Convenient temporary methyl imidate protection of N-acetylglucosamine and glycosylation at O-4

This paper expands on the scope and utility of the temporary conversion of N-acetyl groups to alkyl imidates when attempting to glycosylate at O-4 of N-acetylglucosamine acceptors. The optimized synthesis of alkyl imidate protected glucosamine acceptors at position 4 and carrying various protecting groups at O-3 is described. These imidates were prepared immediately prior to glycosylation by treating the 4-OH acceptors with 0.5 M MeOTf to obtain the corresponding methyl imidates still carrying a free 4-OH group. When preparing these imidates in diethyl ether as the reaction solvent, we observed the unexpected formation of ethyl imidates in addition to the desired methyl imidates. While the 3-O-allyl acceptors were too unstable to be useful in glycosylation reactions, the 3-O-acylated methyl and ethyl imidates of glucosamine were shown to behave well during the glycosylation of the 4-OH with a variety of reaction conditions and various glycosyl donors. Glycosylation of these acceptors was successfully carried out with perbenzylated beta-thioethyl rhamnopyranoside under MeOTf promotion, while activation of this donor under NIS/TMSOTf or NIS/TfOH proved less successful. In contrast, activation of the less reactive perbenzylated alpha-thioethyl and peracetylated beta-thioethyl rhamnopyranosides with NIS/TfOH led to successful glycosylations of the 4-OH. Activation of a peracetylated rhamnosyl trichloroacetimidate by TMSOTf at low temperature also gave a high yield of glycosylation. We also report one-pot glycosylation reactions via alkyl imidate protected acceptor intermediates. In all cases the alkyl imidate products were readily converted to their corresponding N-acetyl derivatives under mild conditions.     

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.     

An orthogonal and reactivity-based one-pot glycosylation strategy for both glycan and nucleoside synthesis: access to TMG-chitotriomycin,lipochitooligosaccharides and capuramycin

Both glycans (O-glycosides) and nucleosides (N-glycosides) play important roles in numerous biological processes. Chemical synthesis is a reliable and effective means to solve the attainability issues of these essential biomolecules. However, due to the stereo- and regiochemical issues during glycan assembly, together with problems including the poor solubility and nucleophilicity of nucleobases in nucleoside synthesis, the development of one-pot glycosylation strategies toward efficient synthesis of both glycans and nucleosides remains poor and challenging. Here, we report the first orthogonal and reactivity-based one-pot glycosylation strategy suitable for both glycan and nucleoside synthesis on the basis of glycosyl ortho-(1-phenylvinyl)benzoates. This one-pot glycosylation strategy not only inherits the advantages including no aglycon transfers, no undesired interference of departing species, and no unpleasant odors associated with the previously developed orthogonal one-pot glycosylation strategy based on glycosyl ortho-alkynylbenzoates, but also highly expands the scope (glycans and nucleosides) and increases the number of leaving groups that could be employed for the multistep one-pot synthesis (up to the formation of four different glycosidic bonds). In particular, the current one-pot glycosylation strategy is successfully applied to the total synthesis of a promising tuberculosis drug lead capuramycin and the divergent and formal synthesis of TMG-chitotriomycin with potent and specific inhibition activities toward β-N-acetylglucosaminidases and important endosymbiotic lipochitooligosaccharides including the Nod factor and the Myc factor, which represents one of the most efficient and straightforward synthetic routes toward these biologically salient molecules.

The first one-pot glycosylation strategy for both glycan and nucleoside synthesis based on glycosyl ortho-(1-phenylvinyl)benzoates has been developed, which is applied to the synthesis of TMG-chitotriomycin, lipochitooligosaccharides and capuramycin.     

Rapid glycoconjugation with glycosyl amines

Conjugation of unprotected carbohydrates to surfaces or probes by chemoselective ligation reactions is indispensable for the elucidation of their numerous biological functions. In particular, the reaction with oxyamines leading to the formation of carbohydrate oximes which are in equilibrium with cyclic N-glycosides (oxyamine ligation) has an enormous impact in the field. Although highly chemoselective, the reaction is rather slow. Here, we report that the oxyamine ligation is significantly accelerated without the need for a catalyst when starting with glycosyl amines. Reaction rates are increased up to 500-fold compared to the reaction of the reducing carbohydrate. For comparison, aniline-catalyzed oxyamine ligation is only increased 3.8-fold under the same conditions. Glycosyl amines from mono- and oligosaccharides are easily accessible from reducing carbohydrates via the corresponding azides by using Shoda''s reagent (2-chloro-1,3-dimethylimidazolinium chloride, DMC) and subsequent reduction. Furthermore, glycosyl amines are readily obtained by enzymatic release from N-glycoproteins making the method suited for glycomic analysis of these glycoconjugates which we demonstrate employing RNase B. Oxyamine ligation of glycosyl amines can be carried out at close to neutral conditions which makes the procedure especially valuable for acid-sensitive oligosaccharides.

