Introduction

Classical lignans consist of two C6–C3 units joined by a direct C8–C8′ carbon–carbon bond. On the basis of this shared linkage, different lignans vary in the oxidation states of oxygen-containing functional groups on their side chains, intramolecular C–O linkages, and additional C–C linkages. These differences can alter the ring systems, oxidation states, and degrees of unsaturation of the molecules, giving rise to lignan skeletons such as the dibenzylbutane, tetrahydrofuran, furofuran, dibenzylbutyrolactone, aryltetralin, arylnaphthalene, and dibenzocyclooctadiene types.[1,2]

These structural types share the same 8–8′ linkage but differ in their modes of cyclization and side-chain oxidation states. C–O cyclization primarily changes the number of oxygen-containing rings; side-chain oxidation can generate lactols or lactones; and the formation of additional C–C bonds alters the extent of carbon-skeleton cyclization and the conjugated system. These three classes of structural variables constitute the principal chemical basis for the skeletal diversity of 8–8′ lignans. The terms “cyclization,” “oxidation,” and “aromatization” used in this article summarize the formal structural relationships among different skeletons and do not imply that all classes of lignans are sequentially converted through the same linear biosynthetic pathway.

1. Major Structural Variables in the 8–8′ Skeleton

1.1 The C8–C8′ Linkage Constitutes the Common Skeletal Basis

In the nomenclature system of the International Union of Pure and Applied Chemistry (IUPAC), the direct C8–C8′ linkage between two C6–C3 units is an important structural basis of the fundamental lignan parent skeleton. The subsequent introduction of oxygen-containing rings, lactones, or new carbocyclic rings represents further structural modification of this fundamental parent skeleton.[1]

Although secoisolariciresinol, lariciresinol, pinoresinol, matairesinol, podophyllotoxin, and the dibenzocyclooctadiene lignans found in Schisandra differ markedly in their ring systems, they all retain the 8–8′ linkage.[2]

1.2 C–O Cyclization, Side-Chain Oxidation, and C–C Cyclization Generate Different Skeletons

The principal structural changes in 8–8′ lignans can be summarized in three categories:

These structural changes are not mutually exclusive. For example, an aryltetralin structure may also contain a lactone, whereas a dibenzocyclooctadiene lignan contains both the original 8–8′ bond and an additional C–C bond between the aromatic rings.

2. C–O Cyclization and the Formation of Tetrahydrofuran and Furofuran Skeletons

2.1 Structural Relationship Between the Open-Chain Dibenzylbutane Type and Oxygen-Containing Ring Skeletons

Secoisolariciresinol is a representative open-chain 8–8′ lignan. Its two aromatic units are connected by a side chain containing the C8–C8′ bond, and the side chain contains no intramolecular ether ring. Compared with tetrahydrofuran- and furofuran-type lignans, it therefore has more rotatable single bonds and greater conformational freedom.

Compared with open-chain structures, oxygen-containing ring skeletons restrict molecular conformational freedom through intramolecular C–O linkages in the side chain. In a pathway validated in Forsythia intermedia, for example, NADPH-dependent pinoresinol–lariciresinol reductase (PLR) catalyzes the sequential reduction of (+)-pinoresinol to (+)-lariciresinol and then to (−)-secoisolariciresinol, causing the corresponding oxygen-containing rings to undergo successive reductive ring opening.[13]

2.2 One C–O Ring Forms a Tetrahydrofuran-Type Lignan

Compounds such as lariciresinol contain one additional intramolecular ether ring on the 8–8′ linkage framework, thereby forming tetrahydrofuran-type lignans. In traditional natural medicinal chemistry, structures of this type are often referred to as “monoepoxy lignans.”[3]

2.3 Two C–O Rings Form a Furofuran Skeleton

When two related C–O linkages form within the 8–8′ skeleton, a furofuran-type lignan can result. Pinoresinol, syringaresinol, and sesamin all belong to this structural system.[2]

The two oxygen-containing rings further rigidify the side chain and also generate multiple stereocenters. Different substituents and stereochemical configurations can give rise to numerous isomers.

3. Side-Chain Oxidation and the Dibenzylbutyrolactone Skeleton

3.1 Oxidation of Terminal Hydroxymethyl Groups Raises the Side-Chain Oxidation State

The terminal C9/C9′ hydroxymethyl groups of open-chain 8–8′ lignans can undergo further oxidation. One terminal hydroxymethyl group is first oxidized to an aldehyde, which then undergoes intramolecular cyclization with the other terminal hydroxyl group to form a five-membered lactol intermediate. Further oxidation of this intermediate produces a γ-lactone. This process raises the oxidation state of the corresponding terminal carbon and closes the open side chain into a five-membered ring.

