Superarming the S-benzoxazolyl glycosyl donors by simple 2-O-benzoyl-3,4,6-tri-O-benzyl protection

The strategic placement of common protecting groups led to the discovery of a new method for "superarming" glycosyl donors. Conceptualized from our previous studies on the O-2/O-5 Cooperative Effect, it was determined that S-benzoxazolyl glycosyl donors possessing both a participating moiety at C-2 and an electronically armed lone pair at O-5, such as the superarmed glycosyl donor shown above, were exceptionally reactive.     

Relevance of the glycosyl donor to the regioselectivity of glycosidation of primary-secondary diol acceptors and application of these ideas to in situ three-component double differential glycosidation

[reaction: see text] Three pairs of primary-secondary diol acceptors have been exposed to armed, disarmed, and n-pentenyl ortho ester glycosyl donors in glycosidation reactions. It is shown that the regioselectivity of those glycosylations is greatly influenced by the armed, disarmed, or ortho ester nature of the glycosyl donors. The selectivities observed have been used to devise efficient in situ three-component glycosylations involving two donors and one acceptor.     

How the arming participating moieties can broaden the scope of chemoselective oligosaccharide synthesis by allowing the inverse armed-disarmed approach

A new method for stereocontrolled glycosylation and chemoselective oligosaccharide synthesis has been developed. It has been determined that complete 1,2-trans selectivity can be achieved with the use of a 2-O-picolyl moiety, a novel neighboring group that is capable of efficient participation via a six-membered intermediate. The application of the picolyl concept to glycosidations of thioimidoyl, thioglycosyl, and trichloroacetimidoyl glycosyl donors is demonstrated. The picolyl moiety also retains the glycosyl donor in the armed state, as opposed to conventional acyl participating moieties. We name this new approach the "inverse armed-disarmed" strategy, because it allows for the chemoselective introduction of a 1,2-trans glycosidic linkage prior to other linkages. In the context of the oligosaccharide synthesis, the strategy provides trans-trans and trans-cis patterned oligosaccharides as opposed to classic Fraser-Reid's armed-disarmed approach leading to cis-trans and cis-cis linkages.     

O,O-dimethylthiophosphonosulfenyl bromide-silver triflate: a new powerful promoter system for the preactivation of thioglycosides

O,O-Dimethylthiophosphonosulfenyl bromide (DMTPSB) in combination with silver triflate provides a powerful thiophilic promoter system. Both "armed" and "disarmed" thioglycoside glycosyl donors can be activated to form glycosidic linkages efficiently by the pre-activation protocol. The usefulness of this new promoter is illustrated by a successful iterative one-pot oligosaccharide assembly.     

An armed-disarmed approach for blocking aglycon transfer of thioglycosides

Thioglycosides are used frequently as glycosyl donors and as mimetics of O-glycosides. While being very useful, thioglycosides are prone to a detrimental side reaction referred to as aglycon transfer. In this letter, it is shown that aglycon transfer can be blocked by matching thioglycoside-containing acceptors with more armed glycosyl donors.     

Stereoselective β-mannosylations and β-rhamnosylations from glycosyl hemiacetals mediated by lithium iodide

Stereoselective β-mannosylation is one of the most challenging problems in the synthesis of oligosaccharides. Herein, a highly selective synthesis of β-mannosides and β-rhamnosides from glycosyl hemi-acetals is reported, following a one-pot chlorination, iodination, glycosylation sequence employing cheap oxalyl chloride, phosphine oxide and LiI. The present protocol works excellently with a wide range of glycosyl acceptors and with armed glycosyl donors. The method doesn''t require conformationally restricted donors or directing groups; it is proposed that the high β-selectivities observed are achieved via an S_N2-type reaction of α-glycosyl iodide promoted by lithium iodide.

Breaking from the current paradigm, a highly selective synthesis of hard-to-make β-mannosides and β-rhamnosides from simple glycosyl hemi-acetals has been achieved without using conformational restrictions.     

"Super armed" glycosyl donors: conformational arming of thioglycosides by silylation

Glycosyl donors protected with bulky silyl protective groups (tert-butyldimethylsilyl, TBS), on the 2-, 3-, and 4-OH groups were found to have superior reactivity compared with benzylated thioglucosides. The enhanced reactivity is explained by the stereoelectronic effects associated with the conformational change induced by the silylation. A TBS silylated thioglucoside donor has axial OR groups, whereas a benzylated thioglucoside has equatorial OR groups, leading to much more favorable charge-dipole interactions in the transition state. This concept could be used to create "super armed" glucosyl, mannosyl, rhamnosyl, and galactosyl donors, which could cross-couple with the armed acceptors, phenyl 2,3,4-tri-O-benzyl-beta-D-thioglucoside or phenyl 2,3,6-tri-O-benzyl-beta-D-thioglucoside, to give the corresponding armed disaccharides in good to excellent yields.     

Efficient glycosylation with glycosyl ortho-allylbenzoates as donors

Glycosylation reactions are significant as they provide access to model compounds that are useful for elucidating biochemical pathways. Herein, we describe the development of glycosyl ortho-alkynylbenzoates as novel, bench-top stable, and readily available glycosyl donors. Glycosylation is promoted by inexpensive trimethylsilyl triflate (TMSOTf) in combination with N-iodosuccinimide (NIS) under mild reaction conditions; hence, the novel glycosyl donors are promising reagents for the synthesis of glycosides.     

