Sucrose-Based Macrocycles: An Update

Abstract

Sucrose is by far the most abundant disaccharide found in nature, consisting of two simple hexose units: d-glucose and d-fructose. This exceptionally inexpensive and widely accessible raw material is produced in virtually limitless quantities. The vast majority is consumed in the food industry either in its native form—as commercial table sugar—or, to a lesser extent, as the basis for artificial sweeteners such as palatinose and sucralose. Beyond its dietary use, sucrose serves as a feedstock for the production of bioethanol, liquid crystals, biodegradable surfactants, and polymers. However, the application of this valuable and extremely cheap raw material (100% optical purity and eight stereogenic centers with precisely defined stereochemistry) in the synthesis of more sophisticated products remains surprisingly limited. In this short review, we focus on the strategic use of the sucrose scaffold in the design and synthesis of fine chemicals. Special attention will be paid to macrocyclic derivatives incorporating the sucrose backbone. These water-soluble structures show promise as molecular receptors within biological environments, offering unique advantages in terms of solubility, biocompatibility, and stereochemical precision.

1. Introduction

Sucrose (1; α-d-glucopyranosyl-β-d-fructofuranoside), a very cheap raw material produced in plants (sugar cane and sugar beets) from the primary products of photosynthesis, is available in practically unlimited quantities. The majority of commercially available sucrose is consumed in its native form as table sugar, primarily in the food industry. To a lesser extent, it also serves as a precursor for the industrial-scale production of sucrose-derived sweeteners such as palatinose and sucralose. Beyond its applications in food technology, sucrose plays an increasingly important role in industrial chemistry. One of its major non-food uses is in the production of bioethanol, where it serves as a fermentable sugar source. Moreover, sucrose has emerged as a versatile starting material in the synthesis of high-value compounds, including liquid crystals, biodegradable surfactants, polymers, and, potentially, cytotoxic antitumor agents (Figure 1) [1].

Despite its exceptional advantages—such as 100% optical purity and eight stereogenic centers with precisely defined stereochemistry—the utilization of sucrose in the synthesis of complex fine chemicals remains surprisingly underexplored. The potential of this structurally rich and sustainable molecule for advanced chemical synthesis has only been modestly realized. Some of these synthetic applications have been discussed in our recent reviews [2,3].

The conformation of sucrose in both the solid state and in solution indicated that the primary hydroxyl groups at the C6 position of the glucose moiety and the C6′ position of the fructose moiety are in close spatial proximity due to strong intramolecular hydrogen bonding, which suggests the feasibility of covalently linking these two positions via a suitable linker (Figure 2) [4].

Such a possibility may open a route to highly functionalized macrocyclic derivatives that are soluble in water, which would allow these compounds to be used as receptors in biological environments. The attempt to utilize sucrose-based macrocycles requires several steps (Figure 3):

• The protection of all secondary hydroxyl groups with temporary blocks (preferably benzyl) that could be easily removed after the desired transformations without the destruction of a highly sensitive glycosidic bond (Figure 3; compounds 2 and 3). This strategy requires temporary protection of the primary hydroxyl groups (C6, C6′ and eventually C1′), benzylation of all remaining OH groups, and the removal of temporary blocks from C6, C6′ (and eventually C1′) positions. The selective protection of the primary OH groups is well known and can be achieved using very expensive bulky silyl chlorides or much cheaper trityl chlorides. However, the removal of the trityl blocks from per-benzylated intermediates was not trivial since this process can only be realized by careful acidic hydrolysis.
• The connection of the terminal positions (C6, C6′ and eventually C1′) should be connected via a proper link (4 and 6).
• Total deprotection, i.e., the removal of all temporary blocks, which should provide macrocyclic derivatives (potential receptors) soluble in water (5 and 7).

During our work on the application of sucrose as a valuable synthon for macrocyclic, water-soluble derivatives, we describe a convenient methodology for the synthesis of so-called “sucrose diol” (2) and “sucrose triol” (3) and other useful partially protected derivatives of this disaccharide; examples are shown in Scheme 1.

Selective silylation of diol 2 afforded product 8 with the free C6-OH group with a very small amount of double-protected compound 9. This high selectivity was rather expected in view of the early observation by Khan, who reported that the reaction of free sucrose with tert-BDPS-Cl afforded 49% of the mono-silylated product in which the silyl group was located at the C6′ (fructose part) position [5].

The double silylated compound 9 could be obtained in high yield by the exhaustive silylation of diol 2. The most important (not expected) observation in our study was the selective de-silylation of 9, which opened a convenient route to regioisomeric mono-alcohol 10 with the free C6′-OH (fructose part) group (Scheme 1). The sulfur, amino-, and phosphorus derivatives were also available, as shown in Scheme 1 [2,3].

