Metal-free synthesis of imino-disaccharides and calix-iminosugars by photoinduced radical thiol–ene coupling (TEC)

Renaud Zelli , Pascal Dumy and Alberto Marra *
Institut des Biomolécules Max Mousseron (IBMM), UMR 5247, CNRS, Université de Montpellier, Ecole Nationale Supérieure de Chimie de Montpellier, 8 Rue de l'Ecole Normale, 34296 Montpellier cedex 5, France. E-mail:

Received 30th January 2020 , Accepted 13th February 2020

First published on 21st February 2020

Radical thiol–ene coupling was exploited for the first time to prepare imino-disaccharides and multivalent iminosugars starting from sugar thiols and iminosugar alkenes or iminosugar thiols and tetra-allylated calixarene, respectively.

The steric and stereochemical resemblance to sugars and the presence of a nitrogen atom replacing the endocyclic oxygen atom confer strong glycosidase (glycoside hydrolase) and glycosyltransferase (glycoside synthase) inhibition properties to iminosugars (e.g.2 and 3, Fig. 1), a family of natural products discovered more than half a century ago.1
image file: d0ob00198h-f1.tif
Fig. 1 Natural sugars and iminosugars.

Aiming to treat the severe pathologies originating from a malfunction of the abovementioned sugar-processing enzymes, a plethora of non-natural monosaccharidic iminosugars have been prepared over the last four decades. However, the poorly selective inhibition activity showed by both natural and synthetic monosaccharidic iminosugars led to their very limited use in therapy. To overcome this serious drawback, two classes of compounds, imino-disaccharides2 and multivalent iminosugars3 (iminosugar units clustered around molecular scaffolds), have recently attracted the attention of the glycosciences research community.

Imino-disaccharides are constituted of a monosaccharide linked to the iminosugar moiety at the reducing (4) or non-reducing end (5) through an O-, S-, N- or C-glycosidic bond (Fig. 2). Also known are some pseudodisaccharides where the linkage between the sugar and 1-deoxy-iminosugar units does not involve their anomeric carbon atoms (6, Fig. 2). Since many glycosidases are able to recognize the sugar linked to the specific monosaccharide to be hydrolysed, compounds bearing a mimic of the hydrolysis intermediate (i.e. the iminosugar) connected to a natural monosaccharide should act as highly selective inhibitors.

image file: d0ob00198h-f2.tif
Fig. 2 Synthetic imino-disaccharide derivatives reported in the literature.

Although more than two hundred imino-disaccharides have been synthesized to date, most of them display labile O- and N-glycosidic bonds at the sugar and/or iminosugar moiety.2a Moreover, among the mere three imino-S-disaccharides reported4 in the literature, only one4a features thioglycosidic bonds, expected to be hydrolytically stable, at both units. Unfortunately, being an N,S-acetal the interglycosidic bond was found to be hydrolysed at pH > 5, whereas the O,S-acetal group was not affected under acidic or basic conditions.4b On the other hand, carbon-linked imino-disaccharides are stable towards acid and base catalysed hydrolysis but their preparation requires complex multistep syntheses.

We envisaged a straightforward synthesis of chemically and enzymatically stable imino-disaccharides where the iminosugar unit is N-linked (7) or anomerically C-linked (8) to the sugar moiety which, in turn, is a S- or C-glycoside (n = 0 or 3, respectively) (Fig. 3).

image file: d0ob00198h-f3.tif
Fig. 3 The two classes of imino-disaccharides prepared in the present work.

In all cases, the two monosaccharidic compounds were connected exploiting the thiol–ene coupling (TEC),5i.e. the photoinduced radical addition of thiols to alkenes. In the presence of a suitable photoinitiator (e.g. the commercially available 2,2-dimethoxy-2-phenylacetophenone, DPAP), the addition can be initiated by UV-A rays (λmax = 365 nm) using cheap household tanning lamps and normal (not quartz) glassware. The coupling takes place in a few minutes at room temperature in almost every kind of solvent, including water and CH2Cl2, even in the presence of atmospheric oxygen. Since TEC proceeds under mild conditions with total atom economy, rapid kinetics and no use of metal-based catalysts, it is particularly suited for the ligation of biomolecules.6 As the thiol–ene coupling has already been exploited by us to prepare thiodisaccharides,7 thioglycosyl amino acids,8 sugar clusters using calixarene,9 octasilsesquioxane10 or cyclopeptide11 scaffolds, and glycosylated dendrimers,12 we planned to synthesize imino-disaccharides also via TEC. It is worth noting that, despite its well-proven usefulness in the field of carbohydrate chemistry, the latter ligation has been neglected for the synthesis of iminosugar derivatives. In fact, only the addition of very simple, achiral thiols to monosaccharidic iminosugars, a C-vinyl,13 two C-allyl14 and a N-butenyl15 derivatives, has been reported in the literature.

