Chemistry and bioactivity of lindenane sesquiterpenoids and their oligomers

Jun Luo; Danyang Zhang; Pengfei Tang; Nan Wang; Shuai Zhao; Lingyi Kong

doi:10.1039/D3NP00022B

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DOI: 10.1039/D3NP00022B (Review Article) Nat. Prod. Rep., 2024, 41, 25-58

Chemistry and bioactivity of lindenane sesquiterpenoids and their oligomers†

Jun Luo , Danyang Zhang , Pengfei Tang , Nan Wang , Shuai Zhao and Lingyi Kong *
Jiangsu Key Laboratory of Bioactive Natural Product Research and State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing, 210009, People's Republic of China. E-mail: cpu_lykong@126.com

Received 26th April 2023

First published on 4th October 2023

Abstract

Covering: 1925 to July 2023

Among the sesquiterpenoids with rich structural diversity and potential bioactivities, lindenane sesquiterpenoids (LSs) possess a characteristic cis, trans-3,5,6-carbocyclic skeleton and mainly exist as monomers and diverse oligomers in plants from the Lindera genus and Chloranthaceae family. Since the first identification of lindeneol from Lindera strychnifolia in 1925, 354 natural LSs and their oligomers with anti-inflammatory, antitumor, and anti-infective activities have been discovered. Structurally, two-thirds of LSs exist as oligomers with interesting skeletons through diverse polymeric patterns, especially Diels–Alder [4 + 2] cycloaddition. Fascinated by their diverse bioactivities and intriguing polycyclic architectures, synthetic chemists have engaged in the total synthesis of natural LSs in recent decades. In this review, the research achievements related to LSs from 1925 to July of 2023 are systematically and comprehensively summarized, focusing on the classification of their structures, chemical synthesis, and bioactivities, which will be helpful for further research on LSs and their oligomers.

Jun Luo

Prof. Jun Luo received his PhD in Traditional Chinese Pharmacology (2010) from China Pharmaceutical University (CPU) under the supervision of Professor Lingyi Kong. He worked in the School of Traditional Chinese Pharmacy of CPU after graduation and as a Visiting Scholar at the Scripps Research Institute in 2017. His research interests are focused on the discovery and biosynthesis of anti-inflammatory terpenoid derivatives, especially Meliaceous limonoids and Chloranthaceaeous lindenane sesquiterpenoid oligomers, from traditional Chinese medicine and medicinal plants.

Danyang Zhang

Danyang Zhang finished his Bachelor's Degree in Science (2019) and Master's Degree in Pharmacy (2022) at North China University of Science and Technology. After graduation, he joined the research group of Prof. Lingyi Kong and Prof. Jun Luo at China Pharmaceutical University as a doctoral candidate. He has been working on the discovery and identification of novel lindenane sesquiterpenoids from Chloranthaceae plants.

Pengfei Tang

Pengfei Tang finished his Bachelor's Degree in Traditional Chinese Pharmacology (2018) at Anhui Medical University. After graduation, he joined the research group of Prof. Lingyi Kong and Prof. Jun Luo at China Pharmaceutical University, received his Master's Degree (2021) and went on to study for a doctorate. He has been working on the anti-inflammatory mechanism and targets of lindenane sesquiterpenoids.

Nan Wang

Nan Wang received his Bachelor's Degree from Shandong First Medical University (2021). After graduation, he joined the research group of Prof. Lingyi Kong and Prof. Jun Luo at China Pharmaceutical University to study for a Master's Degree. He has been working on the discovery and identification of biologically active lindenane sesquiterpenoids from Chloranthaceae plants.

Shuai Zhao

Shuai Zhao received his Bachelor's Degree from China Pharmaceutical University (2019). After graduation, he joined the research group of Prof. Kong Lingyi and Prof. Jun Luo at China Pharmaceutical University to study for a Master's Degree. He has been working on the structural modification and synthesis of lindenane sesquiterpenoids.

Lingyi Kong

Professor Lingyi Kong received his PhD in Medicinal Chemistry in 1992 from Shenyang College of Pharmacy and continued postdoctoral research at China Pharmaceutical University, where he is still working. He was promoted to Full Professor (1997), Dean of the School of Traditional Chinese Pharmacy (1997–2012), and Vice President of CPU in 2013. He was a Visiting Scholar at Meijo University (1998–1999), and a Visiting Professor at Kyushu University (2009). His research interests include the discovery and mechanisms of novel and bioactive natural products and also the discovery of new drug targets and R&D of innovative drugs.

1 Introduction

Sesquiterpenoids are a class of terpenoids with rich structural diversity and potential bioactivities, which have attracted considerable attention from researchers in the field of natural products.^1,2 The Nobel prize was awarded for the discovery of the antimalarial artemisinin, which is a sesquiterpenoid from Artemisia annua,³ and the antitumor sesquiterpenoid elemene is also widely used in the clinical treatment of various malignant tumors.⁴

Lindenane sesquiterpenoids (LSs) are a type of rare, naturally occurring sesquiterpenoids with a characteristic 3,5,6-tricarbocyclic skeleton, which also exist as 50 diverse carbon oligomers (Fig. 1).^5–10 Since the first identification of lindeneol from L. strychnifolia in 1925,^5,11 354 natural LS analogs have been discovered in plants from the Lauraceae,^5,6,12,13 Chloranthaceae,^{6–8,10,14–17} Asteraceae,^18–23 and Cyperaceae²⁴ families, and also the marine animal gorgonian corals.^25,26 Due to the highly conjugated double bonds in LSs,^6,7,27 188 LSs exist as homo-oligomers with different skeletons through diverse addition and rearrangement reactions,^5–10 such as Diels–Alder [4 + 2] cycloaddition,^28,29 [2 + 2] cycloaddition,³⁰ and [6 + 6] cycloaddition.³⁰ It is worth noting that LS and non-LS units (e.g., monoterpene and geranylbenzofuranone) can form hetero-oligomers with unprecedented structural diversity, which have remarkable differences compared with that of other sesquiterpenoids.^31–37


	Fig. 1 Different types of LSs and their oligomers.

Plants containing LSs have been used as famous natural medicines to treat blood stasis, inflammation, drainage, and detoxification.^38,39 Thus, the diverse LSs also show various and significant biological activities, such as anti-inflammation,^40–43 antitumor,^44–46 and anti-infection.^47–50 In particular, 13′-O-methyl succinylshizukaol C has been reported to show about 1000-fold stronger antimalarial activity than that of artemisinin.^48,50 Considering their diverse skeletons and strong bioactivities,^{5–10,44,45,47–50} the total synthesis of LSs and their oligomers has also attracted significant interest from organic chemists, and thus far, complex and bioactive oligomers with seven types of skeletons have been synthesized by several groups.^51–54 The aforementioned information indicates that significant progress has been achieved in the last 100 years regarding the chemistry and bioactivity of LSs and their oligomers.

To date, some mini reviews on LSs and their oligomers,^{6–8,51,53,55–58} as well as secondary metabolites from plants from the Chloranthaceae family^{10,14–17,59–61} and Lindera genus^5,12,13,62 have been published, but a complete and in-depth review is lacking. Therefore, in this review, we provide an overview of the research on 354 naturally occurring LSs since 1925, including their structure determination, distribution, biosynthetic origins, synthesis, and biological activities.

1.1 Structural classification

Although LSs have been discovered for 100 years and 354 natural LSs with 50 diverse carbon skeletons have been reported;^{5–10,31–37} however, a clear and rational structural classification for LSs and their oligomers is lacking. Thus, a classification based on the basic framework and plausible biogenetical pathways of LSs will be proposed in this review.

The characteristic 3,5,6-ring skeleton of LSs is derived from farnesyl diphosphate (FPP) via a series of enzymatic reactions (Fig. 1).^63,64 Through serial post-modification via oxidation, diverse double bonds can be formed in the scaffold of LSs, and these double bonds and the cyclopropane moiety can also undergo oxidative cracking.^5,10,14,17 Thus, the monomers can be classified as ring-intact and ring-seco types, which can be subdivided based on the position of the double bond and the location of the ring splitting.

Because of the diverse structures of reported oligomers,^{5–10,31–37} firstly, they can be classified as homo-oligomers and hetero-oligomers based on the precursors of polymerization (Fig. 2). The term “homo-oligomers” denotes that all the structural units are LSs. In contrast, hetero-oligomers contain other types of units besides LSs, such as monoterpene,^36,37,65 geranylbenzofuranone,³³ and formaldehyde.³² Then, sub-classification, including dimers, trimers, and potential tetramers and pentamers, can be concluded based on the degree of polymerization. In general, the reported LSs and their oligomers can be classified as ring-intact monomer, ring-seco monomer, homo-dimers, hetero-dimers, homo-trimers, and hetero-trimers.


	Fig. 2 Representative LSs with novel skeletons discovered in the last century and their biogenetic relationships.

The carbon skeletons and plausible biosynthetic pathways of LS oligomers indicate that [4 + 2] cycloaddition,^28,29 [2 + 2] cycloaddition,³⁰ [6 + 6] cycloaddition,³⁰ oxygen-involved [2 + 2 + 2] cycloaddition,^34,36,37 C linear linkage from Micheal addition,⁶⁶ and O linear linkage from ether or ester bonds⁶⁷ are the main polymerization patterns in these homo- and hetero- oligomers (Fig. 2), which can be explained by the presence of highly conjugated units (Δ^{15(4),5(6),7(11)}, Δ^15(4),5(6), Δ^11,(13), Δ^7(11),8(O), Δ^7(11),13(O), Δ⁶⁽⁷⁾, Δ⁷⁽¹¹⁾, and Δ⁸⁽⁹⁾) in LSs.^28–30,52 Taking the most abundant and classical [4 + 2] cycloaddition homo-dimer as an example, it is formed by the intermolecular Diels–Alder reaction between Δ^15(4),5(6) and Δ^8′(9′).²⁸ Subsequent oxidative rearrangement further enhances the structural diversity, such as sarglaromatic D,⁶⁸ fortunoid A,⁶⁹ and chlorahupetone G.⁷⁰ Meanwhile, Δ^15(4),5(6) can also react with Δ^11′(13′) and Δ^15′(4′) or other double bonds of the non-LS unit.⁷¹ Also, Δ^7(11),8(O) can exist as a diene moiety and undergo oxygenate [4 + 2] cycloaddition.⁷² Besides the abundant LSs with conjugated units, non-LSs with different skeletons can serve as diene or dienophile units to form hetero-[4 + 2] LS oligomers.^36,37,65,71 The second category of LS oligomers occurs through [2 + 2] cycloaddition between two Δ^8′(9′) and [6 + 6] cycloaddition between the highly conjugated Δ^{15(4),5(6),7(11)}, which is uncommon in nature.^70,73–76 There will still be highly conjugated fragments in the oligomers of LSs after the occurrence of [6 + 6] cycloaddition, also suggesting that the subsequent intramolecular rearrangement and cyclization products will be very rich and unusual (Fig. 2). Recently, a type of interesting hetero-dimer with a peroxide bridge was discovered in Sarcandra species, which was proposed as an oxygen-involved [2 + 2 + 2] cycloaddition product (Fig. 2).^34,36,37,77 Besides these carbon–carbon linkages,^78,79 the aldehyde or carboxyl group from oxidative cracking can lead to the formation of O-linkage oligomers.^67,80 The reactive non-terpenoid moiety, such as formaldehyde and active methylate of phenylacetic acid, can also be intermediary to connect LSs through Michael addition to form diverse hetero-oligomers (Fig. 2).^32,33 According to the above-mentioned analysis, sub-oligomers can be classified as [4 + 2] cycloaddition, [2 + 2] cycloaddition, [6 + 6] cycloaddition, oxygen-participated [2 + 2 + 2] cycloaddition, and C and O linear linkage. The representative LS oligomers with novel skeletons and their biogenetic relationships are summarized and shown in Fig. 2.