2. Sugar Derived Macrocyclic Derivatives with Sucrose Scaffold

The best-known macrocyclic derivatives with sugar platform are—undoubtedly—cyclodextrins, which were obtained from the enzymatic degradation of starch by the end of the XIXth century by French scientist Antoine Villiers. In the second half of the XXth century, the method for their industrial preparation was elaborated by Hungarian chemists. These cyclic oligosaccharides have found widespread applications in chemistry, medicine, and daily life [6,7]. Other macrocyclic sugar-based derivatives are also known [8]. We decided to use sucrose—the most common disaccharide—as a platform to build macrocyclic derivatives, which, being soluble in water, could act as a receptor in a biological environment.

2.1. Synthesis of Macrocyclic Derivatives from “Sucrose Diol” 2

Diol 2 served as a starting material for the preparation of the analogs of crown and aza-crown ethers. Several such targets built on a sucrose platform were prepared by our group; model examples are shown in Scheme 2 [9,10].

For example, diol 2 was treated with polyethylene glycol di-tosylates (15), affording crown ether analog 16. The preparation of aza-crowns required slightly different options. Thus, the elongation of 2 by two carbon atoms at each side (→ 19) followed by a reaction with benzylamine provided macrocycle 17 with one nitrogen atom in the ring. The synthesis of macrocycles with more nitrogen atoms was also possible and was exemplified by compound 18. It was prepared in a few steps from diol 2 by its conversion into di-amine 20, which was elongated to 21 (similarly to 19) and finally treated with benzylamine, affording 18.

In aza-macrocycles 17 and 18, the nitrogen atom in the ring is protected with the benzyl group; it would have been much more convenient to have this atom free, which would have allowed us to introduce various substituents modifying the properties of the target and such a possibility is shown in Scheme 3 [11]. Starting from alcohol 8, it was possible to introduce different units at the position C6 (via a reaction with chloroacetonitrile) and C6′ (via a reaction with ^tbutyl bromoacetate after the deprotection of 6′-OH); this intermediate was subsequently reduced to aminoalcohol 22. This compound was converted, under Garegg’s conditions (imidazole, I₂, Ph₃P), to iodoamine 23, which spontaneously cyclized to aza-crown 24. The alkylation of the nitrogen atom afforded a series of crown ether analogs with a sucrose scaffold [12].

The macrocyclic derivatives presented in Scheme 2 and Scheme 3 are “symmetrical”, i.e., they have the same atoms (oxygen or nitrogen) at both “ends” of sucrose (positions C6 and C6′). The synthesis of “unsymmetrical” aza-crown analogs was, however, possible, as shown in Scheme 4. Alcohol 8 was converted into 25 and further into aminoalcohol 26. The cyclization of this intermediate, induced by a Garegg’s reagent, provided the first “unsymmetrical” azacrown analog 27. The second macrocyclic analog 28 was prepared analogously from regioisomeric alcohol 10 [12].

We also elaborated on the convenient method for the synthesis of macrocyclic sucrose-based derivatives containing sulfur, which is shown in Scheme 5. Sucrose (1) was selectively chlorinated according to the Whistler procedure [13]; then, it was perbenzylated to 29 [14]. The reaction of this intermediate with 2-mercaptoethanol provided diol 30 (X = OH), which was chlorinated (to 31; X = Cl) under Appel conditions. The treatment of this dichloride with either amines (e.g., BnNH₂) or di-amines (BnNHCH₂CH₂NHBn) afforded macrocyclic derivatives 32 or 33, respectively, with a sucrose scaffold [15].

2.2. Synthesis of Other Complex Macrocyclic Sucrose-Based Derivatives

One of the first sucrose-based macrocyclic derivatives—that was not the crown analog—was prepared by us in 2010, as shown in Scheme 6 [16]. Sucrose diol 2 was converted using a few well-defined steps into azido-alcohol 34, which—upon reaction with di-acetylene 35—provided precursor 36 (R = H) at an 80% yield. The activation of both hydroxyl groups as mesylates (37; R = Ms), followed by their reaction with ethylenediamine, afforded macrocycle 38 at a 5% yield. However, when this process was carried out in the presence of a template (l-phenylglycine methyl ester hydrochloride), this yield increased to 25%.

Soon after this pioneering work, we introduced a method for the synthesis of other dimers with a sucrose scaffold, as shown in Scheme 7. Diol 39 (permethylated analog of 2) was converted after mesylation into di-amino derivative 40, which—upon reaction either with di-acid chloride 41a or 41b—gave dimer 42 (head-to-tail dimer a or b) together with its head-to-head analog 43 [17].

The synthesis of urea- and thiourea sucrose dimers is shown in Scheme 8 [18,19]. The treatment of diamine 14 with triphosgene or thiophosgene afforded intermediates 44a or 44b, which were further reacted with diamine 14 to afford urea and thiourea derivatives 45 (head-to-head) and 46 (head-to-tail) dimers. These macrocycles show high affinity to chloride and acetate anions.

