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Catalytic Enantioselective Synthesis of Heterocyclic Vicinal Fluoroamines Using Asymmetric Protonation: A Method Development and Mechanistic Study

preprint
submitted on 02.03.2020, 16:29 and posted on 03.03.2020, 09:35 by Matthew Ashford, Chao Xu, john molloy, Cameron Carpenter-Warren, Alexandra Slawin, Andrew Leach, Allan Watson

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, which undergoes asymmetric protonation upon rearomatization. The reaction accommodates a range of azaheterocycles and nucleophiles, generating the C–F stereocenter in high enantioselectivity, and is also amenable to stereogenic C–CF3 bonds. Extensive DFT calculations have provided insight into the reaction mechanism and the origin of catalyst selectivity. Crystal structure data shows the dominance of non-covalent interactions in the core structure conformation, enabling modulation of the conformational landscape. Ramachandran-type analysis of conformer distribution and protein data bank mining has indicated benzylic fluorination using this approach has potential for improved potency in several marketed drugs.

Funding

Leverhulme Trust RPG-2015-308

University of St Andrews

History

Email Address of Submitting Author

aw260@st-andrews.ac.uk

Institution

University of St Andrews

Country

United Kingdom

ORCID For Submitting Author

0000-0002-1582-4286

Declaration of Conflict of Interest

None

Exports