1.2 Distribution in plant sources

Compared with other types of sesquiterpenoids or terpenoids, the distribution of LSs in natural sources is mainly limited to the Lindera genus and Chloranthaceae family because 338 of the 354 naturally occurring LSs have been isolated from plants of Lindera species^5,13,62,81 and Chloranthus,^{14,16,17,59,60,82}Sarcandra,^10,59,82 and Hedyosmum genera^65,83 of the Chloranthaceae family. The other 13 LSs were discovered from the Asteraceae family,^18–23 1 from the Cyperaceae family,²⁴ and 2 from gorgonian corals.^25,26 The distribution of different types of LSs in the Lindera genus and Chloranthaceae family also has distinct characteristics (Fig. 3). L. aggregata,^32,80,84L. chunii,^79,85 and L. strychnifolia⁸⁶ have the highest frequency of ring-seco monomers, homo-linear-dimers and hetero-oligomers besides hetero-[4 + 2] dimers.^5,12,13 Plants from the genus Chloranthus are characterized by homo-[4 + 2] and homo-[6 + 6] dimers, which are especially abundant in roots^14,16,17,59 and have been studied extensively, including Chloranthus japonicus^87,88 and C. fortune.^89,90Sarcandra plants have been widely studied for their use in traditional Chinese medicine formulations,⁹¹ and almost every type of LS has been reported.^10,59,82 Oxygen-involved [2 + 2 + 2] cycloaddition-type dimers and homo-O-linear oligomers are the characteristic metabolites of this genus.^34,36,67Hedyosmum species have been scarcely studied, which feature rare hetero-[4 + 2] dimers with monoterpene.^37,65


	Fig. 3 Distribution of different types of LSs in Lindera, Chloranthus, Sarcandra, and Hedyosmum genera.

2 Structure of reported natural LSs

The diverse structural units, reaction patterns and sites of precursors, and subsequent rearrangements in diverse sites of LSs reveal their great potential for intriguing monomeric and oligomeric skeletons (Fig. 2), leading to the discovery of 354 natural LSs and their oligomers during the last century. In the following section, we present a systematic and comprehensive summary of the reported LS monomer and oligomers based on the aforementioned classification, including the structures, distribution, and biosynthetic pathway of LSs with novel skeletons. Furthermore, to make this review more concise, only the characteristic LSs with representative or novel skeletons are described and shown in the main text. The other structures, plants resources and bioactivities of each LS can be found in the ESI.†

2.1 Monomers

Ring-intact LS monomers are characterized by a polycyclic framework embedded with a sterically congested cyclopentane, an unusual trans-5/6 ring junction, and an angular methyl. Most naturally monomers occur in ring-intact type (ca. 95 compounds) with different terminal units and degrees of oxidation. From the perspective of plausible biosynthetic pathway (Fig. 4), these ring-intact LSs can be further divided into furan-ring type (1–9), α,β-unsaturated γ-lactone type (10–63), α,β,γ,δ-unsaturated lactone (64–82), γ-epoxide-butenolactone type (83–91) and lactone opening type (92–95). In contrast, fifteen ring-seco monomers have been discovered, including 8,9-seco 8,4-δ-lactone type (96–107), 6,7-seco type (108), 4,5-seco type (109), and 2,3-seco-ring type (110).


	Fig. 4 Hypothetical biosynthesis route of LS monomers.

2.1.1 Ring-intact monomers. Most naturally existing ring-intact monomers incorporate terminal units of either a furan ring or its oxidative α,β-unsaturated lactone moieties. Furthermore, the Δ¹⁵⁽⁴⁾ of these molecules undergo similar oxidation and isomerization, resulting a greater variety of structures (Fig. 4). The first LS monomer to be discovered was lindeneol (1) with a terminal furan-ring and Δ¹⁵⁽⁴⁾ double bond from L. strychnifolia by Kondo and colleagues in 1925.¹¹ To date, furano-LSs have been reported only from the Lindera genus, including lindenenyl acetate (2),^92,93 linderoxide (3),⁹⁴ lindenene (4),⁹⁵ linderene (5),⁵ linderene acetate (6),⁹² isodihydrolinderene (7),⁵ lindenenone (8),⁵ and isolinderoxide (9).⁹⁶

Upon oxidation, the furan ring will transfer to the characteristic α,β-unsaturated γ-lactone moiety of LSs with Δ¹⁵⁽⁴⁾ (10–40), Δ⁴⁽⁵⁾ (41–47), and further oxidation derivatives (48–63), which was also supported by their bio-inspired total synthesis.⁹⁷ Strychnistenolide A (10),⁸⁶ 6α-acetyl-lindenanolide A (11),⁸⁶ strychnilactone 2,6-dihydroxyxanthone (12),⁹⁸ chlorajapolide F (13),⁹⁹ chlojaponilactone G (14),¹⁰⁰ decorone A (15),²⁰ linderin A (16),¹⁰¹ linderolide T (30)¹⁰² and onoseriolide acetate (38)²² all possess a β-orientated lactone ring. Linderin A (16) was isolated from the roots of L. aggregata, which is comprised of an LS lactone and a rare methyl geranylhomogentisate moiety through an ether bond.¹⁰¹ Strychnistenolide B (17),⁸⁶ 6α-acetyl-lindenanolide B (18),⁸⁶ lindenanolide H (19),⁸⁵ shizukanolide (20),¹⁰³ heterogorgiolide (21),²⁶ 9-hydroxy heterogorgiolide (22),¹⁰⁴ chlojaponilactone F (23),¹⁰⁰ chlojaponilactone H (24),¹⁰⁰ chlorajaposide (25),⁸⁸ chloranthalactone E 8-O-β-D-glucopyranoside (26),¹⁰⁵ rosmarylchloranthalactone E (27),¹⁰⁶ decorone B (31),²⁰ sarcandralactone A (32),¹⁰⁷ menelloid C (33),¹⁰⁸ onoseriolide A (34),¹⁹ 8α,9-dihydroonoseriolide senecioute (35),¹⁹ wunderoild (39)²¹ and sibirolide A (40)¹⁸ are LS monomers possessing an α-orientated lactone ring. The configurations of C-8 in chloranthalactones D (28) and E (29) were not determined in the original research.¹⁰⁹ Lindenanolide A (36)¹¹⁰ and linderolide V (37)¹¹¹ have rare Δ⁷⁽⁸⁾ double bonds. In these monomers, 25 and 26 are rare LS glycosides, 30 represents a rare cis-5/6 ring junction, and 33 has the opposite 1S, 2R, 5R, 10R absolute configuration to most LSs and originates from the marine animal gorgonian coral Menella sp. The Δ⁷⁽¹¹⁾ double bonds of onoseriolide acetate (38) underwent reduction reaction and generated a β-saturated lactone ring fused at C7 and C8.²² Sibirolide A (40) contains a rare 6,12-olide.¹⁸

The characteristic Δ¹⁵⁽⁴⁾ can transfer to Δ⁴⁽⁵⁾ and form another type of LS monomer, such as isoshizukanolide (41),⁴⁹ 8β,9α-dihydroxylindan-4(5),7(11)-dien-8α,12-olide (42),¹¹² glabranol A (43),¹¹³ chlorajapolides A–C (44–46),⁸⁸ and chlojaponilactone D (47).¹¹⁴ Also, Δ¹⁵⁽⁴⁾ can be oxidized and form a series of LS monomers with an OH moiety at these carbons, such as linderolides K (48),¹¹⁵ N–S (49–54),¹⁰² sarcandralactone C (55),¹¹⁶ chlojaponilactone E (56),¹¹⁴ chlorajapolides E (57),⁸⁸ H (58),⁹⁹ chlojaponilactone I (59),¹⁰⁰ decorone D (60),²⁰ chlorajapolide D (61),⁸⁸ yinxiancaoside A (62)¹¹⁷ and myrrhalindenane B (63).¹¹⁸ Among them, a unique C-15/C-6 furan ring was formed in 45, 54 and 55 bear opposite trans-5/6 ring conjunction, and 63 possesses rare C-6 and C-12 lactones.

Compounds 64–82 are characteristic LS monomers with an α,β-unsaturated γ-lactone and additional Δ⁸⁽⁹⁾ enolic double bond. In this group, chloranthalactone A (64),¹¹⁹ chlojaponilactone B (65),¹¹⁴ onoseriolide B (66),^120,121 sibirolide B (67)¹⁸ and onoseriolide senecioate (68)¹⁹ possess Δ¹⁵⁽⁴⁾, Δ⁷⁽¹¹⁾, and Δ⁸⁽⁹⁾ double bonds, whereas sarcandralactone D (69)¹¹⁶ has an isomerized Δ⁴⁽⁵⁾. 15-Hydroxyisoonoseriolide senecioate (70),¹⁹ chloranthalactone C (71),¹⁰⁹ shizukanolide C (72),¹²² chloranoside B (73),¹²³ chlorajaponol F (74),¹²⁴ chloranthalactone G (75) with rare and unstable 4,15-epoxide,¹²⁵ shizukanolide F (76),¹²⁶ shizukanolide H (77),¹²⁷ shizukanolide E (78),¹²⁶ chloranoside A (79)¹²³ and linderaggredin B (80)¹²⁸ with anticonfigurational cyclopropane were isolated as the oxidated derivatives of the Δ¹⁵⁽⁴⁾ double bond. Chlorafortulide (81)¹²⁹ and sarglabolide L (82)¹³⁰ possess a rare 18-membered macrolide.