A new method for carbohydrate-oxyamine ligation starting from glycosyl amines 1 instead of the commonly used reducing sugars 2 results in tremendously increased ligation rates without the need for a catalyst, such as aniline.     

Synthetic oligorhamnans related to the most common O-chain backbone from phytopathogenic bacteria

The synthesis of the tetrasaccharide rhamnanic motif α-l-Rha-(1→3)-α-l-Rha-(1→2)-α-l-Rha-(1→2)-α-l-Rha and its dimerization to octasaccharide have been developed. Three different pathways toward the dimerization have been investigated; the best one was based on a [4+2]+2 stepwise condensation of a rhamnose tetrasaccharide with two rhamnosyl N-phenyl trifluoroacetimidates as glycosyl donors and on an orthogonal set of protecting groups consisting of benzoyl, levulinoyl, and allyl groups.     

Direct,stereoselective thioglycosylation enabled by an organophotoredox radical strategy

While strategies involving a 2e⁻ transfer pathway have dictated glycosylation development, the direct glycosylation of readily accessible glycosyl donors as radical precursors is particularly appealing because of high radical anomeric selectivity and atom- and step-economy. However, the development of the radical process has been challenging owing to notorious competing reduction, elimination and/or S_N side reactions of commonly used, labile glycosyl donors. Here we introduce an organophotocatalytic strategy through which glycosyl bromides can be efficiently converted into corresponding anomeric radicals by photoredox mediated HAT catalysis without a transition metal or a directing group and achieve highly anomeric selectivity. The power of this platform has been demonstrated by the mild reaction conditions enabling the synthesis of challenging α-1,2-cis-thioglycosides, the tolerance of various functional groups and the broad substrate scope for both common pentoses and hexoses. Furthermore, this general approach is compatible with both sp² and sp³ sulfur electrophiles and late-stage glycodiversification for a total of 50 substrates probed.

Organophotoredox mediated HAT catalysis is developed for achieving high anomerically selective thioglycosylation of glycosyl bromides.     

Toward the total synthesis of vineomycin B2: application of an efficient glycosylation methodology using 2,3-unsaturated sugars

The application of an efficient glycosylation methodology using 2,3-unsaturated sugars to synthesize critical precursors required for the total synthesis of an antibiotic, vineomycin B₂ (1), was demonstrated. The required disaccharide, the acurosyl rhodinose derivative of 1, was prepared by chemoselective glycosylation using a 2,3-saturated glycosyl acetate corresponding to the rhodinose moiety and a 2,3-unsaturated glycosyl acetate corresponding to the acurose portion. Further, the right-hand side chain of 1, consisting of β-oxo-tert-alcohol and rhodinose, was constructed by a powerful glycosylation approach using a 2,3-unsaturated glycosyl acetate in an ionic liquid under reduced pressure.     

Efficient synthesis of kaempferol 3,7-O-bisglycosides via successive glycosylation with glycosyl ortho-alkynylbenzoates and trifluoroacetimidates

Selective glycosylation of the 3-OH of 5,4′-di-O-acetyl-kaempferol was achieved with glycosyl ortho-alkynylbenzoates as donors under the catalysis of Ph₃PAuNTf₂, and subsequent glycosylation of the remaining 7-OH with glycosyl trifluoroacetimidates under the catalysis of BF₃·OEt₂, after global deprotection, afforded the kaempferol 3,7-O-bisglycosides conveniently.     

An approach to the highly stereocontrolled synthesis of α-glycosides. Compatible use of the very acid labile dimethoxytrityl protecting group with Yb(OTf)3-promoted glycosidation

The very acid labile dimethoxytrityl group is demonstrated to survive Yb(OTf)₃-promoted glycosidations with N-phenyl trifluoroacetimidates as the donors. In addition, the installation of this sterically demanding protecting group at the primary position of the donor allows the achievement of a very high selectivity in the synthesis of α-glycosides with a variety of saccharidic acceptors.     

