Insight into the Ferrier Rearrangement by Combining Flash Chemistry and Superacids

Abstract

The transformation of glycals into 2,3-unsaturated glycosyl derivatives, reported by Ferrier in 1962, is supposed to involve an a,b unsaturated glycosyl cation, an elusive ionic species that has still to be observed experimentally. Herein, while combination of TfOH and flow conditions failed to observe this ionic species, its extended lifetime in superacid solutions allowed its characterization by NMR-based structural analysis supported by DFT calculations. This allyloxycarbenium ion was further exploited in the Ferrier rearrangement to afford unsaturated nitrogen-containing C-aryl glycosides and C-alkyl glycosides under superacid and flow conditions, respectively.

Superacid‐Mediated Late‐Stage Aromatic Polydeuteration of Pharmaceuticals

“…In addition, when deuterated aqueous solutions of mineral acids are used, unwanted hydrolysis of functional groups can occur which could limit their applications for the labeling of elaborated compounds. Our group has recently demonstrated that anhydrous superacids [8] can be used to characterize long-lived polycationic species derived from polyfunctionalized substrates [9] and to directly functionalize complex natural alkaloids and steroids, [10] benefiting from the protection of the functional groups by protonation [11] and from the spectator role of the weakly-basic counter-anions. A superacid is conventionally defined as being more acidic than pure sulfuric acid, [8] which can be quantified by using the Hammett acidity function H 0 .…”

Tris(pentafluorophenyl)borane-Catalyzed Stereoselective C-Glycosylation of Glycals: A Facile Synthesis of Allyl and Alkynyl Glycosides

“…As a result, several reagent systems have been developed to effect the Ferrier glycosylation 5 6 of glycals to obtain 2,3-unsaturated C -glycosides by strongly Lewis acidic salts derived from transition metals or lanthanides, 5a,b superacidic conditions, 5q or the presence of an excess amount of BF 3 ·OEt 2 5r (Scheme 1a ). Also, Tebbe methylenation 15a and thermal Claisen rearrangement are another two-step process to synthesize the 2,3-unsaturated C -glycosides elegantly.…”

A Concise Route to Water-Soluble 2,6-Disubstituted BODIPY-Carbohydrate Fluorophores by Direct Ferrier-Type C-Glycosylation

“…15b , 15d Furthermore, in the course of this work, the attempted reaction of 8-aryl-1,3,5,7-tetramethyl BODIPYs with glycosyl trichloroacetimidate donors failed to provide any C -glycosylated BODIPYs. We, therefore, reasoned that compared to a classical glycosyl oxonium ion, e.g., 4 ( Figure 2 ), arising from a standard glycosyl donor, a more stabilized and less sterically encumbered, allylic oxocarbenium ion, i.e., 5 ( Figure 2 ), 17 , 18 might be able to glycosylate the 4-bora-3a,4a-diaza- s -indacene skeleton. Under such premises, we decided to test the electrophilic Ferrier-type C -glycosylation reaction (which involves allylic cation 5 ) of 8-aryl and 8-methyl 1,3,5,7-tetramethyl BODIPYs 6 and 7 , respectively ( Figure 2 ).…”

“…Ferrier-type glycosylations involve the treatment of Δ 1,2 -unsaturated monosaccharides, 1,5-anhydrohex-1-enitols, commonly termed glycals, e.g., 8 ( Scheme 1 ), with a Lewis acid to generate reactive electrophilic species 5 . 17 , 18 Accordingly, we tested the reaction of meso -phenyl BODIPY 6a with commercially available tri- O -acetyl- d -glucal (3,4,6-tri- O- acetyl-1,5-anhydro-2-deoxy- d -arabino-hex-1-enitol) 8 in the presence of three different Lewis acids, BF 3 ·OEt 2 , InCl 3 , and Yb(OTf) 3 . The best results were observed when 8 (3.0 equiv) and BODIPY 6a were treated with BF 3 ·OEt 2 (0.15 equiv) at −20 °C in dichloromethane.…”