Abstract

Sugar oximes represent a versatile class of compounds with significant potential in drug discovery and development. Their importance in chemistry, coupled with beneficial biological attributes increases the interest placed on these compounds by medicinal chemists, biochemists, and biologists. Sugar oximes proved to be cholinesterase reactivators, functioned as surfactants due to their amphiphilic nature and they also appeared as valuable intermediates in the construction of complex molecular architectures, including glycosylated pharmaceuticals and bioactive materials. Therefore, sugar oximes emerged as a powerful ligation tool for peptides, proteins, lipids, and other biologically and medicinally interesting molecules ligation reactions. Finally, interesting reactions of sugar oximes have been reported including their conversion to isoxazolines and nitiriles as well as their nitrosation reaction. The present review will be focused on the synthesis and properties of sugar oximes and will also explore their critical reactions which lead to structurally diverse molecular frameworks.

Keywords:Sugar Oximes; Enzyme Inhibitors; Oxime Ligation; Isoxazolines; Ether Surfactants

Abbreviations:DMAD: Dimethyl Acetylenedicarboxylate; DMF: N,N-Dimethylformamide; THF: Tetrahydrofuran; MeOH: Methanol

Introduction

Oximes represent a fundamental class of compounds that not only were extensively found in both natural products and pharmaceuticals, but they have been also widely used as synthons in industrial production. Additionally, oximes play a significant role as active components in drugs like Pralidoxime and Obidoxime (acetylcholinesterase reactivators) [1-6], as well as Milbemycin oxime (a potent antiparasitic agent) [7,8]. Besides commercial drugs, oximes demonstrate a wide range of biological activities, including antiviral [9], anticancer [9-11], anticoagulant [10], antimicrobial [9,10], antihelminthicide [10], antihistaminic [10], antidepressant [10], hearth antiarrhythmic [10], antihypertensive[10], and analgesic [9,10] properties. Oxime derivatives also function as peptide modifiers [12-16] and herbicides [17]. In food chemistry, they are used as sweeteners, such as Perillartine [18,19] which is 2000 times sweeter than sugar and widely used in Japan. In materials science, oxime analogues serve as modifiers of polymers [20-22] and heavy metal sorbents[23]. Finally, in organic and organometallic chemistry, oximes are valuable intermediates for synthesizing a wide variety of compounds[24, 25]. On the other hand, carbohydrates are the most plentiful class of natural products, with approximately two-thirds of the carbon in the biosphere existing in this form[25-27]. Over the past decade, oxime coupling with carbohydrates and lipophilic compounds has attracted significant attention and is being utilized in various applications, mainly in the area of bioconjugation[12]. In order to undergo an oxime conjugation reaction, the respective biomolecules, most notably reducing sugars, must contain a carbonyl moiety[25].

This unique feature presents a valuable opportunity for glycoscientists, as it is a selectively addressable functional group, which is rarely found in other biomacromolecules. The reactive carbonyl group enables the direct synthesis of glycoconjugates from natural carbohydrate sources. Additionally, selective alkylation or arylation of the anomeric 1-OH group, the hemiacetal form of the aldehyde, is possible due to its lower pKa compared to other hydroxyl groups[28,29].Consequently, sugar oximes represent a versatile class of compounds with significant potential in drug discovery and development owing to the presence of the sugar moiety, which renders the non-permeable quaternary oximes more permeable through biological membrane. Interestingly, various sugar oximes were proved to act as broad spectrum inhibitors of glycosidases. Especially, amidoxime derivatives with substituents at the exocyclic nitrogen were found to resemble the aglycon found in the natural substrate and to improve selectivity against β-glycosidase, while aldonolactone oxime derivatives, regarded as a neutral inhibitor of α-glycosidase, proved to have a very low basicity and inhibited the α-glycosidase in the low micromolar range[30,31]. Considering the biological importance of the sugar oximes, this class of compounds which contain two of the most prominent medical motifs, the present review will be focused on the synthesis and properties of sugar oximes and will also explore their critical reactions which lead to structurally diverse molecular frameworks.

