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Vasco, A. V.; Méndez, Y.; González, C.; Pérez, C. S.; Reguera, L.; Wessjohann, L. A.; Rivera, D. G.; Advancing multicomponent strategies to macrobicyclic peptides ChemBioChem 24 e202300229 (2023) DOI: 10.1002/cbic.202300229
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Macrocyclization of peptides is typically used to fix specific bioactive conformations and improve their pharmacological properties. Recently, macrobicyclic peptides have received special attention owing to their capacity to mimic protein structures or be key components of peptide-drug conjugates. Here, we describe the development of novel synthetic strategies for two distinctive types of peptide macrobicycles. A multicomponent macrocyclo-dimerization approach is introduced for the production of interconnected β-turns, allowing two macrocyclic rings to be formed and dimerized in one pot. Also, an on-resin double stapling strategy is described for the assembly of lactam-bridged macrobicycles with stable tertiary folds.

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Pick, L. M.; Wenzlaff, J.; Yousefi, M.; Davari, M.; Ansorge-Schumacher, M.; Lipase‐mediated conversion of protecting group silyl ethers: An unspecific side reaction ChemBioChem 24 e202300384 (2023) DOI: 10.1002/cbic.202300384
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Silyl ether protecting groups are important tools in organic synthesis, ensuring selective reactions of hydroxyl functional groups. Enantiospecific formation or cleavage could simultaneously enable the resolution of racemic mixtures and thus significantly increase the efficiency of complex synthetic pathways. Based on reports that lipases, which today are already particularly important tools in chemical synthesis, can catalyze the enantiospecific turnover of trimethylsilanol (TMS)-protected alcohols, the goal of this study was to determine the conditions under which such a catalysis occurs. Through detailed experimental and mechanistic investigation, we demonstrated that although lipases mediate the turnover of TMS-protected alcohols, this occurs independently of the known catalytic triad, as this is unable to stabilize a tetrahedral intermediate. The reaction is essentially non-specific and therefore most likely completely independent of the active site. This rules out lipases as catalysts for the resolution of racemic mixtures alcohols through protection or deprotection with silyl groups.

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