The article discusses a new strategy termed dynamic orbital selection, designed to improve late-stage functionalization in drug development. Traditional methods, such as Friedel-Crafts alkylations, face limitations including poor functional group tolerance and selectivity. The dynamic orbital selection method utilizes in situ formation of two distinct radical species, differentiated by a copper catalyst, to enable selective direct alkylation of arene C-H bonds. This process employs commonly available alcohols and carboxylic acids as alkylating agents, potentially unlocking vast new chemical spaces for more complex drug compounds and enhancing research in the field.
The late-stage introduction of alkyl fragments is particularly desirable due to the high sp3-character and structural versatility of these motifs, enhancing drug optimization efforts.
We report a novel strategy for the selective coupling of differently hybridized radical species, termed dynamic orbital selection, which addresses challenges of traditional alkylation methods.
Our approach allows for direct alkylation of native arene C−H bonds using available alcohols and carboxylic acids, overcoming limitations of Friedel-Crafts methods.
Dynamic orbital selection is expected to serve as a broadly applicable platform for further transformations involving two distinct radical species, expanding possibilities for drug development.
#drug-development #molecular-scaffolds #late-stage-functionalization #dynamic-orbital-selection #radical-chemistry
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