Synthesis, Properties and Utilization of Sugar Oximes

First reported sugar oximes synthesis

The first pentose oximes, as potential substrates for transoximases, were prepared by Masayoshi Iio et al. [32] in 1975. Arabinose, ribose and xylose were reacted with hydroxylamine in anhydrous ethanol and the corresponding oximes were afforded. Free hydroxylamine, obtained by neutralizing its hydrochloride with sodium ethoxide, was gradually added dropwise to the pentose solution. Arabinose (1) and ribose (4) (Figure 1) afforded the crystalline oximes. Although crystallization of xylose oxime was possible under the current reaction conditions, the collected crystals melted into a syrup when left at room temperature. Anti form 2 dominated in the specimen of arabinose oxime that crystallized first, while crystals recovered from mother liquor included more syn form 3. Syrup of xylose oxime always contained more anti form 8. On the other hand, most of ribose oxime existed as syn form 6. All the results strongly indicated the formation of xylose oxime in pure state, although it existed as syrup at room temperature. Finch et al. [33] also described the synthesis and characterization of D-glucose oximes (Figure 2). It was proved by various physical techniques that D-glucose oxime exists in the cyclic β-pyranose form 10 in it solid state. In aqueous solution, it undergoes isomerization, yielding a mixture of β-pyranose (23%), α-pyranose 11 (7%), anti- (Z-) 12 (13.5%) and syn- (E-) 13 (56.5%).

Sugar oximes as acetylcholinesterases reactivators

Acetylcholinesterase reactivators are compounds used to counteract the inhibition of acetylcholinesterase (AChE), an enzyme crucial for breaking down the neurotransmitter acetylcholine in the nervous system. These reactivators are primarily used as antidotes for poisoning by organophosphates (OPs), which are toxic chemicals found in some pesticides and chemical warfare agents, such as sarin, O-ethyl S-2- isopropylaminoethyl methylphosphonothiolate, paraoxon, and diisopropyl phosphorofluoridate[34]. Various sugar oximes have been prepared and evaluated for their potential to reactivate AChE. Alkylation of acetobromo-D-glucose (14) with silver carbonate and 3-chloropropanol afforded 3-chloropropyl tetra-Oacetyl- β-D-glucopyranoside (15) (Figure 3)[35]. Analogue 15 was then reacted with sodium iodide and the 3- or 4-pyridinealdoxime leading to oximes 16a,b which then deacetylated using base hydrolysis to afford 17a,b, respectively. By similar manner, the new sugar oximes 19a-c and 20a-c were synthesized from 8-chlorooctyl tetra-O-acetyl-β-D-glucopyranoside (18), which it was easily obtained from acetobromo-D-glucose and 8-chlorooctanol. The synthesis of compounds 19c and 20c was proved to be more demanding. Analogue 19c was obtained in very low yield (<10%) following the above method. Unfortunately, basic hydrolysis of all acetyl groups to give 20c resulted in multiple degradation products. However, compound 20c was obtained in ∼85% yield, upon recrystallization in methanol/acetone[21].

Finally, the synthesis of the two six-position sugar oximes 23a,b was performed using 1,2:3,4-di-O-isopropylidene-α-Dgalactohexadialdo- 1,5-pyranose (21), (Figure 4) as starting material. The di-isopropylidene intermediates 22a,b were obtained from analogue 21 after treatment with triflic anhydride and 2,6-di-tert-butyl-4-methylpyridine, and upon subsequent acidic hydrolysis isopropylidene protecting groups were removed and the target compounds 23a,b were obtained, in 65% yield[36]. The novel oximes were tested for their potential in reactivating human red blood cell acetylcholinesterase (AChE) and plasma butyrylcholinesterase, both inhibited by DFP, paraoxon, sarin, and O-ethyl S-2-isopropylaminoethyl methylphosphonothiolate. The results revealed that among all oximes tested, compound 20c (Figure 3) was the most potent with a reactivation ability comparable to pralidoxime, a widely known drug that efficiently reactivates AChE in the body. Additionally, oxime 17b exhibited low toxicity, with an LD50 of 1590 mg/kg following a single intramuscular (IM) dose in guinea pigs and greater than 2000 mg/ kg for an intraperitoneal (IP) dose in mice. Finally, no apparent differences in the hippocampus, heart, liver, kidney sciatic nerve, or skeletal muscle between treated and untreated animals were shown by histopathological analysis[37].

