Insight into the Ferrier Rearrangement by Combining Flash Chemistry and Superacids.

Naresh Bhuma,Zahra Abada,Ana Ardá,Ludivine Lebedel,Hiroki Yamashita,Bastien Michelet,Jérôme Désiré,Agnès Martin‐Mingot,Sébastien Thibaudeau,Ali Abou‐Hassan,Jérôme Marrot,Yutaka Shimizu,Masahiro Takumi,Aiichiro Nagaki,Yves Blériot,Jesús Jiménez‐Barbero

doi:10.1002/anie.202010175

Abstract

The transformation of glycals into 2,3-unsaturated glycosyl derivatives, reported by Ferrier in 1962, is supposed to involve an α,β 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.

Highlights

The cation-flow method,[15] in which highly reactive cations are rapidly generated in the absence of nucleophiles using the integrated flow microreactor, is quite effective for the generation of alkoxycarbenium ions[16] and for performing glycosylation reactions involving glycosyl cation intermediates based on an indirect method.[17]
Using an integrated flow microreactor system consisting of two micromixers (M1 and M2) and two microtube reactors (R1 and R2), the treatment of a dichloromethane solution of 1a with triflic acid (TfOH) followed by allyltrimethylsilane to generate the known C-glycoside 2a[18] was examined (Figure 2)
An stereochemical outcome was observed that can be tentatively explained by the pseudo-axial attack on the -face of the 4H3 conformer of the transient 2-deoxyglucopyranosyl oxycarbenium ion as previously observed22a while a long-range participation by the ester or ether at C-4 can not be excluded.13c,13d We evaluated the ability of the flow microreactor system to generate and accumulate ion I to allow its observation by NMR

Summary

Introduction

The cation-flow method,[15] in which highly reactive cations are rapidly generated in the absence of nucleophiles using the integrated flow microreactor, is quite effective for the generation of alkoxycarbenium ions[16] and for performing glycosylation reactions involving glycosyl cation intermediates based on an indirect method.[17]. We report our efforts to characterize this elusive ion combining flow microreactors (Figure 1B), superacid chemistry, NMR analysis and DFT calculations and its use as a glycosyl donor to generate unprecedented nitrogen-containing C-aryl hex-2-enopyranosides (Figure 1C).

Results

Conclusion