Abstract

Once the two-dimensional connectivity of lignans is established, their three-dimensional structures can still differ substantially as a result of tetrahedral stereocenters, restricted biaryl rotation, and changes in ring conformation. Whether a tetrahedral carbon constitutes a stereocenter depends on whether its attached substituents can be distinguished from one another. Multiple stereocenters further give rise to enantiomers, diastereomers, and meso forms; erythro/threo descriptors express the relative configuration of two stereocenters in certain acyclic structures but cannot replace the R/S designation of absolute configuration. Dibenzocyclooctadiene lignans additionally exhibit axial chirality arising from restricted rotation about the biaryl bond, and their axial configuration and eight-membered-ring twist-boat-chair and twist-boat conformations belong to different levels of stereochemical organization. Recent studies have further shown that some dibenzocyclooctadiene lignans do not maintain a single ring conformation but undergo dynamic exchange between different conformations. Central configuration, axial configuration, and conformational freedom together determine the actual three-dimensional arrangement of lignan molecules.

Keywords: lignans; central chirality; stereocenter; axial chirality; diastereomer; meso; erythro; threo; conformation

1 Formation of Tetrahedral Stereocenters

1.1 Stereocenters Depend on the Local Substitution Environment

The atomic connectivity of lignans does not uniquely determine their three-dimensional structures. The IUPAC Gold Book defines a stereogenic unit as an atom or group of atoms that serves as the focus of stereoisomerism in a molecule; for a central stereogenic unit consisting of a central atom and distinguishable ligands, interchange of any two substituents produces another stereoisomer.[1]

For a typical tetrahedral carbon, when the four atoms or groups attached to it are distinguishable from one another, the carbon generally constitutes a central stereogenic unit. In lignans, side-chain positions such as C7, C8, C7′, and C8′ are frequently involved. Whether a particular position has stereochemical significance depends on the specific skeleton, oxidation state, cyclization state, and surrounding substituents.

For example, in the glycerol side chain of guaiacylglycerol 8-O-4′-coniferyl ether (GGCE), C7 is bonded to an aromatic ring, a hydroxy group, C8, and hydrogen, whereas C8 is bonded to C7, an aryloxy group, a hydroxymethyl group, and hydrogen. In this structure, both C7 and C8 have four distinguishable bonding paths and can therefore form two stereocenters. By contrast, the other side of the same molecule retains an unsaturated allylic alcohol structure, and its alkene carbons are not corresponding tetrahedral stereocenters.[4]

Secoisolariciresinol (SECO) mainly involves two stereocenters, C8 and C8′. Each center is bonded to hydrogen, a hydroxymethyl group, an arylmethyl side chain, and the carbon chain leading toward the other stereocenter. Different combinations of the absolute configurations at these two positions therefore generate different stereoisomers.[2,3]

The principal stereogenic positions or units in representative structures are summarized below:

1.2 Cyclization Restricts Spatial Freedom but Does Not Necessarily Create New Stereocenters

Cyclization incorporates several single bonds that could originally rotate independently into a closed structure, thereby restricting certain dihedral angles. However, ring formation itself is not a sufficient condition for the generation of a stereocenter.

A carbon incorporated into a ring must still have distinguishable substitution paths in order to constitute a stereocenter. Likewise, the presence of multiple sp³ carbons in a molecule does not mean that all of them possess R/S configurations. The actual determination depends on connectivity and molecular symmetry.[1]

This distinction is particularly evident in polycyclic lignans: cyclization can either establish new stereocenters or merely reduce the conformational freedom of an existing structure. These two effects must be evaluated separately.

2 Enantiomeric, Diastereomeric, and Meso Relationships in Molecules with Multiple Stereocenters

2.1 Multiple Stereocenters Do Not Simply Correspond to 2ⁿ Independent Stereoisomers

A molecule containing n independent stereocenters and lacking symmetry-related degeneracy can theoretically form up to 2ⁿ configurational combinations. However, molecules with internal symmetry may possess meso forms, reducing the actual number of distinct stereoisomers below 2ⁿ.

