MOP and EE Protecting Groups in Synthesis of ?- or ?-Naphthyl-C-Glycosides from Glycals.
ABSTRACT: The development of effective protection strategies is essential in the synthesis of complex carbohydrates and glycomimetics. This article describes a versatile four-stage protocol for the synthesis of ?- or ?-aryl-C-glycosides from unprotected d-glycals using two acetal protecting groups, ethoxyethyl and methoxypropyl, which are stable under harsh basic conditions and convenient for the C-1 metalation of glycals. Their stability was investigated in subsequent cross-coupling reactions with 1-iodonaphthalene followed by oxidative/reductive transformations to naphthyl-C-glycosides.
Project description:Herein, we report on our findings of the Sonogashira-Hagihara reaction with 1-iodinated and 2-brominated glycals using several aromatic and aliphatic alkynes. This Pd-catalyzed cross-coupling reaction presents a facile access to alkynyl C-glycosides and sets the stage for a reductive/oxidative refunctionalization of the enyne moiety to regenerate either C-glycosidic structures or pyran derivatives with a substituent in position 2.
Project description:Pd(MeCN)2Cl2 enables the ?-stereoselective catalytic synthesis of 2,3-unsaturated O-glycosides from O(3)-acylated glycals without the requirement for additives to preactivate either donor or nucleophile. Mechanistic studies suggest that, unlike traditional (?3-allyl)palladium-mediated processes, the reaction proceeds via an alkoxy-palladium intermediate that increases the proton acidity and oxygen nucleophilicity of the alcohol. The method is exemplified with the synthesis of a range of glycosides and glycoconjugates of synthetic utility.
Project description:A novel metal-free strategy for a rapid and ?-selctive C-alkynylation of glycals was developed. The reaction utilizes TMSOTf as a promoter to generate in situ trimethylsilylacetylene for C-alkynylation. Thanks to this methodology, we can access C-glycosides in a single step from a variety of acetylenes , i.e., arylacetylenes and most importantly aliphatic alkynes.
Project description:Glycals and 4-deoxypentenosides (4-DPs), unsaturated pyranosides with similar structures and reactivity profiles, can exhibit a high degree of stereoselectivity upon epoxidation with dimethyldioxirane (DMDO). In most cases, the glycals and their corresponding 4-DP isosteres share the same facioselectivity, implying that the pyran substituents are largely responsible for the stereodirecting effect. Fully substituted dihydropyrans are subject to a "majority rule", in which the epoxidation is directed toward the face opposite to two of the three groups. Removing one of the substituents has a variable effect on the epoxidation outcome, depending on its position and also on the relative stereochemistry of the remaining two groups. Overall, we observe that the greatest loss in facioselectivity for glycals and 4-DPs is caused by removal of the C3 oxygen, followed by the C5/anomeric substituent, and least of all by the C4/C2 oxygen. DFT calculations based on polarized-? frontier molecular orbital (PPFMO) theory support a stereoelectronic role for the oxygen substituents in 4-DP facioselectivity, but less clearly so in the case of glycals. We conclude that the anomeric oxygen in 4-DPs contributes toward a stereoelectronic bias in facioselectivity whereas the C5 alkoxymethyl in glycals imparts a steric bias, which at times can compete with the stereodirecting effects from the other oxygen substituents.
Project description:The thio-additions of glycals were efficiently promoted by a stoichiometric amount of trimethylsilyl bromide (TMSBr) to produce S-2-deoxyglycosides under solvent-free conditions in good to excellent yields. In addition, with triphenylphosphine oxide as an additive, the TMSBr-mediated direct glycosylations of glycals with a large range of alcohols were highly ?-selective.
Project description:B(C6F5)3 enables the metal-free unprecedented substrate-controlled direct ?-stereoselective synthesis of deoxyglycosides from glycals. 2,3-Unsaturated ?- O-glycoside products are obtained with deactivated glycals at 75 °C in the presence of the catalyst, while 2-deoxyglycosides are formed using activated glycals that bear no leaving group at C-3 at lower temperatures. The reaction proceeds in good to excellent yields via concomitant borane activation of glycal donor and nucleophile acceptor. The method is exemplified with the synthesis of a series of rare and biologically relevant glycoside analogues.
Project description:Au(I) in combination with AgOTf enables the unprecedented direct and ?-stereoselective catalytic synthesis of deoxyglycosides from glycals. Mechanistic investigations suggest that the reaction proceeds via Au(I)-catalyzed hydrofunctionalization of the enol ether glycoside. The room temperature reaction is high yielding and amenable to a wide range of glycal donors and OH nucleophiles.
Project description:Palladium(II) in combination with a monodentate phosphine ligand enables the unprecedented direct and ?-stereoselective catalytic synthesis of deoxyglycosides from glycals. Initial mechanistic studies suggest that in the presence of N-phenyl-2-(di-tert-butylphosphino)pyrrole as the ligand, the reaction proceeds via an alkoxy palladium intermediate that increases the proton acidity and oxygen nucleophilicity of the alcohol. The method is demonstrated with a wide range of glycal donors and acceptors, including substrates bearing alkene functionalities.
Project description:A carbon-Ferrier rearrangement on glycals has been performed by using ceric ammonium nitrate to obtain products in moderate to good yields with high selectivity. The versatility of this method has been demonstrated by applying it to differently protected glycals and by employing several nucleophiles. The obtained C-allyl glycoside has been utilized for the synthesis of a orthogonally protected 2-amino-2-deoxy-C-glycoside.
Project description:Newcastle Disease Virus (NDV), belonging to the Paramyxoviridae family, causes a serious infectious disease in birds, resulting in severe losses in the poultry industry every year. Haemagglutinin neuraminidase glycoprotein (HN) has been recognized as a key protein in the viral infection mechanism, and its inhibition represents an attractive target for the development of new drugs based on sialic acid glycals, with the 2-deoxy-2,3-didehydro-d-N-acetylneuraminic acid (Neu5Ac2en) as their backbone. Herein we report the synthesis of several Neu5Ac2en glycals and of their perfluorinated C-5 modified derivatives, including their respective stereoisomers at C-4, together with evaluation of their in vitro antiviral activity. While all synthesized compounds were found to be active HN inhibitors in the micromolar range, we found that their potency was influenced by the chain-length of the C-5 perfluorinated acetamido functionality. Thus, the binding modes of the inhibitors were also investigated by performing a docking study. Moreover, the perfluorinated glycals were found to be more active than the corresponding normal C-5 acylic derivatives. Finally, cell-cell fusion assays on NDV infected cells revealed that the addition of a newly synthesized C-4α heptafluorobutyryl derivative almost completely inhibited NDV-induced syncytium formation.