 2] cycloaddition/pinacol rearrangement cascade was then employed to convert phenol 160 into the bicyclo[3.2.1] octane skeleton of intermediate 161, ultimately delivering the crucial pentacyclic intermediate 162. Upon treatment with SmI₂, this intermediate underwent a reductive rearrangement cascade, producing the angular triquinane skeleton. The authors then executed a chemoselective hydrogenation using Crabtree's catalyst, followed by a Chugaev elimination.⁶⁶ This was succeeded by further hydrogenation and oxidation to yield ketone 164. A Wolff ring contraction was subsequently applied to generate methyl ester 165, which preserved the core skeleton consistent with the target compound. Although initial efforts to reposition the double bond under various acidic and basic conditions were unsuccessful, the authors ultimately achieved alkene isomerization through a dibromination/elimination sequence, guided by DFT calculations, thus completing the asymmetric total synthesis of (−)-retigeranic acid A (158) (Scheme 14).

This synthesis underscores the synergistic power of combining the ODI-[5 + 2] reaction with rearrangement strategies. By significantly streamlining the synthetic route, this approach offers a promising pathway for the total synthesis of angular triquinane-type natural products, especially those containing C-6 tertiary or oxygen-substituted quaternary carbon centers.

4 Quinone [5 + 2] cycloaddition in natural product synthesis

It is well established that in the classical Diels–Alder reaction, the electron-deficient double bond of para-quinone acts as a dienophile, participating in [4 + 2] cycloaddition.⁶⁷ In fact, the discovery of the Diels–Alder reaction was initially based on the dimerization of para-quinone and cyclopentadiene. In contrast to the classical quinone cycloaddition, para-quinone can also undergo a non-classical type of cycloaddition. In this alternative pathway, five carbon atoms in para-quinone can isomerize to form a “five-center, four-electron [5c–4e]” intermediate, which acts as a diene in [5 + 2] cycloaddition reactions, yielding [3.2.1] bridged bicyclic compounds. Since this reaction was first discovered by Joseph-Nathan in 1965,^68,69 it has gradually attracted attention from various research groups. Although significant progress has been made in understanding this reaction, the application of this reaction in organic synthesis remains severely limited, due to several challenges. Most notably, the high intrinsic stability of para-quinone hinders its isomerization into the [5c–4e] form, typically requiring large excess of Lewis acids to activate the quinone unit. In addition, the reaction is generally restricted to intramolecular cycloadditions between para-quinone and electron-rich alkenes, and the reaction mechanism remains unclear. Compared with oxidopyrylium ylide and ODI [5 + 2] cycloadditions, this class of [5 + 2] cycloaddition displays two distinguishing features: (1) the substrate possesses a higher oxidation state, and (2) the reaction scope can be extended from intramolecular to intermolecular processes (Scheme 15).

4.1 Synthesis of (−)-elisapterosin B

(−)-Elisapterosin B (185) is a diterpene isolated and characterized by Rodriguez and co-workers from the West Indian Sea whip Pseudopterogorgia elisabethae, exhibiting potent antiplasmodial activity against Plasmodium falciparum. It features a unique and highly congested 5/5/6/6 tetracyclic carbocycle, along with seven distinctive stereogenic centers.⁷⁰ The combination of structural intricacy and fascinating biological activity has rendered these terpenes appealing candidates for chemical synthesis.

In 2005, Jacobsen and his colleagues unveiled the total syntheses of (−)-colombiasin A (184) and (−)-elisapterosin B (185), harnessing the Cr-catalyzed asymmetric quinone Diels–Alder reaction.⁷¹ They developed a monomeric chromium complex as an effective catalyst to promote a highly stereoselective Diels–Alder reaction, affording bicyclic adduct 180a and 10b. These intermediates paved the way for the enantioselective synthesis of (−)-colombiasin A (184). Although this was not the first total synthesis of (−)-colombiasin A (184), it remains the only example achieved through a catalytic asymmetric approach. More interestingly, the Diels–Alder product (−)-colombiasin A (184) can be converted into the [5 + 2] cycloaddition product (−) elisapterosin B (185) upon treatment with an excess of BF₃·OEt₂, likely via a retro-Diels–Alder/[5 + 2] cycloaddition cascade. This transformation highlights the competitive interplay between the Diels Alder and [5 + 2] cycloaddition pathways, and reveals a promising strategy to access [5 + 2] cycloaddition products from [4 + 2] adducts (Scheme 16).