Glycosyl disulfides: novel glycosylating reagents with flexible aglycon alteration

[reaction: see text] Glycosyl disulfides have been shown for the first time to be effective glycosyl donors. Glucosylation and galactosylation of a panel of representative alcohol acceptors allowed the formation of 28 simple glycosides, disaccharides, and glycoamino acids in yields of up to 90%. As well as providing a novel class of effective glycosyl donors, the ability to easily alter the nature of the aglycon and the ability to differently activate donors that differ only in their aglycon simply through altering conditions lends glycosyl disulfide donors to their use in latent-active reactivity tuning strategies.     

N-benzyl-2,3-oxazolidinone as a glycosyl donor for selective alpha-glycosylation and one-pot oligosaccharide synthesis involving 1,2-cis-glycosylation

Glycosylation reactions using N-benzyl-2,3-trans-oxazolidinones as the glycosyl donors were shown to be highly alpha-selective. Advantages of the donor include facile preparation in gram-scale preparation and simple deprotection procedures. Subsequently, a one-pot oligosaccharide synthesis involving 1,2-cis glycosidic linkages was demonstrated using the novel glycosyl donors.     

DISAL glycosyl donors for the synthesis of a linear hexasaccharide under mild conditions

[reaction: see text] The new class of glycosyl donors with a methyl 3,5-dinitrosalicylate (DISAL) anomeric leaving group has proved efficient for glycosylation under strictly neutral, mildly basic, or mildly acidic conditions. Here, we report the synthesis of novel DISAL disaccharide glycosyl donors prepared by easy nucleophilic aromatic substitution. These DISAL donors proved efficient in the synthesis of a starch-related hexasaccharide under very mild conditions. Glycosylations proceeded with alpha-selectivity and were compatible with Trt protecting groups.     

Solid-phase synthesis of O-glycosylated Nalpha-Fmoc amino acids and analysis by high-resolution magic angle spinning NMR

Direct O-glycosylation of amino acids bound to TentaGel resin with a number of glycosyl trichloroacetimidate donors results in high yields. The glycosylation reaction can be easily monitored by analyzing the bead-bound amino acids with high-resolution magic angle spinning (HR-MAS) NMR. These studies pave a new way for the construction of "one-bead one-compound" O-glycopeptide libraries with standard amino acid building blocks and appropriate glycosyl trichloroacetimidate donors.     

Going to extremes: "super" armed glycosyl donors in glycosylation chemistry

This concept article gives an overview of stereoelectronic effects in monosaccharide systems and how these can be used to dramatically enhance the reactivity of glycosyl donors in oligosaccharide synthesis.     

Versatile gold catalyzed transglycosidation at ambient temperature

Glycosidation with stable alkyl glycosyl donors using a catalytic amount of gold salts is promising. Herein, 1-ethynylcyclohexanyl glycosides are identified as novel donors at room temperature and mechanistic investigation showed that the leaving group simply extrudes out.     

Revisiting the armed-disarmed concept: the importance of anomeric configuration in the activation of S-benzoxazolyl glycosides

The unexpectedly high reactivity of a (2-benzoxazolyl) per-O-benzoyl-beta-D-thioglucoside and related donors in reactions promoted by copper(II) trifluoromethanesulfonate is revealed, by comparison with the unreactive alpha-anomer, to be the result of neighboring group participation. Revision of the armed-disarmed concept for glycosyl donors is not required.     

An efficient glycosidation method using 2,3-unsaturated glycosyl donors

A novel class of ‘armed’ glycosyl donors containing a double bond at the C-2 position was designed by mimicking the mechanism of lysozyme-initiated hydrolysis. These donors were used to achieve chemoselective glycosidation of hex-2-enopyranosyl acetate and hexopyranosyl acetate, and synthesis of O-glycosidic linkages between highly deoxygenated sugars and tertiary alcohols.     

4-(pyridin-2-yl)thiazol-2-yl thioglycosides as bidentate ligands for oligosaccharide synthesis via temporary deactivation

This study focusses on a new concept for oligosaccharide synthesis based on 4-(pyridin-2-yl)thiazol-2-yl thioglycosides that can either act as effective glycosyl donors or can be deactivated by stable bidentate complexation with palladium(II) bromide.     

Protecting group free glycosidations using p-toluenesulfonohydrazide donors

N'-Glycopyranosylsulfonohydrazides are introduced as glycosyl donors for protecting group free synthesis of O-glycosides, glycosyl azides, and oxazolines. Mono- and disaccharides containing a reducing terminal N-acetylglucosamine residue were condensed with p-toluenesulfonylhydrazide to give the desired beta- d-pyranose donors. These donors can be activated with NBS and then glycosidated with the desired alcohol or transformed to the oxazoline or glycosyl azide.     

First O-glycosylation of hydroxamic acids

The first O-glycosylation of hydroxamic acids is reported. This process involves the use of glycosyl N-phenyl trifluoroacetimidates as glycosyl donors in the presence TMSOTf and 4 A molecular sieves in dichloromethane. Under such conditions, a wide range of new glycosyl donors including glucosyl, galactosyl, mannosyl, glucuronyl, and ribosyl hydroxamates were prepared in good to high yields. This procedure appears to be an advantageous alternative for the synthesis of glycosyl hydroxamates of biological interest.     

Sequential one-pot glycosylation with glycosyl N-trichloroacetylcarbamate and trichloroacetate including dehydrative approach using 1-hydroxy sugars

An efficient sequential one-pot glycosylation has been developed with glycosyl trichlorocarbamate and trichloroacetate activated by the same Lewis acid and enabled by a change in reaction temperature. The αα-selective glycosylation was achieved using glucose, galactose, and mannose substrates after investigation into the reactivities of the two types of glycosyl donors. Sequential one-pot dehydrative glycosylation, including in situ preparation of glycosyl donors followed by generation of two glycosyl bonds, provided three types of trisaccharide.