Periodic Reporting for period 1 - SYNERGISTIC (A direct photocatalytic access to chiral β2-amino acids from alkenes using CO2 as the carbon source)
Période du rapport: 2023-08-01 au 2025-07-31
Currently, a strong focus has been given to the development of catalytic enantioselective transformations due to the high demand of chiral molecules in the pharmaceutical and agrochemical industries. Furthermore, chiral compounds are very important in the biochemistry of living systems since the receptor of a living system is made of enantiomerically pure protein, therefore, preferentially allows only one enantiomer to bind with the active chiral site. Within this context, chiral β2-amino acids (β2-AAs), analogs of α-amino acids where the amino group is attached to the β-carbon instead of the α-carbon, are one of the prime targets as high-demanding chemicals. Particularly, peptides containing β-AA residues tend to have increased resistance to enzymatic degradation. Peptides containing two β-arylalanines, for instance, have been reported to be resistant to carboxypeptidase and chymotrypsin and it is clear that the incorporation of β-AAs improves the half-life of potential peptide-based drugs. Additionally, they have been proven as drugs for human beings, for example, cryptophycin 1, produced from (R)-3-amino-2-methylpropanoic acid is frequently used as an antifungal drug for immunodeficient patients, while the (S)-antipode is either inactive or weakly active in vivo. Therefore, the availability of β2-AAs as chiral building blocks leads to the development of a multitude of pharmaceutically active compounds and potential drugs. However, the development of stereoselective and economically feasible synthetic routes toward β2-AA is a challenging task, being more complicated than the preparation of their well-investigated 3-substituted counterparts (β3-AA).
The proposed research envisions a sustainable strategy for the functionalization of alkenes to access chiral β²-AAs, employing carbon dioxide (CO2) as a renewable and abundant C1 synthon. The proposed core of the strategy lies in a one-pot, two-step transformation. In the first step, alkene substrate 1 undergoes a photocatalytic amino-bromination to generate intermediate 2. This is followed by a photoredox-mediated CO2 insertion step in the presence of a chiral nickel catalyst, enabling a face-selective transformation to afford the enantioenriched β²-AA product. The conceptual mechanism of the overall transformation is outlined in Figure 1a, with the stepwise reaction details and catalytic cycle illustrated in Figure 1b.
The proposed research envisions a sustainable strategy for the functionalization of alkenes to access chiral β²-AAs, employing carbon dioxide (CO2) as a renewable and abundant C1 synthon. The proposed core of the strategy lies in a one-pot, two-step transformation. In the first step, alkene substrate 1 undergoes a photocatalytic amino-bromination to generate intermediate 2. This is followed by a photoredox-mediated CO2 insertion step in the presence of a chiral nickel catalyst, enabling a face-selective transformation to afford the enantioenriched β²-AA product. The conceptual mechanism of the overall transformation is outlined in Figure 1a, with the stepwise reaction details and catalytic cycle illustrated in Figure 1b.
To investigate the feasibility of the proposed transformation, initial studies were conducted using 4-methoxy-anethole and pyrazole as model substrates. These were chosen due to their structural relevance and expected to have better reactivity under amino-bromination conditions. Selective results are summarized in Figure 2. A comprehensive screening of reaction parameters was performed, including variations in photocatalysts, solvents, bases, light sources, and temperatures (see Figures 2a–2b).
Despite extensive optimization efforts, the desired aminobrominated intermediate was not observed under any of the tested conditions. Instead, the major—and in fact exclusive—product across all setups was the dibrominated species. Remarkably, this outcome persisted even in the absence of any photocatalyst or additive, suggesting that the alkene underwent direct bromination under the reaction conditions, likely due to the highly activated nature of the substrate and bromine sources in the system. These findings indicate that, under the current conditions, amino-bromination via the proposed photocatalytic route is outcompeted by bromination pathways, highlighting the need for alternative protocol development. To circumvent the undesired side reaction, the use of brominating reagents was eliminated in favor of a bromine-free pathway. This new strategy aimed to achieve the desired transformation under milder, photocatalytic conditions without the risk of dibromination (see Figure 2c- 2e). We initially screened a series of amine radical precursors, including two well-established imidyl radical sources (J. Am. Chem. Soc. 2023, 145, 24486; Angew. Chem. Int. Ed. 2021, 60, 14399). However, despite extensive optimization—varying photocatalysts, bases, solvents, and metal co- catalysts—the desired β²-AA product was not observed under any tested conditions (Figures 2c–2d). Given these unsuccessful outcomes, we revised our strategy to invert the polarity of the radical generation. Instead of relying on N-centered radicals, we explored a pathway involving direct photooxidation of the alkene to generate a radical cation, followed by nucleophilic amination and subsequent carboxylation. Notably, this shift in mechanism resulted in a consistently high-yielding transformation, delivering the anti-Markovnikov hydroamination product in up to 84% isolated yield in place of β²-AA. This strategy was originally developed by Nicewicz and co-workers. Further mechanistic investigation through control experiments demonstrated that the presence of the organic photocatalyst (Mes-Acr⁺ -Ph) was essential for this transformation. This catalyst is known for its ability to generate alkene radical cations under visible-light irradiation, thereby enabling anti-Markovnikov hydroamination of electron-rich olefins (Nicewicz et al., Angew. Chem. Int. Ed. 2014, 53, 6198-6201).
