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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 Schmidttype 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 b-elimination pathway. We demonstrated the glycosyl cross-coupling results 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 crosscoupling reaction was probed in the total synthesis of salmochelins (siderophores) and commercial anti-diabetic drugs (gliflozins). Combined experimental and computational studies revealed that the b-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 1,2cis 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.

Citation

Feng Zhu, Jacob Rodriguez, Tianyi Yang, Ilia Kevlishvili, Eric Miller, Duk Yi, Sloane O'Neill, Michael Rourke, Peng Liu, Maciej A Walczak. Glycosyl Cross-Coupling of Anomeric Nucleophiles - Scope, Mechanism and Applications in the Synthesis of Aryl C-glycosides. Journal of the American Chemical Society. 2017 Nov 17


PMID: 29148749

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