Reengineering Chemical Glycosylation: Direct, Metal‐Free Anomeric O‐Arylation of Unactivated Carbohydrates

Abstract

To sustain innovation in glycobiology, effective routes to well-defined carbohydrate probes must be developed. For over a century, glycosylation has been dominated by the formation of the anomeric Csp -O acetal junction in glycostructures. A dissociative mechanistic spectrum spanning S 1 and S 2 is frequently operational thereby reducing the efficiency. By reengineering this fundamental process, an orthogonal disconnection allows the acetal to be formed directly from the reducing sugar without the need for substrate pre-functionalisation. The use of stable aryliodonium salts facilitates a formal O-H functionalisation reaction. This allows lactols to undergo mild, metal-free O-arylation at ambient temperature. The efficiency of the transformation has been validated using a variety of pyranoside and furanoside monosaccharides in addition to biologically relevant di- and trisaccharides (up to 85 %). Fluorinated mechanistic probes that augment the anomeric effect were employed. It is envisaged that this strategy will prove expansive for the construction of complex acetals under substrate-based stereocontrol.

The Synthesis and Glycoside Formation of Polyfluorinated Carbohydrates

“…A recent example by the Gilmour group allowing glycosidation of a 2,2difluorinated reducing sugar appears very promising. 521 Establishing efficient protocols to employ polyfluorinated sugar donors in an automated glycan synthesis setting will be another key advancement. It is worth pointing out that enzymatic glycosyl formation with polyfluorinated donors has not yet been achieved.…”

“…The modification of glycosyl donor reactivities by polyfluorination is naturally even more pronounced than with monofluorinated sugars, and perhaps the development of other methodologies than the traditional acid-catalyzed/electrophile-induced or base-mediated anomeric glycosidation will provide extra opportunities. A recent example by the Gilmour group allowing glycosidation of a 2,2-difluorinated reducing sugar appears very promising . Establishing efficient protocols to employ polyfluorinated sugar donors in an automated glycan synthesis setting will be another key advancement.…”

Regioselective Anomeric O‐Benzyl Deprotection in Carbohydrates

“…Further, to evaluate the stability of acid‐sensitive protecting groups, like benzylidene, trityl, and tert ‐butyldimethylsilyl, benzyl glycosides 22 , [10] 24 [10] and 26 were synthesized and subjected to the above regioselective anomeric debenzylation reaction conditions. Again, it was shown that these protective groups are stable, and the only products isolated were the corresponding hemiacetals 23 , [19] 25 [10] and 27 , respectively, in good yield ((Table 2, entries 6–8). These results show that the OTBS, OAc, benzylidene acetal, and trityl protecting groups were stable under the present regioselective anomeric benzyl deprotection reaction conditions [20]…”

Rationalizing the Stereoelectronic Influence of Interglycosidic Bond Conformations on the Reactivity of 1,4-O-Linked Disaccharide Donors

“…(15). 8,69 The compound was synthesized from commercially available lactose (11) using the same procedure as 7. White powder (Final yield of 15 from 1.43 g, 3.2 mmol of 14 = 2.2 g, 64%).…”