Application of Benzylic CH Fluorination for the Formal Synthesis of syn-α,β-Difluoro-γ-amino Acid

Benzylic CH fluorination has emerged as a valuable tool for the introduction of fluorine. However, the power-fulness of benzylic CH fluorination has not been tested in any multi-step synthesis alpha beta-Difluoro-gamma-amino acids are useful entities for biological application owing to the so-called fluorine conformational effect. In this work, benzylic CH fluorination has been successfully utilized as the key step for the formal synthesis of syn-alpha,beta-difluoro-gamma-amino acid 1, a very challenging but useful target. The approach developed in this work could be viewed as more practical compared to the previous one, because: (1) no corrosive and toxic nucleophilic fluorinating reagents are used, (2) the overall yield is 18% (the previous approach is about 5%), and (3) the key benzylic CH reaction developed by Chen and co-workers was scaled up to one gram without decreasing its original efficiency. A staking fluorine effect was observed: a carbon with one fluorine atom on the adjacent carbon is much less reactive than an ordinary carbon for the benzylic CH fluorination.