Sugar oximes as surfactants

Sugar oximes have been studied for their potential applications as surfactants, combining the reactivity of oxime functional groups with amphiphilic properties that are characteristic of surfactants. The incorporation of oxime groups into surfactant structures aims to modify their properties and functions, making them suitable for various industrial and biochemical applications. The first direct synthesis of a novel class of sugar oxime ether surfactants (SOESurf) containing an oxime ether linkage, was reported by Ewan et al.[38]. The chemoselective condensation of an hydrophobic alkoxyamine with the resident aldehyde/ketone moiety on a hydrophilic sugar was the critical step. Notably, this process did not require the protection or deprotection of sugars, and it did not involve extensive product purification. Specifically, alkoxyamines 24-26 were reacted with three commercially available sugars with increasing hydrophilicity (glyceraldehyde, glucose, and maltose) (Figure 5). The previously reported slow kinetics of this type of condensation reaction under neutral conditions have been confirmed once again in this case[39-41]. It was observed that no reaction occurred in the absence of a catalyst (i.e., H⁺), even after prolonged periods of up to one week, while the use of acid catalysts, such as trifluoroacetic acid (TFA), did not notably enhance the condensation and resulted in low yields (i.e., under 10%). The hydrophilic properties of the sugars inhibited the exclusion of H2O from the reaction solvent mixture. As expected, acetal cleavage occurred in the disaccharide maltose within the acidic aqueous reaction medium. Therefore, the reaction of equimolar amounts of alkoxyamines decyloxyamine (24), dodecyloxyamine (25) and adamantyloxyamine (26) with glyceraldehyde, glucose and maltose in the presence of anthranilic acid (30) or 3,5- diaminobenzoic acid (31) afforded the SOESurfs 27-29, in good to excellent yields (53%-98%), while the 1H NMR spectroscopy indicated that the (E)-oxime ether was the major product[42].

The oxime ether condensations were completed within a few hours, while no reaction lasted longer than 24 hours. For SOESurfs 27-29, stoichiometric amounts of 30 or 31 were required to maintain reaction times below 24 hours. Interestingly, for analogues 27 and 28, the removal of 30 or 31 could be accomplished with an aqueous base wash. Rowe et al.[43] also examined the above nine examples of sugar oxime ether surfactants 27-29 (Figure 5). After the evaluation of specific parameters such as thermal stability, melting point, water solubility, effect on surface tension, and critical micelle concentration, it was proved that the tested surfactants exhibited thermal stability and significantly reduced the surface tension of water. Particularly, the surfactants containing straight-chain hydrophobes led to significant reductions in surface tension at micromolar concentrations, whereas those with adamantyl hydrophobes achieved similar reductions only at millimolar concentrations. Additionally, the surfactants with longer hydrophobic chains exhibited lower critical micelle concentration values due to their increased hydrophobicity. Finally, Bejarano et al.[44] presented the synthesis and structural analysis of novel amphiphilic carbohydrate-derived oxime ethers, in order to evaluate their surfactant properties. The β-anomeric glycosides 33a,b were efficiently produced via the biphasic reaction of N-hydroxysuccinimide and acetobromo-α-D-glucose (32a) or D-galactose (32b) (Figure 6). Following hydrazinolysis, condensation with decanal and subsequent deprotection led to the desired products 36a,b. The latter were obtained in good overall yields and with high anomeric and E/Z stereocontrol, while the evaluation of their surfactants properties is currently ongoing.

Sugar oximes ligation reactions

The oxime ligation, one of the most important reactions, has been widely used in the synthesis of cyclic peptides [45] large proteins by fragment assembly[46], protein–polymer conjugates[47], oligonucleotides conjugates[48], glycoconjugates[49], and labeled bioconjugates[14,50]. Interestingly, the conjugation of peptides bearing a N,O-substituted hydroxylamine function with unprotected sugars led to unnatural, N-glycosylated peptides (neo-glycopeptides) via an open-chain oxy–iminium intermediate[51]. Various researchers developed this chemical ligation for the synthesis of more complex analogues [52] as well as N-glycosylated cardenolides, analogues of the cardiac glycoside digitoxin bearing anticancer properties[53]. On the other hand, the O-N-linked disaccharides were prepared by the glycosylation of suitably protected sugar oximes followed by stereoselective reduction of the interglycosidic oxime bond [54]. Hatanaka et al. [55,56] looked at the synthesis of biotinyl photoprobes from unprotected sugars made with an aminooxy linker between the sugar and the photoprobe (Figure 7). The photoreactive agent 38 was coupled to N-acetyllactosamine (37) upon treatment with 50% TFA-DCM at 0 ˚C for 30 min and after evaporation, the residue was dissolved in 80% aq MeCN containing 0.5 eq of sugar. The mixture was incubated at 37 ˚C for 40 hours in the dark at pH 5-6 (adjusted with diisopropylethylamine). A mixture of products (63%) was formed and separated on HPLC. The products were identified as the acyclic oxime 39 (both E and Z isomers) and the cyclic pyranoside 40 in strictly beta confirmation.

