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. 2024 Oct 31;9(45):45047–45052. doi: 10.1021/acsomega.4c05247

One-Pot Stereospecific Synthesis of 1,4-Oligosaccharides by Glycal-Derived Vinyl Epoxides Assembly

Maria Chiara Santangelo †, Dalila Iacopini †, Lucilla Favero †, Riccardo Zecchi ‡, Giuseppe Pieraccini ‡, Sebastiano Di Pietro †,*, Valeria Di Bussolo †,*
PMCID: PMC11561766  PMID: 39554454

Abstract

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Recently, naturally occurring linear 1,4-glycans have attracted remarkable attention for their activity in cancer and neurodegenerative disease treatment. Classical chemical synthetic strategies for linear 1,4-oligosaccharides are considerably time-consuming due to orthogonal protection/deprotection, the introduction of leaving groups, and various forms of activation of the glycosylation reaction. Herein, we present a new one-pot microwave-activated reiterative assembly of glycal-derived vinyl epoxides in an uncatalyzed substrate-dependent stereospecific process for the preparation of both β-1,4-d-Gulo and α-1,4-d-Manno oligosaccharides.

Introduction

Glycans represent key structures in glycobiology in consideration of their capability to encode information for molecular recognition and to serve as determinants of protein folding, stability, and pharmacokinetics.1−3 Recently, natural occurring linear 1,4-glycans have been the object of several studies, such as Mannan, a polysaccharide derived from the yeast cell wall that contains mostly linear β-1,4-linked mannose backbone, which has been used as cancer vaccines,4−6 and GV-971, a natural sodium linear β-1,4-oligomannate as an Alzheimer’s disease (AD) therapeutic agent with a unique multitarget action.7

Although chemical synthesis of oligosaccharides has proven to be an indispensable part of modern glycobiology, it is greatly hampered by its insufficient efficiency, and so far, assembly of polysaccharides remains one of the most challenging tasks for synthetic chemists. Only a limited number of examples have been reported in the literature in the past few decades.8−12

However, chemists have synthesized quite a lot of important oligosaccharides, but the chemical synthesis of oligosaccharides, even for simple linear chains, is often a discrete stepwise process, which still makes extensive use of orthogonal protection protocols, the introduction of leaving groups and activators for total control of the molecular outcome, in an extremely time-consuming fashion.13−15

We now report a new process that allows for the first time direct synthetic access to linear 2,3-unsaturated 1,4-oligosaccharides from glycal-derived vinyl epoxides.

Results and Discussion

Previous work from our laboratories has shown that the vinyl epoxides 1α or 2β represent excellent glycosyl donors for the synthesis of simple 1,4-O- or C-glycosides or more complex glycoconjugates, on the basis of a stereospecific, uncatalyzed glycosylation process, based on the 1,4-conjugated addition of several nucleophiles to the glycal epoxides.16−25 This discovery led us to pursue the prospect of achieving a reiterative glycosylation process to address the long-standing challenge of direct synthesis of 1,4-oligosaccharides, differently functionalized on the first unit, starting from glycal-derived vinyl epoxides. It was envisioned (Scheme 1) that the use of 2,3-unsaturated glycosydes (Iα or Iβ), that are also allylic alcohols, obtained from the typical conjugated addition process of an opportune alcohol nucleophile to the vinyl epoxide 1α or 2β, could represent the first glycosyl acceptor (initiator). This initiator is able to react with the epoxide (glycosyl donor 1α or 2β), to allow the formation of a disaccharide (IIα or IIβ), which now represents the new glycosyl acceptor able to ensure the chain elongation. In fact, this species reacts in situ again with the epoxide donor in a reiterative one-pot assembly process for the construction of well-defined oligosaccharides IIIα or IIIβ (2–6 units, n = 0–4, Scheme 1), which can be further elaborated upon to obtain either β-1,4-d-Gulo or α-1,4-d-Manno oligosaccharides, depending on the vinyl epoxide used (1α or 2β).

Scheme 1. Reiterative Assembly of Vinyl Epoxides 1α and 2β.

Scheme 1

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This hypothesis, unfortunately, using the previously reported protocol,16,17 which consists in the simple reaction of the glycosyl donor with the glycosyl acceptor at room temperature without any catalyst, was not successful. In fact, all the initiators Iα or Iβ, prepared following the reported protocol16 from vinyl epoxide 1α or 2β, using benzyl alcohol (3α or 3β), propargyl alcohol (4β), and N-Cbz protected hexanolamine (5β) as the nucleophiles, when used (3 equiv) in the reaction with vinyl epoxides 1α or 2β (1 equiv),17 allows only irrelevant amounts of the corresponding disaccharides IIα or IIβ. Interestingly, in the search for the reason why the typical protocol did not work with nucleophiles 3α, 3β, 4β, and 5β and cannot be applicable to the reiteration of the process, we demonstrated, by computational studies, that alcohols Iα and Iβ, which are secondary allylic alcohols embedded in a dihydropyran-like structure, unexpectedly, were inert at room temperature for the reaction with vinyl epoxide 1α or 2β. Indeed, a calculation of the local softness on the hydroxyl oxygen atom by means of global softness and Fukui function (Table S1)26−29 showed that 3β, 4β, and 5β are weak nucleophiles. Moreover, the nucleophilicity of the OH group on the C4 position is influenced by the nature of R in the conjugated C1 position (nucleophilicity 3β ≈ 4β > 5β). This discovery led us to pursue the prospect of a necessary activation to realize the reiterative glycosylation process with these relatively unreactive nucleophiles.

