Periodic Reporting for period 1 - SupraPhoCat (Supramolecular photocatalytic late-stage C-H functionalization)
Periodo di rendicontazione: 2023-11-01 al 2025-10-31
Organic synthesis is still one of the main limiting factors in drug-discovery projects in spite of all the astonishing breakthroughs that have been achieved in the last decades. Both academia and industry keep looking for new reactions and synthetic strategies to speed up the generation of compounds libraries. Traditionally, the generation of these libraries requires tedious synthetic routes to introduce modifications into the lead compound, thus the implementation of new methodologies to modify drugs in a selective way in the late stages of their synthesis is highly attractive.
LSF of C-H bonds in drugs has recently emerged as a new strategy for the fast generation of drug derivatives and quick diversification of biologically relevant molecules, without the need to start the synthesis de novo every time a derivative needs to be synthesized. In order to get selectivity, most of the C-H activation protocols described in literature require the covalently introduction of a directing group in the substrate (“directed” C-H bond functionalization), which then needs to be removed. From a synthetic point of view, it is much more attractive to place the directing group in the catalyst rather than the substrate to avoid its introduction and subsequent removal. Nature already uses this approach in enzymes by burying the catalytic center in a binding pocket where the substrate must fit in. Alternatively, it is possible to target specific C-H bonds using molecular recognition, however the examples are much scarcer. Recently, Hydrogen Atom Transfer (HAT) reactions have emerged as a new strategy to tackle selective C-H bond activation in combination with photoredox catalysis.
In SupraPhoCat , several supramolecular receptors will be provided with catalytic activity and combined with photoredox catalysis to achieve unprecedent asymmetric C-H funtionalization reactions with exquisite selectivity. This ambitious project will establish new methodologies for C-H Late-Stage Functionalization of drugs, which is a key point towards the development of libraries of compounds according to EU green chemistry insights. This Fellowship proposes supramolecular receptors with Hydrogen Atom Transfer (HAT) activity which will be combined with photoredox catalysis to achieve unprecedent asymmetric C-H functionalization in molecules, merging photoredox catalysis, supramolecular chemistry, and C-H bond activation reactions. The Marie Sklodowska Curie action merges the expertise of the host group (Prof. Luca Dell’Amico from University of Padova) in photoredox catalysis with the expertise of the fellow on supramolecular chemistry, molecular recognition and organocatalysis.
This process will rely on a photochemical Hydrogen Atom Transfer reaction controlled by a supramolecular receptor which governs the process. The objectives of this proposal include to design and synthesize supramolecular receptors with HAT groups and the selective C-H abstraction in a model substrate. Moreover, asymmetric version of these processes will be evaluated.
LSF of C-H bonds in drugs has recently emerged as a new strategy for the fast generation of drug derivatives and quick diversification of biologically relevant molecules, without the need to start the synthesis de novo every time a derivative needs to be synthesized. In order to get selectivity, most of the C-H activation protocols described in literature require the covalently introduction of a directing group in the substrate (“directed” C-H bond functionalization), which then needs to be removed. From a synthetic point of view, it is much more attractive to place the directing group in the catalyst rather than the substrate to avoid its introduction and subsequent removal. Nature already uses this approach in enzymes by burying the catalytic center in a binding pocket where the substrate must fit in. Alternatively, it is possible to target specific C-H bonds using molecular recognition, however the examples are much scarcer. Recently, Hydrogen Atom Transfer (HAT) reactions have emerged as a new strategy to tackle selective C-H bond activation in combination with photoredox catalysis.
In SupraPhoCat , several supramolecular receptors will be provided with catalytic activity and combined with photoredox catalysis to achieve unprecedent asymmetric C-H funtionalization reactions with exquisite selectivity. This ambitious project will establish new methodologies for C-H Late-Stage Functionalization of drugs, which is a key point towards the development of libraries of compounds according to EU green chemistry insights. This Fellowship proposes supramolecular receptors with Hydrogen Atom Transfer (HAT) activity which will be combined with photoredox catalysis to achieve unprecedent asymmetric C-H functionalization in molecules, merging photoredox catalysis, supramolecular chemistry, and C-H bond activation reactions. The Marie Sklodowska Curie action merges the expertise of the host group (Prof. Luca Dell’Amico from University of Padova) in photoredox catalysis with the expertise of the fellow on supramolecular chemistry, molecular recognition and organocatalysis.
This process will rely on a photochemical Hydrogen Atom Transfer reaction controlled by a supramolecular receptor which governs the process. The objectives of this proposal include to design and synthesize supramolecular receptors with HAT groups and the selective C-H abstraction in a model substrate. Moreover, asymmetric version of these processes will be evaluated.
This project started designing new supramolecular HAT catalysts which include HAT units like quinuclidine in their structures to trigger C-H activation processes. These catalysts have also been designed to incorporate a cavity in charge of the carbonyl association in substrate through H-bonding. Chromane and isophthalic acid structures, among others, have been evaluated and synthesized to test in the photocatalyzed reactions.
