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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. Since the direct use of free carboxylic acids represents a considerable challenge,[25,31] established methods typically rely on the introduction of a more strongly directing exogenous directing group. Over the last years substantial progress could be achieved towards the direct use of free carboxylic acids. For example, we have contributed a broadly applicable β-C(sp3)–H arylation of free carboxylic acids, which tolerates a broad spectrum of α-non-quaternary substrates.[23] In a subsequent study, we could develop the first intermolecular acyloxylation of aliphatic carboxylic acids.[29]

Scheme 1.png

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. Recently, we could report on the first direct olefination of free carboxylic acids in the γ-position, which at the same time constitutes one of very few examples in which the γ-position of free carboxylic acids could be activated.[32] Through a subsequent intramolecular cyclisation this method gives access to a broad spectrum of δ-lactones.

Scheme 2.png

 

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).

Scheme 3.png

These catalysts have already allowed us to develop a number of synthetically useful transformations, such as an arene-limited nondirected olefination of arenes,[24] as well as an analogous cyanation.[28] 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 related methods.These catalysts have already allowed us to develop a number of synthetically useful transformations, such as an arene-limited nondirected olefination of arenes,[24] as well as an analogous cyanation.[28] 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 related methods.

Scheme 4.png

A transition state model derived from DFT calculations enables the rationalization of these observations. The selectivity-determining C–H activation step occurs through a concerted and highly synchronous transition state in which relatively small partial charges occur, thus limiting the influence exerted by electronic properties of the substrate. At the same time the ligands employed create a sterically congested environment on the palladium, thereby allowing for a steric control of the reaction. Building upon these observations, we have developed a sterically controlled alkynylation of arenes.[30] This method allows for the preferential functionalization of sterically favored sites in cases where electronic factors favor a different position. This method proved to be useful in the context of late-stage modification. The ability to override electronic control with steric control is also relevant for the functionalization of heteroarenes. Due to the prominent role of heteroarenes in biologically active compounds complementary tools for their regioselective functionalization are highly attractive. For example, established methods for the C–H olefination of 3-substituted five membered heteroarenes generally lead to the functionalization of the C2-position (due to electronic control for donor-substituents in the 3-position and due to a directing effect for EWG in the 3-position). In contrast, we could develop a method that through steric control favors the C5-position for a broad range of heteroarenes. Importantly, in contrast to many C–H functionalization methods for heteroarenes, this component was employed as the limiting reagent, thereby rendering our method suitable for late-stage modification.[33]

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Synthesis of Alkynes and Olefins

 

Alkynes and olefins represent key structural motifs in many organic molecules, both as the target structures and versatile synthetic intermediates. Complementing methods that deliver such compounds though C–H activation, we investigate further synthetic approaches towards these motifs, especially aiming for otherwise challenging substitution patterns and the use of simple starting materials. For example, we have developed a synthetic method that converts acyloins into internal alkynes in a single step.[27] The method exclusively relies on simple reagents and features a broad substrate scope, which includes unsymmetrical dialkyl-acetylenes that are otherwise difficult to obtain in a selective manner. A key advantage of this method is the use of acyloins as starting materials, since these are themselves easily obtained from a number of fragment coupling protocols. Overall, internal alkynes are therefore generated de novo from two separate fragments in only two steps.

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