Site-Selective Debenzylation of C‑Allyl Iminosugars Enables Their Stereocontroled Structure Diversification at the C‑2 Position Quentin Foucart, † Je ́ rô me Marrot, ‡ Je ́ rô me De ́ sire ́ , † and Yves Ble ́ riot* ,† † Université de Poitiers, IC2MP, UMR CNRS 7285, Equipe “Synthè se Organique”, Groupe Glycochimie, 4 rue Michel Brunet, Poitiers 86073 Cedex 9, France ‡ Institut Lavoisier de Versailles, UMR-CNRS 8180, Université de Versailles, 45 avenue des E ́ tats-Unis, Versailles 78035 Cedex, France * S Supporting Information ABSTRACT: A C-2 regioselective debenzylative cycloetherification/reductive elimination sequence applied to perbenzylated C-allyl iminosugars is described. This NIS/TMSOTf-triggered deprotection was successfully applied to five-, six-, and seven- membered C-allyl iminosugars including 1,2 cis and 1,2 trans stereoisomers. It allows rapid introduction of structural diversity at the key C-2 position in a stereoselective manner exploiting the anchimeric assistance of the intracyclic N-benzyl group, giving access to the 2-acetamido and 2-fluoro D-gluco configured C-allyl iminosugars and to the epimeric D-manno derivative. G lycomimetics are gaining increased interest because they offer the possibility of emulating carbohydrate activities while circumventing their drawbacks as drug candidates. One of the current challenges associated with glycomimetics is the development of efficient methods to extend their structural diversity in order to accelerate the discovery of biologically relevant molecules. 1 C-Allyl iminosugars, sugar analogues in which the endocyclic oxygen has been replaced by nitrogen and that possess a stereodefined pseudoanomeric allylic appendage, have demonstrated synthetic potential as pre- cursors of iminosugar C-glycosides, a class of potent glycosidase inhibitors. 2 They have contributed to the expansion of the chemical space of iminosugars through the generation of iminoglycoconjugates by coupling aglycons of various structures to the terminal alkene. 3,4 They have also been exploited to elaborate bicyclic natural products. 5 Their potential could be further increased if functional diversity could be rapidly introduced at the crucial C-2 position, allowing them to target other types of glycosidases and glycosyltransferases. One strategy to perform this structural modification includes a regioselective deprotection of the hydroxyl group at C-2 and its subsequent conversion into another function. Among carbohydrate protecting groups, the benzyl ether is very popular because of its ease of installation, its stability to a wide range of reaction conditions, and its removal under mild conditions. 6 A vast array of procedures have been reported for the regioselective O-debenzylation of highly benzylated carbohydrates. Most of them exploit either Lewis acids such as SnCl 4 or TiCl 4 , 7 alanes (DIBAL, TIBAL), 8 or BCl 3 9 and usually take advantage of a functional group close to the benzyl ether to be deprotected to guide the regioselectivity. 10 It is noteworthy that the regioselective O- debenzylation of polybenzylated iminosugars is scarce. 11-13 In the 1990s, the group of Nicotra reported an elegant regioselective deprotection of the benzyl group at the C-2 position of C-allyl glucopyranosides using I 2 . 14 In this transformation, the alkene is converted into a iodonium ion opened by the adjacent benzyl ether via a 5-exo-type cyclization with subsequent loss of the benzyl cation to afford an iodocycloether. 15 Its reductive elimination restores the double bond and generates a free hydroxyl group at the C-2 position, the entire process resulting in a regioselective O-2 debenzylation (Scheme 1A). Interestingly, this group also investigated the debenzylative cycloetherification of a D-gluco- configured α-C-allyl iminosugar with N-iodosuccinimide (NIS). The corresponding bicyclic iodocycloether A was obtained in 42% yield along with the competitive formation of the azetidinium ion B detected by mass spectrometry involving the N-benzyl group (Scheme 1B). To the best of our knowledge, iodocycloether A was not further processed to the reductive elimination step. 16,17 We propose that, if this C-2 regioselective O-debenzylation is successful and general in the C-allyl iminosugar series, it would pave the way to the introduction of structural diversity at C-2 position of this important class of iminosugars. Herein, we studied the Received: May 15, 2019 Published: May 30, 2019 Letter pubs.acs.org/OrgLett Cite This: Org. Lett. 2019, 21, 4821-4825 © 2019 American Chemical Society 4821 DOI: 10.1021/acs.orglett.9b01712 Org. Lett. 2019, 21, 4821-4825 Downloaded by BIBCNRS INC at 04:37:18:844 on June 24, 2019 from https://pubs.acs.org/doi/10.1021/acs.orglett.9b01712.