Project 1: These findings redirected the focus of the project toward the broader field of alkene hydrofunctionalization—a transformation of significant importance in the synthesis of natural products, pharmaceuticals, and other value-added organic molecules. While existing photocatalytic methods for hydrofunctionalization have demonstrated remarkable reactivity and selectivity, all of them rely on homogeneous expensive and/or scarce metal-based photocatalysts (e.g. Ir complexes, MesAcr+). These systems pose challenges for industrial scalability and sustainability, as the catalysts are typically lost after the reaction and cannot be easily recovered or reused. To address these limitations, we sought to develop a cost-effective and sustainable alternative by designing a reusable, heterogeneous photocatalyst. In the first part of this effort, we successfully developed a novel porous organic material [covalent-triazine-framework (CTF)] with strong oxidative potential (+2.37 V vs SCE), capable of facilitating hydrofunctionalization reactions under visible-light irradiation (Figure 3a). This material, synthesized through strategic selection and polymerization of monomers, demonstrated excellent photocatalytic performance in hydroamination, hydrocarboxylation, and hydroazidation reactions across a diverse set of alkenes (Figure 3b). Substrates such as styrene derivatives (both electron- donating and electron-withdrawing groups) were effectively transformed, showcasing the broad applicability and robustness of the catalyst. For more details, please check our publication - Angew. Chem. Int. Ed. 2024, 63, e202415624.
Project 2: While the heterogeneous photocatalytic protocol developed in Project 1 enabled diverse anti-Markovnikov hydrofunctionalizations of alkenes, its applicability was largely restricted to activated styrenes and styrene-like substrates. Attempts to extend this method to unactivated alkenes were unsuccessful, highlighting a critical limitation of the system. To overcome this challenge, we designed a new catalytic platform incorporating transition metal centers within a heterogeneous framework. Transition metals can interact directly with alkene π-bonds through metal–alkene coordination, thereby enhancing substrate activation and expanding the reaction scope. As a proof of concept, we focused on the vicinal dichlorination of alkenes—a synthetically valuable transformation present in many bioactive natural products and pharmaceuticals. Mn was selected as the dopant metal due to its known efficacy in promoting dichlorination reactions, its low toxicity as a first-row 3d transition metal, and its capacity to access multiple oxidation states. These redox properties enable Mn to stabilize chlorine radicals generated during the reaction and facilitate their controlled transfer to the alkene substrate. Importantly, we engineered the parent polycarbon nitride scaffold by incorporating aromatics and atomically dispersed Mn sites which lead to maximizing the number of active centers, enhancing the light absoption and lowering down the electron-hole recombination (Figure 4a). This Mn-doped heterogeneous catalyst exhibited excellent activity across a wide range of alkene substrates—including terminal, internal, and complex bioactive molecules—demonstrating broad applicability and high functional group tolerance. Furthermore, the catalyst maintained high performance over six consecutive reaction cycles, with no significant drop in product yield, confirming its robustness and reusability (Figure 4b). To further demonstrate the versatility of our Mn-doped heterogeneous catalyst, we extended its application to a series of alkene difunctionalization reactions beyond vicinal dichlorination. These transformations introduce diverse and synthetically valuable functional groups across the double bond, broadening the utility of the platform in complex molecule synthesis. Specifically, the catalyst proved effective in promoting thio-sulfonylation, selenium-sulfonylation, amino-arylation, and oxo- trifluoromethylation of alkenes (Figure 4c). Each of these reactions introduces two distinct functionalities in a regioselective and efficient manner, offering streamlined access to highly functionalized molecular scaffolds. The method tolerates a broad substrate scope, including both electron-rich and electron-deficient alkenes, and proceeds under mild, operationally simple conditions. For more details, please check our publication - J. Am. Chem. Soc. 2025, 147, 11829–11840.
