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

Abstract

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.

Recent advances in Pd-catalyzed asymmetric cyclization reactions

“…Recently, a remarkable example of this type of annulation was the formation of chiral 1,3-dioxanes 232 bearing tetrasubstituted gem -difluoroalkyl stereogenic centers, which was achieved by the reaction of substituted-2-alkylidenetrimethylene carbonates 222 with gem -difluoroalkyl ketones 231 using a novel phosphoramidite ligand containing a bulky 1,1-dinaphthylmethanamino moiety, a transformation described by Shibata (Scheme 49). 108 Besides cyclic and linear difluoroalkyl ketones, pentafluoroethylketone, an α,α-difluorinated β-ketoester, and a β-ketosulfone were also amenable to this transformation.…”

Transition‐Metal Catalyzed [4+2]‐Cycloaddition Reactions: A Sexennial Update

“…Palladium catalyzed synthesis of chiral 1,3-dioxanes. [102] Scheme 24. Palladium catalyzed synthesis of bridged bicycles.…”

Pd-catalyzed oxa-[4 + n] dipolar cycloaddition using 1,4-O/C dipole synthons for the synthesis of O-heterocycles

“…The Shibata group recently developed Pd-catalyzed enantio-, diastereo- and regioselective oxa-[4 + 2] dipolar cycloaddition of substituted ADTMCs 1 with cyclic- or acyclic gem -fluoroalkyl ketones 34 or 35 to afford chiral 1,3-dioxanes 36 and 37 (Scheme 11B). 21 The reaction was enabled by introducing two fluorine atoms at the α-position of the ketone, thereby increasing the electrophilicity of the carbonyl substrate and stabilizing the hemiketal intermediate. A novel sterically bulky phosphoramidite ligand L13 was designed to provide the cycloadducts 36 and 37 with high efficiencies and regio- and stereoselectivities.…”