SECO provides a clear example. The following forms have been confirmed in flax:

① 8S,8′S-(+)-SECO

② 8R,8′R-(−)-SECO

Both stereocenters are inverted between these two structures. They are nonsuperimposable mirror images and therefore constitute a pair of enantiomers.[2]

Sugahara et al. further achieved the stereoselective synthesis of meso-SECO (meso-secoisolariciresinol), demonstrating that the same basic atomic connectivity can also produce a meso stereoisomer distinct from the two optically active forms described above.[3]

For the structurally symmetric SECO skeleton, opposite configurations at the two stereocenters can generate an internally compensated meso form. The 8R,8′S and 8S,8′R designations correspond to the same meso stereoisomer as a consequence of molecular symmetry.

Thus, the two stereocenters generate three rather than four distinct stereoisomers:

The configurational relationships between the two stereocenters of SECO are summarized below:

A meso molecule contains stereocenters but can be superimposed on its mirror image. Therefore, “containing stereocenters” and “the entire molecule being chiral” are not equivalent criteria.[1]

This structural relationship also demonstrates that the optical rotation signs “(+)” and “(−)” cannot generally substitute for R/S configurations. The direction of optical rotation is an experimental optical property of a particular compound under specified conditions, whereas R/S describes three-dimensional arrangement according to established configurational priority rules.[2]

The main text of this article follows the C8/C8′ numbering convention commonly used for lignans. In systematic nomenclature using butane-1,4-diol as the parent structure, these two stereocenters correspond to C2 and C3. Accordingly, 8R,8′R-SECO corresponds to (2R,3R)-SECO, whereas 8S,8′S-SECO corresponds to (2S,3S)-SECO.

3 Erythro/Threo Relative Configuration and Its Scope of Application

3.1 Erythro/Threo Describes the Relative Relationship Between Two Stereocenters

The terms erythro and threo are mainly used for acyclic structures, or acyclic local structural units, containing two stereocenters.

Erythro/threo describes relative configuration, whereas R/S expresses the absolute configuration after the spatial arrangement at each stereocenter has been established. Relative configuration remains unchanged when the entire molecule is converted into its mirror image. Consequently, an erythro structure may exist as a pair of enantiomers with opposite absolute configurations, and the same applies to a threo structure.[1]

3.2 The Four Stereoisomers of GGCE

Buckler et al. completed the stereoselective synthesis of all four stereoisomers of GGCE, demonstrating that this acyclic neolignan can form two pairs of enantiomers through its C7 and C8 stereocenters.[4]

According to the C7/C8 numbering convention commonly used for this class of compounds:

① erythro-GGCE (eGGCE) corresponds to (7S,8R) and its enantiomer (7R,8S);

② threo-GGCE (tGGCE) corresponds to (7S,8S) and its enantiomer (7R,8R).[4,5]

The relationship between relative and absolute configurations of GGCE is summarized below:

GGCE differs from SECO in this respect. The two ends of GGCE are not equivalent, and the molecule lacks the type of internal symmetry present in SECO that causes mixed configurations to collapse into a single meso form. Consequently, the C7/C8 stereocenters generate four distinct stereoisomers rather than three.

The terms erythro and threo also cannot further specify whether a particular molecule is (7S,8R) or (7R,8S). When a formal structural name or an unambiguous individual stereoisomer is required, absolute-configuration descriptors should still be used.

4 Restriction of the Spatial Relationships Between Stereocenters by Cyclization

4.1 Ring Systems Convert Local Relative Configuration into Spatial Constraints

In acyclic structures, multiple single bonds between stereocenters usually retain a certain degree of rotational freedom. After cyclization, some of these single bonds become part of a ring, substantially narrowing the range of accessible dihedral angles and imposing stronger constraints on the spatial relationships between substituents.

This change makes the spatial consequences of a given stereocenter configuration more pronounced. For example, an aryl group positioned on one side or the other of a ring system can no longer freely interchange these orientations through simple single-bond rotation.

The furofuran lignans sesamin and episesamin [also known as asarinin] have the same composition and basic atomic connectivity. The literature describes episesamin as the C7 epimer of sesamin, meaning that the two compounds differ in configuration at only one corresponding stereocenter.[6]

An epimer is a type of diastereomer. Inversion at a single stereocenter does more than change a local wedge-bond representation; in a ring-constrained structure, it simultaneously changes the orientation of the corresponding substituent relative to the entire bis-tetrahydrofuran system.

