Total Synthesis of Lignan Natural Products

Lignans are a class of dimeric phenylpropanoid natural products characterised by a wide array of biological activities, including antitumour, antiviral and neuroprotective properties. Total synthesis of lignans seeks to replicate and extend nature’s biosynthetic routes, offering access to rare or modified analogues that can probe structure–activity relationships and support drug discovery. Recent advances have focused on concise and divergent strategies that leverage common intermediates, photoredox-mediated radical processes and biocatalytic transformations to assemble the key tetrahydrofuran, dibenzylbutyrolactone and aryltetralin frameworks with high stereocontrol. Integration of biomass-derived monolignols with catalytic radical generation has enabled rapid access to both classical and non-natural lignan scaffolds in one or two steps. Chemoenzymatic approaches combine enzyme-catalysed C–H activation or oxidative coupling with chemical elaboration to furnish complex enantiopure targets such as podophyllotoxin precursors. These methodologies illustrate a growing trend towards modular, scalable routes that can deliver multiple lignan subtypes in fewer steps, with minimal protective-group manipulation and enhanced overall yield.

Research from Nature Portfolio

A divergent photoredox strategy has been developed for the rapid synthesis of structurally diverse lignans directly from dicinnamyl ether derivatives. Under visible-light irradiation and in the presence of catalytic Fukuzumi’s salt and copper or disulfide co-catalysts, radical cation intermediates undergo selective C7-alkoxylation or dialkoxylation to yield both aryltetralin cyclic ethers and dibenzyltetrahydrofuran frameworks in a single step. Variation of alcohol loading or replacement of the copper salt with diphenyl disulfide redirects the reaction pathway, enabling access to aza-, thia- and carba-analogues. This concise approach has been validated by total syntheses of key aryltetralin lignans, including aglacin A and dehydrodimethylconidendrin, demonstrating its broad applicability to classical lignan families.

Total Synthesis of Lignan Natural Products publication trend

The graph below shows the total number of articles in total synthesis of lignan natural products across all publications each year (not limited to Nature Index journals).

Technical terms

Total synthesis: Chemical construction of complex natural products from simple starting materials.

Lignans: Plant-derived dimers of phenylpropanoid units with diverse biological functions.

γ-Butyrolactone: Five-membered cyclic ester motif found in many lignan cores.

Divergent synthesis: Strategy employing a common intermediate to produce multiple target molecules.

Radical cation: Short-lived positively charged species with an unpaired electron, generated under photoredox conditions.

Photoredox catalysis: Use of light-activated catalysts to mediate redox reactions via radical intermediates.

Biocatalytic kinetic resolution: Enzymatic separation of enantiomers based on differential reaction rates.

Monolignols: Biosynthetic precursors such as coniferyl alcohol that give rise to lignan frameworks.

References

1. Synthesis and Anti-Proliferative Evaluation of Arctigenin Analogues with C-9′ Derivatisation. International Journal of Molecular Sciences (2023).
2. Divergent Syntheses of (-)-Chicanine, (+)-Fragransin A2, (+)-Galbelgin, (+)-Talaumidin, and (+)-Galbacin via One-Pot Homologative γ-Butyrolactonization. Molecules (2024).
3. Taming the radical cation intermediate enabled one-step access to structurally diverse lignans. Nature Communications (2022).
4. Chemoenzymatic Total Synthesis of Deoxy‐, epi‐, and Podophyllotoxin and a Biocatalytic Kinetic Resolution of Dibenzylbutyrolactones. Angewandte Chemie International Edition (2019).