In 2003, the Rychnovsky group reported the first total synthesis of (−)-elisapterosin B (185),⁷² employing an intermolecular [5 + 2] cycloaddition strategy. The synthesis began with the preparation of the chiral diene 186, derived from Myers' pseudoephedrine auxiliary and other commercially available materials. A Diels–Alder reaction between intermediate 187a and benzoquinone 187b, promoted by LiClO₄ in diethyl ether, established the cis-decaline serrulatane skeleton. Both regioisomers were advanced through a nine-step sequence to furnish the [5 + 2] precursor 188, whose reaction sites are indicated in the Scheme 16. A large excess of BF₃·OEt₂ at lower temperature effectively promoted the [5 + 2] cyclization, affording the desired (−)-elisapterosin B (185) as a mixture of diastereomers derived from 187a and 187b.

In 2003, Rawal and co-workers achieved a stereoselective total synthesis of the enantiomer of (+)-elisapterosin B (195), using a combination of intramolecular Diels–Alder (IMDA) reaction and biosynthesis-inspired oxidative cyclization. Starting from commercially available building blocks 189 and 190, the constructed IMDA precursor 191 via a 14-step linear sequence. Upon heating in toluene, compound 191 underwent a selective endo-cycloaddition between its (E, Z)-diene unit and the quinone moiety, yielding a single diastereomeric adduct. After several downstream transformations, oxidative cyclization using Ce(NH₄)₂(NO₃)₆ and a final enolization step furnished (+)-elisapterosin B (195) (Scheme 17).⁷³

In 2005, Bourne and co-workers showcased another brilliant intermolecular [5 + 2] strategy for the synthesis of (−)-elisapterosin B (185).⁷⁴ Starting from simple precursors, (E)-diolefin 196 was subjected to a modified in situ Shapiro reaction, in which cyclobutene-1,2-dione 197 was added to a mixture of 191, trisylhydrazine, and butyllithium, yielding compound 198 in 36% yield. A Moore rearrangement of intermediate 199 proceeded via a ketene intermediate under microwave irradiation, affording hydroquinone 200, which was oxidized to quinone 201 in 80% yield upon exposure to air. Inspired by prior studies, treatment with BF₃·OEt₂ at −78 °C enabled simultaneous tert-butyl ether deprotection and intramolecular [5 + 2] cycloaddition, completing the synthesis of (−)-elisapterosin B (185). At 0 °C, the same reagent promoted a clean intramolecular Diels–Alder cycloaddition, culminating in the total synthesis of (−)-colombiasin A (184) (Scheme 17).

This section highlights four distinct total syntheses of elisapterosin B. Among them, Rawal's route employed a classical [4 + 2] IMDA reaction, while the other three (Rychnovsky, Jacobsen, and Bourne) utilized [5 + 2] cycloaddition strategies. Notably, Rychnovsky and Bourne both used BF₃·OEt₂ as a Lewis acid promoter, albeit on different substrates, while Jacobsen's approach involved a [5 + 2] rearrangement triggered by a retro-Diels-Alder process. Bourne's synthesis is particularly remarkable for demonstrating that a [5 + 2] cycloaddition can establish four stereocenters in a single step—one more than typical [4 + 2] pathways. Interestingly, Jacobsen's results also suggest a potential mechanistic link between [4 + 2] and [5 + 2] transformations, hinting at the existence of a Diels–Alder-to-[5 + 2] rearrangement mechanism.

