Introduction

Dimers formed from two C6–C3 phenylpropanoid units are not limited to C8–C8′ linkages. According to the nomenclature rules of the International Union of Pure and Applied Chemistry (IUPAC), compounds in which two C6–C3 units lack a C8–C8′ bond but are connected through another direct C–C bond are classified as neolignans; compounds in which no direct C–C bond exists between the two units and the units are instead connected through an ether oxygen are classified as oxyneolignans.[1]

The skeletal differences among non-8–8′ systems are mainly determined by two structural factors: the atoms and positions involved in linking the two C6–C3 units, and the additional C–O cyclization and changes in ring unsaturation that occur after the basic linkage is established. A C8–C5′ linkage together with a C7–O–C4′ linkage can form a 2,3-dihydrobenzofuran; a direct C–C bond between two aromatic rings forms a biphenyl structure; a C8–O–C4′ linkage forms an open-chain aryl ether; and two adjacent C–O linkages can generate a 1,4-benzodioxane ring.[1,2]

1 Structural Basis of Non-8–8′ Linkages

1.1 Direct C–C Linkages and Ether-Oxygen Linkages

The primary distinction between neolignans and oxyneolignans lies in the basic linkage between the two C6–C3 units.

Linkages such as C8–C5′ and aromatic carbon–aromatic carbon form direct C–C bonds and therefore correspond to neolignans. In structures such as C8–O–C4′, an oxygen atom lies between the two units and no direct C–C bond connects them; these structures therefore correspond to oxyneolignans.[1]

1.2 Basic Linkages and Additional Cyclization

The basic linkage and additional ring closure represent different structural features. An 8–5′ neolignan first contains a direct C8–C5′ C–C bond, after which formation of a C7–O–C4′ bond closes the molecule into a five-membered oxygen-containing ring. Although an ether oxygen is incorporated into the final skeleton, the two C6–C3 units are already connected through a direct C–C bond, so the structural classification remains determined by this linkage.[1]

The 8–O–4′ system is different. Its C8–O–C4′ ether bond itself constitutes the basic linkage between the two C6–C3 units, with no direct C–C bond between C8 and C4′. When an additional C–O bridge generates a six-membered oxygen-containing ring, the parent structure remains an oxyneolignan.[1]

2 C8–C5′ Linkages and Dihydrobenzofuran and Benzofuran Skeletons

2.1 Formation of a Dihydrobenzofuran through C8–C5′ and C7–O–C4′ Linkages

An 8–5′ linkage is formed between C8 of the side chain of one phenylpropanoid unit and C5′ of the aromatic ring of the other unit: C8–C5′

Dehydrodiconiferyl alcohol (DHCA) is a representative compound with this linkage pattern. Its direct C8–C5′ C–C bond and C7–O–C4′ ether bond together form a five-membered oxygen-containing ring corresponding to a 2,3-dihydrobenzofuran skeleton, also referred to as a phenylcoumaran skeleton.[3–5]

Isotope-tracing studies in flax cells have provided further evidence for the actual formation of different dimeric linkage patterns. When [¹³C₂]coniferin was used as a substrate, the same cellular system yielded lariciresinol diglucoside with an 8–8′ linkage, dehydrodiconiferyl alcohol glucoside with an 8–5′ linkage, and guaiacylglycerol–coniferyl alcohol ether glucoside with an 8–O–4′ linkage.[3]

Lee et al. isolated DHCA from pumpkin stems and determined its molecular formula as C₂₀H₂₂O₆ by nuclear magnetic resonance spectroscopy and mass spectrometry.[4]

Figure 1. 2,3-Dihydrobenzofuran structure of dehydrodiconiferyl alcohol.

The two C6–C3 units of dehydrodiconiferyl alcohol are connected through a direct C8–C5′ C–C bond, while a C7–O–C4′ linkage forms the five-membered oxygen-containing ring. Source: Lee et al.[4], Figure 3, used under the CC BY 4.0 license.

2.2 Variations in Side-Chain Functional Groups and Ring Unsaturation

Within 2,3-dihydrobenzofuran-type neolignans sharing the same basic ring system, structural diversity can arise from differences in side-chain oxidation state, aromatic hydroxy and methoxy substitution, and ring-system unsaturation.