The epoxidation of the active Δ⁸⁽⁹⁾ olefinic bond generated a series of 8,9-epoxide LS monomers, such as chloranthalactone B (83),¹¹⁹ oxyonoseriolide (84),¹²⁰ chlojaponilactone C (85),¹¹⁴ shizukanolide D (86),¹²⁶ shizukanolide G (87),¹²⁷ (+)-chloranthalactone B (88),²⁵ 13-desoxyisoonoseriolide (89),²² 8β,9β-epoxyonoseriolide senecioate (90),¹⁹ and sarcaglaboside F (91).¹³¹ It is worth mentioning that 88 is an enantiomer of 83 from the marine animal gorgonian Menella sp.²⁵ Hedyosmone (92),¹²⁰ linderolide U (93),¹³² linderolide L (94),¹¹⁵ and myrrhalindenane A (95)¹¹⁸ have a characteristic C-8 keto group through 8,12-olide opening.

2.1.2 Ring-seco monomers. The majority of the ring-seco monomers known to date are 8,9-seco ring type with 9-aldehyde and 8,4-δ-lactone moieties, such as strychnilactone (96),⁸⁶ lindenanolide G (97),⁸⁵ linderagalactone B (98),¹³³ rotundusolide A (99),²⁴ linderolide M (100),¹¹⁵ chloranerectuslactone V (101),¹³⁴ sarglalactones I-M (102–106)⁶⁷ and linderagalactone C (107).¹³³ The biomimetic conversion of 102–106 verified that these compounds were produced via the cleavage of the Δ⁸⁽⁹⁾.^67,135 Lindenanolide E (108),⁸⁵ linderaggredin C (109),¹²⁸ and linderagalactone A (110)¹³³ have unique 6,7-seco ring, 4,5-seco ring, or 2,3-seco ring skeletons, respectively.

2.2 Dimers

2.2.1 Homo-dimers.
2.2.1.1 [4 + 2] cycloaddition. Among the LS dimers, the most common is the classical [4 + 2] dimer formed by the intermolecular Diels–Alder reaction between Δ^15(4),5(6) and Δ^8′(9′). The highly conjugated double bonds and α,β-unsaturated ketones of these dimers provide key reactive sites for further intramolecular or intermolecular reactions, revealing great potential for unknown intriguing molecules based on the classical lindenane [4 + 2] dimer. The Diels–Alder reaction between Δ^15(4),5(6) and Δ^8′(9′) is also the origin of Δ⁴⁽⁵⁾ in these dimers. The subsequent oxidation rearrangement of the Δ⁴⁽⁵⁾ double bond, oxidation of the Δ^15′(4′) double bond, and C-13′ position methyl, in addition to further esterification yields a variety of structures. Therefore, these compounds can be further divided into different subclasses based on the position and oxidation state of their double bond (Fig. 5).


	Fig. 5 Hypothetical biosynthesis route of classical [4 + 2] dimers.

Shizukaol A (111), the earliest dimer of LS, was initially isolated form C. japonicus and reported by Kawabata and colleagues in 1990,¹³⁶ which can be recognized as the precursor of diverse homo-[4 + 2] dimers and similar derivatives including shizukaol A acetate (112),⁷³ chlojapolides D–F (113–115),¹³⁷ and chlojapolide B (117),¹³⁷ containing Δ⁴⁽⁵⁾, Δ^15′(4′), and Δ⁷⁽¹¹⁾ double bonds and methyl ester side chains with CO-8. Chololactone D (116)⁷⁵ is formed by the migration of the α,β-unsaturated ketone derivative of 111 with the rare Δ^7(8),9(O). Chlojapolide B (117) is the first LS dimer possessing an acetyl oxygenated methylene group at C-14.¹³⁷ In contrast to 111,¹³⁶ chlojapolide C (118) possesses the rare E-type Δ⁷⁽¹¹⁾ double bonds.¹³⁷

The active Δ^15′(4′) and allyl Me-13 undergo oxidation, esterification and rearrangement to form diverse homo-[4 + 2] dimers, including shizukaol N (119),¹³⁸ shizukaol M (120),¹³⁸ shizukaol I (121),¹³⁹ chlorahololide D (122),¹⁴⁰ shizukaol K (123),¹³⁸ multistalide B (124),¹⁴¹ sarcandrolide A (125),¹⁰⁷ shizukaol C (126),¹⁴² shizukaol L (127),¹³⁸ sarcandrolide B (128),⁶¹ 13′-O-methyl succinylshizukaol C (129),⁵⁰ chololactones E–F (130–131),⁷⁵ sarglabolides H–K (132–135),¹⁴³ fortunilide M (136),⁹⁰ chlojapolide A (137),¹³⁷ fortunilides A–C (138–140),⁶⁵ chlorahupetol F (141),¹⁴⁴ shizukaol O (142),¹³⁸ sarcandrolide J (143),¹¹⁶ chlomultiol A (144),¹⁴⁵ sarcanolide E (145),¹⁴⁶ and shizukaols D–E (146–147).^139,142 Chlorahololide D (122) was also reported by Luo's group as henriol D in the same year.¹⁴⁷ Sarcandrolide J (143)¹¹⁶ and shizukaols D–E (146–147)^139,142 possess a dehydroxylated C-4′ tertiary carbon. The migration of the Δ⁷⁽¹¹⁾ double bond to Δ⁶⁽⁷⁾ and the presence of a secondary methyl group at C-11 are the characteristics of chololactone G (148).⁷⁵

Sarcanolides A (149),¹⁴⁸ D (150),¹⁴⁶ B (151),¹⁴⁸ fortunilide N (152),⁹⁰ chololactone A (153),⁷⁵ fortunilides K, L (154, 155),⁴⁹ fortunilide O (156),⁹⁰ sarcanolide C (157),¹⁴⁶ and chlorahupetones G-I (158–160)⁷⁰ possess an additional C–C bond between C-11 and C-7′ by a proton-mediated addition reaction (Scheme 1). Through decarboxylation of the C-12 and subsequent rearrangement of the double bonds and lactone ring, chlorahupetones G–I (158–160) featuring aromatized ring D and a five-membered lactone ring fused at C-11 and C-7′ were formed (Scheme 1).⁷⁰ Sarglaromatics A–E (161–165) with unique naphthalene-like architecture-fused skeletons were discovered in the roots of S. glabra, and the unique naphthalene core skeleton was obtained from classical lindenane [4 + 2] dimers via a free-radical-mediated C11–C11′ bond formation reaction and 12′-decarboxylation (Scheme 1).⁶⁸ The Southern Hemisphere fortunoid C (166),⁶⁹ 15′-O-(4-hydroxytigloyl) fortunoid C (167) and 13′-O-methyl succinyl-15′-O-tigloylfortunoid C (168)⁵⁰ are eudesmane sesquiterpenoids, which may be the products of cleavage the C1–C3 bond of cyclopropane.


	Scheme 1 Structures and proposed biogenetic pathway for 149–165.

The characteristic 18-membered macrolide ring-type LSs, such as shizukaol B (169),¹⁴² shizukaols F–H (170–172),¹³⁹ shizukaol P (173),¹²⁷ chloramultiol A (174),¹⁴⁹ sarcandrolide C (175),¹⁰⁷ sarglabolides B–G (176–181),¹⁴³ henriol C (182)¹⁴⁷ and fortunilide G (183),⁴⁹ can be constructed through further oxidization and esterification. Also, 169 is the first lindenane dimer with an 18-membered macrolide ring¹⁴² and 182 bears a rare E-type Δ⁷⁽¹¹⁾. Sarglabolide A (184) was found to be the first case in which a 17-membered macrocyclic ester ring was constructed.¹⁴³ Sarglafuran A (185)¹⁵⁰ and chlorahupetols C (186) and D (187)¹⁴⁴ possess the [4 + 2]-type LS dimer scaffold with a unique furan ring moiety.

The Δ⁴⁽⁵⁾ double bond can be oxidized, forming the characteristic hydroxyl or peroxy-hydroxyl at C-4 or C-5 and migrating Δ⁴⁽⁵⁾ to Δ⁵⁽⁶⁾ (188–209) and Δ¹⁵⁽⁴⁾ (210–213). Chlorahololides A (188),¹⁵¹ C (189)¹⁴⁰ and spicachlorantin J (190)¹⁵² possess a Δ^15′(4′) double bond, and spicachlorantins E–F (191–192),¹⁵³ sarcandrolide E (193),¹⁰⁷ chlorajaponilide E (194),⁸⁷ spicachlorantin G (195),^152,154 chlorasessilifol A (196),¹⁵⁵ fortunilides D-F (197–199),⁴⁹ chololactone B (200),⁷⁵ multistalide A (201),¹⁴¹ chlomultiol B (202),¹⁴⁵ and sarcaglabrin B (203) feature an additional chiral center at C-4′.¹⁵⁶ The migration of Δ⁷⁽¹¹⁾ affords a rare Δ¹¹⁽¹³⁾, which is the characteristic of multistalide A (201),¹⁴¹ chlomultiol B (202),¹⁴⁵ and sarcaglabrin B (203).¹⁵⁶ The substituent groups at C-13′ and C-15′ form an 18-membered macrolide through their esterification reaction in compounds 204–209. Chloramultilide A (204),¹⁵⁷ sarcandrolide H (208)¹¹⁶ and chlorajaponilide H (209)¹⁵⁸ share the same hydroxyl group at C-4, whereas spicachlorantins C and D (205 and 206)¹⁵³ and sarcandrolide G (207)¹¹⁶ have a peroxyl group attached to their C-4 positions. Sarcandrolide F (210),¹¹⁶ chlorajaponilides F (211)¹⁵⁸ and I (212),¹⁵⁹ and chlorajaponilide G (213)¹⁵⁸ are charactered as Δ¹⁵⁽⁴⁾ derivatives, and subsequently form peroxyl groups at C-5.

Based on the characteristic locations of OH or OOH and double bond in these compounds, a plausible epoxidation or [2 + 2] addition between O₂ and Δ⁴⁽⁵⁾ and subsequent H⁺-mediated cracking and double bond migration can yield derivates with OH-4 and Δ⁵⁽⁶⁾ (188, 189, 193, 195, 196, 201–204, 208, and 209), OOH-4 and Δ⁵⁽⁶⁾ (190–192, 194, 197–200, and 205–207), OH-5 and Δ¹⁵⁽⁴⁾ (151), or OOH-5 and Δ¹⁵⁽⁴⁾ (210–213) (Fig. 6).


