Fragmentation of Carbohydrate Anomeric Alkoxyl Radicals: New Synthesis of Chiral 1‐Fluoro‐1‐halo‐1‐iodoalditols

Abstract

A new general methodology for the synthesis of 1,1,1-trihaloalditols by starting from 1,5-anhydro-2-deoxy-hex-1-enitol derivatives (glycals) is described. The halogens are introduced sequentially in each of the three different steps of the process. The fluorine is introduced in the first step by electrophilic fluorination of the starting glycal; next, hydroxyhalogenation of the resulting vinyl fluoride allows the addition of any halogen (F, Cl, Br or I) at will, and finally, an iodine atom is inserted through an alkoxyl radical fragmentation reaction. This methodology allows the preparation of diverse types of 1,1,1-trihalogenated compounds (R--CF(2)I, R--CFI(2), R--CFClI and R--CFBrI) under mild conditions compatible with sensitive substituents. In some cases, the diastereomeric mixtures generated from R--CFClI and R--CFBrI can be chromatographically separated, and their configuration determined by X-ray crystallographic analysis. The synthetic usefulness of these compounds has been preliminarily assessed by examining the reactivity of the fluorinated radical generated by rupture of the C--I bond.

Synthetic Fluorinated l-Fucose Analogs Inhibit Proliferation of Cancer Cells and Primary Endothelial Cells

“…Compound 10 was treated with Selectfluor 38 in dry nitromethane, followed by adding MgBr 2 as a nucleophile to furnish 2-deoxy-2-fluoro-L-fucosyl bromide (11). 41 Elimination of the anomeric bromide with triethylamine in acetonitrile afforded the desired vinyl fluoride (12) in 60% yield. Subsequent electrophilic fluorination of 12 by using Selectfluor, followed by acetylation of the anomeric position, provided the peracetylated 2,2-difluorofucose (4) in 80% yield over two steps.…”

“…Acetylation of l -fucose, treatment with hydrogen bromide in acetic acid, and subsequent zinc-promoted reductive elimination afforded the diacetyl- l -fucal ( 10 ) in 78% yield over three steps. Compound 10 was treated with Selectfluor in dry nitromethane, followed by adding MgBr 2 as a nucleophile to furnish 2-deoxy-2-fluoro- l -fucosyl bromide ( 11 ) . Elimination of the anomeric bromide with triethylamine in acetonitrile afforded the desired vinyl fluoride ( 12 ) in 60% yield.…”

Intramolecular Metal-Free C(sp3)-H Activation Enables a Selective Mono O-Debenzylation of Fully Protected Aminosugars

“…This is in agreement with a reaction cycle composed of a fast IHAT, which slowly turns over to give rise to the electrophilic species that is eventually attacked by the internal nucleophile to yield the reaction products. We believe that the results presented herein, in conjunction with the mild reaction conditions compatible with the most commonly used protecting groups in organic synthesis, effectively expand the methodology toolbox available to synthetic chemists and along with it, the number of potential strategies to tackle orthogonal derivatization in glycochemistry. Moreover, this procedure could be readily extrapolated to other nonsaccharidic skeletons, thus turning this new approach into a practical and versatile synthetic tool for the entire scientific community.…”

“…First, the standard reaction conditions employed by our research group for the β-fragmentation of anomeric alkoxyl radicals were assayed, obtaining the desired IHAT compound 2a albeit in a poor yield (entries 1 and 2). When the reaction was carried out with a somewhat more oxidative reagent PIFA, a complete consumption of the starting material was observed in just 30 min, although in a nonproductive way, providing a complex mixture of oxidized and partially deprotected products (entry 3).…”

Halogens and noble gases

“…5 Treatment with Selectofluor s of 1,5-anhydro-2-deoxy-hex-1-enitol derivatives has found application in the preparation of chiral 1-fluoro-1-halo-1-iodo-alditols. 6 With the increasing use of fluorous solid phase extraction (FSPE) techniques for the purification of 18 F-labelled radiotracers, significant attention has been focused on tagging and detagging strategies. In the first known detagging process relying on C-H bond formation, fluorous allylsilanes were prepared by cross-metathesis and subsequently subjected to electrophilic fluorodesilylation with Selectfluor s and the resulting allylic fluorides were successfully purified by FSPE.…”