Licarin A contains a 2,3-dihydrobenzofuran core. Both aromatic rings bear methoxy substituents, one aromatic ring additionally contains a phenolic hydroxy group, and the other side retains an (E)-1-propenyl group. Balanophonin likewise contains a 2,3-dihydrobenzofuran core but differs in its side-chain functional groups: a hydroxymethyl group is attached to the ring, whereas the other aromatic ring bears an —CH=CH—CHO-type α,β-unsaturated aldehyde side chain. The carbon–carbon double bond in this side chain is conjugated with the aldehyde carbonyl group.[2,11]

Ring unsaturation is another important structural variable among this class of non-8–8′ neolignans. The C2–C3 bond of a 2,3-dihydrobenzofuran ring is a single bond, whereas the corresponding position in a benzofuran ring contains a double bond, allowing the five-membered oxygen-containing ring to participate in continuous conjugation. Eupomatenoid 5 and Eupomatenoid 6 both possess this benzofuran core but differ in their aromatic substitution patterns; the aryl group of Eupomatenoid 5 contains both methoxy and hydroxy groups, whereas the corresponding aryl group of Eupomatenoid 6 retains only the hydroxy group.[2,11]

C8–C5′-related neolignans therefore include different ring systems such as 2,3-dihydrobenzofuran and benzofuran types. The degree of ring saturation determines the conjugation state of the five-membered oxygen-containing ring, while side-chain alcohol, aldehyde, and alkenyl groups together with aromatic hydroxy and methoxy substituents further generate structural differences within the same linkage type.

In addition, kadsurenone and denudatin B are 8–5′-related 2,3-dihydrobenzofuran-6-one-type neolignans. They have the same molecular formula but differ in configuration at the C3a bridgehead carbon, allowing comparison of stereochemical differences within the same skeletal framework.[11]

3 Direct C–C Linkages between Aromatic Rings and Biphenyl-Type Neolignans

3.1 Formation of the Biphenyl Skeleton

Non-8–8′ direct C–C linkages can also occur between aromatic carbon atoms of two phenylpropanoid units. Direct bonding between the two aromatic rings produces a biphenyl structure, while the respective C3 side chains remain attached to their corresponding aromatic rings.[1,2]

This skeleton differs fundamentally from dibenzocyclooctadiene-type lignans. Dibenzocyclooctadiene lignans retain the C8–C8′ linkage and additionally contain a C–C bond between the aromatic rings. Biphenyl-type neolignans lack the C8–C8′ linkage, and the direct C–C bond between the aromatic rings itself connects the two C6–C3 units.[1,2]

3.2 Magnolol and Honokiol

Magnolol and honokiol are representative biphenyl-type neolignans. Magnolol can be described as 5,5′-diallyl-2,2′-dihydroxybiphenyl, whereas honokiol is 3,5′-diallyl-4,2′-dihydroxybiphenyl. Both have the molecular formula C₁₈H₁₈O₂, but the hydroxy and allyl groups occupy different positions on the two aromatic rings, making them positional isomers.[6]

The biphenyl skeleton connects the two aromatic systems directly through a single C–C bond. Changes in aromatic substitution positions alter the spatial relationship between hydroxy groups, the relative orientation of the aromatic rings, and intramolecular and intermolecular interactions. Although magnolol and honokiol share the same molecular formula and biphenyl core, differences in substitution position still result in differences in physicochemical properties.[6]

4 C8–O–C4′ Linkages and Open-Chain Aryl Ether-Type Oxyneolignans

4.1 C8–O–C4′ Aryl Ether Linkage

In an 8–O–4′ linkage, C8 of the side chain of one phenylpropanoid unit is connected through an ether oxygen to C4′ of the aromatic ring of the other unit:

C8–O–C4′

No direct C–C bond exists between C8 and C4′. The ether oxygen provides the linkage between the two C6–C3 units; therefore, this structure is classified as an oxyneolignan.[1]

Kordbacheh et al. isolated erythro-guaiacylglycerol-8-O-4′-(coniferyl alcohol) ether (eGGCE) and threo-guaiacylglycerol-8-O-4′-(coniferyl alcohol) ether (tGGCE) from soybean xylem sap. A long-range correlation between H-8 and C-4′ in the heteronuclear multiple-bond correlation nuclear magnetic resonance spectrum supported the presence of the C8–O–C4′ ether bond.[7]

Figure 2. Erythro- and threo-guaiacylglycerol-8-O-4′-(coniferyl alcohol) ethers.

