Nazarov Cyclization in Organic Synthesis

The Nazarov cyclization serves as a cornerstone reaction in modern synthetic organic chemistry, enabling the construction of cyclopentenone frameworks via 4π‐electron electrocyclisation of divinyl ketones under acidic conditions. Central to the process is generation of an oxyallyl cation intermediate, which undergoes conrotatory ring closure to form cyclopentane cores bearing diverse substitution patterns. The reaction has been extensively exploited for the synthesis of complex natural products, pharmaceutically relevant scaffolds and chiral building blocks, owing to its capacity for high regio‐, diastereo‐ and enantioselectivity. Advances in catalyst design have broadened substrate scope to include enones, enyne diketones and heteroatom‐substituted derivatives, while cooperative catalysis using Lewis acids and chiral Brønsted acids has delivered asymmetric variants. Interrupted Nazarov processes and tandem sequences now allow rapid assembly of polycyclic architectures and the installation of quaternary stereocentres. The methodology’s versatility has been demonstrated in both racemic and enantioselective syntheses, underscoring its global impact on the construction of bioactive molecules and complex carbocyclic frameworks.

Research from Nature Portfolio

A synergistic cascade involving a classic Nazarov cyclization followed by sequential ring expansions has been developed to access angular tricyclic frameworks containing quaternary carbon centres from 1,3-dicycloalkylidenyl ketones. This protocol features mild conditions, broad substrate tolerance and predictable stereocontrol governed by electronic and steric factors, facilitating the total synthesis of complex natural products in racemic form. In parallel, a new class of enyne diketone substrates has been introduced for asymmetric Nazarov cyclisation, combining metal‐organocatalytic relay steps to generate chiral allene cyclopentenones in high enantiomeric purity. Mechanistic studies reveal a tandem sequence of oxonium ylide formation, sigmatropic rearrangement and alkyne‐to‐allene isomerisation, culminating in an organocatalysed electrocyclisation. These studies underscore the expanding repertoire of substrate design and relay catalysis strategies for stereoselective cyclopentenone synthesis.

Nazarov Cyclization in Organic Synthesis publication trend

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

Technical terms

Nazarov cyclization: A 4π‐electron electrocyclisation of divinyl ketones under acidic conditions to form cyclopentenone rings via an oxyallyl cation intermediate.

Oxyallyl cation: A three-carbon, electron-deficient species generated during the Nazarov cyclization that undergoes conrotatory ring closure.

Divinyl ketone: A ketone bearing two vinyl groups, serving as the primary substrate in Nazarov cyclisations.

Chiral Brønsted acid: An enantioselective acid catalyst that induces asymmetry during proton transfer or cyclisation steps.

Tandem catalysis: A strategy combining sequential catalytic events in one operation, enabling cascade transformations such as relay cyclisation and rearrangements.

References

1. An efficient approach to angular tricyclic molecular architecture via Nazarov-like cyclization and double ring-expansion cascade. Nature Communications (2022).
2. Enyne diketones as substrate in asymmetric Nazarov cyclization for construction of chiral allene cyclopentenones. Nature Communications (2022).
3. Strong and Confined Acids Enable a Catalytic Asymmetric Nazarov Cyclization of Simple Divinyl Ketones. Journal of the American Chemical Society (2019).
4. Enantioselective Nazarov cyclization of indole enones cooperatively catalyzed by Lewis acids and chiral Brønsted acids. Chemical Science (2017).
5. Asymmetric synthesis of multiple quaternary stereocentre-containing cyclopentyls by oxazolidinone-promoted Nazarov cyclizations. Chemical Science (2018).