The Glaser-Hay diyne coupling proved to be an efficient cyclisation approach towards diyne containing peptidic macrocycles. A variety of tetrapeptide-based macrocyclic 1,3-diynes were obtained from O-propargylated serine or tyrosine residues using Cu(OAc)2·H2O and NiCl2 under an O2-atmosphere. The effect of the linear 1,3-diyne on peptide conformations was studied by NMR and compared with a macrocycle bearing a saturated linker.

Macrocyclic tetrapeptide analogues containing a 1,3‐diyne moiety were synthesized by a Glaser–Hay‐type macrocyclization. The obtained 1,3‐diyne was evaluated as a handle to introduce heterocycles into the macrocyclic structure. It was shown that the macrocyclic 1,3‐diynes were successfully transformed into various heterocycles by nucleophilic attack of (bis)nucleophiles to the diyne moiety. Treatment with NaHS or H2O as nucleophiles gave rise to 2,5‐bridged thiophenes or furans, whereas the use of hydrazines and hydroxylamine gave rise to the corresponding pyrazole‐ and isoxazole‐containing macrocycles. In addition, a thermoreversible Diels–Alder cycloaddition of a cyclopeptidic bridged furan was demonstrated.

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The importance of axially chiral biaryls has risen steeply in the recent decades. This structural motif proved to be successful in catalytic asymmetric synthesis and the configuration of the biaryl axis is decisive for the biological activity. A new approach for the atroposelective synthesis of biaryls would be through a cycloaddition between an enantiopure phenyl‐substituted thiophene S‐oxide and an alkyne. Importantly, the chiral center of the thiophene S‐oxide needs to be stable enough to avoid pyramidal inversion during the cycloaddition. Considering that the racemization of thiophene monoxides has been scarcely investigated so far, we perform a thorough quantum chemical study on the inversion barriers of a large number of chiral thiophene S‐oxide derivatives. Our main goal is to identify substitution patterns leading to stable atropisomers at room temperature. Appealingly, the role of stereoelectronic effects and the position of the substituents as well as the importance of aromaticity on the pyramidal inversion barrier are elucidated for the first time.

Short alphahelical peptide sequences were stabilized through Glaser‐Hay couplings of propargylated l‐ and/or d‐serine residues at positions i and i+7. NMR analysis confirmed a full stabilization of the helical structure when a d‐Ser (i), l‐Ser (i+7) combination was applied. In case two l‐Ser residues were involved in the cyclization, the helical conformation is disrupted outside the peptide's macrocycle.

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