H-bond donor catalysts able to modulate the reactivity of ionic substrates for asymmetric reactions have gained great attention in the past years, leading to the development of cooperative multidentate H-bonding supramolecular structures. However, there is still a lack of understanding of the forces driving the ion recognition and catalytic performance of these systems. Herein, insight into the cooperativity nature, anion binding strength, and folding mechanism of a model chiral triazole catalyst is presented. Our combined experimental and computational study revealed that multi-interaction catalysts exhibiting weak binding energies (approximate to 3-4 kcal mol(-1)) can effectively recognize ionic substrates and induce chirality, while strong dependencies on the temperature and solvent were quantified. These results are key for the future design of catalysts with optimal anion binding strength and catalytic activity in target reactions.

A general and highly enantioselective synthesis of oxygen heterocycles from readily available in situ generated pyrylium derivatives has been realized by embracing a multi-coordination approach with helical anion-binding tetrakistriazole catalysts. The high activity of the tetrakistriazole (TetraTri) catalysts, with distinct confined anion-binding pockets, allows for remarkably low catalyst loadings (down to 0.05 mol %), while providing a simple access to chiral chromanones and dihydropyrones in high enantioselectivities (up to 98:2 e.r.). Moreover, experimental and theoretical studies provide new insights into the hydrogen-donor ability and key binding interactions of the TetraTri catalysts and its host:guest complexes, suggesting the formation of a 1:3 species.

AbstractEine allgemeine und hoch enantioselektive Synthese von Sauerstoffheterocyclen aus in situ leicht zugänglichen Pyryliumderivaten wurde durch einen multi‐koordinierenden Triazol‐basierten Anionenbindungskatalyse‐Ansatz realisiert. Die hohe Aktivität der helikalen Tetrakistriazolkatalysatoren (TetraTri) ermöglicht durch diverse Anionenbindungstaschen bemerkenswert niedrige Katalysatorbeladungen (bis zu 0.05 Mol%) und bietet einen einfachen Zugang zu chiralen Chromanonen und Dihydropyronen mit hohen Enantioselektivitäten (bis zu 98:2 e.r.). Darüber hinaus liefern experimentelle und theoretische Studien neue Einblicke in die H‐Donor‐Fähigkeit und wichtige Bindungswechselwirkungen der TetraTri‐Katalysatoren und ihrer Wirt‐Gast‐Komplexe, die auf die Bildung einer 1:3‐Spezies schließen lassen.

A metal-free synthesis of biologically important benzazepines is achieved through a single synthetic operation involving an oxidative C-H bond functionalization and ring expansion with diazomethanes as key reagent. This represents a new, strong methodology for the straightforward construction of the seven-ring N-heterocyclic structures under mild conditions using a 2,2,6,6-tetramethylpiperidine 1-oxyl (TEMPO) oxoammonium salt as oxidant. Moderate to good yields are achieved from simple, readily available tetrahydroisoquinolines, and this methodology has been further successfully applied for the synthesis of the 3-benzazepine drug Lorcaserin. A possible mechanistic pathway for the ring expansion step, comprising the extrusion of nitrogen in a concerted asynchronic process, is proposed based on both mechanistic proof and density function theory (DFT) calculations.

Easily accessible and tunable chiral triazoles have been introduced as a novel class of C-H bond-based H-donors for anion-binding organocatalysis. They have proven to be effective catalysts for the dearomatization reaction of different N-heteroarenes. Although this dearomatization approach represents a powerful strategy to build chiral heterocycles, to date only a few catalytic methods to this end exist. In this work, the organocatalyzed enantioselective Reissert-type dearomatization of isoquinoline derivatives employing a number of structurally diverse chiral triazoles as anion-binding catalysts was realized. The here presented method was employed to synthesize a number of chiral 1,2-dihydroisoquinoline substrates with an enantioselectivity up to 86:14 e.r. Moreover, a thorough study of the determining parameters affecting the activity of this type of anion- binding catalysts was carried out.

The first anion-binding organocatalyzed enantioselective Reissert-type dearomatization of diazarenes has been developed. This reaction represents a synthetic challenge since diazarenes have various reactive sites. The use of a chiral tetrakistriazole as a C-H-based hydrogen-donor catalyst allowed the straightforward highly regio- and enantioselective synthesis of a variety of chiral diazaheterocycles.