Project 3: While our previous two projects successfully established more sustainable visible-light-driven protocols for alkene functionalization, both strategies inherently relied on the use of heterogeneous photocatalysts. In fact, a through review of the literature reveals that most established light-induced methodologies (especially for difunctionalization of alkene)—such as photoredox catalysis, energy transfer (EnT), and ligand-to-metal charge transfer (LMCT)—typically require external photocatalysts to achieve high reactivity. Alternatively, electron donor–acceptor (EDA) complexes have been explored for difunctionalization of alkene, but these methods often rely on specially designed substrates, limiting the scope of this reaction. To overcome these limitations, we develop a DFT-guided approach for identifying suitable radicals for light-mediated difunctionalization of non-activated alkenes in our last project (Figure 5a). This appoach eventually eliminates the requirement of auxiliary catalysts or reagents. Our DFT calculations elucidate general reaction mechanisms and provide insights into regioselectivity. Additionally, time-dependent DFT (TD-DFT) calculations are employed to simulate UV– vis spectra and analyze the orbitals involved in key photoinduced transitions, guiding the selection of appropriate light sources. We further investigated the electrophilic and nucleophilic properties of the generated radicals to predict the regioselectivity of their additions. This study provides a framework for designing atom-economic difunctionalization reactions (chloro-trifluoromethylation, iodo-sulfonylation, sulfonylation, alkyl-sulfonylation, bromo-trifluoromethylation, iodo-trifluoromethylation, thiotrifluoromethyl-sulfonylation) without relying on photocatalysts or substrate-specific EDA complexes, and opens new avenues for further development in this area. A complete list of substrate scope has included in Figure 5b. This work is under review in J. Am. Chem. Soc.
Project 4: Building upon the findings of Project 3, which demonstrated the potential of EDA complex-mediated organic synthesis, we further explored this area. A long-standing limitation in this area lies in the difficulty of forming effective EDA complexes involving ionic species, which often require polar solvents such as DMSO or DMF for solubility. Unfortunately, these solvents may themselves engage in unintended EDA interactions or interfere with ionization equilibria, thereby compromising the reaction’s efficiency and generality. Concurrently, there remains a significant need for practical and modern methods for dehydrogenation reaction, as traditional protocols typically rely on harsh conditions, stoichiometric oxidants, or lack selectivity. To address both challenges, we have developed an innovative dehydrogenation protocol that leverages EDA complex formation between a dihydrogenated substrate and an N-methoxy pyridinium salt (Figure 6a). A critical breakthrough in this system was the use of hexafluoroisopropanol (HFIP) as the reaction medium. Beyond its ability to solubilize ionic components, HFIP acts as a transient hydrogen shuttle, promoting proton-coupled electron transfer (PCET) and significantly lowering the activation barrier for the transformation. This dual role of HFIP enables a mild, efficient, and highly selective desaturation process. The methodology exhibits broad applicability across various heterocyclic carbonyl scaffolds—including quinolinones, coumarins, and flavones—that are widely represented in pharmaceutical and agrochemical compounds. Mechanistic studies, supported by both experimental evidence and DFT calculations, confirm the formation of the EDA complex and elucidate the pivotal role of HFIP in facilitating the transformation. A complete list of substrate scope has included in Figure 6b. This work is under review in Angew. Chem. Int. Ed.
