Periodic Reporting for period 2 - SCAN (Selective Pathways for Carbon-Nitrogen Bond Cleavage)
Periodo di rendicontazione: 2023-03-01 al 2024-08-31
Amines are ubiquitous across natural products, pharmaceuticals, polymers and biomolecules. The number of commercially available amines, from simple to complex, makes them one of the most accessible native functional groups. Therefore, they represent an attractive feedstock for the preparation of functionalized molecules through C-N bond activation. However, the selective catalytic cleavage of C-N bonds in amines is a difficult challenge, mainly due to the high bond dissociation
energy of the carbon-nitrogen bond compared to other carbon-heteroatom bonds, and the ability of the amido leaving group to serve as a strong ligand promoting catalyst deactivation pathways.
SCAN (Selective Pathways for CArbon-Nitrogen Bond Cleavage) is designed to open new directions in the field of C-N bond cleavage by unlocking novel and general deamination pathways. To achieve this goal, the following specific objectives are proposed:
1) Design of novel amine derivatives capable of undergoing homolytic C-N cleavage.
2) Development of novel deamination protocols using photoredox and metallaphotoredox catalysis.
3) Site-selective modifications of peptides through photocatalyzed deaminative transformations.
The successful implementation will allow the use of one of the most readily available functional groups in a myriad of novel catalytic transformations. The prevalence of alkyl amines in pharmaceuticals makes SCAN an ideal tool for late-stage functionalization and molecular editing of drug analogs, providing a tool to accelerate the drug discovery process. Together, the conceptual novelty, the ability to pursue multiple complementary approaches at once, and the various potential applications will ensure high impact of this project in both the academic and industrial communities.
energy of the carbon-nitrogen bond compared to other carbon-heteroatom bonds, and the ability of the amido leaving group to serve as a strong ligand promoting catalyst deactivation pathways.
SCAN (Selective Pathways for CArbon-Nitrogen Bond Cleavage) is designed to open new directions in the field of C-N bond cleavage by unlocking novel and general deamination pathways. To achieve this goal, the following specific objectives are proposed:
1) Design of novel amine derivatives capable of undergoing homolytic C-N cleavage.
2) Development of novel deamination protocols using photoredox and metallaphotoredox catalysis.
3) Site-selective modifications of peptides through photocatalyzed deaminative transformations.
The successful implementation will allow the use of one of the most readily available functional groups in a myriad of novel catalytic transformations. The prevalence of alkyl amines in pharmaceuticals makes SCAN an ideal tool for late-stage functionalization and molecular editing of drug analogs, providing a tool to accelerate the drug discovery process. Together, the conceptual novelty, the ability to pursue multiple complementary approaches at once, and the various potential applications will ensure high impact of this project in both the academic and industrial communities.
During the first part of the project we have been working in the design and development of five different synthetic methods:
1) Development of a novel approach to cleave and functionalize carbon-nitrogen bonds under visible light irradiation. We have demonstrated that isonitriles, easily prepared from primary amines, serve as alkyl radical precursors in light-mediated hydro- and deuterodeamination reactions. The reaction is scalable, shows broad functional group compatibility and potential to be used in late-stage functionalization. Our study shows for the first time the feasibility of generating an alkyl radical from an isonitrile under visible-light irradiation and has opened the door to design further deamination reactions that we are currently developing in our laboratory. These results have been published in Angew. Chem. Int. Ed. 2024, e202317683.
2) Development of a deaminative arylation protocol using isonitriles. We have demonstrated the ability of isonitriles to be used as alkyl radical precursors in a photoredox-catalyzed transformation involving selective C-N cleavage and Csp3-Csp2 bond formation. This protocol allows for the preparation of functionalized heteroarenes from readily available isonitriles through selective C-N cleavage. These results have been posted in the preprint repository Chemrxiv (D O I: 10.26434/chemrxiv-2024-70psv) and are currently under review.
3) Development of a novel reagent for radical cyanation of native functional groups. We have designed a novel cyanating reagent that allows the introduction of a cyano group starting from native and abundant functional group such as carboxylic acids and alcohols. We take advantage of the selective C-N cleavage of isonitriles under visible light irradiation that we have recently developed. We provide a novel reagent that is “cyanide-free” and general for different abundant functional groups. The manuscript related to these results is currently under preparation.
4) Development of a deaminative alkylation protocol using isonitriles. We have used isonitriles as alkyl radical precursors in a photoredox-catalyzed transformation involving selective C-N cleavage and Csp3-Csp3 bond formation. Our method provides a deaminative alkylation protocol that is general for Cα-1º, Cα-2º and Cα-3º alkyl primary amines and provides further support for the general deaminative strategy developed through this grant. The manuscript related to these results is currently under preparation.
5) Development of an enantioselective photocatalytic protocol to prepare ortho-disubstituted benzene bioisosteres. We have developed the first enantioselective catalytic strategy to prepare enantioenriched bicyclo[2.1.1]hexanes as bioisosteres of ortho-disubstituted benzene rings. The bioisostere fragment has been incorporated in different commercialized drugs and the biological activity of the new analogs has been tested. Our study showcases that the control of the absolute configuration and tridimensionality of the drug analogue has a large impact on its bioactivity, highlighting the need for stereoselective methods towards the construction of the bicyclo[2.1.1]hexane core. These results have been posted in the preprint repository Chemrxiv (D.O.I: 10.26434/chemrxiv-2023-f5ll4) and the corresponding manuscript is currently under review.