4.2 Episesamin as an Example Containing Four Stereocenters

The absolute configuration of (+)-episesamin is:

(7S,7′R,8R,8′R)-episesamin.

The molecule therefore contains four tetrahedral stereocenters.[7]

This structure illustrates that the three-dimensional shape of a polycyclic lignan is jointly determined by multiple stereocenters. If only one center is inverted while all others remain unchanged, the resulting structure is no longer the complete mirror image of the original molecule but instead becomes a diastereomer. The ring system further limits the possibility of eliminating this difference by rotation, thereby translating stereocenter configuration into a persistent difference in overall molecular geometry.

The effect of cyclization on three-dimensional structure can be summarized as follows:

Stereocenters determine the spatial directions of local bonds

→ Ring systems reduce rotational freedom

→ Multiple local orientations become coupled

→ The molecule adopts a specific overall fold.

5 Restricted Biaryl Rotation and Axial Chirality

5.1 Chirality Does Not Necessarily Originate from a Tetrahedral Carbon

Axial chirality represents another source of three-dimensional stereochemistry in lignans that is distinct from central chirality.

IUPAC defines axial chirality as stereoisomerism arising from a nonplanar spatial arrangement of four groups positioned in pairs around a chiral axis. Atropisomerism in ortho-substituted biphenyls is a typical example. Axial configuration can be designated using Rₐ/Sₐ.[1]

A biphenyl structure is not inherently associated with stable axial chirality. If the two aromatic rings can readily rotate around the biaryl single bond, the two oppositely twisted arrangements interconvert rapidly and generally cannot exist as stable, independently isolable stereoisomers. When ortho substitution, bridged-ring structures, or other forms of steric congestion increase the barrier to biaryl rotation, this interconversion becomes restricted and stable atropisomers with persistent individual configurations may form.

Note: The IUPAC Gold Book uses descriptors such as Rₐ/Sₐ for axial chirality, whereas some literature on dibenzocyclooctadiene natural products uses the notation (aR)/(aS). When specific literature compounds are cited in this article, the notation used in the original publication is retained.

5.2 The Biaryl Axis in Dibenzocyclooctadiene Lignans

In dibenzocyclooctadiene lignans, the two aromatic rings are connected through a biaryl bond and are simultaneously constrained by ortho substituents and the bridged eight-membered ring. The two aromatic rings cannot readily pass through a near-coplanar arrangement to accomplish axial inversion, allowing stable biaryl axial configurations to form.

In their study of dibenzocyclooctadiene lignans from Schisandra chinensis, Nguyen et al. identified naturally occurring compounds with different axial configurations. For example, gomisin L1 was assigned an aS axial configuration, whereas the newly identified compound gomisin M3 was assigned an aR axial configuration.[8]

The axial configuration and ring R/S stereocenters in these structures should be recorded separately. For example, kadheterin I, reported by Robertson et al. in 2026, has the complete configuration (aS,6R,7S,8R,9R). Here, aS describes the biaryl axis, whereas 6R, 7S, 8R, and 9R describe tetrahedral stereocenters.[10]

The structural differences between central chirality and axial chirality are summarized below:

6 Ring Conformations and Dynamic Exchange in Dibenzocyclooctadienes

6.1 Configuration and Conformation Represent Different Levels of Stereochemical Organization

IUPAC defines “configuration” as an atomic spatial arrangement that cannot be explained solely by conformational differences, whereas “conformation” mainly refers to different spatial arrangements that can interconvert through formal rotation about single bonds.[1]

A single dibenzocyclooctadiene lignan can simultaneously exhibit:

1. R/S configurations at several tetrahedral stereocenters on the ring;

2. an aR/aS configuration of the biaryl axis;

3. different conformations of the eight-membered ring.

Axial inversion of the biaryl unit requires crossing a relatively high rotational barrier, whereas folding of the eight-membered ring can occur without changing either the biaryl axial configuration or the R/S configurations of the tetrahedral stereocenters.

