Excited-State Palladium-Catalyzed α-Selective C1-Ketonylation

Abstract

C-Glycosides are important carbohydrate mimetics found in natural products, bioactive compounds, and marketed drugs. However, stereoselective preparation of this class of glycomimetics remains a significant challenge in organic synthesis. Herein, we report an excited-state palladium-catalyzed α-selective C-ketonylation strategy using readily available 1-bromosugars to access a range of C-glycosides. The reaction features excellent α-selectivity and mild conditions that tolerate a wide range of functional groups and complex molecular architectures. The resulting α-ketonylsugars can serve as versatile precursors for their β-isomers and other C-glycosides. Preliminary experimental and computational studies of the mechanism suggest a radical pathway involving the formation of palladoradical and glycosyl radical that undergoes polarity-mismatched coupling with silyl enol ether, affording the desired α-ketonylsugars. Insight into the reactivity and mechanism will inspire new reaction development and provide straightforward access to both α- and β-C-glycosides, greatly expanding the chemical and patent spaces of glycomimetics.

Keywords: Excited-state catalysis; Palladium; glycosyl radical; ketonylation; silyl enol ethers.

Figure 1.

Development and exploration of ketonylation of carbohydrates.

Figure 2.

Mechanistic studies of C1-ketonylation of carbohydrates. ^aThe dip at around 350 nm is the instrumental artifact as the instrument switches the light sources. ^bAn additional 22% of ketone product 3a was obtained as well. ^cDFT calculations were performed at the M06/SDD-6-311+G(d,p)/SMD//B3LYP-D3/SDD-6-31G(d) level of theory using a simplified model of the glucosyl radical(1), where OMe groups were used in place of the OAc groups at the C3, 4, and 6 positions of the pyranose ring.