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.
Design of Ligands and Reagents
Besides our research immediately targeting novel C–H activation methods, we also use traditional organic synthesis, for example for preparing novel ligands and reagents. In this context, we have also disclosed new transformations that do not involve C–H activation, such as a direct conversion of α-Hydroxyketones into Alkynes,[27] or a method for the olefination of aldehydes with thiols as reaction partners.[46]
It is widely recognized that new target reactions can often only be unlocked through the design and synthesis of advanced catalysts. In the field of palladium-catalyzed C–H activation, bidentate ligands involving a basic site capable of promoting C–H activation through a concerted metallation-deprotonation (or related) mechanism have proven particularly useful. Our group has repeatedly introduced new variants of existing ligand motifs and even novel variants of this design principle, which proved crucial to our method development program.
For example, we showed that anthranilic acids can serve as an alternative backbone to amino acid derivatives allowing for further catalyst fine-tuning.[32] We also introduced unsymmetric diamine derivatives bearing one acyl and one sulfonyl group into the realm of Pd-catalyzed C–H activation[35] and discovered that N-acyl sulfonamide units are valuable anionic donor motifs.[44] These findings are complemented by the discovery that, while simple benzamides typically give inactive ligands, ortho-substituted benzamides are valuable CMD-promoting groups that can deliver higher catalyst activities than acyl groups.[43],[44],[52],[53]
The choice of a suitable reaction partner to induce the desired transformation is also essential when developing novel transformations. Often, solutions can be found using the plethora of reagents known in literature, but in some cases particularly challenging target reactions can require the design of novel reagents. For example, we have shown that a direct fluorination of aliphatic carboxylic acids can be achieved by optimizing both the ligand structure, as well as the steric and electronic properties of the oxidant.[53]
Mechanistic Studies and Screening Techniques
We are convinced that method development should always be accompanied by the quest for fundamental understanding of the underlying reaction mechanisms. Consequently, we have intensively studied the mechanisms of selected reactions developed in our labs.[32],[42],[47],[48] Based on this mechanistic knowledge we have devised screening techniques allowing us to discover novel reaction conditions/transformations with improved efficiency.[43],[44],[52]
Isotopic Labelling
One of the key tools used in our mechanistic studies is to probe the reversibility of the C–H activation elementary step through deuteration or de-deuteration reactions. In these reactions either a deuterated starting material is placed in a non-deuterated medium, or a non-deuterated starting material in a deuterated medium. The incorporation or loss of deuterium under the reaction conditions (referred to as hydrogen isotope exchange, HIE) then indicates a reversible C–H activation. Interestingly, deuterated compounds are required for a variety of applications. When our mechanistic studies uncovered the reversibility of C–H activation with our catalysts, we used our findings as a starting point to develop a series of late-stage isotopic labelling methods.[43],[44],[51],[52] These studies have triggered a number of collaborations aiming at applications of deuterated compounds prepared through our methods.
Late-Stage Functionalization
The beauty of C–H activation technologies is, that no pre-functionalization of the substrate is required. One can in principle directly introduce novel functionalities into existing complex organic compounds, which is of tremendous value in areas such as drug discovery. For this reason, we place a strong focus on the suitability of our methods for such purposes. In many cases, we could explicitly demonstrate the direct late-stage functionalization of bioactive compounds and other complex organic substrates.[24],[30],[41],[43],[44],[48],[52]