Catalytic Enantioselective Synthesis of Heterocyclic Vicinal Fluoroamines by Using Asymmetric Protonation: Method Development and Mechanistic Study.
Matthew W AshfordChao XuJohn J MolloyCameron Carpenter-WarrenAlexandra M Z SlawinAndrew G LeachAllan J B WatsonPublished in: Chemistry (Weinheim an der Bergstrasse, Germany) (2020)
A catalytic enantioselective synthesis of heterocyclic vicinal fluoroamines is reported. A chiral Brønsted acid promotes aza-Michael addition to fluoroalkenyl heterocycles to give a prochiral enamine intermediate that undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C-F stereocentre in high enantioselectivity, and is also amenable to stereogenic C-CF3 bonds. Extensive DFT calculations provided evidence for stereocontrolled proton transfer from catalyst to substrate as the rate-determining step, and showed the importance of steric interactions from the catalyst's alkyl groups in enforcing the high enantioselectivity. Crystal structure data show the dominance of noncovalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran-type analysis of conformer distribution and Protein Data Bank mining indicated that benzylic fluorination by this approach has the potential to improve the potency of several marketed drugs.
Keyphrases
- crystal structure
- ionic liquid
- molecular dynamics simulations
- room temperature
- molecular dynamics
- electronic health record
- density functional theory
- big data
- reduced graphene oxide
- highly efficient
- cystic fibrosis
- visible light
- metal organic framework
- electron transfer
- amino acid
- single molecule
- risk assessment
- machine learning
- molecular docking
- climate change
- solid state
- human health
- protein protein
- mass spectrometry
- gold nanoparticles