4.2 Synthesis of (−)-perezoperezone

In 1885, Anschutz and Leather first observed the transformation of perezone (203) to pipitzols (84 and 198), a transformation later revised along different mechanistic pathways by Sanders and then Remfry.⁸ However, the true structures of these products were not elucidated until 1965, when Joseph-Nathan and co-workers definitively determined their identities. They also observed that the reaction proceeds stereoselectively in the presence of BF₃·OEt₂.

In 2019, Deng and colleagues reported a streamlined synthesis of (−)-perezoperezone (206),⁷⁵ a homodimeric hydroxy p-quinone natural product isolated form Caribbean soft coral pseudopterogorgia rigida.⁷⁶ They developed a Cu(I) catalyzed para-quinone homo-[5 + 2] cycloaddition, which exhibited exclusive endo selectivity and complete regioselectivity. Notably, although the conditions were mild and substrate scope broad, this work represents the first catalytic para-quinone [5 + 2] cycloaddition. Leveraging this method, they achieved the efficient nine-step total synthesis (−)-perezoperezone (206), with an overall yield of 15% (Scheme 18).

Due to the high intrinsic stability of para-quinones, such transformations traditionally require an excess of Lewis acid to promote their isomerization into the reactive [5c–4e] intermediates. This study achieved the first catalytic intermolecular [5 + 2] cycloaddition of para-quinones via transition metal catalysis. The synthetic power of this methodology was underscored by the gram-scale preparation of this marine-derived natural product.

4.3 Synthesis of asperones A and B

Asperones A (217) and B (218) are two dimeric polyketides isolated from the fungus Aspergillus sp. strain, which were obtained from centipede intestines by Yang and Kong in 2018.⁷⁷ Both molecules feature a highly oxidized bicyclo [3.2.1] octane core. In addition, asperone B (218) demonstrated significant inhibition of nitric oxide (NO) production in lipopolysaccharide (LPS)-induced RAW 264.7 macrophage cells.

In 2024, Deng and colleagues accomplished the total synthesis of asperones A (217) and B (218) through a convergent synthesis route.⁷⁸ The synthesis began with the construction of p-quinone fragment: the key diphenol 209 was obtained from dienophile 207 and the diene 208 via a cascade of cyclohexa-1, 3-diene based Diels–Alder and retro-Diels–Alder reactions. The resulting para-quinone 205 was accessed from compound 210a/210b through two alternative routes. In parallel, methyl ketone 212 underwent the Al-salen-catalyzed asymmetric cyanosilylation, followed by a two-step sequence to afford compound 213.⁷⁹ Subsequent Claisen condensation, desilylation, etherification, and double bond isomerization—all performed in one pot—led to the construction of gregatin A (215). Finally, the enantioenriched para-quinone 211 and gregatin A (215) were efficiently coupled through an efficient late-stage organo-catalyzed [5 + 2] cycloaddition reaction, furnishing both asperones A (217) and B (218). This step established four continuous stereocenters, including one all-carbon quaternary chiral center, in a single transformation.

Compared with the homo-[5 + 2] cycloaddition described in the synthesis of (−)-perezoperezone (206), this cross-[5 + 2] cycloaddition is significantly more challenging. The major competing side reactions include homo-[5 + 2] adducts and [4 + 2] cycloaddition products. By employing a cinchona-derived bifunctional organocatalyst, the authors successfully achieved an intermolecular cross-[5 + 2] cycloaddition between para-quinone and an electron-deficient alkene. This work represents the first example of an organocatalyzed intermolecular [5 + 2] cycloaddition of para-quinone with electron-deficient alkenes, and highlights the significant potential for developing new organocatalytic [5 + 2] cycloadditions (Scheme 19).