6.2 Twist-Boat-Chair and Twist-Boat Conformations

The eight-membered ring of dibenzocyclooctadienes commonly involves two types of conformation:

① twist-boat-chair conformation (TBC)

② twist-boat conformation (TB)

Early studies by Gottlieb et al. investigated the conformational characteristics of this type of eight-membered ring and showed that side-chain functional groups and their geometric interactions with the aromatic rings can alter the relative stability of the TB and TBC conformations.[9]

In 2026, Robertson et al. further demonstrated that many naturally occurring dibenzocyclooctadiene lignans that had previously been represented as adopting a single TBC or TB conformation may actually exist in a dynamic equilibrium between the two conformations.[10]

Figure 1. Spatial differences between TBC and TB conformations in dibenzocyclooctadiene lignans

Figure 1 from Robertson et al.[10] depicts the TBC and TB eight-membered-ring folding modes with the same (aS) biaryl axial configuration. The biaryl axial configuration remains unchanged between the two structures, while the change occurs within the cyclooctadiene portion, illustrating the distinction between “axial configurational change” and “ring conformational change.” The article and Figure 1 are licensed under CC BY 4.0.

6.3 Biaryl Rotation and Eight-Membered-Ring Exchange Occur on Different Energy Scales

Robertson et al. noted that dibenzocyclooctadienes generally exhibit substantial steric congestion at positions ortho to the biaryl bond. The barrier to biaryl rotation can reach ≥35 kcal/mol, allowing atropisomers to remain configurationally stable.[10]

In the same study, the activation energies for TBC/TB conformational exchange in kadheterin J and kadheterin K were approximately:

· 13.1 kcal/mol

· 13.2 kcal/mol

respectively, substantially lower than the energy scale required for biaryl axial inversion.[10]

Note: These two values were obtained for kadheterin J and kadheterin K from variable-temperature NMR analysis under the conditions used in that study. They do not indicate that all dibenzocyclooctadiene lignans possess identical conformational-exchange barriers; differences in substitution patterns and experimental temperature can both affect the kinetics of TBC/TB exchange.[10]

The resulting structural relationship can be summarized as follows:

Biaryl axis: high rotational barrier

→ axial configuration can be retained

→ aR/aS represents a relatively stable configurational feature

Eight-membered ring: lower conformational-exchange barrier

→ refolding can occur without disrupting the axial configuration

→ TBC and TB can dynamically interconvert

6.4 Spatial Orientation of Substituents Modulates the TBC/TB Equilibrium

The conformation of the eight-membered ring does not change randomly. Robertson et al. found that the spatial orientation of certain benzylic substituents alters steric interactions between the ring and adjacent aromatic rings.

Using the (aS) skeleton examined in that study as the reference, certain β-substituents at C6 that point toward the interior of the ring produce unfavorable steric contacts with a neighboring aromatic ring in the TBC conformation, thereby relatively destabilizing TBC, increasing the proportion of the TB conformation, and promoting exchange between the two states. Certain substituents at C7 or C8 can modify this steric congestion and relatively stabilize the TBC conformation.[10]

The researchers re-examined the ¹³C NMR data of 71 previously reported dibenzocyclooctadiene lignans, more than 70% of which displayed the same type of characteristic signal broadening. Combined with variable-temperature NMR and computational results, the study associated this signal broadening with TBC/TB conformational exchange and suggested that many compounds previously characterized as adopting a single TBC or TB conformation may in fact exist in a dynamic equilibrium between the two conformations.[10]

These findings demonstrate that the biaryl axis can be highly restricted while the eight-membered ring within the same molecule retains substantial conformational freedom.

7 Hierarchical Relationships Among Central Configuration, Axial Configuration, and Conformation

These three levels are not interchangeable. Identical R/S configurations do not imply identical ring conformations; a change in ring conformation does not imply a change in R/S configuration; and even when the aS/aR axial configuration is fixed, the eight-membered ring may still undergo conformational exchange.

The complete three-dimensional structure of a lignan molecule is jointly determined by the configurations of local stereocenters, the axial configuration generated by restricted rotation, and the remaining conformational freedom. Two-dimensional structure establishes “which atoms are connected to which,” whereas stereochemical structure further determines the actual arrangement of those atoms in three-dimensional space.

