Donor–Acceptor Cyclopropanes in Organic Synthesis

Donor–acceptor cyclopropanes are three-membered ring systems bearing an electron-donating substituent on one carbon and an electron-withdrawing substituent on another. The juxtaposition of these groups polarises the ring, lowers the activation barrier for ring-opening processes and unlocks a wide array of transformations. Upon activation by Lewis acids, photoredox catalysts or electrochemical methods, donor–acceptor cyclopropanes undergo selective C–C bond cleavage to deliver 1,3-difunctionalized products, spirocyclic frameworks and heterocyclic scaffolds. This versatile reactivity enables rapid assembly of complex architectures found in natural products and drug candidates. The release of ring strain provides a thermodynamic driving force, while the polarisation directs regiochemistry and, in many cases, stereochemistry. Modern developments have extended this platform to photoredox-driven radical cation pathways, electrochemical ring-opening, and enantioselective cycloadditions. Together these advances underscore the global significance of donor–acceptor cyclopropanes as modular synthons for convergent synthesis and late-stage functionalisation.

Research from Nature Portfolio

Recent studies have harnessed photoredox activation to effect C–C bond cleavage of arylcyclopropanes under visible light. A single-electron oxidation generates a radical cation intermediate, which undergoes an SN2-like nucleophilic attack to furnish sterically congested C(sp3)–heteroatom bonds, including ethers, amines and azides, with complete stereoinversion. This method broadens access to densely functionalised motifs under mild conditions. In a complementary development, electrochemical C–C bond cleavage of arylcyclopropanes under catalyst- and oxidant-free conditions has been achieved. Anodic oxidation produces a radical cation that collapses to a benzyl cation, enabling 1,3-difunctionalisation such as difluorination, oxyfluorination and dioxygenation with high chemo- and regioselectivity. These approaches exemplify reagent-free activation and underscore the potential for scalable, green processes. Foundational work on spirocyclopropyl oxindoles has also demonstrated a catalytic enantioselective [3+3] cycloaddition with nitrones, offering an efficient route to spirocyclic oxindoles bearing tetrasubstituted stereocentres, a motif of considerable pharmaceutical interest.

Donor–Acceptor Cyclopropanes in Organic Synthesis publication trend

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

Technical terms

Donor–acceptor cyclopropane: A three-membered ring with both electron-donating and electron-withdrawing substituents that polarise the C–C bonds and facilitate selective ring opening.

Ring strain: The increased energy stored in small rings due to bond angle compression, which drives ring-opening reactions.

Photoredox catalysis: Activation of substrates by light-induced single-electron transfer mediated by a photocatalyst.

Radical cation: A positively charged species bearing an unpaired electron, formed by oxidation in photoredox or electrochemical processes.

SN2-like mechanism: A concerted nucleophilic substitution pathway involving simultaneous bond cleavage and bond formation, often operative in ring-opening of cyclopropanes.

References

1. Photoredox-catalyzed C–C bond cleavage of cyclopropanes for the formation of C(sp3)–heteroatom bonds. Nature Communications (2022).
2. Electrochemical C−C bond cleavage of cyclopropanes towards the synthesis of 1,3-difunctionalized molecules. Nature Communications (2021).
3. Diastereo- and enantioselective [3 + 3] cycloaddition of spirocyclopropyl oxindoles using both aldonitrones and ketonitrones. Nature Communications (2017).
4. Rh(I)-Catalyzed Regio- and Enantioselective Ring Opening of Vinyl Cyclopropanes. Journal of the American Chemical Society (2024).
5. (4+3) Annulation of Donor‐Acceptor Cyclopropanes and Azadienes: Highly Stereoselective Synthesis of Azepanones. Angewandte Chemie International Edition (2022).
6. Protic Ionic Liquid as Reagent, Catalyst, and Solvent: 1‐Methylimidazolium Thiocyanate. Angewandte Chemie International Edition (2021).