Enantio‐, Diastereo‐ and Regioselective Synthesis of Chiral Cyclic and Acyclic gem‐Difluoromethylenes by Palladium‐Catalyzed [4+2] Cycloaddition

gem‐Difluoromethylene moieties are attractive in medicinal chemistry due to their ability to mimic other more ubiquitous functional groups. Thus, effective asymmetric methods for their construction are highly desirable, especially for the industrial production of chiral drugs. Using a Pd‐catalyzed a...

Full description

Saved in:
Bibliographic Details
Published in:Angewandte Chemie International Edition 2022-06, Vol.61 (24), p.e202117635-n/a
Main Authors: Uno, Hiroto, Kawai, Koki, Araki, Taichi, Shiro, Motoo, Shibata, Norio
Format: Article
Language:English
Subjects:
Asymmetric Catalysis
Asymmetry
Carbonates
Catalysis
Cycloaddition
Cycloaddition Reaction
Enantioselectivity
Functional groups
gem-Difluoroalkyl
Hydrocarbons, Fluorinated
Industrial production
Ketones
Palladium
Regioselectivity
Substitution reactions
Substrates
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:gem‐Difluoromethylene moieties are attractive in medicinal chemistry due to their ability to mimic other more ubiquitous functional groups. Thus, effective asymmetric methods for their construction are highly desirable, especially for the industrial production of chiral drugs. Using a Pd‐catalyzed asymmetric [4+2] cycloaddition between substituted‐2‐alkylidenetrimethylene carbonates and gem‐difluoroalkyl ketones, we were able to easily access chiral 1,3‐dioxanes that contain a tetrasubstituted difluoroalkyl stereogenic center in cyclic and acyclic skeletons. A novel phosphoramidite ligand, which contains a bulky 1,1‐dinaphthylmethanamino moiety, was developed to provide the products in high yield with excellent enantio‐, diastereo‐, and regioselectivity. Strikingly, the gem‐difluoro substitution pattern promotes the reaction, and pentafluoroethylketone, an α,α‐difluorinated β‐ketoester, and a β‐ketosulfone are suitable substrates for this method. A Pd‐catalyzed asymmetric [4+2] cycloaddition between substituted‐2‐alkylidenetrimethylene carbonates and cyclic or acyclic gem‐difluoroalkyl ketones enabled the synthesis of chiral gem‐difluoromethylene compounds. A novel phosphoramidite ligand, which contains a bulky 1,1‐dinaphthylmethanamino moiety, was the key to providing high yield products with excellent enantio‐, diastereo‐, and regioselectivity.
ISSN:1433-7851
1521-3773
DOI:10.1002/anie.202117635