Final Report Summary - HIPOCAT (High Performance Lewis Acid Organocatalysis)
Organocatalysts function by donating or removing electrons or protons, defining four distinct activation modes: Brønsted base catalysis, Brønsted acid catalysis, Lewis base catalysis, and Lewis acid catalysis. While the vast majority of organocatalysts, including amines, carbenes, and phosphines, act as Lewis bases, Brønsted acid and base organocatalysis is also growing strongly. Remarkably though, the area of organic Lewis acid catalysis has been left almost unexplored. This is understandable considering how few organic functional groups are Lewis acidic and yet how many inorganic, typically metal-based, asymmetric Lewis acid catalysts have already been described. While such inorganic chiral Lewis acids are often not very active catalysts, analogous Lewis acid organocatalysts were essentially none existent at the outset of these studies. A common feature of the majority of asymmetric Lewis acid catalysed processes is that they require relatively high catalyst loadings of typically 10 to even 20 mol%. The resulting comparably low turnover numbers are due to the strong Lewis acid-base interaction of such catalysts with Lewis basic substrates and products causing the catalyst-product dissociation to become rate determining, inhibiting a more rapid turnover. The low rates in combination with the sensitivity to air and moisture of typical chiral Lewis acid catalyzed reactions hampers their wider use in the chemical and pharmaceutical industries.
The List group has pioneered the concept of asymmetric counteranion directed catalysis (ACDC), a generalization of asymmetric Brønsted acid catalysis. Thus, catalytic reactions proceeding via cationic intermediates can be conducted in an asymmetric fashion if a chiral non-racemic counteranion is incorporated into the catalyst. Recent findings of the List group showed that this concept can be used for Lewis acid organocatalysis, which in fact inherits a vast potential for high performance asymmetric catalysis. Thus the goals of this research project were: The design of novel organic Lewis acid catalysts, their exploration in high performance asymmetric catalysis, and their mechanistic understanding. This program has paved the way towards the next generation organocatalysts, which will rival the efficiency of the most active metal- and biocatalysts, while retaining many of their advantages.
To extend the applicability of the disulfonimide catalysis, various new disulfonimide catalysts were synthesized, which were then used to develop a variety of reactions between aldehydes and silicon-containing nucleophiles. These reactions highlighted the vast potential of Lewis acid organocatalysis in overcoming the challenges traditionally faced in asymmetric Lewis acid catalysis. The applications of disulfonimides for the activation of aldehydes encompass enantioselective vinylogous and bisvinylogous Mukaiyama aldol, hetero-Diels-Alder and Hosomi-Sakurai reactions as well as the first catalytic asymmetric Abramov reaction and direct three component amino allylations. All reactions proved to be suitable for various aromatic aldehydes and nucleophiles giving good to excellent yields and enantioselectivities in most cases. It should be noted that catalyst loadings of typically 1-5 mol% were utilized in these reactions, instead of 10-20 mol% as normally required in metal based Lewis acid catalysis. Chiral disulfonimides were found to serve not only as effective pre-catalysts in silicon-based Lewis acid catalysis but also as stronger Brønsted acid catalysts in the asymmetric Torgov cyclization, the reduction of N-alkyl imines and N-H imines. Using disulfonimides as Brønsted acids led to the first successful reduction of N-alkyl imines with Hantzsch esters as a hydrogen source with high yields and excellent enantioselectivities.
Beyond the now broadly expanded and in the meantime commercially available catalyst class of disulfonimides, the new catalyst class of imidodiphosphoric acids was developed during the course of the project, confined Brønsted acid catalysts containing an extremely sterically demanding chiral microenvironment. The next generation of disulfonimide catalysts led to (biaryl)hydroxyl acids that proved to be exceptionally active Lewis acid precursors allowing for catalysis rates unprecedented in Lewis acid organocatalysis. Most recently a new catalyst class was successfully developed, the C–H acids that consist of binaphthyl-allyl-tetrasulfones and upon in-situ silylation were found to be exceptionally active Lewis acid catalysts for enantioselective Diels–Alder reactions of cinnamates with cyclopentadiene.
