Absence of Stereodirecting Participation by 2‑<i>O</i>‑Alkoxycarbonylmethyl Ethers in 4,6‑<i>O</i>‑Benzylidene-Directed Mannosylation

The preparation of a series of mannopyranosyl donors carrying 2-<i>O</i>-(2-oxoalkyl) ethers and their use in glycosylation reactions are described. The formation of cyclic products with the simple 2-<i>O</i>-phenacyl ether and with the 2-<i>O</i>-(<i>t</i>-butoxycarbonylmethyl) ether establishes the stereoelectronic feasibility of participation in such systems. The high β-selectivities observed with the bis-trifluoromethyl phenacyl ether indicate that participation can be suppressed through the introduction of electron-withdrawing substituents. The high β-selectivities and absence of cyclic products observed with the 2-<i>O</i>-(methoxycarbonylmethyl) ether exclude the effective participation of esters through six-membered cyclic intermediates in this series. The results are discussed in terms of the conformation of cyclic dioxenium ions (<i>E</i>,<i>E</i>-, <i>E</i>,<i>Z</i>-, or <i>Z</i>,<i>Z</i>-) and in the context of “neighboring group” participation by nonvicinal esters in glycosylation. Methods for the deprotection of the 2-<i>O</i>-phenacyl and 2-<i>O</i>-(methoxycarbonylmethyl) ethers are described

Synthesis of <i>N</i>,<i>N</i>,<i>O</i>‑Trisubstituted Hydroxylamines by Stepwise Reduction and Substitution of <i>O</i>‑Acyl <i>N</i>,<i>N</i>‑Disubstituted Hydroxylamines

Diverse <i>N</i>,<i>N</i>,<i>O-</i>trisubstituted hydroxylamines, an under-represented group in compound collections, are readily prepared by partial reduction of <i>N</i>-acyloxy secondary amines with diisobutylaluminum hydride followed by acetylation and reduction of the so-formed <i>O</i>-acyl-<i>N</i>,<i>N</i>-disubstituted hydroxylamines with triethylsilane and boron trifluoride etherate. Use of carbon nucleophiles in the last step, including allyltributylstannane, silyl enol ethers, and 2-methylfuran, gives <i>N</i>,<i>N</i>,<i>O-</i>trisubstituted hydroxylamines with branching α- to the <i>O-</i>substituent. <i>N</i>,<i>N-</i>Disubstiuted hydroxylamines are conveniently prepared by reaction of secondary amines with dibenzoyl peroxide followed by diisobutylaluminum hydride reduction

Selective Protection of Secondary Amines as the <i>N</i>‑Phenyltriazenes. Application to Aminoglycoside Antibiotics

Selective protection of secondary amines as triazenes in the presence of multiple primary amines is demonstrated, with subsequent protection of the primary amines as either azides or carbamates in the same pot. Aminoglycoside antibiotic examples reveal broad functional group compatibility. The triazene group is removed with trifluoroacetic acid and, because of the low barrier to rotation, affords sharp ¹H NMR spectra at room temperature

Stereoselective <i>C</i>‑Glycoside Formation with 2‑<i>O</i>‑Benzyl-4,6‑<i>O</i>‑benzylidene Protected 3‑Deoxy Gluco- and Mannopyranoside Donors: Comparison with <i>O</i>‑Glycoside Formation

Unlike alcohols, the reaction of <i>C</i>-nucleophiles with 2-<i>O</i>-benzyl-4,6-<i>O</i>-benzylidene-protected 3-deoxy-gluco- and mannopyranosyl thioglycosides is highly stereoselective providing the α-<i>C</i>-glycosides in the gluco-series and the β-<i>C</i>-glycosides in the manno-series. Conformational analysis of nucleophilic attack of putative intermediate glycosyl oxocarbenium ions suggests that the observed selectivities for C-glycoside formation can be explained by preferential attack on the opposite face of the oxocarbenium to the C2–H2 bond and that eclipsing interactions with this bond are the main stereodetermining factor. It is argued that the steric interactions in the attack of alcohols (sp³-hybridized O) and of typical carbon-based nucleophiles (sp² C) on oxocarbenium ions are very different, with the former being less severe, and thus that there is no a priori reason to expect <i>O</i>- and <i>C</i>-glycosylation to exhibit parallel stereoselectivities for attack on a given oxocarbenium ion

Influence of Side Chain Conformation and Configuration on Glycosyl Donor Reactivity and Selectivity as Illustrated by Sialic Acid Donors Epimeric at the 7‑Position

