| Autor: |
Liu W, Ding D, Yin L, Poore A, Ho YS, Cheng YH, Hsieh CT, Yachuw S, Knieser R, Krause J, Tian S, Cheng MJ |
| Jazyk: |
angličtina |
| Zdroj: |
Research square [Res Sq] 2024 Aug 16. Date of Electronic Publication: 2024 Aug 16. |
| DOI: |
10.21203/rs.3.rs-3645899/v1 |
| Abstrakt: |
Stereochemical-controlled hydrogen bond donors play essential roles in the pharmaceutical industry. Consequently, organic molecules that bear difluoromethyl (CF2H) groups at chiral centers are emerging as pivotal components in pharmaceuticals due to their distinct hydrogenbonding property. However, a general approach for introducing CF2H groups in an enantioselective manner remained elusive. Here, we show that enantioconvergent difluoromethylation of racemic alkyl electrophiles, through alkyl radical intermediates, represents a new strategy for constructing CF2H-containing stereocenters. This strategy is enabled by using copper catalysts bound with a chiral diamine ligand bearing electron-deficient phenyl groups, and a nucleophilic difluoromethyl-zinc reagent. This method allows for the high-yield conversion of a diverse range of alkyl halides into their alkyl-CF2H analogs with excellent enantioselectivity (up to 99% e.e.). Mechanistic studies, supported by DFT calculations, revealed a route involving asymmetric difluoromethylation of alkyl radicals and crucial non-covalent interactions in the enantio-determining steps. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
|