These new supramolecular catalysts were evaluated in photocatalyzed HAT protocols using different model substrates and radical acceptors. Lactams, amides, esters, sulfones, sulfonamides and other functional groups present in the model substrate were tested as binding units to promote the association with the catalyst and trigger the remote C-H functionalization. The putative radical was then exposed to electron-deficient alkenes to trap it and form the new C-C bond. These studies showed that the quinuclidine core was only able to remove labile hydrogen atoms, for instance the hydrogens in alpha to a heteroatom. Unfortunately, no remote functionalization was observed using substrates with non-activated positions.
At this point, using sulfones and sulfonamides as binding units, a new research line came up regarding the photocatalyzed ring expansion of sulfonium salts to obtain cyclic sulfides. These sulfides can be easily transformed into the corresponding sulfone and can be used in the remote C-H functionalization with the HAT catalysts. However, only the photocatalytic transformation was reported, as no reactivity towards the remote abstraction was observed.
With the aim of corroborate the association with the substrate, different titration experiments were performed. These studies include competitive titrations where two receptors are confronted towards the association of the same guest at the same time. Model receptors have also been prepared and used in these experiments. Similar behaviour towards the association of the lactam were observed when the catalyst and the model receptors were analysed. Apparently the quinuclidine core, after oxidation with a suitable photocatalyst, is not able to remove non-activated C-H bonds, so new groups should be evaluated in the proposal.
As predicted in the proposal, the energy of the radical generated should be critical to the aliphatic C-H functionalization, therefore the HAT group should also be tuned in order to achieve more challenging C-H abstractions (as it has been predicted in the search risk as well). Thus, pyridine N-oxides were taking into consideration, as they have been proved to be effective in HAT processes where the C-H bond is not activated. The workflow started again in the catalyst’s design to include the HAT unit into the cavity to associate the carbonyl from the substrate. A new set of catalysts were designed, synthesized and evaluated in the abstraction of non-activated C-H bonds. These new catalysts achieved the activation of these bonds in low yields, however, multiple trials to improve the yield and the regioselectivity did not give the expected results.
Photocatalyst’s degradation was also observed after the reaction course during the screening analysis. This is a big issue in photocatalyzed processes as changes on the photocatalyst’s structure leads to lose of reactivity. Some experiments were carried out in order to analyse the photocatalyst’s stability under different conditions, such as solvents and light irradiation, among others. To speed up the analysis, High-Throughput Experimentation was employed.
During the course of the fellowship, new reactivity has been found using some of the catalysts prepared in this work. Weaker C-H bonds were susceptible to be removed using that catalysts and, taking into consideration that after the HAT process the catalyst is protonated, the proton delivery to the final product is governed by the catalyst. Should the environment be chiral, the proton delivery should be chiral as well, leading to an enantiocontrolled protonation.
There are not many reports regarding the enantiocontrolled protonation in the literature, and they usually include the use of transition metal catalyst with complex ligands prepared ad hoc for the substrates. In this work, the use of the previously prepared HAT catalysts are envisioned to do a dual activation mechanism: not only activate the C-H bond in the substrate but also the acceptor through H-bonding. This protocol simplifies the current methods to obtain enantiopure compounds in photochemical processes, as it includes the HAT and H-bond scaffold to activate the acceptor, which also fixes the molecules to control the hydrogen delivery, in the same catalyst.
This new research line is currently under development, where enantioenriched products have been obtained using the HAT catalysts prepared in this work.
These new supramolecular catalysts were evaluated in photocatalyzed HAT protocols using different model substrates and radical acceptors. Lactams, amides, esters, sulfones, sulfonamides and other functional groups present in the model substrate were tested as binding units to promote the association with the catalyst and trigger the remote C-H functionalization. The putative radical was then exposed to electron-deficient alkenes to trap it and form the new C-C bond. These studies showed that the quinuclidine core was only able to remove labile hydrogen atoms, for instance the hydrogens in alpha to a heteroatom. Unfortunately, no remote functionalization was observed using substrates with non-activated positions.
At this point, using sulfones and sulfonamides as binding units, a new research line came up regarding the photocatalyzed ring expansion of sulfonium salts to obtain cyclic sulfides. These sulfides can be easily transformed into the corresponding sulfone and can be used in the remote C-H functionalization with the HAT catalysts. However, only the photocatalytic transformation was reported, as no reactivity towards the remote abstraction was observed.
With the aim of corroborate the association with the substrate, different titration experiments were performed. These studies include competitive titrations where two receptors are confronted towards the association of the same guest at the same time. Model receptors have also been prepared and used in these experiments. Similar behaviour towards the association of the lactam were observed when the catalyst and the model receptors were analysed. Apparently the quinuclidine core, after oxidation with a suitable photocatalyst, is not able to remove non-activated C-H bonds, so new groups should be evaluated in the proposal.