Matairesinol is a typical representative of this structural transformation. NAD⁺-dependent secoisolariciresinol dehydrogenase (SDH) can catalyze, in an enantioselective manner, the conversion of secoisolariciresinol into matairesinol through a lactol intermediate.[4,5]

3.2 Lactonization Alters Both the Oxidation State and Conformational Freedom

Lactone formation not only adds a ring but is also accompanied by pronounced functional-group changes:

① The carbon associated with the primary alcohol is converted to a higher oxidation state;

② A carbonyl C=O group appears;

③ A cyclic ester is formed intramolecularly;

④ The originally more flexible side chain is fixed into a five-membered ring.

Therefore, the distinction between the dibenzylbutane and dibenzylbutyrolactone types fundamentally results from the combined effects of an increased side-chain oxidation state and intramolecular cyclization.[6]

Matairesinol, arctigenin, hinokinin, and yatein are representative members of this skeletal class.

4. Additional C–C Cyclization and the Formation of Aryltetralin and Arylnaphthalene Skeletons

4.1 A Second C–C Bond Changes the Topology of the 8–8′ Skeleton

After the C8–C8′ bond establishes the fundamental coupling between the two C6–C3 units, the aromatic ring can form an additional C–C bond with the side chain of the other unit. This new carbon–carbon linkage converts an open dibenzylbutane-related structure into a six-membered carbocyclic ring, thereby producing a cyclolignan skeleton.[1,2]

This change differs from the C–O cyclization of tetrahydrofuran-type lignans:

C–O cyclization primarily establishes an oxygen-containing ring;

Formation of an additional C–C ring directly changes the topology of the carbon skeleton and produces tetralin- or naphthalene-related ring systems.

The six-membered ring formed through cyclization can also have different degrees of unsaturation, thereby giving rise to aryltetralin-, aryldihydronaphthalene-, and arylnaphthalene-related structures.

Figure 1. Structural comparison of aryltetralin, aryldihydronaphthalene, and arylnaphthalene skeletons among 8–8′ cyclolignans.[3] All three skeletons feature a six-membered carbocyclic ring formed through an additional C–C cyclization; their principal difference lies in the degree of unsaturation of this ring system. The aryltetralin type on the left is more highly hydrogenated, the aryldihydronaphthalene type in the center contains one additional unsaturated bond, and the arylnaphthalene type on the right contains an aromatic naphthalene ring.

4.2 The Degree of Unsaturation Alters the Conjugated System and Three-Dimensional Structure

The aryltetralin type contains more sp³ carbon atoms; its ring system can generate multiple stereocenters, giving the molecule a pronounced three-dimensional structure. As the degree of unsaturation increases, the proportion of sp² carbon atoms in the aryldihydronaphthalene skeleton rises.

The arylnaphthalene type further develops an aromatic naphthalene system, substantially extending π conjugation, while correspondingly reducing the three-dimensional structural features generated by multiple saturated stereocenters.

Modern reviews of lignans generally list the aryltetralin and arylnaphthalene types as major classical skeletons; the aryldihydronaphthalene type represents a partially unsaturated cyclolignan skeleton intermediate between the two.[2]

5. Aryltetralin Lactones and the Podophyllotoxin Skeleton

5.1 C–C Cyclization and a Lactone Can Coexist

Aryltetralin and dibenzylbutyrolactone are not mutually exclusive structural features. A lignan molecule can contain both a carbocyclic ring formed through additional C–C cyclization and a side-chain lactone.

Podophyllotoxin is a typical aryltetralin lactone lignan. Its core structure retains the fundamental 8–8′ linkage and also contains a six-membered carbocyclic ring formed through additional C–C bond formation, a γ-lactone, and multiple contiguous stereocenters.

This skeleton combines carbocyclic ring construction, lactone formation, and stereochemical control within a single molecule and has long been a focus of research on the synthesis of aryltetralin lignans.