Additionally, the photoreactive reagent was also attached successfully to the important probes Lewis X trisaccharide and sialyl Lewis X tetrasaccharide (Figure 8). Both of these gave a mixture of oxime and pyranoside products 41-44 (78% for the triand 71% for the tetrasaccharide). Perouzel et al.[57] synthesized glycolipids for the fuctionalization of liposomes and lipoplexes using the aminooxy functionality. A functionalized lipid was coupled to unprotected monosaccharides and oligosaccharides (mannose, glucose, galactose, glucuronic acid, maltose, lactose, maltotriose, maltotetraose, and maltohepatose) and led to the neoglycolipids of general structure 47a-i (Figure 9). Coupling reactions were performed in a DMF/aqueous acetic acid buffer system with pH 4; at this pH the proton concentration is optimal for the reaction to give the cyclic product. Reactions took 1-7 days at room temperature; with more complex sugars taking longer. Yields were moderate to high, ranging from 40 to 85%. The selectivity remained consistent with the various sugars, favouring the β-anomer, 85:15. Though the reaction times are somewhat lengthy, it is favourable because only pyranose derivatives are formed and in decent yields. A proposed mechanism for the reaction between glucose (45) (and other carbohydrates with reducing ends) and aminoxy lipid 46 (R = 4-aza-N⁶-(cholesteryloxycarbonylamino) hexylamine) is illustrated in Figure 9. Following the formation of an oxime bond, intramolecular acetalization led to the formation of a cyclic carbohydrate, resulting in closed-ring glycolipids.

Finally, Vila-Perelló et al. [58] provided another example of oxime chemical ligation reaction between the Aoa–GFAKKG peptide 49 and an oligosaccharide 48 (Figure 10). An equilibrium is established between the imino 50 and amino 51 (both α and β) forms that shows the diversity of the applications of the aminooxy linker. The method was successfully used to immobilize carbohydrates on a surface for carbohydrate-lection interaction studies. In 2002, Peri et al. [59] synthesized the methyl 6-deoxy- 6-methoxyamino-D-glucopyranoside (55) (Figure 11), which was successfully coupled to glucose, galactose and N-acetylglucosamine in high yields (80-92%) after 4-6 hours (Figure 11). Reactions were performed in either DMF/acetic acid (2:1) or aqueous sodium acetate buffer (pH 4.5). The reactions with glucose and N-acetylglucosamine gave exclusively the β-anomers 56 and 62, respectively; there was a small amount of the α-anomer (7:1 β/α) in the case of galactose. The reaction with mannose did not proceed as smoothly and only gave 35% yield with a 1:5 (β/α) ratio of anomers. The methodology was successfully extended to synthesize a trisaccharide in 65% yield and could also be used in solid phase peptide synthesis. This methodology offers some appealing advantages over other solid phase peptide synthesis techniques such as that it can be carried out in the presence of water, the glycosylation promoter is not required and, in the case of glucose and N-acetylglucosamine, the β-product is obtained. Through further studies it was shown that these carbohydrate mimetics have similar conformational behaviour to their natural counterparts.