	Fig. 6 Hypothetical biosynthesis route of OH/OOH-4 or OH/OOH-5 in classical [4 + 2] dimers.

An α,β-unsaturated lactone ring fused at C-7 and C-8 and Δ⁵⁽⁶⁾ double bond are the characteristics of compounds 214–239. Chlorahololide E (214),¹⁴⁰ spicachlorantins H (215),¹⁵² I (216)¹⁵² and chlojapolide G (217)¹³⁷ possess a Δ^15′(4′) double bond. Chloramultilide D (218),¹⁶⁰ chloramultiol D (219),¹⁴⁹ chloramultiol B (220),¹⁴⁹ chloramultiol C (221),¹⁴⁹ chlorahololide F (222),¹⁴⁰ chloramultiol E (223),¹⁴⁹ sarcandrolide D (224),¹⁰⁷ chlorasessilifol B (225),¹⁵⁵ fortunilide I (226)⁴⁹ and chlorahupetol F (228)¹⁴⁴ were obtained via various oxidation and derivatization reactions involving the Δ^15′(4′) double bond and the methyl group at C-13′.

The appearance of the 18-membered macrolide in 229–239 indicates that the substituent groups of C-13′ and C-15′ are linked through the esterification reaction. Regarding their macrolides, chlorahololide B (229),¹⁵¹ chloramultilide B (230),¹⁶⁰ and yinxiancaol (234)¹⁶¹ contain methyl groups at the C-3′′ position. Conversely, the methyl group of chloramultilide C (231),¹⁶⁰ tianmushanol (232),¹⁶² 8-O-methyltianmushanol (233),¹⁶² spicachlorantin A (235),¹⁶³ chlorajaponilide D (236),⁸⁷237,⁴⁰ sarcandrolide I (238),¹¹⁶ chlomultiol C (239)¹⁴⁵ and 240 (ref. 40) is situated at the C-2′′ position. The Δ¹⁵⁽⁴⁾ double bonds of 240–245 were constructed by the dehydration of the hydroxyl group at C-4. Chloraserratolide B (240),⁴⁰ chloramultiol F (241),¹⁴⁹ and fortunilide H (242)⁴⁹ bear two α,β-unsaturated γ-lactone rings and Δ¹⁵⁽⁴⁾, Δ⁵⁽⁶⁾, and Δ⁷⁽¹¹⁾, and the reduction of Δ⁵⁽⁶⁾ formed fortunilide J (243),⁴⁹ chlorajaponilide A (244)⁸⁷ and chlorajaponilide B (245).⁸⁷ However, 237 and 240 were not named by the author at the time of publication.⁴⁰

Chloramultiol G (246)¹⁶⁴ is the first 8,9-seco-lindenane dimer formed via the oxidative cleavage between C-8 and C-9 and esterification based on the classical [4 + 2] dimer (Scheme 2).¹⁶⁴ Fortunoid A (247) was a rearranged lindenane dimer with a bicyclo[3.3.1]nonane core in the Northern Hemisphere,⁶⁹ which was converted through oxidative cleavage of the Δ⁴⁽⁵⁾ double bond and subsequent nucleophilic addition (Scheme 2). According to the basic structures, the eudesmane moiety of fortunoid B (248),⁶⁹ chlorahupetols B (249)¹⁴⁴ and A (250),¹⁴⁴ and horienoid B (251)¹⁶⁵ may originate in LSs via opening of the cyclopropane moiety (Scheme 2). Thus, we classify these compounds as homo-dimers, where 248 (ref. 69) is the first example of this scaffold and 251 (ref. 165) is a rare intermolecular Diels–Alder dimer between Δ^11(13),6(7) and Δ^8′(9′) (Scheme 2).


	Scheme 2 Biogenetic pathway proposed for 247–251.

To date, only three compounds formed by other types of endo-Diels–Alder addition between Δ^15(4),5(6) and Δ^15′(4′) (252 and 253),²⁷ as well as hetero-Diels-Alder addition between Δ^7(11),8(O) and Δ^15′(4′) (254) have been discovered.⁷² Chlotrichenes A (252) and B (253) possess a spirocarboncyclic dimeric framework formed by the endo-Diels–Alder reaction between Δ^15(4),5(6) and Δ^15′(4′), and the structure of 252 features a unique 3/5/6/6/6/6/5/3-fused octacyclic skeleton by the subsequent plausible epoxidation–cyclization reactions of 253 (Scheme 3).^27,166 Spirolindemer A (254), a novel LS dimer equipped with an oxaspiro[4.5]decane unit, was discovered from the medicinal plant C. henryi.⁷²


	Scheme 3 Biogenetic pathway proposed for 252 and 253.

2.2.1.2 [2 + 2] and [6 + 6] cycloaddition. The dimerization of Δ⁸⁽⁹⁾ of LS with active an α,β,γ,δ-unsaturated moiety via [2 + 2] cycloaddition has also been observed in chloranthalactone F (255),^73,167 chololactone H (256),⁷⁵ sarglalactone N (257),¹⁵⁰ and sarglalactone O (258).¹⁵⁰ The structure and absolute configuration of 255 were not determined through total synthesis and X-ray diffraction analysis until 2012, which were achieved by total synthesis.¹⁶⁸ Cycloshizukaol A (259), the first example of a [6 + 6] cycloaddition-type dimer,¹⁶⁹ was reported in many species of Chloranthaceae. 9-O-β-glucopyranosylcycloshizukaol A (260)¹²⁷ and japonicones A–C (261–263)⁷⁶ are produced from 259 through oxidation-reduction and glycosylation reactions. Chlorahupetones A–E (264–268) have extremely thick carbon skeletons, particularly 264–266 given that they have the uncommon coexistence of 3–7 carbon rings in a single molecule.⁷⁰ Chlorahupetone F (269) is a unique C₂-symmetric cyclic rearranged lindenane-type sesquiterpenoid dimer.⁷⁰ Guided by the MS/MS molecular network strategy, chlospicenes A and B (270 and 271) are the first examples of LS [6 + 6] cycloaddition dimers with cracked cyclopropane.⁷⁴ The highly conjugated Δ^{4(5),6(7),8(O)} fragment of 259 facilitated a series of rearrangement and intramolecular cyclization reactions (Scheme 4). The key cyclopropylcarbinyl rearrangement of 259 gave rise to 270 and 271,⁷⁴ and 264–269 were formed from 259via biradical rearrangement of vinylcyclopropane and intramolecular [2 + 2] cyclization reactions (Scheme 4).⁷⁰


	Scheme 4 Biogenetic pathway proposed for 259–271.

2.2.1.3 Linear linkage. In addition to the above-mentioned dimers connected by a ring system, single C or O bond linked LS dimers were also discovered. Shizukaol J (272) represents the first documented linear LS dimer featuring a C linear linkage mode at C-11/C-15′.⁶⁶ Lindenanolide F (273)⁸⁵ and linderanoids L–O (274–277)⁷⁸ belong to the C linear linkage type incorporating a C-8/C-8′ dimerization pattern of two LSs from plants of the Lindera genus. Linderanoid J (278)⁷⁸ and lindenanolide I (279)⁷⁹ feature a rare C-8/C-11′ linkage, and linderanoids H, I, K_a and K_b (280–283) are C-12/C-6′ linkage type from the roots of L. aggregate.⁷⁸ The keto–enol tautomers of 282 and 283 (2 [thin space (1/6-em)]

5) were determined based on the protonated molecule and NMR.⁷⁸ Similar to that of 248–251,^69,144,165 the eudesmane unit of C-8/C-8′-linked linderanoids D (284) and E (285) may originate from lindenane by opening of the C1–C3 bond.⁷⁸

Chlojapolactone A (286),¹³⁵ sarglalactones D–G (287–290)⁶⁷ and chlojapolactone B (291)¹⁷⁰ are O linear linkage-type LS dimers with a unique 1,3-dioxolane linkage and comprised of a rare dimaleate featuring an 8,9-seco lindenane monomer. The theoretical analysis and biomimetic conversion confirmed that the oxidative cleavage of the Δ⁸⁽⁹⁾ double bond of chloranthalactone A (64), an abundant lindenane-type sesquiterpenoid in Chloranthaceae plants, generates 8,9-secolindenane (103) with active aldehyde and maleic anhydride fragments, which can capture other fragments and produce these dimers.⁶⁷ In addition to this 1,3-dioxolane linkage, the units of linderaggrenolides A–G (292–298), J–N (299–303),⁸⁰ and sarglalactone H (304)⁶⁷ are linked through C8–O–C12′, C8–O–C8′, CO12–O–C15′, and CO9–O–C9′, respectively.

2.2.2 Hetero-dimers.
2.2.2.1 [4 + 2] cycloaddition. Bolivianine (305), a novel sesquiterpenoid with an unprecedented skeleton, was isolated from the trunk bark of H. angustifolium (Chloranthaceae), together with isobolivianine (306), an isomer formed under acidic conditions.⁶⁵ Sarcaglabrin A (307),¹⁵⁶ dyosmunoid A (308),³⁷ and 7′-oxyisosarcaglabrin A (309)⁷⁷ can be recognized as the possible biogenic precursors of 305 and 306, which may be produced by hetero-[4 + 2] cycloaddition between LS and monoterpene units (Scheme 5). The intriguing 305 and 306 were also synthesized using a biomimetic hetero-[4 + 2] cycloaddition approach, which will be discussed later in the Synthesis section.⁶⁵ Chlorfortunones A (310) and B (311) represent a new type of LS hetero-[4 + 2] cycloaddition dimers between LS and acrane sesquiterpenoid monomers possessing an unprecedented 3/5/6/6/6/5 hexacyclic system with a unique dispiro[4,2,5,2]-pentadecane-6,10,14-trien moiety, which were discovered recently.^171,172


	Scheme 5 Biogenetic pathway proposed for 305–309.

