Dataset Information

Diastereoselective Synthesis of Aryl C-Glycosides from Glycosyl Esters via C-O Bond Homolysis.

ABSTRACT: C-aryl glycosyl compounds offer better in vivo stability relative to O- and N-glycoside analogues. C-aryl glycosides are extensively investigated as drug candidates and applied to chemical biology studies. Previously, C-aryl glycosides were derived from lactones, glycals, glycosyl stannanes, and halides, via methods displaying various limitations with respect to the scope, functional-group compatibility, and practicality. Challenges remain in the synthesis of C-aryl nucleosides and 2-deoxysugars from easily accessible carbohydrate precursors. Herein, we report a cross-coupling method to prepare C-aryl and heteroaryl glycosides, including nucleosides and 2-deoxysugars, from glycosyl esters and bromoarenes. Activation of the carbohydrate substrates leverages dihydropyridine (DHP) as an activating group followed by decarboxylation to generate a glycosyl radical via C-O bond homolysis. This strategy represents a new means to activate alcohols as a cross-coupling partner. The convenient preparation of glycosyl esters and their stability exemplifies the potential of this method in medicinal chemistry.

SUBMITTER: Wei Y

PROVIDER: S-EPMC8044010 | biostudies-literature | 2021 Apr

REPOSITORIES: biostudies-literature

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Publications

Diastereoselective Synthesis of Aryl C-Glycosides from Glycosyl Esters via C-O Bond Homolysis.

Wei Yongliang Y Ben-Zvi Benjamin B Diao Tianning T

Angewandte Chemie (International ed. in English) 20210310 17

C-aryl glycosyl compounds offer better in vivo stability relative to O- and N-glycoside analogues. C-aryl glycosides are extensively investigated as drug candidates and applied to chemical biology studies. Previously, C-aryl glycosides were derived from lactones, glycals, glycosyl stannanes, and halides, via methods displaying various limitations with respect to the scope, functional-group compatibility, and practicality. Challenges remain in the synthesis of C-aryl nucleosides and 2-deoxysugars ...[more]

PMID: 33438338

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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 β-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 β-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.

Dataset Information

Diastereoselective Synthesis of Aryl C-Glycosides from Glycosyl Esters via C-O Bond Homolysis.

Publications

Diastereoselective Synthesis of Aryl C-Glycosides from Glycosyl Esters via C-O Bond Homolysis.

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