Frustrierte Helizität: Zusammenführung divergierender Enden einer stabilen aromatischen Amid‐Helix zu einem fluxionalen Makrocyclus

Abstract

Die Makrocyclisierung eines stabilen zweiwindigen helikalen aromatischen Pentamids -e ine Struktur mit zwei divergierenden Enden, die nicht anfällig füreinen Ringschluss sind -w urde durch die transiente Einführung von Helizitätsstçrern in Form von säurelabilen tertiären Dimethoxybenzylamiden mçglich gemacht. Nachd em Entfernen der Helizitätsstçrern zeigen NMR-Spektroskopie,K ristallstrukturanalyse und theoretischeS tudien, dass die Makrocyclen eine gespannte Struktur besitzen,d ie sie dazu veranlasst, einen mçglichst hohen Grad an Helizitäta nzustreben, obwohl es sich immer nochumeine cyclische Struktur handelt. Zwei mçgliche Punkte füre ine solcheS tçrung in ihrer Helizitäts ind insbesondere cis-amidische Bindungen. Auff luxionale Art und Weise kçnnen sich diese Stçrungen in der Helix entlang des Makrocyclus in definierten Bahnen ausbreiten, und somit zehn degenerierte Konformationen erzeugen.

Accessing Improbable Foldamer Shapes with Strained Macrocycles

“…We have extended our trimer, [7] tetramer [7] and pentamer, [17] series of synthesized and experimentally characterized cyclic Q n oligomers to the hexamer and heptamer. Simulated annealing molecular dynamics allowed us to formulate general rules and to make reasonable predictions about the conformation behavior of longer homomeric macrocycles up to the 16mer.…”

“…We have previously taken advantage of this conformation change to produce cyclic pentamer 3 from noncyclic precursors containing two DMB groups. [17] In order to produce the equivalent hexameric and heptameric macrocycles, a series of noncyclic precursors 6 and 7 was synthesized (Scheme 2, see Supporting Information for synthetic Schemes and experimental procedures). We found that cyclization failed for all sequences containing a single DMB group and for 6 b which contains two consecutive DMB groups at the C-terminus.…”

“…shown at the same scale. [7,17] Included solvent molecules, isobutyl groups, and protons other than amide NHs have been removed for clarity. (d) Cis to trans amide conformational transition upon removing a dimethoxybenzyl group (DMB) from an aromatic amide bond.…”

“…Joining the diverging ends of these longer helices to form larger homomeric macrocycles does not occur spontaneously. In a recent report, [17] we showed that the introduction of removable 2,4-dimethoxybenzyl (DMB) substituents on some amide nitrogen atoms disrupted the helix, allowing for the cyclization of a pentamer in the same series (Scheme 1c). After DMB removal, pentamer 3 was produced and characterized (Figure 1c,d).…”

“…Chemical structures of (a) non cyclic 8-amino-2-quinolinecarboxylic acid oligoamides, and (b) macrocycles 1-5. (c) Crystal structures of 1-3shown at the same scale [7,17]. Included solvent molecules, isobutyl groups, and protons other than amide NHs have been removed for clarity.…”