To explore the potential of applying this approach iteratively for the synthesis of oligosaccharide mimetics, sugar 65 (Figure 12), derived from compound 64 using a similar method as for sugar 54, yielded disaccharide 66, in 75% yield. The oxime group of 66 was reduced with NaCNBH₃, leading to the formation of an amino(methoxy) disaccharide, which was subsequently reacted with 65 to produce trisaccharide mimic 67 (65% yield). Further, compound 67 was fully O-acetylated and transformed into derivative 68, which was fully characterized. Monomer 65 serves as an excellent scaffold for the synthesis of oligosaccharide analogues, offering the two necessary functionalities for chemoselective ligation, one of which is the amino(methoxy) group, protected as an O-methyloxime. An efficient microwave-mediated method for the synthesis of both mono- and multivalent oxime-linked linkers and glycoclusters was reported by McReynolds et al. [60]. The aldehyde/ketone group of the sugars reacted with an aminooxy moiety of the linker/trivalent core molecules, yielding acidstable oxime linkages in the products. The reaction occured using equimolar quantities of reactants under mild aqueous conditions. Due to the chemoselectivity of the reaction, sugars can be added without the need for protecting groups, and the reactions can be finalised in 30 minutes using a microwave. For the synthesis of the monovalent sugar linkers, the common aldose mono-, di- and tri-saccharides (N-acetyl glucosamine, cellobiose, gentiobiose, lactose, maltose, maltotriose and melibiose, 69-75, (Figure 13) were evaluated.

For the synthesis of trivalent glycocluster, an aldose reducing disaccharide, cellobiose (70), two ketose sugars, sialic acid (84), the α-2→8-linked dimer of sialic acid, disialic acid (85), were utilised with the trivalent aminooxy-terminated hydrophilic core 83 (Figure 14)[61]. In order to prove that the glycosidic bonds present in 70 and 85 would be stable to the microwave heating conditions at a pH of 4.5, the above sugars were selected. In addition to the below, sialic acid-containing glycans are crucial markers in disease states such as cancer, influenza and meningococcal meningitis[62,63]. The synthesized glycoclusters feature a stable oxime linkage resistant to acid and glycosidase, which helps maintain the integrity of the molecules for potential use in biological applications[64-66]. Considering that the reducing end sugar will exist as a mixture of the native closed ring conformation and the open ring oxime, longer oligosaccharides may be necessary and may impact the resultant biological activity. Therefore, the fully substituted trivalent molecules 86, 87 and 88 were obtained as the major products, in excellent yields (93.9%, 81.6% and 87.6%, respectively). In 2012, Yu et al. [54] reported for the first time an effective approach to the synthesis of the N-O linked saccharides achieved via direct glycosylation of sugar oximes by using glycosyl ortho-hexynylbenzoates as donors under the catalysis of PPh₃AuOTf. Initially, the glycosylation of 6-deoxyglucopyranoside 4-oxime 90a (Figure 15) was examined, with perbenzoyl glucopyranosyl ortho-hexynylbenzoate 89a[67-69] (1.2 equiv) under standard conditions (0.2 equiv of PPh₃AuOTf, 5 Å MS, CH₂Cl₂, r.t.) (Figure 15). The reaction produced the desired disaccharide 91 (E) as a single isomer with a 27% yield, while the major byproduct was the corresponding orthoester. Thus, the coupling with 90a performed with the more reactive glucopyranosyl ortho-hexynylbenzoate 89b as a glycosyl donor, which is equipped with a superarmed protecting pattern. [70] Under the same conditions, disaccharide 92 was obtained in a high 90% yield as a mixture of the Z/E isomers (Z/E = 1:5.4). Similarly, 90a was coupled with the 6-deoxy perbenzoyl pyranose donors, L-rhamnosyl and L-talosyl ortho-hexynylbenzoates 89c and 89d, to provide the corresponding disaccharides 93 (96%, Z/E = 1:9.7) and 94 (93%, Z/E =1:6.8), in excellent yields in favor of the E isomers. Additionally, direct glycosylation of 90a performed with perbenzoyl D-ribosyl ortho-hexynylbenzoate 89e, a furanose donor, providing disaccharide 95 cleanly (92%, Z/E = 1:6.4). The scope of the reaction was further investigated with 1,2:5,6-di- O-isopropylidene glucofuranoside 3-oxime (90b)[71,72] and 1,2:3,4-di-O-isopropylidene galactopyranoside 6-oxime (90c)[73] as acceptors. The furanose oxime 90b was directly glycosylated with donors 89b-e under standard conditions, affording the desired disaccharides 96-99, in excellent yields (85%-97%). Contrary to the previous reaction whereas oxime 90a was the acceptor, the conjugation with 90b favoured the formation of the Z isomer (Z/E = 2.1:1 to 5.0:1). Under identical conditions, the glycosylation of aldehyde oxime 90c afforded the disaccharides 100-103 in lower yields (73%-95%) in favor of the Z isomer (Z/E = 2.0:1 to 6.9:1). It can be concluded that the Z/E outcome of this reaction is mainly determined by the structure of the coupling oximes. Interconversion between the coupled disaccharide Z/E isomers was not observed during purification, structure analysis, and storage.