A represents the erythro isomer eGGCE, and B represents the threo isomer tGGCE. Both contain the same basic C8–O–C4′ linkage and differ in the relative stereochemical relationship between C7 and C8. The study by Kordbacheh et al. did not assign a single absolute configuration to C7 and C8. Source: Kordbacheh et al.[7], Figure 2, CC BY.

4.2 Structural Differences between 8–5′ Dihydrobenzofurans and 8–O–4′ Aryl Ethers

Both dehydrodiconiferyl alcohol and GGCE contain C–O bonds, but the structural roles of these C–O bonds differ between the two skeletons.

The erythro/threo difference between eGGCE and tGGCE corresponds to different relative stereochemical relationships at C7/C8 and does not alter the basic C8–O–C4′ linkage. Studies of 8–O–4′ aryl ethers in Eucommia ulmoides likewise show that this class of compounds can occur as different erythro and threo diastereomers.[8]

4.3 8–O–4′ Aryl Ether- and Diaryl Ether-Type Oxyneolignans

Within 8–O–4′-type oxyneolignans sharing the same basic linkage, multiple structural members can arise through differences in aromatic hydroxy and methoxy substitution and side-chain functional groups.

Machilin D contains a typical C8–O–C4′ linkage, in which C8 of the side chain of one phenylpropanoid unit is connected through an ether oxygen to C4′ of the aromatic ring of the other unit. No direct C–C bond exists between the two C6–C3 units. Virolin, the methyl ether of machilin D, retains the same 8–O–4′ linkage but differs in that one phenolic hydroxy group of machilin D is methylated to a methoxy group.[1,10] This aromatic O-methylation changes the oxygen-containing substitution pattern but does not alter the oxyneolignan skeleton defined by the C8–O–C4′ linkage.

Oxygen linkages can also occur directly between two aromatic rings. Obovatol has a diaryl ether structure bearing two allyl substituents; 3,4-dihydroxy-5-(p-allylphenoxy)cinnamaldehyde (obovatal) likewise retains an aromatic ring–O–aromatic ring linkage, with one C3 side chain present as an α,β-unsaturated aldehyde.[12] Neither compound contains a direct C–C bond connecting the two C6–C3 units, and both belong to diaryl ether-type oxyneolignans.[1,12]

The difference between the 8–O–4′ and diaryl ether types lies mainly in the atoms at the two ends of the ether linkage: the former is side-chain C8—O—aromatic C4′, whereas the latter is aromatic ring—O—aromatic ring. In both cases, the ether oxygen provides the basic linkage between the two C6–C3 units, but the linkage positions differ, producing distinct open-chain oxyneolignan skeletons.

5 Double C–O Linkages and 1,4-Benzodioxane-Type Oxyneolignans

5.1 Formation of a Six-Membered Oxygen-Containing Ring through Two C–O Linkages

When an aryl ether linkage is accompanied by formation of a second C–O bond at an adjacent position, a six-membered ring containing two oxygen atoms can be generated and fused with an aromatic ring to form a 1,4-benzodioxane skeleton.[1,9]

In one typical skeleton listed by IUPAC, the C8–O–C4′ bond provides the basic interunit ether linkage, while a C7–O–C3′ bridge is formed simultaneously:

C8–O–C4′ + C7–O–C3′ → 1,4-benzodioxane skeleton

The two C–O linkages together constrain the spatial relationship between the two phenylpropanoid moieties, converting an open-chain aryl ether into a cyclic oxygen-containing skeleton. Natural 1,4-benzodioxane oxyneolignans also exhibit different regiochemical linkage patterns, giving rise to structural types such as 2-aryl and 3-aryl derivatives.[1,9]

5.2 2-Aryl and 3-Aryl 1,4-Benzodioxanes

1,4-Benzodioxane-type oxyneolignans can be classified into 2-aryl and 3-aryl types according to whether the aryl group is attached at C2 or C3 of the heterocyclic ring. Among reported natural products, the 3-aryl type is relatively common, with isoamericanin A belonging to this group; the 2-aryl type is less common, with americanin A serving as a representative compound.[9]

