The van Gemmeren
Research Lab
Research
In the van Gemmeren Lab we are interested in the development of Catalyst Controlled Selective Transformations and Ligand Design.
Our motivation derives from the observation that for many chemical processes the respective scopes are limited by the inherent preferences of the substrates employed or even restricted to specifically engineered substrate classes. This is particularly true in such timely research areas as C–H activation methodologies, but also extends to other areas of synthetic organic chemistry. While C–H activation reactions bear the potential to substantially improve the efficiency of organic synthesis, their inherent advantages are in practice often outweighed by limitations such as the need for complex directing groups (DGs) that have to be introduced into the substrate before the desired reaction and removed again afterwards. Our research program aims to address this situation and develop C–H activation processes that do not suffer from these limitations, but employ simple, DG-free substrates or simple DGs that occur naturally in the substrate and product structures. To achieve these goals, the group targets the rational design of novel ligands, catalysts, and reaction conditions. Additionally, the group makes use of the cutting-edge screening technologies available at the institute in the optimization of the methodologies developed.
Ultimately, the research conducted in the van Gemmeren Lab aims to open up for novel approaches towards valuable chemical compounds that would otherwise not be accessible with a comparable efficiency.
The Direct Activation of Aliphatic C-H Bonds in Free Carboxylic Acids
The functionalization of aliphatic carboxylic acid constitutes an attractive synthetic goal due to the prevalence of carboxylic acids in biologically active compounds and as key synthetic intermediates. The functionalization of carboxylic acids through C–H activation bears particular potential since its regioselectivity is inherently complementary to established routes. Considering the challenges associated with free carboxylic acids as directing groups,[25,31] many methods rely on the introduction of a more strongly directing exogenous directing group. Our research program is directed towards the direct use of free carboxylic acids without such exogenous directing groups. For example, we have contributed a β-C(sp3)–H arylation of free carboxylic acids,[23] the first intermolecular acyloxylation of aliphatic carboxylic acids,[29] a direct alkynylation of carboxylic acids[35], and a late-stage deuteration of carboxylic acids.[43]
The selective functionalization of distal positions represents a substantial challenge in the field of C–H activation. Such activations are linked to kinetically disfavored ring sizes and lower stabilities of the intermediate metallacycles. In this context, we described the first direct olefination of free carboxylic acids in the γ-position.[32] Through a subsequent intramolecular cyclisation this method gives access to a broad spectrum of δ-lactones.
The Arene-Limited Nondirected C-H Activation/Functionalization of Arenes.
Despite the fact that nondirected C–H activations of arenes by palladium had been known for a long time, such methods had received comparably less attention than related processes with directing groups. Such methods have traditionally required the use of an excess of the arene component to induce a sufficient reactivity, which limited their applicability to simple arenes.[26] We have designed palladium catalysts that overcome this limitation through the cooperative action of two complementary ligands (a pyridine-derivative and an N-acyl amino acid).[50]
Interestingly, in these methods the regioselectivity proved to be comparably sensitive to steric effects and at the same time less sensitive to electronic effects than for related methods. These catalysts have already allowed us to develop a number of synthetically useful transformations, such as an arene-limited nondirected olefination,[24] cyanation,[28] as well as alkynylation[30] of arenes. Similarly, heteroarenes can be functionalized with steric control.[33],[39] Detailed mechanistic investigations[42] allowed us to extend this reactivity to isotopic labelling,[44] a sterically controlled iodination of arenes,[48] and a charge-controlled olefination.[47] In all of these cases it is particularly noteworthy that the products obtained differ from those accessible from traditional synthetic approaches such as aromatic substitution or directed functionalization.