In order to prepare a series of N-linked imino-disaccharides (see 7 in Fig. 3), the reaction conditions were optimized using the known,15 free-OH 1-deoxy-D-nojirimycin alkene 9 and the fully deprotected glucosyl thiol1610 (Scheme 1). When 9 and an excess (1.4 equiv.) of 10 were irradiated (UV-A) for 30 min at room temperature in the presence of DPAP (10 mol%) as already reported by us for the preparation of thiodisaccharides and sugar clusters, the reaction did not occur at all. Not surprisingly, the sugar thiol was deprotonated by the iminosugar, actually a quite basic tertiary amine, thus preventing the formation of a thiyl radical. However, irradiation in the presence of a carboxylic acid (3 equiv.) led to the expected imino-S-disaccharide 14 with a conversion directly related to the pKa of the added acid (e.g. CH3CO2H: 15%, ClCH2CO2H: 22%, Cl2CHCO2H: 30%, and CCl3CO2H: 44%). After experimentation, we found that trifluoroacetic acid (TFA) allowed a quantitative conversion of the alkene 9 to 14 (1H-NMR analysis of the crude mixture).

image file: d0ob00198h-s1.tif
Scheme 1 Synthesis of N-linked imino-disaccharides by thiol–ene coupling.

To recover the very polar imino-disaccharide 14 we developed an efficient “catch and release” technique based on the use of strongly basic and strongly acidic ion-exchange resins (Scheme 2). The crude reaction mixture was directly eluted from a short column of Dowex 1X8 (OH form) to remove the excess TFA and to free the amine function of the imino-disaccharide. The solution, containing 14, a residual photoinitiator, excess thiol 10 and its disulfide derivative 18, was then eluted from a short column of Amberlyst 15 (H+ form) to immobilise the sole basic compound present in the crude mixture, i.e. the imino-S-disaccharide 14, and remove all the others. Finally, the target product was released from this column as a free amine, in a pure form, upon elution with a 2 M solution of ammonia in methanol (78% yield).

image file: d0ob00198h-s2.tif
Scheme 2 “Catch and release” method for purification of imino-disaccharide 14.

The same reaction conditions and purification method allowed us to obtain the imino-disaccharides 15 and 16 in good isolated yields (74 and 80%) starting from two other anomeric thiols, the β-D configured 2-acetamido-1-thio-glucose1611 and the 1-thio-α-D-glucose1612, respectively (Scheme 1). As already observed in our previous works,7–12 the 1H-NMR spectra of the imino-disaccharides 14–16 proved that the TEC did not affect the anomeric configuration of the starting thiols 10–12 (see ESI). On the other hand, the coupling of the C-glycoside thiol1013 with the N-butenyl-1-deoxy-nojirimycin 9 required a larger excess of 13 (2 instead of 1.4 equiv.) to give 17 in satisfactory yield (62%). Indeed, although stereochemically stable, this thiol is prone to oxidation leading to the corresponding disulfide that cannot generate the thiyl radical. Therefore, 13 should be prepared immediately before use and its contamination by variable amounts of the disulfide derivative should be evaluated for each batch.

