Indeed, the group of researchers identified tripeptide H-DPro-αMePro-Glu-NH2 as the best candidate after screening common proline-based organocatalysts and optimization of the reaction conditions. In fact, this tripeptide presents an amine that enables the activation of the aldehyde moiety of the substrate as enamine; this is followed by a chiral spacer set in a β-turn conformation, and a carboxylic acid. This last moiety allows the preorganization of the linear substrate for macrocyclization and C–C bond formation thanks to its non-covalent interaction as H-donor to the vinyl ketone of the linear model substrate. In this fashion, the catalyst enables the macrocylization via 1,4-conjugate addition of 12- to 18-membered linear precursors with 20:1 diastereoselectivity and 99% enantiomeric excess, also limiting the macrocycle-to-dimer ratio to >20:1 in most cases. Computational calculations confirmed the stereochemical induction model, and the enthalpic penalties for rings smaller than 12 members that disfavours their synthesis. The researchers also expanded the scope to other Michael acceptor groups such as enamides; while the incorporation of sp2- and sp-hybridized carbons in the linear backbone does not affect the yields much, the catalyst is ultimately responsible for the reaction stereocontrol, even in the presence of backbone stereocentres. The group finally showed functionalization at the aldehyde handle, as well as applicability of the catalyst to obtain a macrocycle that is the core of robotnikinin, a pharmacophore of therapeutic interest associated with selective binding to the Sonic Hedgehog protein.
This bifunctional catalyst will certainly become a practical tool to construct macrolides of potential biomedical use, thanks to its predictive diastereoselective macrocylization of linear achiral substrates.
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