In addition to the para-quinone [5 + 2] cycloaddition, there exists a less explored variant: the ortho-quinone [5 + 2] cycloaddition. Compared to para-quinone, ortho-quinone displays lower intrinsic stability but significantly higher reactivity. In fact, most ortho-quinone species are too unstable to be isolated or characterized, which has historically limited studies on their [5 + 2] cycloaddition chemistry. Notably, since ortho-quinone must be generated in situ, the catalyst employed must be orthogonal to the oxidant to avoid undesired mutual interference. Furthermore, the stereoselectivity and regioselectivity of the ortho-quinone based [5 + 2] cycloadditions remain largely unexplored and require comprehensive investigation. The pioneering work by Trauner in the biomimetic synthesis of epicolactone opened the door to the development and application of ortho-quinone [5 + 2] cycloaddition in the synthesis of complex natural products.

4.4 Synthesis of epicolactone

The fungal natural product epicolactone, which manifests both antimicrobial and antifungal activity, was first extracted from the endophytic fungus Epicoccum nigrum by Marsaioli and coworkers in 2012.⁸⁰ It comprises a highly oxygenated pentacyclic structure, including bicyclo [3.2.1]octane core and difuran bridging rings, along with four contiguous tetrasubstituted stereocenters.

In 2018, Carreira and colleagues reported a total synthesis of epicolactone ingeniously utilizing an exquisite [2 + 2] photocycloaddition as the key step.⁸¹ This synthesis started with the preparation of a planar precursor 219 from commercially available materials. Upon blue LED irradiation of a benzene solution of 219, a clean [2 + 2] cycloaddition occurred, delivering cyclobutane 220 as a single diastereomer in 76% yield, producing all three quaternary centers of epicolactone in one step. Treatment of olefin 220 with OsO₄ and NMO, followed by oxidative cleavage of the resulting diols using lead tetraacetate, afforded ketone 221 effectively. Ring expansion was achieved by exposing 221 to excess BF₃·2HOAc, yielding cyclopentanol 223 as the sole product in good yield. Construction of the multicyclic framework was completed in five steps, followed by six additional transformations to furnish the natural product epicolactone (225) (Scheme 20).

Despite the considerable complexity, Trauner and his team achieved the first total synthesis of epicolactone in 2015 using a biomimetic cascade strategy, completing the longest linear sequence in only eight steps.⁸² The key intermediates, catechol 227 and epicoccine (226), were synthesized from vanillyl alcohol and eudesmic acid in six and five steps, respectively. Initiated by potassium ferricyanide, a remarkable oxidative dimerization via [5 + 2] cycloaddition generated a mixture of lactones 229 and 230. The formation of 231 was proposed to involve an intramolecular nucleophilic attack by a pendant primary alcohol, leading to lactone 232, followed by a vinylogous aldol addition to yield 233. Final demethylation of key methoxy groups in 233 and 235, after separation, afforded epicolactone (225) and isoepicolactone (236), respectively. Interestingly, epicoccine (226) was also found to undergo homodimerization to generate dibefurin, an achiral metabolite with calcineurin inhibitory activity.⁸³ This concise chemical synthesis strongly suggests that the racemic natural product epicolactone likely arises from a cascade reaction between two polyhydroxylated arenes, providing valuable insight into its biosynthetic origin.

Both Carreira's and Trauner's syntheses relied on cycloaddition reactions to construct critical intermediates. Carreira's approach demonstrated precise oxidation state control and structural regulation of key intermediates, while Trauner's strategy showcased the advantage of [5 + 2] cycloaddition, enabling the rapid and efficient assembly of highly oxidized polycyclic frameworks (Scheme 21).

