Macrocycles are useful scaffolds in drug discovery and common among natural products. The entropic and enthalpic penalties during ring closure render the synthesis of such rings with 12 or more atoms a formidable challenge. Established methods generate planar bonds through e.g. acylation or ring-closing metathesis, moieties that do not contain a stereogenic center.
We have developed the first stereoselective organocatalytic macrocyclization.¹ Key to the controlled macrocyclization with exquisite control over the generated stereogenic centers (>20:1 d.r., 85–99% ee) is the bifunctional catalyst H-DPro-αMePro-Glu-NH₂. This tripeptide is an excellent catalyst for conjugate addition reactions, even tolerating competitive solvents and the presence of enzymes.^2–4 During the macrocyclization, the unique conformation of the peptide preorganizes the linear substrate for ring closure through synergistic non-covalent and covalent interactions. Our approach uses an intramolecular conjugate addition to form 12–18-membered macrocycles. The method tolerates a broad range of functional groups, including electron-rich and electron-poor aromatic and aliphatic substrates. The reaction proceeds with catalyst control as exemplified by macrocyclizations of enantiomeric starting materials. We highlight the value of our method for the construction of architecturally complex molecules by the synthesis of the Robotnikinin macrocyclic core with stereochemical control.

[1] Jonas W. Rackl, Linus B. Boll, Helma Wennemers Manuscript to be submitted, 2025
[2] Tobias Schnitzer, Jonas W. Rackl, Helma Wennemers Chem. Sci., 2022, 13, 8963–8967.
[3] Martin Schnurr, Jonas W. Rackl, Helma Wennemers J. Am. Chem. Soc., 2023, 145, 23275–23280.
[4] Jasper S. Möhler, Matthias Pickl, Tamara Reiter, Setfan Simić, Jonas W. Rackl, Wolfgang Kroutil, Helma Wennemers Angew. Chem. Int. Ed. 2024, e202319457.