Synthesis of di-branched heptasaccharide by one-pot glycosylation using seven independent building blocks

[reaction: see text] We describe an efficient synthesis of di-branched heptasaccharide 1 having phytoalexin elicitor activity in soybeans by one-pot glycosylation. The synthesis involves chemo- and regioselective sequential six-step glycosylations using seven independent building blocks and sequential removal of acyl- and benzyl ether-type protecting groups. The coupling of seven building blocks requires only four chemoselective activitable leaving groups of glycosyl donors. Both the glycosylation and deprotection reactions can be achieved utilizing a parallel manual synthesizer.     

Remarkably efficient activation of glycosyl trichloro- and (N-phenyl)trifluoroacetimidates with bismuth(III) triflate

Easily handled and nontoxic Bi(OTf)₃ is a powerful activator for trichloro- and (N-phenyl)trifluoroacetimidate glycosyl donors. This catalyst allows glycosidations to be performed at low temperatures in very short times. Rewarding yields were obtained from a wide range of donors of varying reactivity.     

Stereoselectivity investigation on glycosylation of oxazolidinone protected 2-amino-2-deoxy-d-glucose donors based on pre-activation protocol

Diverse 2,3-oxazolidinone protected 2-amino-2-deoxy-d-glucose thioglycosides were prepared and studied as glycosyl donors at low temperature by BSM/Tf₂O pre-activation protocol before the addition of glycosyl acceptors. The stereochemistry outcomes of a series of glycosylations were investigated. Different stereoselectivities of the coupling reactions were obtained, arising from the different protecting groups in the oxazolidinone donors. 4,6-Di-O-benzyl-N-benzyl-oxazolidinone protected thioglycoside donor 1c underwent glycosylation with general β-anomeric selectivity and the stereoselectivity could be also affected by glycosylation conditions.     

Stereocontrolled total synthesis of (+)-pederine

A mild one-pot method for the synthesis of acyclic N-(1-methoxyalkyl)amides starting from carboxylic acid and methyl imidates has been developed and applied to the first total synthesis of (+)-pederine (1), a potent insect poison. Furthermore, the stereocontrolled total synthesis of 1 was also achieved by employing acid catalyzed double alkoxy-exchange reaction of N-(1 -methoxylakyl)amide group as key step.     

C2-amidoglycosylation. Scope and mechanism of nitrogen transfer

A one-pot C2-amidoglycosylation reaction for the synthesis of 2-N-acyl-2-deoxy-beta-pyranosides from glycals is described. Glycal donors activated by the reagent combination of thianthrene-5-oxide (11) and Tf2O, followed by treatment with an amide nucleophile and a glycosyl acceptor, lead to the formation of various C2-amidoglycoconjugates. Both the C2-nitrogen transfer and the glycosidic bond formation proceed stereoselectively, allowing for the introduction of both natural and nonnatural amide functionalities at C2 with concomitant anomeric bond formation in a one-pot procedure. Tracking of the reaction by low-temperature NMR spectroscopy employing 15N- and 18O-isotope labels suggests a mechanism involving the formation of the C2-sulfonium glycosyl imidate 39 as well as oxazoline 37 as key intermediates in this novel oxidative glycosylation process.     

Armed-disarmed effect of remote protecting groups on the glycosylation reaction of 2,3-dideoxyglycosyl donors

The armed-disarmed effect of remote protecting groups at the C-4 and/or C-6 position(s) on the glycosylation reactions of 2,3-dideoxyglycosyl donors was investigated. It was found that under various glycosylation conditions, 4- or 6-O-Bn 2,3-dideoxyglycosyl donors were much more reactive than the corresponding 4,6-di-O-Bz 2,3-dideoxyglycosyl donors. Based on these results, an effective and chemoselective glycosylation reaction using 4,6-di-O-Bn glycosyl acetate and 4-OH-6-O-Bz glycosyl acetate was realized, producing a 2,3-dideoxydisaccharide in good yield with high α-stereoselectivity.     

