Organocatalyst-controlled stereoselective head-to-tail macrocyclizations
Summary
Chiral macrocycles are key to the discovery of new medicines. Their synthesis is, however, challenging and typically requires the often-cumbersome installation of stereochemical features in a linear precursor. In this study, we report a catalyst-controlled stereoselective head-to-tail macrocyclization. The method utilizes a bifunctional peptide catalyst to template the terminal functional groups of the linear precursor, thereby favoring intra- over intermolecular reaction and enabling exqu
Content
# Organocatalyst-controlled stereoselective head-to-tail macrocyclizations
*Published: 2026 Feb 26*
Chiral macrocycles are key to the discovery of new medicines. Their synthesis
is, however, challenging and typically requires the often-cumbersome
installation of stereochemical features in a linear precursor. In this study, we
report a catalyst-controlled stereoselective head-to-tail macrocyclization. The
method utilizes a bifunctional peptide catalyst to template the terminal
functional groups of the linear precursor, thereby favoring intra- over
intermolecular reaction and enabling exquisite control over the stereochemistry
of the emerging stereogenic centers. Diverse 12- to 18-membered macrocyclic
lactones and lactams were obtained from achiral linear precursors. The
organocatalyst even dictates the stereochemical outcome upon cyclizing a chiral
linear precursor. This catalyst-controlled stereoselective head-to-tail
macrocyclization provides a practical route to chiral macrocycles with
predictable stereochemical outcomes. The utility was highlighted by synthesizing
the core of the natural product robotnikinin.
DOI: 10.1126/science.aec8992