Total Synthesis and Cycloaromatization of Enediyne Compounds

The total synthesis of enediyne compounds centres on constructing the defining enediyne core—a conjugated system comprising two alkynes flanking a double bond—through a sequence of strategically orchestrated bond formations. Synthetic routes commonly employ metal-mediated couplings, radical cyclizations and tethered cycloaddition cascades to assemble strained ten- to twelve-membered rings. Once formed, these enediyne precursors undergo cycloaromatization via pathways such as the Bergman and Myers–Saito cyclizations, yielding highly reactive diradical intermediates. These intermediates can abstract hydrogen atoms or engage in intermolecular additions that install functionality onto aromatic cores. Such transformations are at the heart of both natural product mimicry and the design of responsive materials. Recent advances in protecting-group design, catalytic activation and mechanistic elucidation have expanded the scope of accessible enediynes, enabling fine control over ring size, substitution pattern and activation trigger. The synergy of innovative synthetic methods with detailed computational and kinetic studies has deepened understanding of the parameters that govern selectivity between competing cycloaromatization channels. These insights underpin applications ranging from antitumour agents—where enediyne-derived diradicals cleave DNA—to the self-assembly of conjugated nanomaterials via controlled polymerization initiated by enediyne activation. Overall, the field balances the challenge of forging strained enediyne architectures with the opportunity to harness their exceptional cycloaromatization chemistry for both medicinal and materials science.

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Total Synthesis and Cycloaromatization of Enediyne Compounds publication trend

The graph below shows the total number of articles in total synthesis and cycloaromatization of enediyne compounds across all publications each year (not limited to Nature Index journals).

Technical terms

Total synthesis: The complete chemical assembly of a complex target molecule from simple starting materials through successive bond-forming reactions.

Cycloaromatization: A reaction that converts a non-aromatic polyunsaturated precursor into an aromatic ring, often via a diradical intermediate.

Enediyne: A molecular motif featuring two conjugated alkyne units separated by an alkene, prone to cycloaromatization under suitable activation.

Bergman cyclization: A thermal cycloaromatization of enediyne compounds that forms a 1,4-diradical intermediate capable of hydrogen abstraction or cross-coupling.

Nicholas reaction: A cobalt-mediated coupling involving propargyl cations that enables cyclization of polyalkyne substrates to form cyclic enediynes under mild conditions.

References

1. (Hetero)aromatics from dienynes, enediynes and enyne–allenes. Chemical Society Reviews (2016).
2. Functionalized 10-Membered Aza- and Oxaenediynes through the Nicholas Reaction. Molecules (2022).
3. A novel sulfonamide non-classical carbenoid: a mechanistic study for the synthesis of enediynes. Organic & Biomolecular Chemistry (2017).