2.2.2.2 [2 + 2 + 2] cycloaddition. Sarglaperoxides A and B (312 and 313),³⁴ 6α-hydroxysarglaperoxide A (314),⁷⁷ dyosmunoid B (315),³⁷ sarcaglarols A–D (316–319)³⁶ and sarcaglarone A (320)⁷⁷ are characteristic sesquiterpene–monoterpene hetero-dimers with an apparent [2 + 2 + 2] cycloaddition skeleton conjugated by a peroxide bridge discovered in the last decade. The intermolecular enzymatic [2 + 2 + 2] cycloaddition among lindenane, monoterpene, and singlet O₂ may play a key role in the plausible biosynthesis pathway of the 1,2-dioxane moiety-fused lindenane–monoterpene heterodimer skeleton (Scheme 6). Recently, the targeted discovery of 316–319 was guided by the MS/MS molecular networking-based strategy, which can be recognized as the biogenetic precursors of reported lindenane–normonoterpene conjugates (312–315).^34,36,165 Sarcaglarone A (320) displayed an unprecedented monocyclic monoterpene moiety formed by a free radical-mediated C1′–C5′ bond formation reaction from terminal aldehyde (Scheme 6).⁷⁷ Sarglaoxolane A (321), the first lindenane–normonoterpene heterodimer fused by tetrahydrofuran, was also discovered in S. glabra guided by the first proposed single-node-based molecular networking approach.³⁵ Moreover, two pseudonatural derivatives, sarglaoxolanes B and C (322 and 323), with an oxa-difuranofurone moiety were transformed from 321, which was confirmed by X-ray diffraction, and also proven to exist in a plant extract.³⁵


	Scheme 6 Biogenetic pathway proposed for 312–320.

2.2.2.3 Linear linkage. Aggreganoids C–F (324–327), which are examples of additional carbon-bridged hetero-lindenane dimers between the furan ring of lindenane and other reactive units (aldehyde or ketone), were isolated from L. aggregata.³² Linderanoids A–C (328–330) and F–G (331–332), which are five linear linkage hetero-dimers comprised of a noreudesmane unit (328–330) or elemanolide unit (331 and 332), were also isolated and identified from the roots of L. aggregata.⁷⁸ Besides above-mentioned C-linkage, hedyorienoid A (333) possessing an aromadendrane sesquiterpenoid connected by an 1,3-dioxolane ring as 286–291 [thin space (1/6-em)]

⁸³ and linderaggrenolides H and I (334 and 335) with a C8–O–C8′ linkage between 8,9-seco eudesmane and LS were also discovered.⁸⁰

2.3 Trimers

Among the numerous oligomers, only nineteen trimers (336–354) have been identified to date.^{32,33,66,67,72,89,173} It is noteworthy that all the homo-trimers were discovered in the Chloranthaceae family,^{66,67,72,89,173} while all the hetero-trimers were isolated from the Lindera genus.^32,33

2.3.1 Homo-trimers.
2.3.1.1 [4 + 2] cycloaddition. Trishizukaol A (336), consisting of three lindenane units connected by [4 + 2] cycloaddition and apparent C linear linkage, was firstly isolated from the roots of C. japonicus in 1998,⁶⁶ and also from C. spicatus and C. fortunei.^89,173 Recently, diverse derivatives of 336, trichloranoids A–D (337–340) and chlofortunins B–D (341–343) were likely formed biogenetically via key vinylcyclopropane and Cope rearrangement and keto–enol tautomerism (Scheme 7), which was confirmed by their biomimetic conversion from 336 to 337, 338, 342, and 343 by adding a 365 nm ultraviolet lamp and a free radical initiator.^89,173 Chlofortunin A (344) was the first trimer linked by an unprecedented C-15–C-15′ bond.⁸⁹ Inspired by recent biomimetic synthesis,¹⁷⁴ the C linear linkage in these compounds may originate from breaking of the C–C bond by [4 + 2] cycloaddition (Scheme 8).^89,174 Spirolindemer B (345),⁷² as the first example of a homo-trimer through C–C and C–O [4 + 2] cycloaddition, can be recognized as the hybrid of chlotrichene B (253)²⁷ and spirolindemer A (254) and form a complex oxaspiro[4.5]decane and spiro[4.5]decane skeleton.⁷²


	Scheme 7 Biogenetic pathway proposed for 336–344.


	Scheme 8 Another biogenetic pathway proposed for the C linear linkage of 336 and 344.

2.3.1.2 Linear linkage. Sarglalactones A–C (346–348), three LSs monomer connected by 1,3-dioxolane and esterification, were also discovered in S. glabra, which are the only O linear linkage trimers reported to date. They originated from the O linear linkage dimer (286–280) by subsequent esterification between the free COOH-12′ and OH-8′′ or OH-9′′.⁶⁷

2.3.2 Hetero-trimers. Five hetero-trimers, aggreganoids A and B (349–350)³² and linderalides A–D (351–354),³³ have been discovered from L. aggregate recently. The two LSs units of 349 and 350 are connected by methine- or methylene, similar to that of hetero-dimers 324 and 327, which may originate from the endogenous formaldehyde.³²351–354 represent the first examples of disesquiterpenoid–geranylbenzofuranone hybrids directly linked by two C–C bonds.³³ Although only two LS units exist in these compounds, geranylbenzofuranone is the dominant unit, and thus we define them as hetero-trimers.

3 Synthesis of LSs

3.1 Chemical synthesis

The highly complex oxidized polycyclic architectures and intriguing bioactivities of LSs and their oligomers have attracted significant attention from organic chemists; however, they present challenges. The construction of the characteristic cis, trans-3,5,6-carbocyclic skeleton embedded with a sterically congested cyclopentane and complex polycyclic skeletons originating from biomimetic [4 + 2] cycloaddition were the focus in the synthesis of LSs. Also, the configuration of OH-9 is another key but difficult point because all natural oligomers have a sterically hindered β-orientation. Under the guidance of the above-mentioned three key points, more progress in the chemical synthesis of LSs has been achieved in the last fifteen years.

3.1.1 Monomers. The characteristic 5,6-carbocyclic skeleton of LSs is common in natural cyclic terpenoids, but 3- or 3/5-carbocyclic moiety is rare. Thus, using cyclic pseudo-terpenoids with ready-made 6, 5/6, or 6/6 ring systems as starting materials and subsequent cyclopropanation as key steps is a common strategy for the synthesis of an intact 3,5,6-carbocyclic skeleton. Another strategy is de novo synthesis from cheap and commercially available raw materials. Since 2007, nine natural LS monomers have been synthesized, which also lay a solid foundation for the synthesis of diverse LS oligomers.
3.1.1.1 Metal-catalyzed intramolecular cyclopropanation strategy. The use of the common and commercial Hagemann's ester, a pseudo-monoterpenoid with active hexatomic ring, as the starting material and highly diastereoselective metal-catalyzed intramolecular cyclopropanation (Hodgson) was the earliest strategy to construct the challenging cis, trans-3/5/6 tricyclic LS skeleton. In 2007, Baldwin's group first developed this strategy to synthesized epi-lindenene and iso-lindenene (Scheme 9).¹⁷⁵ The introduction of a vinyl group in the hexatomic ring, construction of a furan ring and extension of the formate chain to the 2C unit, resulted in the formation of the key six-membered ring intermediate with adjacent vinyl and ketone chain for intramolecular cyclopropanation. Then, Cu-catalyzed intramolecular cyclopropanation was employed to achieve the cis, trans-3/5/6 tricyclic skeleton of epi-lindenene and iso-lindenene in one step.¹⁷⁵ Unlike Baldwin, Liu's group¹⁷⁶ chose to extend the formate chain to the 3C unit rather than 2C, and Li-catalyzed intramolecular cyclopropanation was used to construct the more complete LS skeleton with Δ¹⁵⁽⁴⁾, avoiding the extra methylation at C-4 to synthesize an exocyclic alkene (Δ¹⁵⁽⁴⁾). Together with aldol reaction and DBU-promoted cyclization, chloranthalactone A (64) was synthesized in 12 steps and 14% overall yield in 2011 (Scheme 9).¹⁷⁶ The synthesis of chloranthalactone B (83), 9-hydroxy heterogorgiolide (22) and shizukanolide E (78) was also accomplished by Liu's group using a similar strategy in 2012.¹⁷⁷ To refine the key step for the extension of the carboxyl chain of Hagemann's ester, Liu's group used verbenone, a natural bicyclic monoterpenoid with an isopropyl bridge (3C unit), as the precursor to efficiently synthesize onoseriolide (66) in 2013, which was the first successful example of Pd-catalyzed intramolecular cyclopropanation of an allylic diazo compound (Scheme 9), and the intramolecular cyclopropanation product (355) with cis, trans-3/5/6 tricyclic skeleton was also an important intermediate in the synthesis of oligomers.¹⁷¹ Alternatively, the CAN-catalyzed construction of the furan ring first and the Rh-catalyzed cyclopropanylation between alkenes and a diazo group was also developed to build an LS monomer (356, 357) by Liu's group in 2019,¹⁷⁸ and they also modified the method of metal-catalyzed cyclization to construct ring B and increase the yield with Me₄NBH(OAc)₃ as the catalyst recently.¹⁷⁹


	Scheme 9 Strategy for the synthesis of LS monomers by metal-catalyzed intramolecular cyclopropanation.

This metal-catalyzed intramolecular cyclopropanation strategy from Hagemann's ester could shorten the number of steps and reduce the difficulty, which was also used and improved by other groups. For example, Lee's group¹⁸⁰ accomplished the synthesis of lindenene with metal Rh and Zografo's group¹⁸¹ reported the synthesis of natural sarcandralactone A (32) using Pt as the catalyst in 2016. Meanwhile, the mechanisms of intramolecular cyclopropanation with Pt(II) and Au(I) salts were studied via DFT methods by the Enrique Gómez-Bengoa group in 2019.¹⁸² The metal-catalyzed intramolecular cyclopropanation strategy provides ideas for the racemic and asymmetric total synthesis of interesting LS monomers and oligomers.