Aiming to obtain a new series of imino-disaccharides featuring the iminosugar anomerically linked to the sugar unit, the L-ido configured, fully deprotected allyl C-iminoglycoside 21 (Scheme 3) was employed as a substrate for the thiol–ene coupling. This alkene was prepared from the known17N- and O-protected derivative 19 by oxidative removal17a of the N-p-methoxybenzyl group to give 20 (78%) followed by reductive deprotection of the O-benzyl groups under Birch conditions (Scheme 3). While the rather apolar, benzylated iminosugar 20 was easily isolated by flash chromatography on silica gel, the very polar compound 21 was quantitatively recovered from the basic reaction medium by immobilisation on Amberlyst 15 resin (H+ form) and subsequent release using 1 M aqueous ammonia. As already reported for other L-ido configured C-iminoglycosides,18 the 1H-NMR analysis demonstrated that the N-protected iminosugars 19 adopt a 4C1 conformation, whereas the corresponding free-amine derivatives 20 and 21 exist in a 1C4 conformation. In fact, the signals of the H-2, H-3 and H-4 protons of 20 and 21 displayed small vicinal coupling constants (2–4 Hz) indicating equatorial–equatorial or equatorial–axial arrangements for the ring hydrogen atoms. Moreover, the long-range (W) coupling constant observed for both 20 (4J2,4 = 0.7 Hz) and 21 (4J2,4 = 1.5 Hz) proved that these C-iminoglycosides adopt a 1C4 configuration.

image file: d0ob00198h-s3.tif
Scheme 3 Synthesis of C-linked imino-disaccharides by thiol–ene coupling.

The photoinduced radical addition of the free-OH sugar thiols 10–13 to the C-allyl iminosugar 21 was carried out in the presence of trifluoroacetic acid as described for the coupling of the N-butenyl iminosugar 9 (see Scheme 1) to give the corresponding imino-disaccharides 22–25 in 54–65% isolated yields (Scheme 3). Also in this case, the desired adducts were recovered exploiting the “catch and release” technique based on the use of the Dowex 1X8 ion exchange resin.

The above-mentioned imino-disaccharides 14–17 and 22–25 could act as new glycosidase inhibitors. To this end, a preliminary study was carried out using the N-linked imino-disaccharide 16, which bears an α-D-glucoside moiety (see Scheme 1). Its inhibition properties were evaluated against the commercially available α-glucosidase (from yeast), β-glucosidase (from almond), Jack bean α-mannosidase, α-galactosidase (from green coffee bean), and trehalase (from porcine kidney), and compared with those exhibited by 1-deoxy-D-nojirimycin (1-DNJ, 3, Fig. 1), a well-known reference inhibitor. The inhibition activity of 16 was evaluated using a standard spectrophotometric assay based on the measurement of the residual hydrolytic activities of the glycosidase in the presence of its substrate and the inhibitor. Comparing the Ki values of 16 with those found in our laboratory for 3 (Table 1), it appears that the imino-disaccharide 16 is a more selective glycosidase inhibitor. In fact, 16 does not inhibit the α-glucosidase and is a weaker inhibitor of the β-glucosidase and α-mannosidase than the 1-deoxy-D-nojirimycin (3); however, it is a significantly stronger inhibitor of both α-galactosidase and trehalase. The Lineweaver–Burk plots indicated a competitive mode of inhibition against β-glucosidase, α-mannosidase and α-galactosidase (Fig. S1–S3 in the ESI), and a mixed-mode of inhibition against trehalase (Fig. S4 in ESI). Interestingly, the latter finding is in contrast to the competitive mode of inhibition against the trehalase shown by 3 (Fig. S5 in ESI), a feature already described in the literature.19

Table 1 Inhibition constants (Ki, μM) against five commercially available glycosidases
Compound α-Glucosidase β-Glucosidase α-Mannosidase α-Galactosidase Trehalase
3 65.9 ± 12.7 173 ± 14 213 ± 15 440 ± 19 12.7 ± 1.4
16 n.i. 306 ± 27 555 ± 61 168 ± 23 5.0 ± 1.3

Then, we decided to prepare multivalent iminosugars3 under metal-free conditions20 taking advantage of the thiol–ene coupling (TEC) between an iminosugar thiol and a multivalent scaffold21 such as the tetra-O-allyl-calix[4]arene 32 (see Scheme 5).22 To this end, the thiols 28 and 31 were synthesized starting from the corresponding iminosugar alkenes 26 and 29, the key step being the photoinduced radical addition of thioacetic acid to the latter substrates (Scheme 4). In particular, the known,15 peracetylated N-butenyl 1-deoxy-D-nojirimycin 26 was irradiated in the presence of thioacetic acid (3 equiv.) and a photoinitiator (DPAP) to afford the thiocetate derivative 27 in 90% yield after column chromatography on silica gel. This compound was converted into the fully deprotected thiol 28 by treatment with ammonia in methanol immediately before the subsequent TEC reaction and without intermediate purification to avoid its oxidation to a disulfide (Scheme 4).

image file: d0ob00198h-s4.tif
Scheme 4 Synthesis of iminosugar thiols from the corresponding alkenes.

image file: d0ob00198h-s5.tif
Scheme 5 Synthesis of a calixarene-based tetravalent iminosugar cluster.

