Article Cite This: J. Org. Chem. 2017, 82, 11406-11417
pubs.acs.org/joc
Boronic Acids as Phase-Transfer Reagents for Fischer Glycosidations in Low-Polarity Solvents Sanjay Manhas and Mark S. Taylor* Department of Chemistry, University of Toronto, 80 St. George Street, Toronto, ON M5S 3H6, Canada S Supporting Information *
ABSTRACT: Protocols employing phenylboronic acid as a phase-transfer reagent for Fischer glycosidations in low-polarity organic solvents are described. In addition to providing rate acceleration, the formation of a substrate-derived boronic ester alters the course of the reaction by selective promotion of a furanoside- or pyranoside-selective pathway. Computational modeling of the relative energies of the glycoside-derived boronic esters provides results that are qualitatively consistent with the observed distributions of furanoside versus pyranoside products. The boronic esters that are obtained as direct products of these reactions serve as protected intermediates for the synthesis of functionalized glycosides. Complexation of particular diol groups by the boronic acid also enables selective transformations of mixtures of carbohydrates.
■
INTRODUCTION
Limited precedent exists for using boronic acids as phasetransfer reagents or catalysts in carbohydrate chemistry. Boronic acids have been investigated as additives for enzymecatalyzed transformations of sugars in organic solvents.7,8 For example, the solubilizing effect of phenylboronic acid facilitated the β-glucosidase-catalyzed condensation of glucose to form mixtures of disaccharides in benzene. Boric acid (B(OH)3) was used to promote copper-catalyzed aminoalkynylation reactions of unprotected sugars in dioxane.9 Although a phase-transfer effect was not mentioned, the authors proposed that boric acid−carbohydrate adducts were intermediates in these processes. We sought to employ in situ boronic ester formation to accelerate the Fischer glycosidation,10 the prototypical protective-group free glycosidation,11 and an important preparative method. In the initially reported protocol, hydrogen chloride was employed as catalyst and the glycosyl acceptor (alcohol) as the solvent. Although refinements have been described, including the use of alternative solvents12 and catalysts,13 the method remains primarily applicable to lowboiling acceptors that can be used in large excess and in situations where the desired glycoside is the product of thermodynamic control.
Interactions between boronic acids and sugars have been applied in diverse ways in molecular recognition, including in the design of receptors for mono- and oligosaccharides, affinity materials for glycosylated molecules, and probes for molecular imaging.1 These interactions have also been employed in carbohydrate synthesis, primarily to protect 1,2- or 1,3-diol motifs through boronic ester formation,2 although activation of such motifs as tetracoordinate organoboron adducts has also been demonstrated.3 Complexation of an organoboron compound not only influences the reactivity of the sugar but can also alter its solubility properties. Smith and co-workers took advantage of this effect by employing hydrophobic boronic acids as transporters of sugars across lipid membranes.4 Another illustration of this phenomenon is the “phase switching” approach developed by the group of Hall, whereby boronic acids are drawn into aqueous solvent through complexation with a water-soluble sugar alcohol.5 A related effect has been employed to achieve chemoselective oxidations of arylboron reagents.6 Here, we describe studies aimed at using the phase-transfer properties of boronic acids to enable chemical transformations of unprotected carbohydrates in organic media. We show that phenylboronic acid promotes Fischer glycosidations of free sugars in low-polarity (hydrocarbon or chlorinated hydrocarbon) solvents. In addition to increasing the reaction rate, the formation of sugar-derived boronic esters influences the distribution of furanoside and pyranoside products, providing access to isomers distinct from those obtained under conventional conditions. © 2017 American Chemical Society
■
RESULTS AND DISCUSSION Reaction Optimization. The condensation of D-mannose and n-octanol, catalyzed by (S)-camphorsulfonic acid (CSA), was used as a model reaction to assess the effect of arylboronic Received: July 27, 2017 Published: October 16, 2017 11406
DOI: 10.1021/acs.joc.7b01880 J. Org. Chem. 2017, 82, 11406−11417
Article
The Journal of Organic Chemistry
furanosides under the conditions of Fischer glycosidation with concurrent isopropylidene ketal formation.22 When methyl α-mannopyranoside was subjected to the conditions shown in Table 1, entry 4, furanoside 1a was generated, but the rate of this reaction was lower than that using mannose as the substrate (Scheme 1). This result
acids on Fischer glycosidations in low-polarity solvents (Table 1). To determine the product distributions, the obtained Table 1. Effect of Boronic Acids on the Condensation of DMannose and n-Octanol in Low-Polarity Solvents
Scheme 1. Conversion of Methyl α-Mannopyranoside to α1a in the Presence of PhB(OH)2.a
a
entry
solvent
R
1aa (%)
2aa (%)
1 2 3 4 5 6 7 8
DCE DCE heptane heptane heptane heptane heptane heptane
b Ph b Ph Phc 3,5-(CF3)2C6H3 4-(MeO)C6H4 cyclohexyl