3.1.1.2 Bicyclic pseudo-terpenoids as precursors. Bicyclic pseudo-terpenoids with a 5/6 or 6/6 ring system are closer to the basic skeleton of LSs, which were also used as precursors by several groups. Zhao's group selected chiral (R)-Hajos–Parrish ketone with a 5/6 bicyclic system as the starting material and Simmons–Smith cyclopropanation as the key step to successfully construct a core 3/5/6 tricyclic skeleton (358) and LS intermediate (359) only lacking Δ¹⁵⁽⁴⁾ (Scheme 10).¹⁷⁸ Subsequently, a modified strategy involving Horner–Wadsworth–Emmons reaction, CrO₃-mediated oxidative lactonization, and DDQ-involved oxidative enol-lactonization was used to accomplish the asymmetric total synthesis of chloranthalactone A (64), lindenene (4), shizukanolide (20),¹⁶⁸ and sarcandralactone A (32) (Scheme 10).¹⁸³ Mehta's group also reported the construction of the key intermediate with a 5/6 bicyclic system by RCM reaction and using Simmons–Smith cyclopropanation as the key step to achieve the synthesis of a series of LSs.¹⁸⁴ Besides the 5/6-bicyclc precursor, Peng's group developed a bionic transformation strategy using a Wieland–Miescher ketone with a 6/6-bicyclc skeleton as the starting material. The key step involved S_N2-type intramolecular nucleophilic substitution to construct the cis, trans-3/5/6 tricyclic skeleton (360),¹⁸⁵ together with a wittig reaction or silyl migration and lactonization to build the unsaturated lactone ring of dienophile (361) and diene (362) (Scheme 11).¹⁸⁶ Besides, Snyder's group accomplished the synthesis of sarcandralactone A (32) in 2015 (ref. 187) and lindenatriene in 2019,¹⁸⁸ which also proved the biosynthetic transformation between lindenane and eudesmane. Compared with 5/6-bicyclc, the 6/6-bicyclc precursor can be more concise and efficient, which also supplied useful evidence for the biogenetic relationship between lindenane and eudesmane sesquiterpenoids.


	Scheme 10 Strategy for the synthesis of LS monomers by Zhao's group.


	Scheme 11 Strategy for the synthesis of LS monomers by Peng's group.

3.1.1.3 De novo synthesis strategy. In addition to using cyclic pseudo-terpenoids as starting materials, the strategy of de novo synthesis also was developed. In 2010, Nan's group first constructed the 3/5/6 tricyclic skeleton from butyrolactone with a cyclopropane by using reductive cyclization and an unusual endo-type intramolecular Heck reaction as key steps.¹⁸⁹ However, the configuration of Me-14 was different to natural LSs due to the steric hindrance of cyclopropane. Subsequently, they used copper-catalyzed intramolecular cyclopropanation, oxime and alkene intramolecular cycloaddition as key steps to complete the assembly of shizukaol J.¹⁹⁰ Liu's group also used propionyl chloride and methacrolein as starting materials, and Corey–Chaykovsky cyclopropanation, olefin metathesis, aldol condensation, and Pd-catalyzed Stille coupling as key steps to complete the synthesis of the LS framework with β-orientated hydroxyl C-9 (363–365) (Scheme 12), which were key intermediates in their synthesis of LS oligomers.¹⁹¹


	Scheme 12 De novo synthesis strategy to construct LS monomers by Liu's group.

Compared to the above-mentioned synthetic strategies for LSs, the metal-catalyzed intramolecular cyclopropanation strategy from Hagemann's ester was earliest and widely used. The use of cyclic terpenoids as starting materials can bypass complex reaction steps, and significantly improve the efficiency of synthesis. However, the correct configuration of OH-9 can be constructed by the de novo synthesis strategy, which is advantageous for the synthesis of LS oligomers.

3.1.2 Oligomers. Based on the structural features of reported LS oligomers, polymerization is based on Diels–Alder [4 + 2] cycloaddition catalyzed by potential Diels–Alderase in plants. Thus, the biomimetic Diels–Alder reaction in vitro between appropriate LS precursors with different diene and dienophile units is a common strategy. Meanwhile, the β-configurated OH-9 is another key point in the synthesis of LS oligomers. To date, 18 natural LS oligomers have been synthesized by the Liu and Peng groups.
3.1.2.1 [4 + 2] cycloaddition. According to the aforementioned summary in Section 2, the classical [4 + 2] dimer formed between Δ^15(4),5(6) and Δ^8′(9′) of two LS units occupies the largest proportion. Thus, the construction of a congested oligomeric molecular skeleton through intermolecular [4 + 2] cycloaddition presents a considerable synthetic challenge. Meanwhile, the construction of appropriate LS precursors with diene (Δ^15(4),5(6)) and dienophile (Δ⁸⁽⁹⁾) moieties is also very important, and even critical for the biomimetic Diels–Alder cycloaddition. The cycloaddition cannot work if the reactivity of the Δ^15(4),5(6) diene unit is insufficient; otherwise, auto-polymerization will occur preferentially. Accompanied by diverse post-modification, natural LS dimers can be achieved. The Liu and Peng groups developed different strategies to solve these problems.

Based on the biogenetic hypothesis and their efforts on inverse-electron-demand Diels–Alder reaction toward [4 + 2]-type LS homo-dimers in 2014,¹⁷² Liu's group developed an acid condition catalysis strategy to achieve the first synthesis of the [4 + 2]-type LS dimers shizukaol D (146) and sarcandrolide J (143) in 2017, involving the slow formation of a highly active diene unit (Δ^15(4),5(6)) to avoid its self-polymerization, and the desired dimerization with the dienophile (Δ⁸⁽⁹⁾) proceeded smoothly.¹⁹² In the presence of benzoic acid and heating, the stable precursor 365 with Δ^4(5),6(7) and β-OMOM at C-9 slowly isomerized to the unstable diene 366 with the desired Δ^15(4),5(6), accompanied by the undesirable racemization of OMOM-9. Together with the introduction of the LS dienophile with Δ⁸⁽⁹⁾ (367), the targeted Diels–Alder cycloadducts 368 (14%) and 369 (83%) with α/β-OMOM at C-9 were produced in high yield. After isolation and removal of all the MOM ethers, 370 with the classical [4 + 2] cycloaddition skeleton and correct β-OH-9 was achieved. Subsequently, it underwent Kornblum–DeLaMare rearrangement and esterification, finally producing natural sarcandrolide J (143) and shizukaol D (146) (Scheme 13). To avoid the uncertainty of the configuration of C-9 and synthesis LS dimers with dihydroxy groups at C-4 and C-15, Liu's group developed an alkaline condition catalysis strategy to avoid the acid-promoted exo/endo cyclic alkene isomerization.¹⁹³ In the presence of pyridine and heating, the gradual elimination of OAc-6 in 357 with β-OMOM at C-9 generated the key intermediate diene 371 with Δ^{15(4),5(6),7(8)}, which underwent intermolecular [4 + 2] dimerization with dienophile 372 to form the desired endo-cycloadduct 373 in 74% yield. Subsequent deprotection, photolytic oxidation of the furan and esterification led to sarglabolide I (133), multistalide B (124), shizukaol C (126), shizukaol I (121), and chololactone F (131) (Scheme 14).¹⁹³ This acid- or base-promoted strategy builds a correct and stable [4 + 2]-type molecular skeleton and lays a solid foundation for the total synthesis of other LS dimers.


	Scheme 13 Total synthesis of 143 and 146 by Liu's group in 2017.


	Scheme 14 Total synthesis of 121, 124, 126, 131 and 133 by Liu's group in 2019.

Peng's group also began their research on methods for the polymerization of LS dimers in 2011, where they first employed diverse diene and dienophile precursors to assemble the heptacyclic core of LS dimers.^185,194 After many attempts, they achieved the desired [4 + 2] cycloaddition by preparing and slowly adding a highly active diene (362) to the reaction system in 2018.¹⁸⁶ Their synthesis commenced with a commercial material, i.e., Wieland–Miescher ketone, generating an unstable diene precursor (362) with Δ^{15(4),5(6),7(11)} and α-orientated C8/9-epoxide, and also a stable dienophile with Δ⁸⁽⁹⁾ (64). Under the condition of xylene and heating (160 °C), slowly adding 362 to 64 provided the endo-cycloadduct 375 in 29% yield, and the by-product was the homo-dimerization product of 362. Subsequent methanolysis of 375 afforded 376 with α-orientated OH-9, and oxidation and reduction of OH-9 in 376 inverted the stereochemistry of the secondary alcohol at C-9 to achieve shizukaol A (111) (Scheme 15). Using a similar method, shizukaol E (147) was also obtained.¹⁸⁶ In general, the Liu and Peng groups developed two biomimetic routes to achieve the desirable [4 + 2] cycloaddition and avoid the self-polymerization of the active dienes. Between them, Liu's work had higher productivity, while Peng's work was more biomimetic through the use of natural LSs as precursors.


	Scheme 15 Total synthesis of 111 by Peng's group in 2018.

Based on these structures, other [4 + 2] cycloaddition oligomers may be self-polymerized producers due to the high reactivity of LS precursors with Δ^{15(4),5(6),7(11)} or Δ^{4(5),6(7),11(13)} produced by methanolysis of the n-butenolide moiety. Liu's group attempted to demonstrate that triene is a potential biosynthetic intermediate in the asymmetric total synthesis of other LS [4 + 2] cycloaddition oligomers in 2022. They synthesized 378 using chloranthalactone as the precursor, and after obtaining the triene LS precursor (379) with Δ^{15(4),5(6),7(11)}, the natural endo-[4 + 2] cycloadduct chlotrichene B (253) and artificial 381 were generated by the head-to-head homodimerization of Δ^15(4),5(6) and Δ¹⁵⁽⁴⁾ or Δ^15(4),5(6) and Δ⁷⁽¹¹⁾ in two 379, respectively. Simultaneously, the endo-[4 + 2] head-to-tail heterodimer 382 was also achieved from Δ^15(4),5(6) in 379 and Δ¹¹⁽¹³⁾ in its isomer 380 (Scheme 16).¹⁷⁴ This research provides further inspiration for the biosynthesis and chemical synthesis of various non-classical LS oligomers.


	Scheme 16 Total synthesis of 253 by Liu's group in 2022.

In addition to these homo-dimers, Liu's group also reported their study on bolivianine (305), a hetero-dimer with a glaring heptacyclic skeleton and nine stereogenic centers via the [4 + 2] cycloaddition between LSs and a monoterpene unit in 2013.¹⁷¹ Inspired by the hypothesized pathway, Liu's group accomplished the total synthesis in a 14-step pathway involving in palladium-catalyzed intramolecular cyclopropanation and a Diels–Alder/intramolecular hetero-Diels–Alder cascade reaction as key steps.¹⁷¹ Besides, Peng's group also reported their synthesis of bolivianine (305) and isobolivianine (306) in 2014 (Scheme 17).¹⁷²


	Scheme 17 Total synthesis of 305 and 306 by Liu's group in 2013.