4.5 Synthesis of merocytochalasan

In 2018, Tang and colleagues reported the first total syntheses of asperchalasines A–E.⁸⁴ Their synthesis commenced with the preparation of aspochalasin B (246), a pivotal cytochalasan monomer. After multi-step derivatizations and Diels–Alder reaction, compounds 243 and 244 were transformed to aspochalasin B (246), which served as a dienophile in a key intermolecular Diels–Alder reaction.⁸⁵ The diene partner was derived from hemiacetal 241 through dehydration, and the reaction furnished adducts 242 and 243 in 80% yield combined yield (242:243 = 2:3). The major adduct was treated with Raney Ni/H₂, yielding triol 244, which was then subjected to air oxidation to generate the ortho-quinone intermediate. A subsequent elegant [5 + 2] cycloaddition cascade proceeded smoothly, ultimately affording the target asperchalasine A (246) in a 57% yield (Scheme 22).

In 2022, Tang and colleagues achieved a biomimetic synthesis of another heterotrimer, asperflavipine B (250),⁸⁶ building upon their prior research. In this endeavor, the proficient [5 + 2] cycloaddition reaction between triphenol 244 and hemiacetal 247, mediated by K₃Fe(CN)₆, produced the minor adduct 249 and its major regioisomer 251. Subsequent treatment of the minor adduct 249 with aqueous HCl facilitated the formation of asperflavipine B (250) via dehydration. In a pioneering move, Tang's team successfully stabilized the inherently unstable major regioisomer 251 by converting it into a more stable compound 252, through hemiketal exchange with methanol replacing water. This transformation offers valuable insight into the low overall yield (5%) of asperflavipine B (250) from precursor 243, and suggests that isomer 252 could potentially be a naturally occurring compound that remains undetected due to its intrinsic instability (Scheme 22).

At the same time, Deng and colleagues unveiled the first total syntheses of the several cytochalasan dimers, including asperchalasines A, D, E, and H.⁸⁷ Their strategy emphasized the modular construction of the merocytochalasan framework, beginning with the synthesis of monomer aspochalasin B (240) via a highly stereoselective intermolecular Diels–Alder reaction, followed by a Horner–Wadsworth–Emmons macrocyclization. To forge the link between several monomeric cytochalasans, the hemiacetal 253 underwent a 1,4-elimination of water, yielding the highly reactive isobenzofuran intermediate under acidic conditions. This intermediate was subsequently captured by aspochalasin B (240) as the dienophile. Reductive deallylation then yielded the dimeric adducts asperchalasine H (254) and 244 with a commendable yield of 78%. Completion of the trimeric cytochalasin was achieved via an intermolecular ortho-quinone [5 + 2] cycloaddition, in which adduct 244 and aspochalasin B (240) were treated with K₃Fe(CN)₆ and NaHCO_3. This cascade produced asperchalasine A (246) in 49% yield (Scheme 23), alongside regioisomer 257 in 9% yield, showcasing the efficiency and practicality of this transformation.

In 2021, Deng and colleagues further reported the bioinspired divergent syntheses of ten merocytochalasans,⁸⁸ including asperflavipines A and B. Building upon their prior work, thy strategically designed the synthesis of asperflavipine A (262) from asperchalasines F (259) and G (258) via cross-[5 + 2] cycloaddition. However, the desired ortho-quinone [5 + 2] cycloaddition was hindered by competing homodimerization and heterodimerization pathways. Notably, both reactants were capable of acting as either a diene (the 5-part of [5 + 2] heterodimerization) or a dienophile (the 2-part of [5 + 2] heterodimerization), but only one configuration led to the desired asperflavipine A (261). Fortunately, by treating both asperchalasine G (258) and asperchalasine F (259) with buffered K₃[Fe(CN)₆] solution, followed by acidification to promote hemiketal ring formation, the team successfully isolated asperflavipine A (261) in 43% yield (Scheme 24).

For the synthesis of asperflavipine B (250), they employed triphenol 244 and hemi-acetal 248 as the [5 + 2] substrates, directly forming adduct 249, which was then converted to the final product. However, the suboptimal yield was attributed to the fact that only the minor product of the [5 + 2] cycloaddition could undergo subsequent dehydration, ultimately leading to the formation of the more stable furan derivative, asperflavipine B (250)—a result consistent with Tang's findings.

