Peptide Stapling with Anion‐π Catalysts

Abstract

We report design, synthesis and evaluation of a series of naphthalenediimides (NDIs) that are bridged with short peptides. Reminiscent of peptide stapling technologies, the macrocycles are conveniently accessible by a chromogenic nucleophilic aromatic substitution of two bromides in the NDI core with two thiols from cysteine sidechains. The dimension of core-bridged NDIs matches that of one turn of an α helix. NDI-stapled peptides exist as two, often separable atropisomers. Introduction of tertiary amine bases in amino-acid sidechains above the π-acidic NDI surface affords operational anion-π catalysts. According to an enolate chemistry benchmark reaction, anion-π catalysis next to peptides occurs with record chemoselectivity but weak enantioselectivity. Catalytic activity drops with increasing distance of the amine base to the NDI surface, looser homocysteine bridges, mismatched, shortened and elongated α-helix turns, and acyclic peptide controls. Elongation of isolated turns into short α helices significantly increases activity. This increase is consistent with remote control of anion-π catalysis from the α-helix macrodipole.

Anion–π Catalysis Enabled by the Mechanical Bond**

“…These catalysts were found to be highly selective in an established benchmarking reaction for anion–π catalysis, with a dependence of catalyst activity and selectivity on the length of azide half‐axle used in the AT‐CuAAC synthesis. The selectivity obtained with readily accessible [3]rotaxane catalyst 13 is comparable to the most effective example previously reported [11f] . Control experiments demonstrated the importance of the interlocked structure and the NDI unit to catalyst selectivity.…”

“…In THF, the reaction was complete after 16 h with a high selectivity for 12 (5.9) whereas In CDCl 3 the reaction was complete in just 3 h with still higher chemoselectivity (18.6). Most strikingly, the activity of 13 remained high even at 7 °C in CDCl 3 , with only 16 h required for complete conversion of 7 and a significant further enhancement in chemoselectivity (62.3), which is one of the highest values reported to date [11f] …”

Inhibition of Thiol‐Mediated Uptake with Irreversible Covalent Inhibitors

“…Other applications include further derivatizations of cysteines, [28,29] peptide Cys‐Cys and Cys‐Lys stapling, [30] functional terminators of CPDs, [31] and classical use as alkynylation reagents in organic synthesis [32,33] . The results from irreversible inhibition of thiol‐mediated uptake with hypervalent iodine reagents are then compared to classical and modern irreversible thiol‐reactive agents [34–45] . Hypervalent iodine reagents emerge top, together with Fukuyama ’s nosyl protecting group [34] and super‐cinnamaldehyde ligands of the pain receptor TRPA1, [35] all rivaling the best reversible inhibitors.…”

Anion-π Catalysis: A Novel Supramolecular Approach for Chemical and Biological Transformations

“…These results regarding anion-π catalysis will serve as an appropriate starting material subsequent to peptides in order to be in operation in larger protein structures and development of anion-π enzymes. [28] Anion-π catalysis play a significant role in the asymmetric synthesis and leads to the generation of chiral isomers selectively. In this regard, the same group has also incorporated NDI moiety in between a carboxylate base and a proline unit for the construction of an anion-π catalyst (13).…”