Based on their experience in the successful synthesis of [4 + 2]-type dimers, the synthesis of LS trimers trichloranoid C (339) and trishizukaol A (336) was achieved by Liu's group in 2022 (Scheme 18).¹⁷⁴ In their research, diastereoselective nucleophilic substitution (Pinnick oxidation) between substrates 384 and 363 led to the construction of the quaternary stereogenic center (C-11) of intermediate 385. Subsequently, 386 was obtained by Stille coupling and esterification of 385, and the linear-linkage homo-dimer 272 was generated by subsequent deprotection of MOM ether. Mixing 386 and 371 with benzoic acid and heating led to the formation of the desired Diels–Alder cycloadduct trimer 387. Then, one-pot deprotection at 60 °C produced trichloranoid C (339), which was hydrolyzed with potassium hydroxide and esterified with trimethylsilyl diazomethane to produce trishizukaol A (336) (Scheme 18).¹⁹¹


	Scheme 18 Total synthesis of dimer 272 and trimers 339 and 336 by Liu's group in 2022.

3.1.2.2 [2 + 2] and [6 + 6] cycloaddition. The naturally existing [2 + 2] and [6 + 6]-type LS oligomers have also attracted interest from researchers. Inspired by their biosynthetic pathway, Zhao's group illustrated the application of photocatalysis in [2 + 2]-type dimers, and they accomplished the asymmetric total synthesis of chloranthalactone F (255) in 14 steps from a (R)-Hajos–Wiechert ketone and achieved [2 + 2] cycloaddition by photocatalysis (Scheme 19).¹⁶⁸ Afterwards, Liu's group also accomplished the total synthesis of chloranthalactone F (255) via photocatalysis.¹⁷⁷ In 2022, Liu's group used an ingenious method with simple conditions to achieve the synthesis of the [6 + 6]-type dimer cycloshizukaol A (259) and rearranged product chlorahupetone F (269)through cracking the head to tail endo-[4 + 2] cycloaddition dimer 381 from triene 379 (Scheme 19).¹⁷⁴ This research not only paves the way for the total synthesis of lindenane oligomers and their derivatives, but also indicates that the [6 + 6]-type dimer may be produced via the photocatalytic cleavage and cyclization of [4 + 2]-type dimers.


	Scheme 19 Synthesis of [2 + 2]- and [6 + 6]-type LS oligomers.

3.2 Biomimetic conversion

The conjugated Δ⁸⁽⁹⁾ in LSs not only makes them a good dienophile in cycloaddition, but also have high reactivity in oxidation and cleavage, which may be the biosynthetic pathway of 8,9-seco LSs. Yin's group obtained the 8,9-seco LS monomer chloranerectuslactone V (101), the precursor of dimer chlojapolactone A (286), through biomimetic oxidative conversion from chloranthalactone A (64) in 2015.¹³⁵ Luo's group also reported research on the biomimetic conversion of 8,9-seco LSs and achieved the synthesis of 8,9-seco LS dimers (Scheme 20) in 2019.⁶⁷ The biomimetic oxidative cleavage of chloranthalactone A (64) under O₂ and metal-free conditions generated 8,9-seco LS monomer 388 and chloranerectuslactone V (101), and a subsequent acetal reaction successfully produced dimeric chlojapolactones A–C (286–288) and artifact 389. Recently, Luo's group reported the biomimetic conversion of six LS trimers (336–338 and 341–343) under the condition of a 365 nm ultraviolet lamp and a free radical initiator (Scheme 21).⁸⁹ The keto–enol tautomerism, Cope rearrangement and vinylcyclopropane rearrangement may be the plausible mechanisms in this conversation, which also inspired more ideas about the biosynthesis and chemical synthesis of various non-classical LS oligomers (Scheme 7).


	Scheme 20 Biomimetic conversion of 8,9-seco LSs.


	Scheme 21 Biomimetic conversion of LS trimers.

3.3 Biosynthesis

In the past decade, initial studies on the biosynthesis of LSs have been conducted and preliminary achievements have been obtained, mainly including genome and transcriptome sequencing and establishing biosynthesis platforms. In 2020, the transcriptome of L. aggregate was sequenced and de novo assumed, and a total of 119 [thin space (1/6-em)]

255 predicted coding sequences was obtained.¹⁹⁵ In the same year, differentially expressed genes of S. glabra under three LED light conditions were identified by transcriptomic profiling.¹⁹⁶ One year later, transcriptome sequencing of S. glabra and S. glabra ssp. Brachystachys was conducted using the Illumina HiSeq X Ten platform, and differentially expressed genes of terpenoid backbone biosynthesis were revealed by KEGG pathway analysis.¹⁹⁷ In 2021, a high-quality chromosome-level C. sessilifolius genome was assembled by combining nanopore, illumina, and Hi-C sequencing and the genes related to the synthesis of sesquiterpenes were further identified.¹⁹⁸ In the same year, a high-quality chromosome-level genome of C. spicatus was assembled and the genes of the sesquiterpenes synthases were predicted.¹⁹⁹ Additionally, the complete chloroplast genome of S. glabra,^200,201C. henryi,²⁰²C. spicatus,²⁰³ and L. aggregate²⁰⁴ and the complete plastid genome sequence of C. fortunei were reported.²⁰⁵ The establishment of a biosynthesis platform is the basis for biosynthesis research on plant natural products. In 2021, the callus platform of S. glabra, which can biosynthesis the LS chloranthalactone A under ultraviolet-B radiation stress, was established.²⁰⁶ In summary, the above-mentioned studies fill the gap in research on the biosynthesis of LSs and provide a valuable foundation for further research.

4 Biological activities

LSs are mainly distributed in plants from the Chloranthaceae family and Lindera genus, which are widely used to treat arthritis and traumatic injuries, promote blood circulation and relieve pain in China.⁹¹ Previous studies on LSs mainly focused on the discovery of novel scaffolds and active compounds, whereas research on their biological activity mechanism have been flourishing in recent years. Modern pharmacological studies have shown that LSs possess various biological activities, such as anti-inflammation, antitumor, anti-infection, regulation of glucose metabolism, and inhibition of potassium ion channels (Fig. 7).


	Fig. 7 Main biological activity of LSs in different plant resources.

4.1 Anti-inflammatory activity

Based on the traditional efficacy of Chloranthaceae plants, the anti-inflammatory activity of LSs has been studied widely. LSs can inhibit the release of inflammatory factors, inhibit the expression of cell adhesion factors, and reduce the antioxidant stress of inflammatory mediators. In the following section, the anti-inflammatory activity of LSs will be summarized into immunoinflammation, neuroinflammation, and periodontal inflammation.

4.1.1 Immunoinflammation. LSs showed inhibitory activity against NO, TNF-α, IL-1β, and IL-6 release by targeting MKK3/6,²⁰⁷ HMGB1,⁴¹ and TRAF6 (ref. 208) in RAW 264.7 cells (Fig. 8). The LS monomers chlojaponilactone B (65) and chloranthalactone B (83) inhibited the NO level to suppress inflammation. Chlojaponilactone B (65) could inhibit the nuclear translocation of NF-κB, the expression of iNOS, and the levels of inflammatory cytokines, thus improving the symptoms of ear swelling and the level of neutrophil infiltration,²⁰⁹ and also blocked the activation of TLR4 and MyD88, thereby reducing ROS production.²¹⁰ Chloranthalactone B (83) inhibited the levels of NO, TNF-α, and IL-1β, and inhibited the phosphorylation levels of MAPK signaling pathway proteins by targeting MKK3/6.²⁰⁷ LS dimer linderolides A–F showed NO production and cell growth inhibition activity.²¹¹ LS dimers shizukaol D (146) and shizukaol A (111) inhibited the nuclear translocation of NF-κB. Shizukaol D (146) improved the activity of SOD and GSH peroxidase by up-regulating the AKT/Nrf2/HO-1 signaling pathway.²¹² Shizukaol A (111) inhibited oxidative stress damage by targeting HMGB1 to up-regulate the Nrf2/HO-1 signaling pathway.⁴¹ The LS trimer trishizukaol A (336) could effectively inhibit the levels of IL-6, ROS, and TNF-α, and promote the level of IL-10 by targeting TRAF6.²⁰⁸


	Fig. 8 Targets for the anti-inflammatory activity of LSs.

4.1.2 Neuroinflammation. LSs are also effective against neuroinflammation. LS dimers shizukaol B (169), shizukaol C (126), chloramultilide A (104), and spicachlorantin G (195) showed great antineuroinflammatory activity by inhibiting the production of NO in BV2 cells,^213–215 especially, shizukaol B (169) inhibited the secretion of IL-1β and the expression of JNK, NOS, and COX-2 and blocked the DNA binding activity of AP-AP-1 to relieve neuroinflammation.²¹³ Lindenenyl acetate (2) effectively prevented glutamate-induced oxidative damage and showed strong neuroprotective effects against glutamate-induced neurotoxicity by inducing HO-1 expression in mouse hippocampal HT22 cells.²¹⁶

Besides, LSs are also effective against periodontal inflammation. LS lindenenyl acetate (2) suppressed the responses of PGE2 and proinflammatory cytokines, an upregulated P-AMPK and its upstream kinase activator, indicating its anti-inflammatory activity in human periodontal ligament cells.²¹⁷ The above-mentioned studies on anti-inflammatory activity not only provide more evidence for LSs and its oligomers as materials in Chloranthaceae plants, but also their potential to be developed as anti-inflammatory drugs.

4.2 Antitumor activity

Malignant tumors are harmful to human health, and thus the discovery of new antitumor drugs is necessary. In recent years, it was found that LSs show good antitumor activity in liver cancer, gastric cancer colon cancer, and leukemic cells. The therapeutic effects of LSs are mainly achieved by promoting cell apoptosis, inhibiting tumor cell migration, and inhibiting cell proliferation (Fig. 9). However, most studies only remained at the screening level, and thus deep antitumor mechanism investigations are needed in the future.


	Fig. 9 Antitumor activity of representative LSs.

4.2.1 Promoting apoptosis and inhibiting migration. By promoting cell apoptosis and inhibiting cell migration, LSs inhibit the proliferation of various cancers, such as liver cancer, leukemia, and breast cancer. Shizukaol D (146) induced apoptosis in SMMC-7721 and SK-HEP1 cells by modulating the Wnt signal pathway.²¹⁸ Shizukaol F (170), shizukaol B (169), and cycloshizukaol A (259) have antitumor cell migration activity and could inhibit the PMA-induced aggregation of HL-60 cells.⁴⁴ Sarglalactone D (287) decreased the expression level of HMGB1 to doxorubicin-resistant strains of MCF-7 cells.⁶⁷ Shizukanolides E and F (78 and 76) showed remarkable antimetastasis breast cancer activity.²¹⁹

4.2.2 Inhibiting cell proliferation. By inhibiting cell proliferation, LSs inhibit the development of various cancers such as leukemia, liver cancer, and stomach cancer. Shizukaol D (146) has significant antitumor activity, which could inhibit the proliferation of HepG2 cells by regulating β-catenin.²¹⁸ Shizukaol C (126) inhibited not only HepG2, but also MGC803 and HL-60 cells by inhibiting their proliferation.¹²⁴ Chlotrichene A (252) and chlotrichene B (253) exhibited good inhibitory effects on U2OS cells.²⁷ Also, sarcandrolide F (210) and sarcandrolide H (208) inhibited the proliferation of HL-60 cells significantly.¹¹⁶

4.3 Anti-infective activity

LSs are mainly isolated from Chloranthaceae plants, which are often used to treat infections caused by bacteria and fungi.^220,221 Recent studies found that LSs and their oligomers have a significant anti-infective effect, including bacterial, fungal, and viral infections. Importantly, the antiplasmodium efficacy of 13′-O-methyl succinylshizukaol C (129) was much stronger than artemisinin,⁵⁰ which provides a good candidate for the development of antimalarial drugs.