As predicted in the proposal, the energy of the radical generated should be critical to the aliphatic C-H functionalization, therefore the HAT group should also be tuned in order to achieve more challenging C-H abstractions (as it has been predicted in the search risk as well). Thus, pyridine N-oxides were taking into consideration, as they have been proved to be effective in HAT processes where the C-H bond is not activated. The workflow started again in the catalyst’s design to include the HAT unit into the cavity to associate the carbonyl from the substrate. A new set of catalysts were designed, synthesized and evaluated in the abstraction of non-activated C-H bonds. These new catalysts achieved the activation of these bonds in low yields, however, multiple trials to improve the yield and the regioselectivity did not give the expected results.
Photocatalyst’s degradation was also observed after the reaction course during the screening analysis. This is a big issue in photocatalyzed processes as changes on the photocatalyst’s structure leads to lose of reactivity. Some experiments were carried out in order to analyse the photocatalyst’s stability under different conditions, such as solvents and light irradiation, among others. To speed up the analysis, High-Throughput Experimentation was employed.
During the course of the fellowship, new reactivity has been found using some of the catalysts prepared in this work. Weaker C-H bonds were susceptible to be removed using that catalysts and, taking into consideration that after the HAT process the catalyst is protonated, the proton delivery to the final product is governed by the catalyst. Should the environment be chiral, the proton delivery should be chiral as well, leading to an enantiocontrolled protonation.
There are not many reports regarding the enantiocontrolled protonation in the literature, and they usually include the use of transition metal catalyst with complex ligands prepared ad hoc for the substrates. In this work, the use of the previously prepared HAT catalysts are envisioned to do a dual activation mechanism: not only activate the C-H bond in the substrate but also the acceptor through H-bonding. This protocol simplifies the current methods to obtain enantiopure compounds in photochemical processes, as it includes the HAT and H-bond scaffold to activate the acceptor, which also fixes the molecules to control the hydrogen delivery, in the same catalyst.
This new research line is currently under development, where enantioenriched products have been obtained using the HAT catalysts prepared in this work.
The results derived from this work can be divided into three categories:
Quinuclidine-derived catalysts were evaluated in the C-H functionalization of lactams and other compounds. Unfortunately, only reactivity on the more labile hydrogen atoms were observed. Key experiments were performed to test their ability to bind the substrate, confirming their association. However, only activated positions were successfully functionalized.
On the other hand, pyridine N-oxide catalysts did trigger the aliphatic C-H functionalization. However, their performance was intrinsically linked to the structure of the catalyst, where small changes dropped the reactivity. Moreover, while testing their ability towards only one C-H bond, no regiocontrol were observed.
New reactivity was found to obtain cyclic sulfides from cyclic sulfonium salts under flow conditions.
The stability of certain commonly used photocatalysts depends on the reaction conditions, such as solvent, light irradiation, inert atmosphere, etc. These secondary processes lead to the photocatalyst's degradation, thus halting the photocatalytic performance of the reaction.
These HAT catalysts can be used in a HAT – enantiocontrolled protonation process. The catalysts include the HAT and H-bond scaffold to activate the acceptor, which also fixes the molecule to control the hydrogen delivery, in the same structure. This new methodology allows the preparation of enantioenriched compounds with high interest in different industries in a single step. Further studies and experiments are needed to fully understand the reaction mechanism, and to improve the reaction yield/enantiocontrol with other substrates. This results are expected to be published and presented in different conferences within next year.
Quinuclidine-derived catalysts were evaluated in the C-H functionalization of lactams and other compounds. Unfortunately, only reactivity on the more labile hydrogen atoms were observed. Key experiments were performed to test their ability to bind the substrate, confirming their association. However, only activated positions were successfully functionalized.
On the other hand, pyridine N-oxide catalysts did trigger the aliphatic C-H functionalization. However, their performance was intrinsically linked to the structure of the catalyst, where small changes dropped the reactivity. Moreover, while testing their ability towards only one C-H bond, no regiocontrol were observed.
New reactivity was found to obtain cyclic sulfides from cyclic sulfonium salts under flow conditions.
The stability of certain commonly used photocatalysts depends on the reaction conditions, such as solvent, light irradiation, inert atmosphere, etc. These secondary processes lead to the photocatalyst's degradation, thus halting the photocatalytic performance of the reaction.
These HAT catalysts can be used in a HAT – enantiocontrolled protonation process. The catalysts include the HAT and H-bond scaffold to activate the acceptor, which also fixes the molecule to control the hydrogen delivery, in the same structure. This new methodology allows the preparation of enantioenriched compounds with high interest in different industries in a single step. Further studies and experiments are needed to fully understand the reaction mechanism, and to improve the reaction yield/enantiocontrol with other substrates. This results are expected to be published and presented in different conferences within next year.