Enantioselective Synthesis of β‑Fluoro Amines via β‑Amino α‑Fluoro Nitroalkanes and a Traceless Activating Group Strategy

Preparation of a range of enantioenriched β-fluoro amines (α,β-disubstituted) is described in which the nitrogen and fluorine atoms are attached to sp3-hybridized carbons. The key finding is a chiral bifunctional Brønsted acid/base catalyst that can deliver β-amino-α-fluoro nitroalkanes with high en...

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Published inJournal of the American Chemical Society Vol. 138; no. 42; pp. 13794 - 13797
Main Authors Vara, Brandon A, Johnston, Jeffrey N
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 26.10.2016
Amer Chemical Soc
Subjects
Chemistry
Chemistry, Multidisciplinary
Physical Sciences
Science & Technology
ASYMMETRIC MANNICH REACTION
DIRECTING GROUP
ALPHA,BETA-UNSATURATED KETONES
MICHAEL-ADDITION
CHEMISTRY
STEREOSELECTIVE-SYNTHESIS
FLUORINATION
AZIRIDINES
CONJUGATE ADDITION
CARBOXYLIC-ACIDS
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Summary:Preparation of a range of enantioenriched β-fluoro amines (α,β-disubstituted) is described in which the nitrogen and fluorine atoms are attached to sp3-hybridized carbons. The key finding is a chiral bifunctional Brønsted acid/base catalyst that can deliver β-amino-α-fluoro nitroalkanes with high enantio- and diastereoselection. A denitration step renders the nitro group “traceless” and delivers secondary, tertiary, or vinyl alkyl fluorides embedded within a vicinal fluoro amine functional group. A synthesis of each possible stereoisomer of a β-fluoro lanicemine illustrates the potential ease with which fluorinated small molecules relevant to neuroscience drug development can be prepared in a stereochemically comprehensive manner.
Bibliography:NIH RePORTER
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ISSN:0002-7863
1520-5126
DOI:10.1021/jacs.6b07731