4.3.1 Antiplasmodium. Malaria is a mortal infectious disease transmitted by the bite of plasmodium mosquitoes, which is difficult to treat and progresses rapidly because of the resistance to quinine and artemisinin.²²² The antiplasmodium activity of LS dimers has attracted attention from Yue's group, who was also interested in the discovery of LSs from Chloranthaceae plants. In 2017, they found that chololactone F (131) had a significant antimalarial effect with an IC₅₀ of 1.1 ± 0.2 nM (artemisinin IC₅₀ = 4.0 ± 4.2 nM),⁴⁷ which is the powerful natural product with antimalarial activity. The LS dimer fortunilide A (138) and sarglabolide J (134) were also found to show significant antimalarial activity with IC₅₀ of 5.2 ± 0.6 nM and 7.2 ± 1.3 nM, respectively.⁴⁹ It is worth mentioning that 13′-O-methyl succinylshizukaol C (129) (IC₅₀ = 4.3 pM) was reported to show about 1000-fold stronger antimalarial activity than artemisinin in 2021.⁵⁰ The SARs of antiplasmodial LS dimers through in-depth analysis of their antimalarial activities and structural features were also summarized by this group (Fig. 10), which indicated that changes in the substitution groups at C-13′ and C-15′ will influence the antimalarial activity significantly, indicating that they are very important modification sites.⁵⁰ Therefore, LSs can be a potential source for antimalarial candidates.


	Fig. 10 Structure of 129 and brief SAR of antiplasmodial LS dimers.

4.3.2 Antivirus, antibacteria, and antifungus. In recent years, LS dimers have also been found to inhibit viral replication, particularly against HIV. The LS dimers chlorajaponilides F (211) and G (213) could significantly inhibit the replication of wild-type HIV-1 with an EC₅₀ of 3.08–17.16 μM.¹⁵⁸ Shizukaol F (170) had inhibitory activity against HIV-1 replication and could inhibit the production of HIV-1 retro-transcriptional products LTR/Gag, and specifically inhibit the activity of RNase H.²²³ Shizukaol A (111) showed significant antiviral activity against SARS-CoV-2 by inhibiting the activity of nsp14, which is a key component of the replication–transcription process that facilitates the life cycle of SARS-CoV-2.²²⁴ These results indicate that LSs have a significant inhibitory effect on viruses, but their mechanism needs to be further studied.

In terms of antibacterial and antifungal activity, LSs also have good inhibitory effects. Shizukaol C (126), shizukaol F (170), and chlorahololide D (122) showed strong antifungal activity against a variety of plant pathogenic fungi in vitro. Among them, chlorahololide D (122) showed the strongest antifungal activity (MICs = 1–32 μg mL⁻¹) in vitro against various phytopathogenic fungi such as Alternaria kikuchiana, Botrytis cinerea, Colletotrichum lagenarium, Magnaporthe grisea, Pythium ultimum, and Phytophthora infestans.²²⁰ Shizukaol C (126) and shizukaol F (170) showed weaker inhibitory activity against Fusarium oxysporum and Solanaceae solanacearum.²²¹ Linderene (5) and linderene acetate (6) showed significant PEP inhibitory activity in flavobacterium and some competitive inhibitory activity against PEP in the supernatant of Flavobacterium and rat brain.²²⁵ These results indicate that LSs may be the material basis for the antibacterial and antifungal effect of Chloranthaceae herbs.

4.4 Other activity

In addition to the above-mentioned activities, LSs have also been reported to inhibit potassium ions, regulate metabolism, and analgesic activities. The abnormal function of potassium channels has been implicated in atrial fibrillation,²²⁶ epilepsy,²²⁷ and Alzheimer's disease,^228,229 and the effects of LSs on potassium channels have been discovered in recent years. Chlorahololides A (188) and B (229) exhibited potent inhibition on the delayed rectifier K⁺ current, suggesting that LS can regulate body homeostasis by inhibiting K⁺ efflux.¹⁵¹ In addition, chlorahololides C–F (189, 122, 214, and 222, respectively) could effectively delay K⁺ channels.¹⁴⁰ The above-mentioned reports indicate that LSs are promising candidates for the treatment of K⁺ channel disorders. LSs also can regulate cell metabolism and maintain cell homeostasis. Shizukaol F (170) regulated glucose metabolism and promoted depolarization of mitochondrial membranes by inhibiting AMPK.²³⁰ In addition, shizukaol D (146) alleviated liver metabolic diseases by inhibiting energy production in mitochondria and impeding the AMPK pathway.²³¹ Chlospicenes A (270) and B (271) showed significant antinonalcoholic steatohepatitis activity in free fatty acid-induced HepG2 cells by decreasing intracellular lipid accumulation.⁷⁴ These results indicate that LSs can be used as lead compounds to regulate glucose metabolism and liver metabolism. LSs also have analgesic effects, for example, onoseriolide B (13-hydroxy-8,9-dehydroshizukanolide) (66) exhibited dose-related antinociception in a chemical model of nociception in mice.²³²

The above-mentioned findings indicate that LSs have good and diverse biological activities, which also have potential as drug candidates for anti-inflammation, antitumor, and anti-infection drugs; however, further deep studies about their mechanism and safety are needed in the future.

5 Conclusions and prospect

Despite being a small subset of sesquiterpenoids in structure and distribution, the research interest in LSs and their oligomers in the field of natural products is growing due to the fantastic skeletons originating from the highly conjugated LS structural fragments. To date, 354 LSs and their oligomers with diverse skeletons have been reported from plants from the Lauraceae, Chloranthaceae, Asteraceae, and Cyperaceae families, together with the marine animal gorgonian corals, and 2/3 exist as diverse oligomers, seven of which were selected as “hot off the press” in Nat. Prod. Rep. Considering the reported structures, the Diels–Alder [4 + 2] cycloaddition between two LSs with dienes or dienophiles is prone to forming various types of homo-[4 + 2] cycloaddition oligomers, and the most popular type was the Diels–Alder reaction between Δ^15(4),5(6) and Δ^8′(9′). Meanwhile, the discovery of hetero-oligomers of LS and other active fragments, such as O₂, formaldehyde, monoterpene, and phenylacetic acid derivatives with active methylate, further enhanced the diversity of LS oligomers. Due to the presence of diverse double bond or conjugated fragments, the diverse rearrangements from the biradical of the vinylcyclopropane and cyclopropylcarbinyl also further enhanced the potential of structural diversity and novelty of LSs and their oligomers. Considering the above-mentioned three main aspects, i.e., precursors, polymerized type, and further rearrangements, it is expected that LSs and their oligomers will be a gold mine for the discovery of natural products with unprecedented carbon skeletons.

The distinctive molecular structure and diverse polymer types of LSs offer great possibilities as molecular templates to synthetic chemists, while simultaneously posing significant challenges. In particular, their synthesis has witnessed a breakthrough over the past decade. However, although more than 20 molecules have been synthesized, the process is quite lengthy and their synthesis at the gram level still has to be achieved, which limits their practical applications. Furthermore, it is possible to achieve diverse synthesis using different strategies and a variety of precursors, guided by biological sources for pharmacological and biological activity research. In addition, there are few studies on the structure modification of LSs based on activity, which is also a worthy direction for future research. Compared with chemical synthesis, the biosynthesis of LSs is still a blank except for several studies about the genome of the Chloranthaceae plant. The vast majority of oligomers are [4 + 2] cycloaddition type between Δ^15(4),5(6) and Δ^8′(9′) of two LS moieties and further formed macrolides, which should be catalyzed by Diels–Alderase and specific acyltransferase in Chloranthaceae plants. Thus, Diels–Alderase catalyzing the [4 + 2] cycloaddition framework of LS dimers and acyltransferase catalyzing the macrolide in related plants offer great potential and significance to investigate. These enzymes will provide more prospects and strategies in utilizing synthetic biological methods to achieve the synthesis of bioactive LS oligomers.

At present, LSs exhibit significant structural specificity and a wide range of biological activities, such as antitumor, anti-inflammation, and antimalarial effects. However, research is mainly focused on activity screening, and further investigation into their mechanisms is necessary. Given that medicinal plants rich in LSs are primarily used to treat inflammatory diseases, it is essential to conduct more in-depth research into their anti-inflammation mechanisms and targets. Moreover, inflammation is closely linked to tumorigenesis and metabolic regulation, highlighting the potential impact of research in this area. Currently, no drugs containing LSs are available for clinical use or undergoing clinical trials, but it is anticipated that breakthroughs will be made shortly.

In conclusion, LSs and their oligomers possess great potential and prospects in the discovery of novel and bioactive natural products, new chem-synthesis methods, novel Diels–Alderase and acyltransferase reactions, and lead compounds for antimalarial, antitumor, and anti-inflammatory innovative drugs, which deserve more attention from researchers in the field of natural products.

6 Author contributions

Prof. L. Y. Kong and J. Luo are mainly responsible for the conception, organization and revision of this review and also gaining the fundings. The structures of reported natural LSs part was mainly organized and wrote by D. Y. Zhang. The biological activity part was mainly contributed by P. F. Tang. N. Wang mainly conducted literature research, summarizing of part structures and prepared the ESI.† The synthesis part was mainly contributed by S. Zhao.

7 Conflicts of interest

There are no conflicts of interest to declare.

8 Acknowledgements

The research was supported in part by the National Natural Science Foundation of China (32070389) and the “Double First-Class” University Project of China Pharmaceutical University (CPU2022QZ29). The 111 Project from Ministry of Education of China (B18056). We appreciate Yuhang Zhou and Dr Chunhua Han from China Pharmaceutical University for their contributions to this manuscript.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: https://doi.org/10.1039/d3np00022b