Person:

Rötheli, Andreas René

Over the past decade, organocatalysis has emerged as a thriving area of research in the field of small-molecule asymmetric catalysis. In this context, the development of highly efficient catalysts—i.e. TON ≥ 1000, TOF ≥ 1000 h-1—that enable scalable syntheses of valuable chiral building blocks remains a challenge. The dissertation presented herein discusses the prospects of using chiral dual hydrogen bond donors with anion-binding abilities to address this problem. This strategy is particularly fascinating and bears great promise, as these catalysts have been shown to operate by the same principles (e.g. hydrogen bonding-, electrostatic-, steric-, cation-π interactions) that Nature uses to promote catalysis with some of her most active and selective enzymes.

In the first chapter, a simple yet highly efficient anion-binding thiourea catalyst that promotes additions of enolate equivalents to N-acylpyridinium ions is described. This methodology enabled the regio-, diastereo-, and enantioselective preparation of interesting 1,4- and 1,6-dihydropyridines, starting from nicotinic acid derivatives. Detailed mechanistic studies revealed an intriguing kinetic scenario, wherein the catalytic rate was independent of the catalyst loading. Furthermore, co-crystallographic evidence between the thiourea and an N-alkylpyridinium chloride model substrate implicated potential key interactions responsible for stereo- and regioselectivity during the addition step. Of much broader significance, this method represents one of the most efficient—i.e. catalyst loadings as low as 0.025 mol%—organocatalytic systems discovered to date.

Inspired by the ultra-low catalyst loadings utilized during nucleophilic additions to N-acylpyridinium ions, the remainder of the thesis is dedicated towards uncovering mechanistic and structural features critical to the design of new and highly effective anion-binding organocatalysts. In this vein, the thermodynamic parameters behind fundamental anion-binding and anion-abstraction processes, using isothermal titration calorimetry and a newly developed UV/Vis spectrophotometric assay, were characterized and quantified. From our investigations, it was gleaned that under catalytic conditions dual hydrogen bond donors such as ureas, thioureas, squaramides and guanidinium ions preferred to adopt a 2:1-binding stoichiometry with chloride anions. In conjunction with kinetic studies, a mathematical correlation between anion-abstraction and catalysis in a model system supported the initial hypothesis that stronger anion-binding catalysts would lead to improved reactivity. Additionally, the thermodynamic studies allowed for the quantification of newly discovered catalyst-catalyst- and catalyst-substrate interactions.

Finally, the design of novel cholic acid-derived hydrogen bond donor catalysts with exceptional chloride-binding affinity and unprecedented kinetic activity in a variety of challenging nucleophilic addition reactions, is disclosed. Binding experiments in solution and the solid state confirmed a tight 1:1-binding complex between the catalysts and chloride anions. Furthermore, this new family of hydrogen bond donors achieved the overarching goal of this thesis: the development of highly efficient organocatalysts for synthetically relevant transformations. This was demonstrated by promoting reactions between highly reactive carbocations and weakly nucleophilic olefins at parts per million catalyst loadings within short reaction times.