Radical Cascade Cyclization in Organic and Heterocyclic Synthesis

Radical cascade cyclization is a highly efficient strategy in modern synthetic chemistry whereby a single radical species initiates successive bond-forming events to assemble complex carbocyclic and heterocyclic frameworks in one pot. By exploiting the reactivity of transient radicals, chemists achieve rapid construction of five- to medium-sized rings, including bridged and spiro architectures that are prevalent in natural products and active pharmaceutical ingredients. Advances in photoredox catalysis, electrochemical oxidation and decarboxylative protocols have enabled these cascades under mild, sustainable conditions, often avoiding stoichiometric metals or harsh reagents. Substrates such as enynes, dienes and aryl alkenes serve as versatile radical acceptors, while control over regio- and stereochemistry is afforded by judicious choice of catalyst and reaction parameters. The global significance of radical cascade cyclization is underscored by its application in late-stage functionalisation, total synthesis and scalable industrial processes aimed at reducing waste and improving atom economy.

Research from Nature Portfolio

Recent studies have demonstrated a photoinduced decatungstate-catalysed [3+2] cycloaddition of internal alkynes with aliphatic aldehydes to furnish cyclopentanones in full atom economy under mild conditions. The sequence begins with hydrogen-atom abstraction from the aldehyde, followed by radical addition to the alkyne, a 1,5-hydrogen transfer and an anti-Baldwin 5-endo-trig cyclization, concluding with back hydrogen abstraction to deliver stereodefined products. This approach permits late-stage elaboration of medicinally relevant scaffolds and has been applied to the total or formal synthesis of complex natural products such as β-cuparenone and laurokamurene B, showcasing its versatility for diversity-oriented synthesis.

Radical Cascade Cyclization in Organic and Heterocyclic Synthesis publication trend

The graph below shows the total number of articles in radical cascade cyclization in organic and heterocyclic synthesis across all publications each year (not limited to Nature Index journals).

Technical terms

Radical cascade cyclization: A one-pot sequence in which a single radical intermediate undergoes multiple intramolecular additions and cyclizations to build polycyclic structures.

Photoredox catalysis: Use of light-activated catalysts to drive single-electron transfer processes that generate or quench radicals under mild conditions.

Hydrogen atom transfer (HAT): A mechanistic step in which a hydrogen atom (proton plus electron) moves between two species, commonly employed to generate or stabilise radicals.

Enyne: A molecule containing both an alkene (C=C) and an alkyne (C≡C) moiety, which can participate as radical acceptors in cascade reactions.

Decarboxylation: Cleavage of a carboxyl group from a molecule, releasing carbon dioxide and often producing a radical or anion intermediate.

5-endo-trig/5-exo-trig cyclization: Modes of radical-mediated ring closure defined by Baldwin’s rules; ‘endo’ indicates bond formation inside the forming ring and ‘exo’ outside, both involving a trigonal centre.

References

1. Electrosynthesis of bridged or fused sulfonamides through complex radical cascade reactions: divergence in medium-sized ring formation. Chemical Science (2023).
2. [3+2] Cycloaddition of alkyl aldehydes and alkynes enabled by photoinduced hydrogen atom transfer. Nature Communications (2022).
3. Visible-light-promoted decarboxylative radical cascade cyclization to acylated benzimidazo/indolo[2,1- a ]isoquinolin-6(5 H )-ones in water. RSC Advances (2022).
4. Traceless Thioacid-Mediated Radical Cyclization of 1,6-Dienes. The Journal of Organic Chemistry (2023).