Periodic Reporting for period 1 - ALCO2-FUNC (A Remote-carboxylation Strategy for Alcohols via a Dual-catalytic System)
Période du rapport: 2020-03-01 au 2022-02-28
The ability to introduce functionality into molecules in a regio- and chemoselective manner is of primary importance in the construction of high value molecular compounds, but still remains a major challenge for synthetic chemists. The utilization of functionalities present in readily available and inexpensive starting materials to direct the introduction of further complexity is an attractive strategy which has become increasingly popular. Despite recent advances, the remote functionalization of aliphatic alcohols still remains largely underdeveloped. Considering their prevalence in natural products, pharmaceuticals and chemical feedstocks, efforts to address this problem were deemed necessary.
ALCO2-FUNC aimed to merge (reductive) nickel catalysis with photoredox catalysis to exploit advantages of both disciplines, enabling the development of a divergent strategy by careful control of key catalytic steps (Figure 1). Moreover, carbon dioxide was to be utilized as an abundant and economical C1 synthon to provide a valuable carboxylation strategy.
See Figure 1
The development of mild and green synthetic procedures to quickly and selectively produce active pharmaceutical agents is of great importance for global health as it streamlines the discovery and production processes, resulting in less time to market and to benefit those in need. In addition, the application of carbon dioxide is also relevant, as it contributes to the circular economy concept, where waste CO2 streams can be used to produce value-added chemicals.
The main objective of ALCO2-FUNC was to develop site-selective, catalytic C–C bond-formation of abundant aliphatic alcohols at distal sp3 C–H sites, thus turning simplicity into complexity for accessing valuable products from simple precursors. The specific objectives were the following:
1. To implement a β-carboxylation of alcohols with CO2 via dual photoredox/ nickel-catalysis.
2. To enable a remote-carboxylation of aliphatic alcohols with CO2 at distal sp3 C–H sites via a chain-walking scenario.
3. To perform electrochemical and mechanistic study on key Ni-alkyl species.
ALCO2-FUNC aimed to merge (reductive) nickel catalysis with photoredox catalysis to exploit advantages of both disciplines, enabling the development of a divergent strategy by careful control of key catalytic steps (Figure 1). Moreover, carbon dioxide was to be utilized as an abundant and economical C1 synthon to provide a valuable carboxylation strategy.
See Figure 1
The development of mild and green synthetic procedures to quickly and selectively produce active pharmaceutical agents is of great importance for global health as it streamlines the discovery and production processes, resulting in less time to market and to benefit those in need. In addition, the application of carbon dioxide is also relevant, as it contributes to the circular economy concept, where waste CO2 streams can be used to produce value-added chemicals.
The main objective of ALCO2-FUNC was to develop site-selective, catalytic C–C bond-formation of abundant aliphatic alcohols at distal sp3 C–H sites, thus turning simplicity into complexity for accessing valuable products from simple precursors. The specific objectives were the following:
1. To implement a β-carboxylation of alcohols with CO2 via dual photoredox/ nickel-catalysis.
2. To enable a remote-carboxylation of aliphatic alcohols with CO2 at distal sp3 C–H sites via a chain-walking scenario.
3. To perform electrochemical and mechanistic study on key Ni-alkyl species.
At the beginning of the project, it was unknown whether alpha-bromide-silylethers (A, Figure 2) would be applicable with Ni-catalysis. It was clear from previous reports that the regioselectivity was highly dependent on the substrate substitution pattern. Therefore, to avoid such substrate control, an alternative precursor class (B, Figure 2) was proposed containing a phthalimide moiety that should also undergo reductive activation but in this case generating an electrophilic oxy-radical intermediate with an alternative reactivity profile. Precursors of this structure were unknown so an efficient synthesis was devised. Reaction of the alcohol and N-hydroxyphthalimide across a dichlorosilane was realized after careful selection of the reaction conditions to avoid the formation of side-products. Although challenging to purify, B proved stable on the bench under air allowing investigation into its reactivity. Unfortunately, no positive results were obtained for the proposed remote carboxylation reactions (Figure 2), nor any other catalytic C–C bond forming reactions.
See Figure 2
It was eventually discovered during the investigation of hydroxyl-silylethers as a possible precursor class (C, Figure 3, top) that the generation of the desired silyoxy-radical leads to the formation of alkyl radicals via intermolecular addition onto another silyl-center, likely driven by the formation of the strong Si−O bond. Consequently, this suggested that B or C are not suitable precursors to direct remote radical functionalizations of alcohols. On the other hand, the possibility to catalytically generate alkyl radicals from silanols is in itself attractive and was explored following this discovery (Figure 3, bottom). The generality of this protocol is now under investigation.
See Figure 3
The utilization of α-bromo-silylether precursors (A, Figure 2) yielded more positive results. Although no reactivity for the proposed remote carboxylation was detected, an alternative remote arylation reaction was possible (Figure 4) with selectivity for the γ-position observed. Side-reactions such as arylation and homocoupling at the initial α-silylether position were significant and extremely challenging to avoid. Consequently, a maximum yield ~30% was achieved for this remote-arylation protocol employing both heterogeneous metal reductant (Figure 4, left) or photoredox catalysis conditions (right), even after extensive study of all reaction variables.
