Synthesis Strategies for Polycyclic Ether Natural Products

Polycyclic ether natural products exhibit intricate architectures featuring multiple oxygen-containing rings linked in ladder, spirocyclic or bridged motifs. Synthetic strategies blend linear and convergent approaches to achieve these frameworks with high stereochemical fidelity. Biomimetic epoxide-opening cascades remain a central tactic, enabling rapid ring assembly via regioselective activation of epoxides under acid or neutral conditions. Metal-catalysed methods such as ring-closing metathesis and Tsuji–Trost allylation construct medium- and large-sized oxacycles with precise diastereocontrol, while Prins and Friedel–Crafts cyclisations build 1,3-dioxane and tetrahydropyran subunits. Emerging biocatalytic routes employ engineered enzymes to catalyse Baldwin-rule-guided cyclisations, reducing reliance on protecting groups and harsh reagents. Radical cyclisations and ring-expansion sequences extend access to seven- and eight-membered polyethers. Throughout, protecting-group strategies and orthogonal activation schemes orchestrate multistep assemblies. These advances underpin syntheses of therapeutics, marine toxins and pheromones, offering scalable pathways to bioactive molecules and informing future drug discovery.

Research from Nature Portfolio

Recent studies have exploited in silico enzyme design to reprogramme epoxide hydrolases for Baldwin-rule cyclisations. Rational mutagenesis of active-site residues suppresses native hydrolytic activity and directs intramolecular nucleophilic attack of hydroxy- or amino-substituted epoxides. The resulting biocatalysts achieve ring closure to chiral six-membered O-heterocycles with up to 99% conversion and enantiomeric ratios exceeding 99:1. Structural and computational analyses elucidate substrate positioning within reshaped active sites, guiding the development of sustainable, highly selective routes to polycyclic ethers.

Synthesis Strategies for Polycyclic Ether Natural Products publication trend

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

Technical terms

Polycyclic ether: A compound containing two or more interconnected oxygen-bearing rings.

Epoxide-opening cascade: A sequence of intramolecular epoxide ring openings that simultaneously forms multiple ether rings.

Baldwin rules: Predictive guidelines for the favoured pathways in ring-closure reactions based on ring size and bond geometry.

Prins reaction: An acid-catalysed coupling of an aldehyde with an alkene to yield oxygen-containing rings, typically 1,3-dioxanes.

Ring-closing metathesis: A metal-catalysed process that forms cyclic alkenes by reorganising terminal olefins via a metal carbene intermediate.

Biocatalysis: The use of enzymes, often engineered, to perform chemical transformations with high selectivity under mild conditions.

References

1. Hydroxymethylation hydroxylation of 1,3-diarylpropene through a catalytic diastereoselective Prins reaction: cyclization logic and access to brazilin core. Natural Products and Bioprospecting (2024).
2. Rational enzyme design for enabling biocatalytic Baldwin cyclization and asymmetric synthesis of chiral heterocycles. Nature Communications (2022).
3. Synthesis of Marine Polycyclic Polyethers via Endo-Selective Epoxide-Opening Cascades. Marine Drugs (2010).
4. Stereoselective Synthesis of Medium-Sized Cyclic Ethers by Sequential Ring-Closing Metathesis and Tsuji–Trost Allylation. Organic Letters (2018).
5. Unified synthesis of NOPQ and STUV rings of brevisulcenal-F. Chemistry Letters (2024).
6. Advancements in the synthesis of polyoxygenated oxepanes and thiepanes for applications to natural products. Organic Chemistry Frontiers (2024).