5.2 Selective C–C Cyclization Can Be Used to Prepare the Podophyllotoxin Skeleton

Studies of podophyllotoxin-related biosynthesis have identified enzymes capable of catalyzing the key oxidative cyclization. In a chemoenzymatic route, Li, Zhang, and Renata used the 2-oxoglutarate-dependent non-heme dioxygenase deoxypodophyllotoxin synthase (DPS) to catalyze intramolecular oxidative C–C coupling of (−)-yatein, converting it into (−)-deoxypodophyllotoxin and thereby constructing the aryltetralin core. This enzymatic reaction can also be used to synthesize several related aryltetralin lignans.[7]

In addition to enzymatic oxidative cyclization, Yin et al. reported in 2025 that 5-alkenyl malonates can first undergo conformation-assisted I₂-mediated radical C(sp³)–H iodocarbocyclization, followed by lactonization, thereby constructing the aryltetralin lactone skeleton. This strategy was used in the asymmetric total synthesis of nine cyclolignans of this class.[8]

6. C–C Bond Formation Between Aromatic Rings and the Dibenzocyclooctadiene Skeleton

6.1 An Interaromatic Linkage Is Added in Addition to the Original 8–8′ Bond

Dibenzocyclooctadiene lignans are also commonly referred to as biphenyl cyclooctene lignans in traditional Chinese medicinal chemistry sources.[2,3]

This skeleton retains the C8–C8′ linkage while also forming a direct C–C bond between the two aromatic rings, thereby closing into a conformationally restricted eight-membered carbocyclic ring system; its fundamental parent skeleton remains an 8–8′ lignan.

Figure 2. Basic skeleton of dibenzocyclooctadiene lignans and the representative structure of γ-schisandrin.[3] The left side shows the dibenzocyclooctadiene skeleton formed collectively by the two aromatic rings and the side chain associated with the 8–8′ linkage. On the right, γ-schisandrin has the typical skeleton of this class together with multiple oxygen-containing substituents, including methoxy and methylenedioxy groups. γ-Schisandrin (γ-schizandrin) is also a commonly used synonym for Schisandrin B.

Following formation of the eight-membered ring, the substitution patterns of the aromatic rings, the biaryl-axis torsion angle, and the conformation of the eight-membered ring jointly determine the molecule’s three-dimensional structure. Restricted rotation can also produce stable axial chirality; consequently, Schisandra lignans are an important system for studying axial chirality, conformation, and stereoselectivity.

6.2 Structural Distinction from Biphenyl-Type Neolignans

Biphenyl-type neolignans such as magnolol and honokiol lack the fundamental 8–8′ linkage; their two C6–C3-related units are connected by a direct C–C bond between the aromatic rings.

Dibenzocyclooctadiene lignans, in contrast, contain both:

an 8–8′ linkage + an additional C–C linkage between the aromatic rings.

Both structural classes may contain a biaryl moiety, but their fundamental linkage relationships differ.

7. Research Questions Associated with Skeletal Construction

7.1 Cyclolignan Synthesis Focuses on the Efficiency and Selectivity of C–C Cyclization

One of the central challenges in the synthesis of aryltetralin and arylnaphthalene lignans is the efficient construction of the second C–C bond in addition to the 8–8′ framework.

In 2026, Vasiutovich et al. reported that allylbenzenes can first undergo Ru-catalyzed olefin metathesis to generate 1,4-diaryl-2-butenes, followed by DDQ-mediated oxidative cyclization promoted by methanesulfonic acid or FeCl₃ to construct arylnaphthalene cyclolignans. A representative arylnaphthalene product could then be converted into an aryltetralin derivative through selective Birch reduction. This strategy links construction of the 8–8′ bond with subsequent oxidative cyclization and provides a short chemical synthetic route for forming the second C–C bond of cyclolignans.[9]

7.2 Unresolved Steps Remain in the Biosynthesis of the Dibenzocyclooctadiene Skeleton

The complete pathway by which dibenzocyclooctadiene lignans are formed in Schisandra has not yet been fully elucidated.[12]

Qiang et al. identified the coniferyl alcohol acyltransferase ScCFAT in Schisandra chinensis and demonstrated that it can catalyze the acetylation of coniferyl alcohol, providing experimental evidence for an early precursor transformation in the proposed pathway.[10]

A subsequent study identified the isoeugenol synthase ScIGS1 and confirmed its activity in catalyzing the formation of isoeugenol in a heterologous Escherichia coli system. However, direct enzymological evidence is still lacking as to whether and how isoeugenol proceeds into the formation of dibenzocyclooctadiene lignans.[11]

The key current questions center on:

① Which enzymatic system establishes the key C–C bond between the aromatic rings;

② How the regioselectivity and stereoselectivity of the eight-membered ring are controlled;

③ The sequence of subsequent modifications, including methoxylation and methylenedioxy formation;

④ How the complete skeleton can be reconstructed in a heterologous system.

These questions directly connect research in natural-product biosynthesis, enzyme engineering, and synthetic biology.