Despite extensive optimization efforts, the desired aminobrominated intermediate was not observed under any of the tested conditions. Instead, the major—and in fact exclusive—product across all setups was the dibrominated species. Remarkably, this outcome persisted even in the absence of any photocatalyst or additive, suggesting that the alkene underwent direct bromination under the reaction conditions, likely due to the highly activated nature of the substrate and bromine sources in the system. These findings indicate that, under the current conditions, amino-bromination via the proposed photocatalytic route is outcompeted by bromination pathways, highlighting the need for alternative protocol development. To circumvent the undesired side reaction, the use of brominating reagents was eliminated in favor of a bromine-free pathway. This new strategy aimed to achieve the desired transformation under milder, photocatalytic conditions without the risk of dibromination (see Figure 2c- 2e). We initially screened a series of amine radical precursors, including two well-established imidyl radical sources (J. Am. Chem. Soc. 2023, 145, 24486; Angew. Chem. Int. Ed. 2021, 60, 14399). However, despite extensive optimization—varying photocatalysts, bases, solvents, and metal co- catalysts—the desired β²-AA product was not observed under any tested conditions (Figures 2c–2d). Given these unsuccessful outcomes, we revised our strategy to invert the polarity of the radical generation. Instead of relying on N-centered radicals, we explored a pathway involving direct photooxidation of the alkene to generate a radical cation, followed by nucleophilic amination and subsequent carboxylation. Notably, this shift in mechanism resulted in a consistently high-yielding transformation, delivering the anti-Markovnikov hydroamination product in up to 84% isolated yield in place of β²-AA. This strategy was originally developed by Nicewicz and co-workers. Further mechanistic investigation through control experiments demonstrated that the presence of the organic photocatalyst (Mes-Acr⁺ -Ph) was essential for this transformation. This catalyst is known for its ability to generate alkene radical cations under visible-light irradiation, thereby enabling anti-Markovnikov hydroamination of electron-rich olefins (Nicewicz et al., Angew. Chem. Int. Ed. 2014, 53, 6198-6201).
Project 1: These findings redirected the focus of the project toward the broader field of alkene hydrofunctionalization—a transformation of significant importance in the synthesis of natural products, pharmaceuticals, and other value-added organic molecules. While existing photocatalytic methods for hydrofunctionalization have demonstrated remarkable reactivity and selectivity, all of them rely on homogeneous expensive and/or scarce metal-based photocatalysts (e.g. Ir complexes, MesAcr+). These systems pose challenges for industrial scalability and sustainability, as the catalysts are typically lost after the reaction and cannot be easily recovered or reused. To address these limitations, we sought to develop a cost-effective and sustainable alternative by designing a reusable, heterogeneous photocatalyst. In the first part of this effort, we successfully developed a novel porous organic material [covalent-triazine-framework (CTF)] with strong oxidative potential (+2.37 V vs SCE), capable of facilitating hydrofunctionalization reactions under visible-light irradiation (Figure 3a). This material, synthesized through strategic selection and polymerization of monomers, demonstrated excellent photocatalytic performance in hydroamination, hydrocarboxylation, and hydroazidation reactions across a diverse set of alkenes (Figure 3b). Substrates such as styrene derivatives (both electron- donating and electron-withdrawing groups) were effectively transformed, showcasing the broad applicability and robustness of the catalyst. For more details, please check our publication - Angew. Chem. Int. Ed. 2024, 63, e202415624.
Project 2: While the heterogeneous photocatalytic protocol developed in Project 1 enabled diverse anti-Markovnikov hydrofunctionalizations of alkenes, its applicability was largely restricted to activated styrenes and styrene-like substrates. Attempts to extend this method to unactivated alkenes were unsuccessful, highlighting a critical limitation of the system. To overcome this challenge, we designed a new catalytic platform incorporating transition metal centers within a heterogeneous framework. Transition metals can interact directly with alkene π-bonds through metal–alkene coordination, thereby enhancing substrate activation and expanding the reaction scope. As a proof of concept, we focused on the vicinal dichlorination of alkenes—a synthetically valuable transformation present in many bioactive natural products and pharmaceuticals. Mn was selected as the dopant metal due to its known efficacy in promoting dichlorination reactions, its low toxicity as a first-row 3d transition metal, and its capacity to access multiple oxidation states. These redox properties enable Mn to stabilize chlorine radicals generated during the reaction and facilitate their controlled transfer to the alkene substrate. Importantly, we engineered the parent polycarbon nitride scaffold by incorporating aromatics and atomically dispersed Mn sites which lead to maximizing the number of active centers, enhancing the light absoption and lowering down the electron-hole recombination (Figure 4a). This Mn-doped heterogeneous catalyst exhibited excellent activity across a wide range of alkene substrates—including terminal, internal, and complex bioactive molecules—demonstrating broad applicability and high functional group tolerance. Furthermore, the catalyst maintained high performance over six consecutive reaction cycles, with no significant drop in product yield, confirming its robustness and reusability (Figure 4b). To further demonstrate the versatility of our Mn-doped heterogeneous catalyst, we extended its application to a series of alkene difunctionalization reactions beyond vicinal dichlorination. These transformations introduce diverse and synthetically valuable functional groups across the double bond, broadening the utility of the platform in complex molecule synthesis. Specifically, the catalyst proved effective in promoting thio-sulfonylation, selenium-sulfonylation, amino-arylation, and oxo- trifluoromethylation of alkenes (Figure 4c). Each of these reactions introduces two distinct functionalities in a regioselective and efficient manner, offering streamlined access to highly functionalized molecular scaffolds. The method tolerates a broad substrate scope, including both electron-rich and electron-deficient alkenes, and proceeds under mild, operationally simple conditions. For more details, please check our publication - J. Am. Chem. Soc. 2025, 147, 11829–11840.