See Figure 4
The proposed silyl-directed carboxylation methodology may have been extended to include amines in which β-carboxylation would generate β- or γ-amino acids (Figure 5, top), valuable building blocks that have shown promise as peptidomimetics. However, α-bromo-silylamines (D) are even less stable than their alcohol analogues. An alternative strategy could be to apply aziridines in which Ni-catalyzed C(sp3)-N cleavage followed by CO2 insertion would also lead to beta-amino acid products. This proved possible with the application of hindered and electron rich bipyridine ligand L key for high selectivity in the Ni-catalyzed carboxylation of N-Tosyl aziridines under CO2 atmoshphere (Figure 5, bottom). Most intriguing about this protocol was the almost unique ability of MeOH to promote reactivity, with mechanistic studies pointing towards it playing a role in stabilizing key Ni-species such as the ring-opened zwitterionic intermediate proposed by Hillhouse. As well as the high impact publication that resulted from this work, it was disseminated by oral presentation at a Merck Sharp & Dohme–ICIQ networking event.
See Figure 5
See Figure 2
It was eventually discovered during the investigation of hydroxyl-silylethers as a possible precursor class (C, Figure 3, top) that the generation of the desired silyoxy-radical leads to the formation of alkyl radicals via intermolecular addition onto another silyl-center, likely driven by the formation of the strong Si−O bond. Consequently, this suggested that B or C are not suitable precursors to direct remote radical functionalizations of alcohols. On the other hand, the possibility to catalytically generate alkyl radicals from silanols is in itself attractive and was explored following this discovery (Figure 3, bottom). The generality of this protocol is now under investigation.
See Figure 3
The utilization of α-bromo-silylether precursors (A, Figure 2) yielded more positive results. Although no reactivity for the proposed remote carboxylation was detected, an alternative remote arylation reaction was possible (Figure 4) with selectivity for the γ-position observed. Side-reactions such as arylation and homocoupling at the initial α-silylether position were significant and extremely challenging to avoid. Consequently, a maximum yield ~30% was achieved for this remote-arylation protocol employing both heterogeneous metal reductant (Figure 4, left) or photoredox catalysis conditions (right), even after extensive study of all reaction variables.
See Figure 4
The proposed silyl-directed carboxylation methodology may have been extended to include amines in which β-carboxylation would generate β- or γ-amino acids (Figure 5, top), valuable building blocks that have shown promise as peptidomimetics. However, α-bromo-silylamines (D) are even less stable than their alcohol analogues. An alternative strategy could be to apply aziridines in which Ni-catalyzed C(sp3)-N cleavage followed by CO2 insertion would also lead to beta-amino acid products. This proved possible with the application of hindered and electron rich bipyridine ligand L key for high selectivity in the Ni-catalyzed carboxylation of N-Tosyl aziridines under CO2 atmoshphere (Figure 5, bottom). Most intriguing about this protocol was the almost unique ability of MeOH to promote reactivity, with mechanistic studies pointing towards it playing a role in stabilizing key Ni-species such as the ring-opened zwitterionic intermediate proposed by Hillhouse. As well as the high impact publication that resulted from this work, it was disseminated by oral presentation at a Merck Sharp & Dohme–ICIQ networking event.
See Figure 5
Previously unknown N-hydroxyphthalimide-silylethers (e.g. B) can be efficiently synthesized and they have good stability with bulky alkyl groups on the silyl-center.
· On the other hand, B and related hydroxy-silylethers (C) are not viable radical precursors for intramolcular HAT because of competing intermolecular addition of the siloxy-radical onto another silyl-center.
· A proof-of-principle generation of alkyl radicals from silanols under Ce-catalysis was demonstrated and the generality of this methodology is currently being explored.
· Preliminary results on the remote arylation of α-bromo-silylethers under reductive Ni-catalysis, both with heterogeneous metal reductant or photoredox catalysis, were obtained.
· A novel Ni-catalyzed carboxylation of aziridines under CO2 atmosphere was developed (Davies, J; Janssen-Müller, D.; Zimin, D. P.; Day, C. S.; Yanagi, T.; Elfert, J.; Martin, R. J. Am. Chem. Soc. 2021, 143, 4949-4954). This methodology provides a direct route to valuable β-amino acid building blocks including biologically relevant molecules such as Sitagliptin and 13C-labelled L-DOPA derivatives.
· Overall, this fellowship has allowed the researcher to gain knowledge of several areas of chemistry which he did not previously have experience and become a more independent researcher with skills developed in leadership, teaching and project management which will be crucial for him to transition to a responsible role in an industrial research setting.
· On the other hand, B and related hydroxy-silylethers (C) are not viable radical precursors for intramolcular HAT because of competing intermolecular addition of the siloxy-radical onto another silyl-center.
· A proof-of-principle generation of alkyl radicals from silanols under Ce-catalysis was demonstrated and the generality of this methodology is currently being explored.
· Preliminary results on the remote arylation of α-bromo-silylethers under reductive Ni-catalysis, both with heterogeneous metal reductant or photoredox catalysis, were obtained.
· A novel Ni-catalyzed carboxylation of aziridines under CO2 atmosphere was developed (Davies, J; Janssen-Müller, D.; Zimin, D. P.; Day, C. S.; Yanagi, T.; Elfert, J.; Martin, R. J. Am. Chem. Soc. 2021, 143, 4949-4954). This methodology provides a direct route to valuable β-amino acid building blocks including biologically relevant molecules such as Sitagliptin and 13C-labelled L-DOPA derivatives.
· Overall, this fellowship has allowed the researcher to gain knowledge of several areas of chemistry which he did not previously have experience and become a more independent researcher with skills developed in leadership, teaching and project management which will be crucial for him to transition to a responsible role in an industrial research setting.