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Acyl Glycosides through Stereospecific Glycosyl Cross-Coupling: Rapid Access to C(sp³)-Linked Glycomimetics.

ABSTRACT: Replacement of a glycosidic bond with hydrolytically stable C-C surrogates is an efficient strategy to access glycomimetics with improved physicochemical and pharmacological properties. We describe here a stereoretentive cross-coupling reaction of glycosyl stannanes with C(sp²)- and C(sp³)-thio(seleno)esters suitable for the preparation C-acyl glycosides as synthetic building blocks to obtain C(sp³)-linked and fluorinated glycomimetics. First, we identified a set of standardized conditions employing a Pd(0) precatalyst, CuCl additive, and phosphite ligand that provided access to C-acyl glycosides without deterioration of anomeric integrity and decarbonylation of the acyl donors (>40 examples). Second, we demonstrated that C(sp³)-glycomimetics could be introduced into the anomeric position via a direct conversion of C1 ketones. Specifically, the conversion of the carbonyl group into a CF₂ mimetic is an appealing method to access valuable fluorinated analogues. We also illustrate that the introduction of other carbonyl-based groups into the C1 position of mono- and oligosaccharides can be accomplished using the corresponding acyl donors. This protocol is amenable to late-stage glycodiversification and programmed mutation of the C-O bond into hydrolytically stable C-C bonds. Taken together, stereoretentive anomeric acylation represents a convenient method to prepare a diverse set of glycan mimetics with minimal synthetic manipulations and with absolute control of anomeric configuration.

SUBMITTER: Zhu F

PROVIDER: S-EPMC6311691 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Stereoselective manipulations at the C1 anomeric position of saccharides are one of the central goals of preparative carbohydrate chemistry. Historically, the majority of reactions forming a bond with anomeric carbon has focused on reactions of nucleophiles with saccharide donors equipped with a leaving group. Here, we describe a novel approach to stereoselective synthesis of C-aryl glycosides capitalizing on the highly stereospecific reaction of anomeric nucleophiles. First, methods for the preparation of anomeric stannanes have been developed and optimized to afford both anomers of common saccharides in high anomeric selectivities. We established that oligosaccharide stannanes could be prepared from monosaccharide stannanes via O-glycosylation with Schmidt-type donors, glycal epoxides, or under dehydrative conditions with C1 alcohols. Second, we identified a general set of catalytic conditions with Pd2(dba)3 (2.5 mol%) and a bulky ligand (JackiePhos, 10 mol%) controlling the ?-elimination pathway. We demonstrated that the glycosyl cross-coupling resulted in consistently high anomeric selectivities for both anomers with mono- and oligosaccharides, deoxysugars, saccharides with free hydroxyl groups, pyranose, and furanose substrates. The versatility of the glycosyl cross-coupling reaction was probed in the total synthesis of salmochelins (siderophores) and commercial anti-diabetic drugs (gliflozins). Combined experimental and computational studies revealed that the ?-elimination pathway is suppressed for biphenyl-type ligands due to the shielding of Pd(II) by sterically demanding JackiePhos, whereas smaller ligands, which allow for the formation of a Pd-F complex, predominantly result in a glycal product. Similar steric effects account for the diminished rates of cross-couplings of 1,2-cis C1-stannanes with aryl halides. DFT calculations also revealed that the transmetalation occurs via a cyclic transition state with retention of configuration at the anomeric position. Taken together, facile access to both anomers of various glycoside nucleophiles, a broad reaction scope, and uniformly high transfer of anomeric configuration make the glycosyl cross-coupling reaction a practical tool for the synthesis of bioactive natural products, drug candidates, allowing for late-stage glycodiversification studies with small molecules and biologics.

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Acyl Glycosides through Stereospecific Glycosyl Cross-Coupling: Rapid Access to C(sp³)-Linked Glycomimetics.

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Acyl Glycosides through Stereospecific Glycosyl Cross-Coupling: Rapid Access to C(sp3)-Linked Glycomimetics.

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OmicsDI is part of the ELIXIR infrastructure

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Acyl Glycosides through Stereospecific Glycosyl Cross-Coupling: Rapid Access to C(sp³)-Linked Glycomimetics.