2.3. Synthesis of Macrocyclic Derivatives from “Sucrose Triol” 3

After the successful preparation of the relatively simple analogs of crown and aza-crown ethers (some of which showed interesting complexing properties; see the next chapter), we turned our attention to more sterically demanding molecules in which the molecular cavity responsible for complexation would be much more rigid (see models 6 and/or 7 in Figure 3). Such a possibility requires the connection of all three “ends” of the sucrose molecule, i.e., positions C1′, C6, and C6′. The first example of such a complex derivative, shown in Scheme 9, was prepared by us in 2019 [20]. Triol 3 was used as the starting material for the preparation of sucrose-based cryptands; this was the first (and up-to-date the only one) example of such derivatives. The elongation of all three terminal positions of triol 3 by a –CH₂CH₂-O-CH₂CH₂-I unit (→ 47) followed by a reaction with tripodal amine 48 afforded cryptand 49 at a very high yield (45.5%).

A special case is represented, however, by the objects in which the sucrose platform is connected to a tripodal chiral unit. Thus, the reaction of a racemic C₃-symmetrical cyclotriveratrylene unit (CTV, 50) with elongated (by two carbon atoms at all terminal positions) sucrose triiodide 51 provided two (out of four possible) diastereoisomeric cages, M-52 and P-52, as shown in Scheme 10. The benzyl groups protecting the sucrose backbone were easily removed by simple hydrogenation-affording capsules that were soluble in water (M-53 and P-53) [21]. The formation of only two diastereoisomeric cages (52) from 51 and rac-50 resulted (most likely) from the fact that the ethylene linker connecting both units was too short.

For longer than the ethylene linker, the possibility of the formation of all four possible stereoisomers increased significantly. Indeed, the reaction of compound 54 (another analog of sucrose triol 3) with racemic CTV (50) afforded four diastereoisomeric cages (P-55, M-55, P-56, and M-56), as shown in Scheme 11 [22,23].

Another example of such molecular cages containing CTV and sucrose moieties connected via the naphthalene linkers is shown in Figure 4 (only two out of four isomers formed are shown). These cages were found to be selective and efficient fluorogenic sensors for the detection of acetylcholine or choline. Compound P-57 has a better affinity for choline over acetylcholine, while cage M-57 exhibits a higher constant association for acetylcholine over choline [23].

Molecular switches built on the sucrose platform were also available, as shown in Scheme 12. Diol 2 was converted in a few simple steps into di-iodide 58, which—upon its reaction with azobenzene 59—gave macrocycle 60 at a high yield with the trans isomer strongly predominated over the cis one. After irradiation with green light, isomer trans-60 underwent conversion into the cis isomer, while the irradiation of cis-60 with blue light (or just heating) induced its conversion into the more thermodynamically stable trans isomer [24]. The complexing properties of both isomers towards achiral cations were rather low but slightly differed from each other, as shown in Scheme 12.

3. Complexing Properties

Macrocycles with a sucrose scaffold presented above (crown, aza-crown analogs, and cryptand 49) show complexing properties towards achiral cations (mostly inorganic) or anions (ureas 45a and 45b). However, the application of such highly functionalized, enantiomerically pure receptors to complex achiral guest is not interesting; we performed these studies only to check if such compounds have the complexing abilities. The application of these sucrose-based hosts for the complexation of chiral guests was, however, quite promising. We proved that they are able to distinguish both enantiomers of the phenylethylamine cation; thus, the enantioselective complexation of chiral guests is possible, at least for simple model guests. The first interesting results were reported in our earlier study (from 2008) on the synthesis of sucrose-base receptors. The preferred complexation of (S)-phenylethylamine cation (62) was noted by receptor 18, while receptor 61 formed a strong complex with the (S)-enantiomer only (Figure 5) [9]. This selectivity towards the (S)-62 over the (R)-62 was also noted for “unsymmetrical” receptors 27 and 28 (Figure 5) [12].

4. Conclusions

We have proved that sucrose, a very cheap raw material available in almost unlimited quantities, can be used (besides in “commercial” applications) as a building block for the synthesis of fine products with high added value. Several types of macrocyclic derivatives with sucrose scaffold are available. Some of them show interesting complexing properties and are able to differentiate between the two enantiomers of simple chiral guests.

The sucrose platform in our syntheses was fully protected with benzyl groups, which could be removed (as we proved in a few cases) under mild conditions, not affecting the very sensitive glycosidic bond. Such “free” (not protected) receptors, which are soluble in water, might find an application in studies of the complexation of chiral guests in biological environments.

Especially interesting is the field of molecular cages incorporating sucrose and the CTV unit. These two partners can be connected by appropriate linkers of different lengths, which opens a convenient way for cages with various cavities to be able to differentiate between important biologically active compounds.

Also, the molecular switches built from sucrose and azobenzene open a promising field of study. Depending on the light (green or blue), such derivatives change their configuration (from trans to cis and vice versa), thus modifying their cavity and, hence, the complexing properties towards various cations.

As shown in this short note, sucrose can also find an application in the synthesis of fine chemicals, which can be useful in many fields. Thus, this disaccharide is available in practically unlimited quantities, which is ignored in most typical organic laboratories, and can be used as a starting material for the synthesis of various types of optically pure fine chemicals.