Macrocycles, rings with 12 or more atoms, are widespread in natural products and engineered therapeutics. Chiral macrocycles open new pharmacological avenues, but their synthesis remains a formidable challenge. Converting a flexible linear precursor into a macrocyclic product reduces conformational freedom while introducing torsional and transannular strain, favoring intermolecular oligomerization over the desired ring closure. Installing stereogenic centers during macrocyclization compounds the challenge. Conventional approaches rely on stereochemical bias embedded in the linear precursor to relay configuration to newly formed centers through conformational preorganization or coordination to a catalyst or stoichiometric reagent. This strategy often yields unpredictable stereochemical outcomes and requires cumbersome synthesis of stereochemically defined starting materials. An ideal macrocyclization would use a catalyst to control newly formed stereogenic centers while cyclizing achiral substrates, at best even overriding preexisting stereochemical bias in chiral precursors.
Researchers in the Wennemers Group at ETH Zürich, published in Science, developed a bifunctional tripeptide catalyst that templates head-to-tail macrocyclizations through dual substrate engagement. The organocatalyst bears a secondary amine for covalent enamine formation with a terminal aldehyde and a carboxylic acid for hydrogen bonding to a terminal ketovinyl ester or amide. This bifunctional architecture tethers the reactive termini in a conformation conducive to intramolecular stereoselective carbon-carbon bond formation. The team optimized the catalyst structure through systematic variation, identifying H-dPro-αMePro-Glu-NH2 as the most effective. At just 3 mol% loading in chloroform and isopropanol at 2.5 millimolar substrate concentration, this tripeptide converted an achiral linear precursor to a 16-membered macrocyclic lactone in 97% yield with greater than 20:1 diastereoselectivity and 99% enantiomeric excess. The macrocycle-to-dimer ratio reached 37:1, suppressing intermolecular oligomerization. The catalyst operates in greener ethyl acetate with only modest erosion in selectivity.
The methodology furnishes 12- to 18-membered macrocycles with consistently high stereoselectivity. Ring sizes of 13 atoms and larger formed in 92 to 97% yield with greater than 20:1 diastereoselectivity and 99% enantiomeric excess. The 12-membered ring, bearing the highest calculated ring strain, formed with a lower macrocycle-to-dimer ratio, yet still with 78% isolated yield. Computational analysis revealed an inverse correlation between the macrocycle-to-dimer ratio and ring strain, corroborating the rising enthalpic penalty for smaller rings. The stereochemical outcome follows a Re/Re facial approach of an s-trans, E-configured enamine intermediate onto the E-configured acceptor, consistent with the observed (S,R)-configuration. The method tolerates electron-rich and electron-deficient aromatic substituents, aliphatic ketones, catechol, alkyne, and lactam functionality. Macrocycles bearing amide bonds alongside esters formed with excellent selectivity despite potential competing hydrogen bonding interactions with the catalyst. The aldehyde moiety in the products serves as a versatile handle. Hydrazone formation proceeded quantitatively, oxidation yielded carboxylic acids for peptide coupling, and rhodium-mediated decarbonylation excised the formyl group to access synthetically challenging alpha-substituted macrolactones.
Most remarkably, the catalyst dictates stereochemistry even when cyclizing chiral linear precursors. Combining an (R)-configured substrate bearing a stereogenic center adjacent to an ester with the catalyst H-dPro-αMePro-Glu-NH2 yielded the 12-membered macrocycle with (S,R)-configuration at the newly formed centers in 93% yield and greater than 99% enantiomeric excess. Using the enantiomeric catalyst with the same (R)-configured substrate delivered the diastereoisomeric macrocycle with (R,S)-configuration in 92% yield and greater than 99% enantiomeric excess, demonstrating complete catalyst control over stereochemical induction. Thus, this stereodivergent strategy accesses diastereoisomeric macrocycles from a single chiral precursor without altering reaction conditions. The team showcased utility by synthesizing the core of robotnikinin, a pharmacophore that selectively binds Sonic Hedgehog protein, with orthogonal handles for downstream diversification and structure-activity relationship studies. This peptide-catalyzed approach provides a practical, predictable route to chiral macrocycles for medicinal chemistry and materials science.
