Periodic Reporting for period 3 - LACOPAROM (Lewis acid promoted copper catalysis to functionalise and dearomatise arenes)
Période du rapport: 2021-09-01 au 2023-02-28
Aromatic compounds are cheap and readily available, making them ideal starting materials for preparing chiral alicyclic compounds, important building blocks for natural products and drug discovery. For this, however, the aromatic ring present in these compounds must be broken. This process, called dearomatisation, is difficult and there are no general, efficient catalytic strategies available for it.
This proposal aims to fill this gap by developing general asymmetric methods for dearomatisation reactions. Our innovative approach, based on activation of the arenes using Lewis acids and subsequent copper catalyzed reactions, has a special focus on environmentally friendly and cost-effective processes and allows for the first time selective catalytic asymmetric dearomatisations of various classes of aromatic molecules following a general, unified concept. Furthermore, since several reactions take place sequentially in a single operation, complex molecules can be made much cheaper and more efficiently, thereby contributing to a more sustainable future.
Consequently, there is huge potential for this strategy to become an invaluable instrument to access a wide variety of chiral carbocyclic compounds that are useful for a variety of applications, for example in the production and discovery of new drugs. To achieve this overarching goal, the following specific sub-projects are pursued:
1. Dearomatisation of electron-deficient aromatic systems
2. Dearomatisation of heteroaromatic systems
3. Dearomatisation of electron rich aromatic systems
4. Dearomatisation of benzylic aromatic systems
This proposal aims to fill this gap by developing general asymmetric methods for dearomatisation reactions. Our innovative approach, based on activation of the arenes using Lewis acids and subsequent copper catalyzed reactions, has a special focus on environmentally friendly and cost-effective processes and allows for the first time selective catalytic asymmetric dearomatisations of various classes of aromatic molecules following a general, unified concept. Furthermore, since several reactions take place sequentially in a single operation, complex molecules can be made much cheaper and more efficiently, thereby contributing to a more sustainable future.
Consequently, there is huge potential for this strategy to become an invaluable instrument to access a wide variety of chiral carbocyclic compounds that are useful for a variety of applications, for example in the production and discovery of new drugs. To achieve this overarching goal, the following specific sub-projects are pursued:
1. Dearomatisation of electron-deficient aromatic systems
2. Dearomatisation of heteroaromatic systems
3. Dearomatisation of electron rich aromatic systems
4. Dearomatisation of benzylic aromatic systems
The main focus during the period covered by this report was on sub-projects 2 and 3. Most of the effort was directed to finding solutions for the main challenges of this dearomatization chemistry: overcoming the energetic unfavourableness of dearomatisation, the compatibility of Lewis acids with carbon-nucleophiles and copper catalysis, and the control of the overall selectivity of the reaction sequence, including chemo-, regio-, and enantioselectivities.
The first part of the work was devoted to dearomatisations of heteroaromatics, compounds that play an important role in the field of heterocyclic chemistry. In sub-project 2 we aim at developing catalytic methods to dearomatise heteroaromatic compounds in order to access their saturated analogues, which are important motifs found in natural products and modern pharmaceuticals. We first studied the role of Lewis acids in weakening the heteroaromatic ring. The initial reactivity studies were carried out using relatively easier substrates, namely partially saturated heteroaromatics such as pyridones, dihydropyridones and quinolones. Subsequently the research effort was dedicated to applying what we learned to the main targets: heteroaromatics such as pyridines and quinolines. In parallel to making racemic mixtures (mixtures of mirror images) of dearomatised products, significant effort was also devoted to stereoselective processes using catalysis, since enantiopure (containing only one mirror image) compounds are crucial in many natural and farmaceutical products. For this purpose various chiral ligands were synthesized and studied in combination with copper catalysts. Finally, in this sub-project major effort was devoted to demonstrating the applicability of the developed strategy in the synthesis of biologically relevant molecules.
The second part of the work (sub-project 3) was aimed at the dearomatisation of electron rich molecules such as phenol/naphthol and aniline/naphtylamine derivatives, important substrates for dearomatisation reactions and thus building blocks for the synthesis of complex bioactive molecules. Our strategy was based on a mechanistically distinct, consecutive dearomatisation/carbon-carbon bond forming process, in which tautomerisation of these aromatic molecules plays a crucial role. Initial experiments were directed at studying this tautomerisation process and stabilizing the dearomatised keto-ketimine tautomers using Lewis acids. Following this, a variety of functionalised molecules could be accessed by reacting these stabilized products with various nucleophiles under copper catalysis.
The first part of the work was devoted to dearomatisations of heteroaromatics, compounds that play an important role in the field of heterocyclic chemistry. In sub-project 2 we aim at developing catalytic methods to dearomatise heteroaromatic compounds in order to access their saturated analogues, which are important motifs found in natural products and modern pharmaceuticals. We first studied the role of Lewis acids in weakening the heteroaromatic ring. The initial reactivity studies were carried out using relatively easier substrates, namely partially saturated heteroaromatics such as pyridones, dihydropyridones and quinolones. Subsequently the research effort was dedicated to applying what we learned to the main targets: heteroaromatics such as pyridines and quinolines. In parallel to making racemic mixtures (mixtures of mirror images) of dearomatised products, significant effort was also devoted to stereoselective processes using catalysis, since enantiopure (containing only one mirror image) compounds are crucial in many natural and farmaceutical products. For this purpose various chiral ligands were synthesized and studied in combination with copper catalysts. Finally, in this sub-project major effort was devoted to demonstrating the applicability of the developed strategy in the synthesis of biologically relevant molecules.
