Acyclic Branched α-Fluoro Ketones for the Direct Asymmetric Mannich Reaction Leading to the Synthesis of β-Tetrasubstituted β-Fluoro Amines
Corresponding Author
Prof. Dr. Barry M. Trost
Department of Chemistry, Stanford University, 333 Campus Dr, Stanford, CA, 94305 USA
Search for more papers by this authorJacob S. Tracy
Department of Chemistry, Stanford University, 333 Campus Dr, Stanford, CA, 94305 USA
These authors contributed equally to this work.
Search for more papers by this authorTas Yusoontorn
Department of Chemistry, Stanford University, 333 Campus Dr, Stanford, CA, 94305 USA
These authors contributed equally to this work.
Search for more papers by this authorChao-I Joey Hung
Department of Chemistry, Stanford University, 333 Campus Dr, Stanford, CA, 94305 USA
Search for more papers by this authorCorresponding Author
Prof. Dr. Barry M. Trost
Department of Chemistry, Stanford University, 333 Campus Dr, Stanford, CA, 94305 USA
Search for more papers by this authorJacob S. Tracy
Department of Chemistry, Stanford University, 333 Campus Dr, Stanford, CA, 94305 USA
These authors contributed equally to this work.
Search for more papers by this authorTas Yusoontorn
Department of Chemistry, Stanford University, 333 Campus Dr, Stanford, CA, 94305 USA
These authors contributed equally to this work.
Search for more papers by this authorChao-I Joey Hung
Department of Chemistry, Stanford University, 333 Campus Dr, Stanford, CA, 94305 USA
Search for more papers by this authorGraphical Abstract
Break the cycle: Simple branched acyclic vinyl and alkynyl fluoro ketones undergo direct asymmetric Mannich reactions with aldimines to form β-fluoro amines bearing tetrasubstituted fluorine stereocenters. The zinc-ProPhenol-catalyzed transformation proceeds in excellent yield, and with high levels of diastereo- (up to <20:1) and enantioselectivity (up to 99 %).
Abstract
The preparation of acyclic β-fluoro amines bearing tetrasubstituted fluorine stereocenters is described via a direct Zn/ProPhenol-catalyzed Mannich reaction. The reaction utilizes branched vinyl or alkynyl α-fluoro ketones that can be coupled with a range of aryl, heteroaryl, vinyl, or cyclopropyl aldimines in high yield and with excellent diastereo- (up to >20:1) and enantioselectivity (up to 99 %). The use of readily cleaved tert-butoxycarbonyl (Boc) or carboxybenzyl (Cbz) imine protecting groups adds utility to the reaction by allowing for easy access to the free amine products under mild and chemoselective reaction conditions.
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