For the synthesis of aspergilasine A (270), the team devised a transformation of aspergilasine D (266) and trimer 267—two adducts derived from the intermolecular [5 + 2] cycloaddition of 263 and epicoccine (226)—via a sunlight-mediated [2 + 2] cycloaddition,⁸⁹ followed by an acyloin rearrangement cascade,⁹⁰ affording the desired product in excellent yield.⁹¹

To address challenges in the synthesis of epicochalasines A (271) and B (269) from trimer 267 and aspergilasine D (266), the team employed a Morita–Baylis–Hillman (MBH) reaction, as the carbonyl-ene pathway proved ineffective. They proposed that PMe₃ acts as a nucleophile, initiating an intramolecular Michael addition, followed by an intramolecular aldol addition and elimination of the PMe₃ adduct, thereby affording epicochalasine B (269). Similarly, epicochalasine A (271) was accessed from trimer 267 under comparable conditions (Scheme 25).

5 Conclusion and prospects

Recent advancements in the three types of [5 + 2] cycloaddition reactions in natural product synthesis have highlighted the remarkable potential of this strategy for constructing complex bridged [3.2.1]octane frameworks and quaternary chiral centers with exceptional efficiency. This capability is particularly impressive when compared to other established synthetic methodologies. In addition to the cases discussed above, numerous other examples demonstrate the utility of [5 + 2] cycloadditions for assembling natural product skeletons. However, due to space limitations, these were not covered in detail. Collectively, these achievements underscore the unparalleled value of [5 + 2] cycloaddition reactions in the total synthesis of complex natural products (Fig. 3).

Despite these successes, research on catalytic asymmetric [5 + 2] cycloadditions remains underdeveloped,⁹² especially in contrast to the extensive body of work on catalytic asymmetric Diels–Alder ([4 + 2]) reactions. Among the three major types, the oxidopyrylium ylide-type [5 + 2] cycloaddition has been most widely applied, while the ODI-type and quinone-type variants are still in their early stages and offer significant room for advancement, particularly in terms of reaction conditions and substrate scope. Moreover, similar to the [4 + 2] reaction, [5 + 2] cycloadditions are predominantly employed in the early stages of total synthesis. Expanding their application to the middle and late stages of complex molecule construction remains a promising but largely unexplored direction. Another important consideration is that, compared to the well-established Diels–Alder ([4 + 2]) reaction, the [5 + 2] cycloaddition remains less reliable in terms of overall yield, functional group tolerance, and steric sensitivity around the reaction site. These limitations often stem from the structural complexity and synthetic inaccessibility of the required reaction precursors, as well as the lack of broadly applicable catalytic systems. Therefore, the development of more general and modular strategies for constructing well-defined [5 + 2] precursors—alongside the discovery of more robust and efficient catalytic conditions—will be essential for unlocking the full potential of [5 + 2] cycloadditions in organic synthesis.

In summary, the past decade has witnessed significant progress in the development and application of [5 + 2] cycloaddition reactions—not only for the efficient formation of seven-membered and bridged [3.2.1] ring systems, but also for the construction of highly complex natural product frameworks. The examples highlighted in this review demonstrate the untapped potential of this strategy. We believe that future progress will rely on the development of new catalysts, expanded substrate diversity, and broader applications of asymmetric [5 + 2] cycloadditions, which together will continue to advance this powerful tool in organic synthesis.

6 Conflicts of interest

There are no conflicts to declare.

7 Acknowledgements

Financial supported from the National Natural Science Foundation of China (nos. 22222105, 22371142 to J. D.), Frontiers Science Center for New Organic Matter, Nankai University (no. 63181206 to J. D.), Key project at central government level: The ability establishment of sustainable use for valuable Chinese medicine resources (no. 2060302 to J. D.), and the Fundamental Research Funds for the Central Universities (no. 23JCYBJC01410) are gratefully acknowledged.

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Footnote

† These authors contributed equally.

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