Glycosyl Cross-Coupling of Anomeric Nucleophiles: Scope, Mechanism, and Applications in the Synthesis of Aryl C-Glycosides

Abstract

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 Pd(dba) (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.

Direct Dehydrative Glycosylation of C1‐Alcohols

“…Beyondt he wide scope of acceptors tolerated by these conditions, Walczak and co-workersd emonstrated the method's utility in the synthesis of axinelloside Abuilding blocks [72] as well as in orthogonal glycosylation strategies employing anomeric nucleophiles as an ew typeofg lycosyl acceptor. [73] Despite the high yields afforded under the optimized conditions, anomeric selectivities were suboptimal with initial results showing a:b diastereoselectivities of 1:1.2. As highlighted at variousp oints in this review,a sw ell as in the seminalw ork published by Lemieux, [30] poor anomeric selectivities can often times be ameliorated by halide-ion assisted anomerization of the glycosyl intermediate and can result in more reactive b anomeric halides.…”

Design and synthesis of glycomimetics: Recent advances

“…Anomeric stannanes are configurationally stable nucleophiles that can be stored and manipulated under ambient conditions without loss of stereochemical integrity, even after extended periods of time (6 months at room temperature or 1 year at −20°C). They can be easily prepared starting from the corresponding glycal 130 , affording either 1,2‐ cis or 1,2‐ trans glycosides, thus allowing formation of both C(1) anomers …”

Rethinking Carbohydrate Synthesis: Stereoretentive Reactions of Anomeric Stannanes

“…[20] With these conditions in hand, we were able to prepare as eries of linear and branched saccharides. [20] Given the ease with which anomeric stannanes can be elaborated into oligosaccharides using established glycosylation techniques, while maintaining their configurationals tability,t he utility of this class of reagents is not restricted to the preparation of simple building blocks and is viable for the preparation of more complex starting materials.…”

“…We wondered if anomeric stannanes would be suitable for the preparation Cglycosides through astereoretentive process and thus focusing our initial work on establishing whether or not C1-stannanes could participate in the Stille reaction. [20,23] At the outset of these studies, we anticipated the competing b-elimination to plague the cross-coupling process. We found that removal of the C2 substituent and subsequentg lycal formation could be prevented by aj udiciouss election of the appropriate phosphine ligand.…”

“…[29] Other applications of the glycosyl-cross coupling methodi nvolve the synthesis of TGE (tri-glucosylated enterobactin, Salmonella siderophore), on-resin glycosylation, and glycodiversification of peptides, small molecule drugs, and natural products. [20,30]…”