1) Development of a novel approach to cleave and functionalize carbon-nitrogen bonds under visible light irradiation. We have demonstrated that isonitriles, easily prepared from primary amines, serve as alkyl radical precursors in light-mediated hydro- and deuterodeamination reactions. The reaction is scalable, shows broad functional group compatibility and potential to be used in late-stage functionalization. Our study shows for the first time the feasibility of generating an alkyl radical from an isonitrile under visible-light irradiation and has opened the door to design further deamination reactions that we are currently developing in our laboratory. These results have been published in Angew. Chem. Int. Ed. 2024, e202317683.
2) Development of a deaminative arylation protocol using isonitriles. We have demonstrated the ability of isonitriles to be used as alkyl radical precursors in a photoredox-catalyzed transformation involving selective C-N cleavage and Csp3-Csp2 bond formation. This protocol allows for the preparation of functionalized heteroarenes from readily available isonitriles through selective C-N cleavage. These results have been posted in the preprint repository Chemrxiv (D O I: 10.26434/chemrxiv-2024-70psv) and are currently under review.
3) Development of a novel reagent for radical cyanation of native functional groups. We have designed a novel cyanating reagent that allows the introduction of a cyano group starting from native and abundant functional group such as carboxylic acids and alcohols. We take advantage of the selective C-N cleavage of isonitriles under visible light irradiation that we have recently developed. We provide a novel reagent that is “cyanide-free” and general for different abundant functional groups. The manuscript related to these results is currently under preparation.
4) Development of a deaminative alkylation protocol using isonitriles. We have used isonitriles as alkyl radical precursors in a photoredox-catalyzed transformation involving selective C-N cleavage and Csp3-Csp3 bond formation. Our method provides a deaminative alkylation protocol that is general for Cα-1º, Cα-2º and Cα-3º alkyl primary amines and provides further support for the general deaminative strategy developed through this grant. The manuscript related to these results is currently under preparation.
5) Development of an enantioselective photocatalytic protocol to prepare ortho-disubstituted benzene bioisosteres. We have developed the first enantioselective catalytic strategy to prepare enantioenriched bicyclo[2.1.1]hexanes as bioisosteres of ortho-disubstituted benzene rings. The bioisostere fragment has been incorporated in different commercialized drugs and the biological activity of the new analogs has been tested. Our study showcases that the control of the absolute configuration and tridimensionality of the drug analogue has a large impact on its bioactivity, highlighting the need for stereoselective methods towards the construction of the bicyclo[2.1.1]hexane core. These results have been posted in the preprint repository Chemrxiv (D.O.I: 10.26434/chemrxiv-2023-f5ll4) and the corresponding manuscript is currently under review.
During the first half of SCAN we have introduced the use of isonitriles as suitable partners in photocatalyzed deaminative cross-coupling reactions to forge new C-H, Csp2-Csp3 and Csp3-Csp3 bonds.
The use of isonitriles as primary amine derivatives in visible light promoted deamination reactions represents a significant advance in the field of carbon-nitrogen bond cleavage. Isonitriles have been extensively used in organic chemistry in reactions that involve the functionalization of the multiple NC bond. However, the selective cleavage and functionalization of the single C-N bond was limited to the hydrodeamination using toxic reagents and high temperatures (Bu3SnH, refluxing toluene). We have been able to selective cleavage and functionalize the C-N bond in isonitriles under extremely mild conditions using photoredox catalysis. We are currently working in expanding the use of isonitriles in further deaminative transformations
Additionally, we have developed the first enantioselective catalytic strategy to prepare enantioenriched bicyclo[2.1.1]hexanes as bioisosteres of ortho-disubstituted benzene rings, based on a Lewis acid-catalyzed [2+2] photocycloaddition. This achievement was not included in the original proposal but evolved while looking to apply our deaminative protocols. The enantioenriched bioisostere fragments prepared have been incorporated in different commercialized drugs and the biological activity of the new analogs has been tested. Our study showcases that the control of the absolute configuration and tridimensionality of the drug analogue has a large impact on its bioactivity. This protocol represents the first enantioselective method to prepare enantioenriched benzene bioisosteres. Due to the high interest of the pharmaceutical industry in the use of sp3-rich scaffolds that can act as bioisosteres of aromatic rings, and the need to prepare chiral drugs as single enantiomers, our results could have an important impact in drug discovery.
The use of isonitriles as primary amine derivatives in visible light promoted deamination reactions represents a significant advance in the field of carbon-nitrogen bond cleavage. Isonitriles have been extensively used in organic chemistry in reactions that involve the functionalization of the multiple NC bond. However, the selective cleavage and functionalization of the single C-N bond was limited to the hydrodeamination using toxic reagents and high temperatures (Bu3SnH, refluxing toluene). We have been able to selective cleavage and functionalize the C-N bond in isonitriles under extremely mild conditions using photoredox catalysis. We are currently working in expanding the use of isonitriles in further deaminative transformations
Additionally, we have developed the first enantioselective catalytic strategy to prepare enantioenriched bicyclo[2.1.1]hexanes as bioisosteres of ortho-disubstituted benzene rings, based on a Lewis acid-catalyzed [2+2] photocycloaddition. This achievement was not included in the original proposal but evolved while looking to apply our deaminative protocols. The enantioenriched bioisostere fragments prepared have been incorporated in different commercialized drugs and the biological activity of the new analogs has been tested. Our study showcases that the control of the absolute configuration and tridimensionality of the drug analogue has a large impact on its bioactivity. This protocol represents the first enantioselective method to prepare enantioenriched benzene bioisosteres. Due to the high interest of the pharmaceutical industry in the use of sp3-rich scaffolds that can act as bioisosteres of aromatic rings, and the need to prepare chiral drugs as single enantiomers, our results could have an important impact in drug discovery.