Total Synthesis Strategies for Natural Products and Derivatives

Total synthesis of natural products encompasses the design and execution of synthetic routes to assemble complex molecular architectures found in nature. Traditional approaches distinguish between linear strategies, in which intermediates are formed sequentially, and convergent strategies, which unite preassembled fragments to improve overall efficiency. Central to these endeavours are retrosynthetic analyses that guide disconnections, the judicious use of protecting groups, and the application of stereoselective catalysis to establish multiple stereocentres. Recent advances have harnessed C–H activation, cascade or tandem reactions and biomimetic transformations to streamline pathways and reduce step counts. Increasingly, green chemistry principles—such as solvent selection, renewable feedstocks and energy-efficient techniques—are being integrated to address sustainability. The practical impact of total synthesis spans drug discovery, agricultural chemistry and the provision of scarce natural derivatives in preparative quantities, underscoring its global significance.

Research from Nature Portfolio

Recent studies have reported the total synthesis of indolosesquiterpenoids featuring divergent routes to elaborate complex carbazole cores. Two distinct radical cyclisation tactics were employed to forge trans-decalin frameworks, followed by late-stage oxidation to introduce hydroxyl functionality, enabling antiviral evaluation against herpes simplex virus. In another development, a tandem C–H oxidation/cyclization/rearrangement sequence has been applied to isochroman-derived substrates, delivering tricyclic benzoxa scaffolds in enantioenriched form and facilitating the asymmetric syntheses of brussonol and przewalskine E. These works exemplify how coupling multiple bond-forming events in one operation can enhance step economy and stereocontrol.

Total Synthesis Strategies for Natural Products and Derivatives publication trend

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

Technical terms

Total synthesis: The complete chemical construction of a complex natural product from simple starting materials.

Convergent strategy: A synthetic design in which independent fragments are assembled separately before a key coupling step.

Linear strategy: A sequential synthetic route in which each step builds directly on the previous intermediate.

Retrosynthesis: The process of deconstructing a target molecule into simpler precursors by imagining reverse reactions.

C–H activation: Catalytic functionalisation of typically inert carbon–hydrogen bonds to form new C–X bonds.

Tandem reaction: A sequence of two or more bond-forming transformations carried out in a single operation without intermediate isolation.

References

1. Total synthesis and antiviral activity of indolosesquiterpenoids from the xiamycin and oridamycin families. Nature Communications (2015).
2. Tandem C–H oxidation/cyclization/rearrangement and its application to asymmetric syntheses of (−)-brussonol and (−)-przewalskine E. Nature Communications (2015).
3. Biorenewable Deep Eutectic Solvent for Selective and Scalable Conversion of Furfural into Cyclopentenone Derivatives. Molecules (2018).
4. Applications of ultrasound in total synthesis of bioactive natural products: A promising green tool. Ultrasonics Sonochemistry (2021).
5. Applications of Friedel–Crafts reactions in total synthesis of natural products. RSC Advances (2018).