Organocatalytic Annulations in Organic Synthesis

Organocatalytic annulations represent a powerful strategy for the construction of cyclic frameworks using exclusively organic catalysts. By leveraging chiral amines, phosphines or cinchona alkaloid derivatives, these methods combine dual activation of electrophiles and nucleophiles to promote cycloaddition processes such as [4 + 2] and [3 + 2] annulations. Central to many protocols are Morita–Baylis–Hillman adducts, which serve as versatile partners in ring-forming reactions that deliver complex polycyclic scaffolds with high diastereo- and enantioselectivity. Recent innovations have extended the repertoire of organocatalytic annulations to include cascade and domino sequences, enabling the rapid assembly of multiple bonds and stereocentres in a single operation. The operational simplicity, sustainability and broad substrate scope of organocatalytic annulations continue to drive their adoption in the synthesis of natural products, pharmaceuticals and advanced materials.

Research from Nature Portfolio

Recent studies have demonstrated the enantioselective allylic alkylation of Morita–Baylis–Hillman carbonates with anthrones under cinchona alkaloid catalysis, achieving excellent yields and enantioselectivities without the need for metals. By finely tuning the alkaloid scaffold, this work extends the scope of Lewis base organocatalysis to new electrophilic partners and elaborates chiral centres adjacent to aromatic carbonyl systems. The methodology showcases the continued evolution of metal-free annulation strategies and their applicability to complex molecule construction.

Organocatalytic Annulations in Organic Synthesis publication trend

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

Technical terms

Organocatalysis: Catalysis of reactions by small organic molecules devoid of metal centres.

Annulation: A reaction that forms a ring by creating two new covalent bonds, often via cycloaddition.

Morita–Baylis–Hillman (MBH) adduct: An allylic alcohol or ether generated from the coupling of activated alkenes and aldehydes, used as an electrophilic building block in annulations.

Diastereoselectivity: The preferential formation of one diastereomer over another in a chemical reaction.

Diels–Alder cycloaddition: A thermal pericyclic reaction between a conjugated diene and a dienophile to yield a six-membered ring.

References

1. Substrate-Controlled Diversity-Oriented Synthesis of Novel Polycyclic Frameworks via [4 + 2] and [3 + 2] Annulations of Ninhydrin-Derived MBH Adducts with 3,4-Dihydroisoquinolines. Molecules (2023).
2. Phosphine-Catalyzed Domino Regio- and Stereo-Selective Hexamerization of 2‑(Bromomethyl)acrylates to 1,2-Bis(cyclohexenyl)ethenyl Derivatives. Organic Letters (2023).
3. Expanding the scope of Metal-Free enantioselective allylic substitutions: Anthrones. Scientific Reports (2015).