Conversion of sugar oximes to isoxazoles and nitriles

Yokoyama et al.[74] reported the synthesis of chiral isoxazolines bearing a sugar moiety via the reaction of sugar oximes with DMAD. The reaction of 2,3:4,6-di-O-(tetraisopropyldisiloxane-1,3-diyl)- glucose oxime (104) with DMAD proceeded through a nitrone intermediate 105, resulting in the formation of the corresponding tetraisopropyldisiloxanediyl (TIPDS)-protected isoxazoline glucoside (106), in 87% yield (α/β 3/7). Additionally, both the α and β isomers were separated into two epimers differing at the C-3 position of the isoxazoline ring. The major products were the α and β glucosides, obtained in 20% and 53% yields, respectively. Treatment of the α-glucoside with 5% HCI-MeOH to afford the corresponding isoxazoline analogue 107 as the (─)-form ([α] D~ -1470 (c 0.48, CHCI3) in 51% yield, while the β-glucoside afforded the (+)-form of compound 106 {[a]D +1470 (c 0.48, CHCI₃)) in 61% yield (Figure 16). Deprotection of compound 106 can be easily performed by treatment with tetrabutylammonium fluoride. D-Ribose was then used as a chiral auxiliary in this reaction. Treatment of 2,3-O-isopropylidene-5-O-trityl-D-ribose oxime (108) (Figure 17) with DMAD under the same conditions as before, yielding the expected 2,3-O-isopropylidene-5-Otritylribofuranosyl isoxazoline (110), in 98% yield via the nitrone intermediate 109. The product consisted of α riboside (52% and 5.5%) and β riboside (27% and 13.5%) isomers. The main α and β ribosides had specific rotation values of +1130 (c 0.50, CHCl₃) and -440 (c 0.52, CHCl3), respectively. Detritylation of the α and β ribosides by FeCI3, afforded the same 2-(2,3-O-isopropylidene-β-Dribosyl)- 3,4,5-tris(methoxycarbonyl)-3-methoxycarbonylmethyl- 2,3-dihydroisoxazole (111), in 79% yield based on the β-form. Treatment of compound 111 with 5% HCI-MeOH afforded the (-)-form of compound 107, in 69% yield (Figure 17). This indicates that during the detritylation step, the α-riboside 110α converts to the β-riboside 110β, and that the carbon-3 atoms in the isoxazoline rings of compounds 110α and 108β share the same stereochemistry. Based on the isolated products, the increased α-selectivity (α/β ratio 3/2) observed for 108, compared to oxime 104 (α/β ratio 3/7), appears to be caused by the presence of the bulky 5-O-trityl group. Due to the fact that the absolute configurations of products 107 are not certainly known, the mechanism of chiral induction still remains unclear. The isoxazolines 107 produced in the reaction remain stable in CHCl₃ solution at room temperature for up to a week and can be stored in a freezer for several months without any decomposition.