Two <i>N</i>-acetyl 4<i>O</i>,5<i>N</i>-oxazolidinone-protected sialyl thioglycosides epimeric at the 7-position have been synthesized and their reactivity and stereoselectivity in glycosylation reactions have been compared. It is demonstrated that the natural 7<i>S</i>-donor is both more reactive and more α-selective than the unnatural 7<i>R</i>-isomer. The difference in reactivity is attributed to the side chain conformation and specifically to the proximity of O7 to the anomeric center. In the natural <i>7S</i>-isomer, O7 is closer to the anomeric center than in its unnatural 7<i>R</i>-epimer and, therefore, better able to support incipient positive charge at the locus of reaction. The difference in selectivity is also attributed to the side conformation, which in the unnatural 7<i>R</i>-series is placed perpendicularly above the α-face of the donor and so shields it to a greater extent than in the 7<i>S</i>-series. These observations are consistent with earlier conclusions on the influence of the side chain conformation on reactivity and selectivity derived from conformationally locked models in the glucose and galactose series and corroborate the suggestion that those effects are predominantly stereoelectronic rather than torsional. The possible relevance of side chain conformation as a factor in the influence of glycosylation stereoselectivity by remote protecting groups and as a control element in enzymic processes for glycosidic bond formation and hydrolysis are discussed. Methods for assignment of the anomeric configuration in the sialic acid glycosides are critically surveyed

Facile Synthesis of 3‑<i>N</i>‑Alkyl Pyrimidin-2,4-diones from <i>N</i>‑Sulfonyloxy Maleimides and Amines

Reaction of variously substituted <i>N</i>-trifluoro­methane­sulfonyl­oxy maleimides with primary amines in the presence of potassium carbonate in DMF at room temperature results in the formation of 3-<i>N</i>-alkyl pyrimidin-2,4-diones in good yield

Asymmetric Synthesis of Polyhydroxylated <i>N</i>-Alkoxypiperidines by Ring-Closing Double Reductive Amination: Facile Preparation of Isofagomine and Analogues

A de novo synthesis of novel polyhydroxylated <i>N</i>-alkoxypiperidines based on the ring-closing double reductive amination of 1,5-dialdehydes, obtained by oxidative cleavage of cyclopentene derivatives, with O-substituted hydroxylamines is reported. Isofagomine was accessed by cleavage of the N–O bond of an <i>N</i>-alkoxypiperidine

Stereoselective Synthesis of the Equatorial Glycosides of Legionaminic Acid

The synthesis of a legionaminic acid donor from <i>N</i>-acetylneuraminic acid in 15 steps and 17% overall yield is described. Activation of the adamantanyl thioglycoside in the donor with <i>N</i>-iodosuccinimide and trifluoromethanesulfonic acid in dichloromethane and acetonitrile at −78 °C in the presence of primary, secondary and tertiary alcohols affords the corresponding glycosides in excellent yield and good to excellent equatorial selectivity. In particular, coupling to the 4-OH of a suitably protected neuraminic acid derivative affords a disaccharide that closely resembles the glycosidic linkage in the polylegionaminic acid from the lipopolysaccharide of the <i>Legionella pneumophila</i> virulence factor. A straightforward deprotection sequence enables conversion of the protected glycosides to the free <i>N</i>,<i>N</i>-diacetyllegionaminic acid glycosides

Probing the Influence of Protecting Groups on the Anomeric Equilibrium in Sialic Acid Glycosides with the Persistent Radical Effect

A method for the investigation of the influence of protecting groups on the anomeric equilibrium in the sialic acid glycosides has been developed on the basis of the equilibration of <i>O</i>-sialyl hydroxylamines by reversible homolytic scission of the glycosidic bond following the dictates of the Fischer–Ingold persistent radical effect. It is found that a <i>trans</i>-fused 4<i>O</i>,5<i>N</i>-oxazolidinone group stabilizes the equatorial glycoside, i.e., reduces the anomeric effect, when compared to the 4<i>O</i>,5<i>N</i>-diacetyl protected systems. This effect is discussed in terms of the powerful electron-withdrawing nature of the oxazolidinone system, which in turn is a function of its strong dipole moment in the mean plane of the pyranose ring system. The new equilibration method displays a small solvent effect and is most pronounced in less polar media consistent with the anomeric effect in general. The unusual (for anomeric radicals) poor kinetic selectivity of anomeric sialyl radicals is discussed in terms of the planar π-type structure of these radicals and of competing 1,3-diaxial interactions in the diastereomeric transition states for trapping on the α- and β-faces of the radical