Mechanistic studies were also conducted, which support the catalytic cycle originally suggested for our disulfonimide catalyzed Mukaiyama aldol reaction. The mechanism features an in situ activation of the Brønsted acidic disulfonimide to its catalytically active silylated form and a catalytic cycle involving ion pairs of silylated substrate/product and the disulfonimide counteranion.
In a long term perspective, this work is expected to result in processes, which feature low to very low catalyst loadings, catalyst recyclability, high yields and enantioselectivities and a broad substrate scope, rendering the systems described highly attractive for industrial purposes.
The List group has pioneered the concept of asymmetric counteranion directed catalysis (ACDC), a generalization of asymmetric Brønsted acid catalysis. Thus, catalytic reactions proceeding via cationic intermediates can be conducted in an asymmetric fashion if a chiral non-racemic counteranion is incorporated into the catalyst. Recent findings of the List group showed that this concept can be used for Lewis acid organocatalysis, which in fact inherits a vast potential for high performance asymmetric catalysis. Thus the goals of this research project were: The design of novel organic Lewis acid catalysts, their exploration in high performance asymmetric catalysis, and their mechanistic understanding. This program has paved the way towards the next generation organocatalysts, which will rival the efficiency of the most active metal- and biocatalysts, while retaining many of their advantages.
To extend the applicability of the disulfonimide catalysis, various new disulfonimide catalysts were synthesized, which were then used to develop a variety of reactions between aldehydes and silicon-containing nucleophiles. These reactions highlighted the vast potential of Lewis acid organocatalysis in overcoming the challenges traditionally faced in asymmetric Lewis acid catalysis. The applications of disulfonimides for the activation of aldehydes encompass enantioselective vinylogous and bisvinylogous Mukaiyama aldol, hetero-Diels-Alder and Hosomi-Sakurai reactions as well as the first catalytic asymmetric Abramov reaction and direct three component amino allylations. All reactions proved to be suitable for various aromatic aldehydes and nucleophiles giving good to excellent yields and enantioselectivities in most cases. It should be noted that catalyst loadings of typically 1-5 mol% were utilized in these reactions, instead of 10-20 mol% as normally required in metal based Lewis acid catalysis. Chiral disulfonimides were found to serve not only as effective pre-catalysts in silicon-based Lewis acid catalysis but also as stronger Brønsted acid catalysts in the asymmetric Torgov cyclization, the reduction of N-alkyl imines and N-H imines. Using disulfonimides as Brønsted acids led to the first successful reduction of N-alkyl imines with Hantzsch esters as a hydrogen source with high yields and excellent enantioselectivities.
Beyond the now broadly expanded and in the meantime commercially available catalyst class of disulfonimides, the new catalyst class of imidodiphosphoric acids was developed during the course of the project, confined Brønsted acid catalysts containing an extremely sterically demanding chiral microenvironment. The next generation of disulfonimide catalysts led to (biaryl)hydroxyl acids that proved to be exceptionally active Lewis acid precursors allowing for catalysis rates unprecedented in Lewis acid organocatalysis. Most recently a new catalyst class was successfully developed, the C–H acids that consist of binaphthyl-allyl-tetrasulfones and upon in-situ silylation were found to be exceptionally active Lewis acid catalysts for enantioselective Diels–Alder reactions of cinnamates with cyclopentadiene.
Mechanistic studies were also conducted, which support the catalytic cycle originally suggested for our disulfonimide catalyzed Mukaiyama aldol reaction. The mechanism features an in situ activation of the Brønsted acidic disulfonimide to its catalytically active silylated form and a catalytic cycle involving ion pairs of silylated substrate/product and the disulfonimide counteranion.
In a long term perspective, this work is expected to result in processes, which feature low to very low catalyst loadings, catalyst recyclability, high yields and enantioselectivities and a broad substrate scope, rendering the systems described highly attractive for industrial purposes.