Compound 108a was also used as a key starting material for synthesizing sugar substituted isoxazoles (Figure 18). Reaction of a mixture of D-ribose oxime 108a and DMAD with 5% aq. NaOCl in the presence of triethylamine afforded the corresponding isoxazole 98a, in 86% yield. Following the same procedure, the reaction of oxime 113a with ethyl propiolate gave the corresponding isoxazole 113b, in 37% yield. It was proved that the intermediate nitrile oxide 112 remains stable at 0⁰C but gradually transformed at room temperature into (E)-2,3-Oisopropylidene- 5-O-trityl-D-ribonohydroximo-1,4-lactone (118). The reaction of compound 112 with styrene gave regioselectively, the corresponding isoxazoline 114. Sugar-substituted isoxazole 116 was also produced, in 37% yield, by the reaction of compound 112 with divinyl sulphone followed by treatment with Na/ Hg. Deprotection of compound 116 by treatment with 5% HCI led to analogue 117, in 95% yield. Finally, heating a mixture of compound 118, methyl acrylate, and dry toluene at 120 ⁰C, provided (3S,5R)-8,9-isopropylidenedioxy-3-methoxycarbonyl- 1-[2΄-(methoxycarbonyl)ethyl]-7-(trityloxymethyl)-2,6-dioxa-1- azaspiro[4.4]nonane (120), in 80% yield as a white powder. The reaction proceeded initially by the formation of a sugar nitrone 119 through a Michael addition, where the oxime nitrogen atom attacks methyl acrylate. This is followed by a 1,3-dipolar cycloaddition with another molecule of methyl acrylate. In 2009 Talukdar[75] developed a novel method for converting sugar oximes into sugar nitriles using Grubbs’ catalyst as well as other ruthenium salts (Figure 19). Interestingly, a mixture of oximes 121-127 and ruthenium salts 3 mol % of Cl₂(PCy₃)₂Ru=CHPh/ Cl₂Ru(PPh₃) or 10 mol % of RuCl3 were heated in benzene to yield the desired nitriles 128-134. The reaction proved to be high yielding (70%-90%), with a simple workup procedure and mild conditions, allowing acid labile isopropylidene groups to remain unaffected.

Nitrosation of sugar oximes

In 2006, Brand et al.[67] reported the nitrosation reaction of various sugar oximes. Nitrosation of the oximes of glucose, xylose, and lactose using NaNO₂/HCl yielded 2-(β-glycopyranosyl)- 1-hydroxydiazene-2-oxides, which were isolated as salts 138, 147 and 153, respectively (Figure 20 and Figure 21). Nitrosation of disaccharide lactose oxime mixtures 151 and 152 (Figure 21) using NaNO₂/HCl produced (after neutralization with NH₃ or alternatively with NaHCO₃, KHCO₃, CsOH, pyridine, BuNH₂, 4-MeOC ₆H₄NH₂, or Ph₂CH-NH₂) led to the corresponding diazene-1-olate- 2-oxides, of which the benzhydrylammonium salt 153 (72% yield) (Figure 21) was crystallized and purified more easily. Treatment of aqueous solutions of the oxime 155 with NaNO₂/HCl afforded (after neutralization with NH₃ or NaHCO₃ or KHCO₃) amorphous mixtures of 2-(D-mannopyranosyl)diazene-1-olate-2-oxides, mannose, and some unidentified mannose derivatives. Although the separation of the mixtures was difficult, the neutralization with p-anisidine afforded the solid p-anisidinium salt 156, which was converted into the pure acid 157 and p-anisidine by dissolution in THF/MeOH. The crystalline sodium salt 158 was afforded upon neutralization of acid 130 with NaHCO₃ in H₂O, and it was found quite stable. However, reaction of isopentyl nitrite with 155 in aqueous solutions of CsOH or KOH resulted in the formation of the 2-(α-D-mannofuranosyl)-1-hydroxydiazene-2-oxide salts 159 and 160 (Figure 22), respectively. Finally, nitrosation of open chain oxime 154 furnished fructose.

Conclusion

Sugar oximes not only serve as versatile building blocks for synthesising various heterocycles but they also possess very important activities, which arise from the combination of the oxime’s reactive functional group and the sugar’s bioavailability and recognition characteristics. In this review, we have presented the synthesis of both furano and pyrano sugar oximes and we have highlighted their properties as acetylcholinesterase reactivators as well as their applications as surfactants. We focused our attention on oxime chemical ligation reactions which lead to various photoreactive conjugates (tri-and tetrasaccharides) and novel closed-ring glycolipids. As an extention of this kind of reactions we also described the synthesis of oligosaccharide mimetics, various glycoclusters and N-O linked saccharides. Finally, the significance of sugar oximes as valuable synthons for the synthesis of complex isoxazoles and nitriles and their interesting nitrosation reactions were emphasised. We conclude the present review with the hope that it will inspire researchers to develop highly versatile and highly effective methods for synthesizing a wide variety of organic compounds from sugar oximes and to provide a useful background towards future developments.

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