Regioselective and 1,2‐cis‐α‐Stereoselective Glycosylation Utilizing Glycosyl‐Acceptor‐Derived Boronic Ester Catalyst

Regioselective and 1,2‐cis‐α‐stereoselective glycosylations using 1α,2α‐anhydro glycosyl donors and diol glycosyl acceptors in the presence of a glycosyl‐acceptor‐derived boronic ester catalyst. The reactions proceed smoothly to give the corresponding 1,2‐cis‐α‐glycosides with high stereo‐ and regioselectivities in high yields without any further additives under mild reaction conditions. In addition, the present glycosylation method was successfully applied to the synthesis of an isoflavone glycoside.     

Highly effective and chemoselective hydrodeoxygenation of aromatic alcohols

Effective hydrodeoxygenation (HDO) of aromatic alcohols is very attractive in both conventional organic synthesis and upgrading of biomass-derived molecules, but the selectivity of this reaction is usually low because of the competitive hydrogenation of the unsaturated aromatic ring and the hydroxyl group. The high activity of noble metal-based catalysts often leads to undesired side reactions (e.g., saturation of the aromatic ring) and excessive hydrogen consumption. Non-noble metal-based catalysts suffer from unsatisfied activity and selectivity and often require harsh reaction conditions. Herein, for the first time, we report chemoselective HDO of various aromatic alcohols with excellent selectivity, using porous carbon–nitrogen hybrid material-supported Co catalysts. The C–OH bonds were selectively cleaved while leaving the aromatic moiety intact, and in most cases the yields of targeted compounds reached above 99% and the catalyst could be readily recycled. Nitrogen doping on the carbon skeleton of the catalyst support (C–N matrix) significantly improved the yield of the targeted product. The presence of large pores and a high surface area also improved the catalyst efficiency. This work opens the way for efficient and selective HDO reactions of aromatic alcohols using non-noble metal catalysts.

Porous carbon–nitrogen hybrid material-supported Co catalysts can effectively promote the chemoselective hydrodeoxygenation reaction of a various of aromatic alcohols in ethanol and hydrogen atmosphere, under relatively mild conditions.     

Mesoionic N-heterocyclic olefin catalysed reductive functionalization of CO2 for consecutive N-methylation of amines

A mesoionic N-heterocyclic olefin (mNHO) was introduced as a metal-free catalyst for the reductive functionalization of CO₂ leading to consecutive double N-methylation of primary amines in the presence of 9-borabicyclo[3.3.1]nonane (9-BBN). A wide range of secondary amines and primary amines were successfully methylated under mild conditions. The catalyst sustained over six successive cycles of N-methylation of secondary amines without compromising its activity, which encouraged us to check its efficacy towards double N-methylation of primary amines. Moreover, this method was utilized for the synthesis of two commercially available drug molecules. A detailed mechanistic cycle was proposed by performing a series of control reactions along with the successful characterisation of active catalytic intermediates either by single-crystal X-ray study or by NMR spectroscopic studies in association with DFT calculations.

Mesoionic N-heterocyclic olefin (mNHO) catalysed consecutive N-methylation of primary and secondary amines was accomplished under 1 atm CO₂ pressure in the presence of 9-BBN as a reducing agent nearly at room temperature.     

An efficient glycosylation reaction for the synthesis of asialo GM2 analogues

We investigated the coupling reaction of glycosyl donors N-trichloroethoxycarbonyl-galactosamine-O-trichloroacetimidate (2a) and N-p-nitrobenzyloxycarbonyl-galactosamine-O-trichloroacetimidate (2b) with the 4′-OH of lactose derivatives (3a-d) to synthesize key intermediates of asialo GM2 analogues, and found that the glycosylation yield with 2a was 90% or more in all investigated cases.     

Deep eutectic solvent-assisted one-pot synthesis of 2-aminothiazole and 2-aminoxazole derivatives

Choline chloride–urea-based deep eutectic solvent (DES) has been found to be a highly effective catalyst and reaction medium for the one-pot synthesis of 2-aminothiazole and 2-aminoxazole derivatives. Three-component reactions of active methylene compounds, urea or thiourea and N-bromosuccinimide NBS in deep eutectic solvent furnished structurally diverse 2-aminoxazoles and 2-aminothiazoles in good to excellent yields under mild reaction conditions and short reaction times. DES is inexpensive, biodegradable and more accessible in any laboratory and industry.