Enantioselective Synthesis of Chiral Macrocycles

Chiral macrocycles encompass a broad class of large ring molecules in which the spatial arrangement of substituents confers non-superimposable mirror-image forms. These structures are found in natural products, pharmaceuticals and advanced materials, owing to their defined three-dimensional cavities and unique stereochemical properties. Enantioselective synthesis of such macrocycles seeks to establish a single enantiomer predominantly, rather than a racemic mixture, through catalytic or substrate-controlled strategies. Contemporary methods employ organocatalysts, metal complexes or enzyme mimetics to orchestrate bond formation around the ring, while controlling stereochemistry at key steps. Approaches such as desymmetrisation of prochiral precursors, dynamic kinetic resolution and asymmetric macrocyclisation have emerged as powerful tools. These techniques facilitate access to macrocycles bearing planar, axial or central chirality, enhancing their performance in asymmetric catalysis, molecular recognition and chiral optoelectronic applications. Strides in catalyst design have delivered higher enantiomeric ratios and broader substrate scopes, enabling the synthesis of medium- to large-sized rings with high stereocontrol. Ongoing developments promise to expand the chemical space of chiral macrocycles, forging new avenues in drug design, supramolecular chemistry and functional materials.

Research from Nature Portfolio

Recent studies have unveiled carbene-catalysed routes to planar-chiral macrolactones from achiral precursors, where N-heterocyclic carbenes (NHCs) mediate both macrocyclisation and stereochemical induction to yield rings of sixteen to twenty members in excellent enantiomeric purity. A complementary strategy leverages dynamic kinetic resolution under NHC catalysis to convert racemic cyclophane precursors into enantioenriched planar-chiral macrocycles, with mechanistic insights highlighting the role of reversible coordination and migratory insertion in stereocontrol. Further progress in metal-free organocatalysis has enabled desymmetrisation of prochiral paracyclophanes, affording a diverse array of enantiopure cyclophane derivatives on gram scale. These advances demonstrate the power of small-molecule catalysts in forging chiral macrocyclic frameworks without reliance on stoichiometric chiral reagents.

Enantioselective Synthesis of Chiral Macrocycles publication trend

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

Technical terms

Macrocycle: A large cyclic molecule, typically comprising more than twelve atoms in the ring. Enantioselective synthesis: A process that preferentially produces one enantiomer over the mirror-image form. Planar chirality: A form of stereoisomerism arising from restricted rotation in a plane, common in cyclophanes and paracyclophanes. Desymmetrisation: The selective transformation of a prochiral or symmetric molecule into a chiral product. Dynamic kinetic resolution: A method combining racemisation and enantioselective reaction to convert a racemic mixture into a single enantiomer. N-heterocyclic carbene (NHC): A class of neutral, strong organocatalysts featuring a divalent carbon centre within a heterocycle.

References

1. Carbene organic catalytic planar enantioselective macrolactonization. Nature Communications (2024).
2. N-Heterocyclic carbene-catalyzed enantioselective synthesis of planar-chiral cyclophanes via dynamic kinetic resolution. Nature Communications (2024).
3. Organocatalytic desymmetrization provides access to planar chiral [2.2]paracyclophanes. Nature Communications (2024).
4. Inherently chiral resorcinarene cavitands through ionic catalyst-controlled cross-coupling. Chem (2024).
5. Inherently chiral calixarenes by a catalytic enantioselective desymmetrizing cross-dehydrogenative coupling. Chemical Science (2023).
6. Enantioselective Synthesis, Crystal Structures, and Stereoisomerism of Substituted o,m,o,p‑Tetraphenylenes. Organic Letters (2024).