8 Representative Product Classification and Research Applications Related to Central Chirality, Axial Chirality, and Conformational Restriction in Lignans

Table 1. Dibenzocyclooctadiene Lignans: Biaryl Axial Chirality, Ring Stereocenters, and Eight-Membered-Ring Conformation

Table 2. Furofuran Lignans: Multiple Stereocenter Configurations, Epimerism, and Molecular Symmetry

Table 3. Acyclic, Monotetrahydrofuran, and Butyrolactone Lignans: Central Chirality and Cyclization-Induced Restriction

Table 4. Podophyllotoxin-Type Lignans: Polycyclic Multiple-Center Chirality and Epimerism

Note: The products listed above are representative Aladdin products relevant to scientific research. The “Product Features and Applications” descriptions primarily provide research-selection and structural-comparison considerations based on chemical structural characteristics and do not imply that the specific experimental applications have been validated in the literature. Actual use should be determined according to the product specification, batch-specific COA, and the intended research system. Additional information on product specifications, grades, and COAs can be retrieved from the Aladdin website using the product name, CAS number, or catalog number.

References

[1] International Union of Pure and Applied Chemistry (IUPAC). Compendium of Chemical Terminology (the Gold Book), 5th ed.; online version 5.0.0, 2025. Relevant entries: stereogenic unit, chirality centre, absolute configuration, relative configuration, configuration, conformation, axial chirality, atropisomers, erythro/threo. DOI: 10.1351/goldbook.

[2] Hemmati S, von Heimendahl CBI, Klaes M, et al. Pinoresinol-lariciresinol reductases with opposite enantiospecificity determine the enantiomeric composition of lignans in the different organs of Linum usitatissimum L. Planta Med. 2010;76(9):928-934. DOI: 10.1055/s-0030-1250036.

[3] Sugahara T, Yamauchi S, Kondo A, et al. First stereoselective synthesis of meso-secoisolariciresinol and comparison of its biological activity with (+)- and (−)-secoisolariciresinol. Biosci Biotechnol Biochem. 2007;71(12):2962-2968. DOI: 10.1271/bbb.70358.

[4] Buckler JN, Banwell MG, Kordbacheh F, et al. Developing neolignans as proangiogenic agents: stereoselective total syntheses and preliminary biological evaluations of the four guaiacylglycerol 8-O-4′-coniferyl ethers. ACS Omega. 2017;2(10):7375-7388. DOI: 10.1021/acsomega.7b01459.

[5] Khallouki F, Hull WE, Würtele G, et al. Isolation of the major phenolic compounds in the pits of brined green olive drupes: structure elucidation by comprehensive ^1H/^13C-NMR spectroscopy. Nat Prod Commun. 2019;14(7). DOI: 10.1177/1934578X19857365.

[6] Bussey RO III, Sy-Cordero AA, Figueroa M, et al. Antimycobacterial furofuran lignans from the roots of Anemopsis californica. Planta Med. 2014;80(6):498-501. DOI: 10.1055/s-0034-1368352.

[7] Trowitzsch-Kienast W, Rühl M, Kim KY, et al. Absolute configuration of antifibrotic (+)-episesamin isolated from Lindera obtusiloba Blume. Z Naturforsch C. 2011;66(9-10):460-464. DOI: 10.1515/znc-2011-9-1004.

[8] Nguyen TN, Lee YG, Kim HG, et al. New dibenzocyclooctadiene lignan from Schisandra chinensis (Turcz.) Baill. fruits. Appl Biol Chem. 2021;64:46. DOI: 10.1186/s13765-021-00618-1.

[9] Gottlieb HE, Mervič M, Ghera E, Frolow F. Conformational study of dibenzocyclo-octadiene systems related to the schizandrin-type lignans. J Chem Soc Perkin Trans 1. 1982:2353-2358. DOI: 10.1039/P19820002353.

[10] Robertson LP, Xu W, Brieskorn L, et al. Rules for dibenzocyclooctadiene conformational dynamics. J Nat Prod. 2026;89(2):528-538. DOI: 10.1021/acs.jnatprod.5c01348.

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