8. Structural Relationships Among the Major 8–8′ Lignan Skeletons

9. Classification, Structural Features, and Research Applications of Representative Chemicals with the Major 8–8′ Lignan Carbon Skeletons

Table 1. Open-Chain, Tetrahydrofuran-Type, and Furofuran-Type 8–8′ Lignans

Table 2. Dibenzylbutyrolactone-, Aryltetralin Lactone-, and Arylnaphthalene Lactone-Type 8–8′ Lignans

Table 3. Dibenzocyclooctadiene-Type 8–8′ Lignans

Note: The products listed above are representative Aladdin products relevant to scientific research. Their specific uses should be determined in accordance with the product specifications, batch certificate of analysis (COA), and the intended reaction or evaluation system. Additional information on product specifications, grades, and COAs can be retrieved from the Aladdin website using the “product name/CAS number/product number.” The product names Secoisolariciresinol, Pinoresinol, and Matairesinol correspond, respectively, to the same compounds referred to under alternative Chinese names in the main text.

References

[1] Moss GP. Nomenclature of Lignans and Neolignans (IUPAC Recommendations 2000). Pure and Applied Chemistry. 2000, 72(8): 1493–1523. doi:10.1351/pac200072081493.

[2] Teponno RB, Kusari S, Spiteller M. Recent advances in research on lignans and neolignans. Natural Product Reports. 2016, 33: 1044–1092. doi:10.1039/C6NP00021E.

[3] Fan K, ed. Illustrated New Thinking: Chemistry of Traditional Chinese Medicine. Beijing: Chemical Industry Press, 2023. ISBN 978-7-122-41829-6.

[4] Xia ZQ, Costa MA, Pelissier HC, Davin LB, Lewis NG. Secoisolariciresinol dehydrogenase purification, cloning, and functional expression: implications for human health protection. Journal of Biological Chemistry. 2001, 276(16): 12614–12623. doi:10.1074/jbc.M008622200.

[5] Moinuddin SGA, Youn B, Bedgar DL, et al. Secoisolariciresinol dehydrogenase: mode of catalysis and stereospecificity of hydride transfer in Podophyllum peltatum. Organic & Biomolecular Chemistry. 2006, 4: 808–816. doi:10.1039/B516563F.

[6] Runeberg PA, Brusentsev Y, Rendon SMK, Eklund PC. Oxidative transformations of lignans. Molecules. 2019, 24(2): 300. doi:10.3390/molecules24020300.

[7] Li J, Zhang X, Renata H. Asymmetric chemoenzymatic synthesis of (−)-podophyllotoxin and related aryltetralin lignans. Angewandte Chemie International Edition. 2019, 58: 11657–11660. doi:10.1002/anie.201904102.

[8] Yin R, Wang X, Zhou R, Zhu L, Huang J. Unified asymmetric synthesis of aryltetralin lactone cyclolignans via conformation-assisted radical C–H cyclization. JACS Au. 2025, 5: 5690–5697. doi:10.1021/jacsau.5c01176.

[9] Vasiutovich K, Fadeev AA, Čambal P, Matoušová E. Dimerization of allylbenzenes into cyclolignans by a metathesis-oxidation sequence. Journal of Organic Chemistry. 2026, 91: 3669–3676. doi:10.1021/acs.joc.5c02949.

[10] Qiang TY, Liu JS, Dong YQ, et al. Identification, molecular cloning, and functional characterization of a coniferyl alcohol acyltransferase involved in the biosynthesis of dibenzocyclooctadiene lignans in Schisandra chinensis. Frontiers in Plant Science. 2022, 13: 881342. doi:10.3389/fpls.2022.881342.

[11] Qiang T, Chen Y, Li B, et al. Transcriptome-wide analysis of PIP reductase gene family identified a phenylpropene synthase crucial for the biosynthesis of dibenzocyclooctadiene lignans in Schisandra chinensis. Synthetic and Systems Biotechnology. 2024, 9(1): 78–87. doi:10.1016/j.synbio.2023.11.011.

[12] Jafernik K, Motyka S, Calina D, Sharifi-Rad J, Szopa A. Comprehensive review of dibenzocyclooctadiene lignans from the Schisandra genus: anticancer potential, mechanistic insights and future prospects in oncology. Chinese Medicine. 2024, 19: 17. doi:10.1186/s13020-024-00879-0.

[13] Dinkova-Kostova AT, Gang DR, Davin LB, Bedgar DL, Chu A, Lewis NG. (+)-Pinoresinol/(+)-lariciresinol reductase from Forsythia intermedia: protein purification, cDNA cloning, heterologous expression and comparison to isoflavone reductase. Journal of Biological Chemistry. 1996, 271(46): 29473–29482. doi:10.1074/jbc.271.46.29473.

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