Project 3: While our previous two projects successfully established more sustainable visible-light-driven protocols for alkene functionalization, both strategies inherently relied on the use of heterogeneous photocatalysts. In fact, a through review of the literature reveals that most established light-induced methodologies (especially for difunctionalization of alkene)—such as photoredox catalysis, energy transfer (EnT), and ligand-to-metal charge transfer (LMCT)—typically require external photocatalysts to achieve high reactivity. Alternatively, electron donor–acceptor (EDA) complexes have been explored for difunctionalization of alkene, but these methods often rely on specially designed substrates, limiting the scope of this reaction. To overcome these limitations, we develop a DFT-guided approach for identifying suitable radicals for light-mediated difunctionalization of non-activated alkenes in our last project (Figure 5a). This appoach eventually eliminates the requirement of auxiliary catalysts or reagents. Our DFT calculations elucidate general reaction mechanisms and provide insights into regioselectivity. Additionally, time-dependent DFT (TD-DFT) calculations are employed to simulate UV– vis spectra and analyze the orbitals involved in key photoinduced transitions, guiding the selection of appropriate light sources. We further investigated the electrophilic and nucleophilic properties of the generated radicals to predict the regioselectivity of their additions. This study provides a framework for designing atom-economic difunctionalization reactions (chloro-trifluoromethylation, iodo-sulfonylation, sulfonylation, alkyl-sulfonylation, bromo-trifluoromethylation, iodo-trifluoromethylation, thiotrifluoromethyl-sulfonylation) without relying on photocatalysts or substrate-specific EDA complexes, and opens new avenues for further development in this area. A complete list of substrate scope has included in Figure 5b. This work is under review in J. Am. Chem. Soc.
Project 4: Building upon the findings of Project 3, which demonstrated the potential of EDA complex-mediated organic synthesis, we further explored this area. A long-standing limitation in this area lies in the difficulty of forming effective EDA complexes involving ionic species, which often require polar solvents such as DMSO or DMF for solubility. Unfortunately, these solvents may themselves engage in unintended EDA interactions or interfere with ionization equilibria, thereby compromising the reaction’s efficiency and generality. Concurrently, there remains a significant need for practical and modern methods for dehydrogenation reaction, as traditional protocols typically rely on harsh conditions, stoichiometric oxidants, or lack selectivity. To address both challenges, we have developed an innovative dehydrogenation protocol that leverages EDA complex formation between a dihydrogenated substrate and an N-methoxy pyridinium salt (Figure 6a). A critical breakthrough in this system was the use of hexafluoroisopropanol (HFIP) as the reaction medium. Beyond its ability to solubilize ionic components, HFIP acts as a transient hydrogen shuttle, promoting proton-coupled electron transfer (PCET) and significantly lowering the activation barrier for the transformation. This dual role of HFIP enables a mild, efficient, and highly selective desaturation process. The methodology exhibits broad applicability across various heterocyclic carbonyl scaffolds—including quinolinones, coumarins, and flavones—that are widely represented in pharmaceutical and agrochemical compounds. Mechanistic studies, supported by both experimental evidence and DFT calculations, confirm the formation of the EDA complex and elucidate the pivotal role of HFIP in facilitating the transformation. A complete list of substrate scope has included in Figure 6b. This work is under review in Angew. Chem. Int. Ed.
Although the proposed reaction—aminocarboxylation of alkenes using CO2 to produce chiral β-amino acids—did not yield satisfactory results despite extensive experiments, the research led to valuable alternative findings. In the course of the project, I discovered three notable outcomes related to the functionalization of alkene bonds and one outcome related to dehydrogenation via EDA complex formation.