The peracetylated C-allyl iminosugar 29 could be obtained by conventional acetylation of the isolated aminotetrol 21; however, it was more conveniently prepared by full acetylation of the crude 21 obtained after the Birch reduction of the tetra-O-benzyl derivative 20 (Scheme 4). The TEC with thioacetic acid gave the thioacetate 30 (92% isolated yield) which was selectively deprotected to afford the N-acetyl thiol 31 immediately before its use in the following TEC reaction.

Interestingly, the cyclic tertiary amide 29 was isolated as a ca. 55[thin space (1/6-em)]:[thin space (1/6-em)]45 mixture of rotamers 29-M and 29-m (Fig. 4). At room temperature, the 1H-NMR spectrum (CDCl3) showed two sets of sharp signals which coalesced to single peaks only at 110 °C (DMSO-d6), indicating a high rotational energy barrier around the exocyclic C–N partial double bond. The rotamers were identified on the basis of the chemical shifts of the H-1 and H-5 ring protons, i.e. the hydrogen atoms close to the acetamide function (Fig. 4). The orientation of the carbonyl oxygen in the major rotamer 29-M led to a large downfield shift of the (pseudo)anomeric hydrogen H-1 (5.32 ppm), whereas in the minor rotamer 29-m the proximity of this oxygen to the ring hydrogen H-5 was the reason for its strong deshielding (5.46 ppm). The thioacetate derivative 30 was isolated as a 3[thin space (1/6-em)]:[thin space (1/6-em)]1 mixture of rotamers 30-M (δH-1 = 5.18, δH-5 = 4.63) and 30-m (δH-1 = 4.33, δH-5 = 5.51), the major one being again the rotamer featuring the amide carbonyl oxygen oriented toward the H-1 hydrogen atom.

image file: d0ob00198h-f4.tif
Fig. 4 Selected 1H-NMR data (400 MHz, CDCl3, r.t.) of the major (29-M) and minor (29-m) rotamers of the iminosugar tertiary amide 29. See also Fig. S6 in the ESI.

First we attempted the thiol–ene coupling between the iminosugar N-alkylthiol 28 and the allylated calixarene 32 under standard conditions (3 equiv. of TFA per iminosugar, DPAP as the photoinitiator, room temperature). Unfortunately, the desired tetravalent calix-iminosugar derivative (not shown) did not form even in the presence of a large excess of 28 upon prolonged UV-A irradiation. Instead, complex mixtures of incomplete adducts and other by-products were observed. On the other hand, when the iminosugar C-alkylthiol 31 (4 equiv. per allyl group) was allowed to react with calixarene 32 (UV-A, DPAP, DMF, r.t.), the 1H-NMR analysis of the crude mixture revealed the absence of alkene hydrogen atoms after only 30 min irradiation (Scheme 5). It is worth mentioning that the TEC reaction did not require any added acid because the N-acetylated iminosugar 31 was lacking the basic nitrogen atom found in the iminosugar thiol 28. Since the N-protected cluster 33, easily isolated by column chromatography on Sephadex LH-20, was a mixture of rotamers difficult to analyse by NMR spectroscopy, it was treated with hydrazine hydrate to afford 34 (75% total yield) which could be fully characterized.


In the present preliminary work, we demonstrated that the photoinduced radical addition of thiols to alkenes, carried out under carefully controlled conditions, can be applied also to the preparation of complex iminosugar derivatives. In particular, these results pave the way for further syntheses of multivalent systems based on different scaffolds and/or iminosugar moieties.

Conflicts of interest

There are no conflicts to declare.


We thank the Ecole Nationale Supérieure de Chimie de Montpellier for financial support and Carla Eller (ENSCM) for help with glycosidase inhibition experiments.

Notes and references

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Electronic supplementary information (ESI) available: Complete experimental procedures, Lineweaver–Burk plots and copies of NMR spectra of all new compounds. See DOI: 10.1039/d0ob00198h

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