Isoamericanin A and americanin A possess the same basic 1,4-benzodioxane ring system, but their aryl groups are attached at C3 and C2 of the heterocycle, respectively, resulting in different regiochemical linkage patterns.[9]

6 Correspondence between Non-8–8′ Linkage Patterns and Major Skeletons

The major skeletons of non-8–8′ neolignans and oxyneolignans are jointly determined by the atoms involved in linking the two C6–C3 units, the linkage positions, and additional cyclization relationships.[1,2]

Variations in side-chain alcohol, aldehyde, and alkenyl groups and in aromatic hydroxy and methoxy substituents generate structural differences within the same basic linkage type but do not alter the classification as a neolignan or oxyneolignan determined by the interunit linkage pattern.

7 Classification and Structural Research Applications of Representative Non-8–8′ Neolignan and Oxyneolignan Products

Table 1. 8–5′-Related Cyclic Neolignans

Table 2. Biphenyl-Type Neolignans and Diaryl Ether-Type Oxyneolignans

Note: The above are representative Aladdin products related to scientific research. Specific applications should be determined according to product specifications, batch COA, and the intended reaction or evaluation system. Additional information on product specifications, grades, and COAs can be searched on the Aladdin official website using the product name, CAS number, or catalog number.

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] Beejmohun V, Fliniaux O, Hano C, et al. Coniferin dimerisation in lignan biosynthesis in flax cells. Phytochemistry. 2007, 68(22–24): 2744–2752. doi:10.1016/j.phytochem.2007.09.016.

[4] Lee J, Kim D, Choi J, et al. Dehydrodiconiferyl Alcohol Isolated from Cucurbita moschata Shows Anti-adipogenic and Anti-lipogenic Effects in 3T3-L1 Cells and Primary Mouse Embryonic Fibroblasts. Journal of Biological Chemistry. 2012, 287(12): 8839–8851. doi:10.1074/jbc.M111.263434.

[5] Attoumbre J, Hano C, Mesnard F, et al. Identification by NMR and accumulation of a neolignan, the dehydrodiconiferyl alcohol-4-β-D-glucoside, in Linum usitatissimum cell cultures. Comptes Rendus Chimie. 2006, 9(3–4): 420–425. doi:10.1016/j.crci.2005.06.012.

[6] Usach I, Alaimo A, Peris JE, et al. Magnolol and Honokiol: Two Natural Compounds with Similar Chemical Structure but Different Physicochemical and Stability Properties. Pharmaceutics. 2021, 13(2): 224. doi:10.3390/pharmaceutics13020224.

[7] Kordbacheh F, Carruthers TJ, Bezos A, et al. Promotion of mammalian angiogenesis by neolignans derived from soybean extracellular fluids. PLoS ONE. 2018, 13(5): e0196843. doi:10.1371/journal.pone.0196843.

[8] Lourith N, Katayama T, Suzuki T. Stereochemistry and biosynthesis of 8-O-4′ neolignans in Eucommia ulmoides: diastereoselective formation of guaiacylglycerol-8-O-4′-(sinapyl alcohol) ether. Journal of Wood Science. 2005, 51: 370–378. doi:10.1007/s10086-004-0660-0.

[9] Pilkington LI, Barker D. Synthesis and biology of 1,4-benzodioxane lignan natural products. Natural Product Reports. 2015, 32: 1369–1388. doi:10.1039/C5NP00048C.

[10] Ahn BT, Lee S, Lee SB, et al. Low-Density Lipoprotein-Antioxidant Constituents of Saururus chinensis. Journal of Natural Products. 2001, 64(12): 1562–1564. doi:10.1021/np0006061.

[11] National Center for Biotechnology Information. PubChem Compound Summary: Licarin A (CID 6442393), Balanophonin (CID 21582569), Eupomatenoid 5 (CID 6443783), Eupomatenoid 6 (CID 6261723), Conocarpan (CID 10999992), Kadsurenone (CID 122159), and Denudatin B (CID 442834).

[12] Ito K, Iida T, Ichino K, Tsunezuka M, Hattori M, Namba T. Obovatol and Obovatal, Novel Biphenyl Ether Lignans from the Leaves of Magnolia obovata Thunb. Chemical and Pharmaceutical Bulletin. 1982, 30(9): 3347–3353. doi:10.1248/cpb.30.3347.

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