The second part of the work (sub-project 3) was aimed at the dearomatisation of electron rich molecules such as phenol/naphthol and aniline/naphtylamine derivatives, important substrates for dearomatisation reactions and thus building blocks for the synthesis of complex bioactive molecules. Our strategy was based on a mechanistically distinct, consecutive dearomatisation/carbon-carbon bond forming process, in which tautomerisation of these aromatic molecules plays a crucial role. Initial experiments were directed at studying this tautomerisation process and stabilizing the dearomatised keto-ketimine tautomers using Lewis acids. Following this, a variety of functionalised molecules could be accessed by reacting these stabilized products with various nucleophiles under copper catalysis.
The history of dearomatisation reactions dates back more than a century. Although many spectacular and useful transformations have been developed, most lack general applicability and broad scope or require specifically designed substrates. New discoveries in this field are highly desirable, in order to provide more general, sustainable strategies towards complex molecules, particularly chiral and enantiopure. In this regard major results have already been obtained in this ERC funded project during the period covered by this report, which are discussed below.
In an effort to achieve dearomatisation of heteroaromatics (sub-project 2) we first demonstrated our Lewis acid, copper catalysis strategy as proof of concept in application to partially dearomatised substrates. This work resulted in two novel synthetic strategies, namely the synthesis of chiral, nitrogen-containing heterocyclic precursors, which can be applied in the synthesis of chiral piperidine and tetrahydroquinoline derivatives, and the first general protocol for the alkylation of nitrogen-containing heterocycles using organomagnesium reagents and a copper based catalytic system in combination with Lewis acids. These reactions proceed with excellent yields and selectivities, can be carried out at room temperature, and we have also demonstrated the application of the methodology to natural products to showcase its efficiency.
Having gained significant knowledge on the catalytic system we then moved to direct dearomatisation of heteroaromatics, namely quinoline derivatives. The only successful strategies known in the literature require quinolinium salts and afford access to only one out of two possible products, namely the so-called C2-addition products. We were able to develop the first catalytic system that allows enantioselective dearomatization of quinolines where the C4-addition products can be obtained with excellent selectivities and chemical yields. Furthermore, thanks to our mechanistic studies we are starting to understand the underlying processes in detail.
Following these groundbreaking developments we expect that in the coming period even more challenging transformations involving pyridine derivatives, applications of the methodology to the synthesis of natural products, as well as further mechanistic insights can be achieved.
Our experimental work for sub-project 3 has resulted in a novel methodology for the dearomatisation of naphthol derivatives. Using molecular modeling we have also proposed a mechanistic rationale for this Lewis acid promoted dearomatization process. Furthermore, our initial results confirm that similar transformations are possible with naphthylamines and this is work in progress. Future studies will be directed towards the development of synthetic methodologies based on this strategy and, even more importantly, we anticipate that the same strategy can also be used for the dearomatisation of phenol derivatives.
In an effort to achieve dearomatisation of heteroaromatics (sub-project 2) we first demonstrated our Lewis acid, copper catalysis strategy as proof of concept in application to partially dearomatised substrates. This work resulted in two novel synthetic strategies, namely the synthesis of chiral, nitrogen-containing heterocyclic precursors, which can be applied in the synthesis of chiral piperidine and tetrahydroquinoline derivatives, and the first general protocol for the alkylation of nitrogen-containing heterocycles using organomagnesium reagents and a copper based catalytic system in combination with Lewis acids. These reactions proceed with excellent yields and selectivities, can be carried out at room temperature, and we have also demonstrated the application of the methodology to natural products to showcase its efficiency.
Having gained significant knowledge on the catalytic system we then moved to direct dearomatisation of heteroaromatics, namely quinoline derivatives. The only successful strategies known in the literature require quinolinium salts and afford access to only one out of two possible products, namely the so-called C2-addition products. We were able to develop the first catalytic system that allows enantioselective dearomatization of quinolines where the C4-addition products can be obtained with excellent selectivities and chemical yields. Furthermore, thanks to our mechanistic studies we are starting to understand the underlying processes in detail.
Following these groundbreaking developments we expect that in the coming period even more challenging transformations involving pyridine derivatives, applications of the methodology to the synthesis of natural products, as well as further mechanistic insights can be achieved.
Our experimental work for sub-project 3 has resulted in a novel methodology for the dearomatisation of naphthol derivatives. Using molecular modeling we have also proposed a mechanistic rationale for this Lewis acid promoted dearomatization process. Furthermore, our initial results confirm that similar transformations are possible with naphthylamines and this is work in progress. Future studies will be directed towards the development of synthetic methodologies based on this strategy and, even more importantly, we anticipate that the same strategy can also be used for the dearomatisation of phenol derivatives.