However, thermal reflux conditions were still ineffective; in fact, only starting material was recovered at 80 °C for 12 h, or decomposition of the starting material was observed when the reaction was heated at 100 °C for 5 h. Then the possibility of using microwave irradiation, a more efficient (based on an electromagnetic radiation absorption rather than a heat transfer), safer, and greener way to heat up chemical processes, was explored: much to our delight, the use of simple microwave irradiation gave the needed kinetic activation to promote a dramatic efficiency of the glycosylation process, resulting in the regio- and stereoselective formation of 2,3-unsaturated 1,4-oligosaccharides. This experimental result suggests specific nonthermal effects of MW, able to determine an efficient reactivity of these inert nucleophiles that cannot be explained by thermal effects.30−32

For example, in the optimized procedure (Scheme 2), treatment of benzyl glycoside 3β (1 equiv) and vinyl epoxide 2β (6 equiv), prepared in situ by base catalyzed cyclization of trans-hydroxy mesylate 2, in THF and subsequent microwave irradiation at 80 °C for 10 min, led to an efficient reiterative straightforward glycosylation process. After aqueous workup, the reaction crude exclusively included 2,3-unsaturated-1,4-oligosaccharides and only traces of unreacted initiator 3β (Figures S16 and S17).

Scheme 2. Microwave-Activated Reiterative Assembly of Vinyl Epoxide 2β with Initiator 3β.

Scheme 2

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The postworkup 1H-NMR spectrum (Figure S16) is remarkably clean, and it is in line with a mixture of 2,3-unsaturated 1,4-O-glycosides underlining, for this new reiterative process, a complete 1,4-regiocontrol of the reaction. All of the main oligomers were isolated by chromatography and characterized by NMR. In particular, the NMR study of pentasaccharide (penta-3β) allowed us to determine its stereochemistry (see the SI for details). The absolute configuration of all the new C1 and C4 stereocenters generated in the reaction was determined on the basis of the known configurations of C1, C4, and C5 of the initiator-terminus unit and of C5 of all other units.25Figure 1 reports a detail of the NOESY map of penta-3β, which clearly confirms the total β-stereoselectivity of the process, thanks to the repetitive NOE correlation (Figure 1, gold) between the H4 and the H1 proton atoms of the adjacent units. As a further proof, the intraunit NOE cross peaks (Figure 1, green) between every H5 and H1 atom independently confirm the β-configuration of all the anomeric carbons. Therefore, the reiterative assembly of epoxide 2β gave rise exclusively to 2,3-unsaturated- β-1,4-oligosaccharides. This close correspondence demonstrated between the configuration of the pentasaccharide (penta-3β) and that of the starting epoxide (2β) is rationalizable on the basis of the expected coordination between the O-nucleophile and the epoxide oxygen atom in the form of a hydrogen bond.18

Figure 1.

Figure 1

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NOESY map for penta-3β with key NOE effects highlighted.

The molar distribution of the oligomers was estimated by HPLC, by normalizing each peak area over the number of phenyl rings in the structure. For the described oligomerization of 2β with 3β (Table 1, entry 1), the distribution was centered between the trimer and the tetramer. The conversion of the process was calculated on the basis of the decrease in the level of initiator 3β assessed by HPLC by means of calibration plots. Moreover, for the oligomerization of 2β with 3β, the conversion is remarkably good, around 73%.

Table 1. Synthesis of 1,4-Oligosaccharides by Assembly of Epoxide 2β with Different Initiators.

graphic file with name ao4c05247_0008.jpg

graphic file with name ao4c05247_0009.jpg

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a

Normalized HPLC areas; see SI for details.

b

Based on the decrease of the HPLC peak area of the initiator; see SI for details.

c

Oligosaccharides in bold are isolated and characterized.

To stress the versatility of the process, we realized the assembly of epoxide 2β with initiator 4β (terminal alkyne, key functionality for next elaborations by click chemistry, Table 1, entry 2) and 5β (Cbz-protected amine, useful linker toward the synthesis of glycoconjugates, Table 1, entry 3). The molar distribution of the oligosaccharides obtained and the overall conversion are reported in Table 1.

Both entry 2 and 3 in Table 1 involving initiator 4β and 5β, respectively, were characterized by slightly lower conversions with respect to entry 1, and a molar distribution centered between disaccharide and trisaccharide. This is probably due, as previously mentioned, to the lower nucleophilicity of both of these initiators (Table S1), which affects the rate of formation of the disaccharide, which represents the rate-determining step of all of the processes. As for the oligomerization of 2β with 3β, all the oligosaccharides isolated from the assembly of 2β with 4β and 5β were characterized by NMR (for tri-4β and tri-5β, the identity was also confirmed by MALDI, SI) confirming the complete 1,4-regio and β-stereoselectivity of the process.

The 2,3-unsaturated oligosaccharides synthesized are key compounds for the construction of deoxy and fully oxygenated sugars.10,23 This way, penta-3β derivative has been fully dihydroxylated by means of N-methyl morpholine N-oxide (NMMO)/OsO4 protocol, to afford oligosaccharide 6, by a complete sterically favored α-facial stereoselective electrophilic addition (Scheme 3).10,23,24

Scheme 3. Dihydroxylation of penta-3β.

Scheme 3

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The d-gulo stereochemistry of pentasaccharide 6 was assessed by NMR (and the identity was also confirmed by MALDI, SI), confirming that the dihydroxylation process occurred on the less hindered α-face of the alkene present in each unit of penta-3β. This is clearly demonstrated by the upfield change of the anomeric resonances from 5.25 to 5.15 ppm in penta-3β to 4.65–4.75 ppm in 6, with a change in their J constant from 2.8 to 8.2 Hz, that are typical of trans diaxial scalar coupling.23

To extend the scope of this method for the stereocontrolled one-pot synthesis of linear 2,3 unsaturated 1,4 oligosaccharides, we also carried out the reiterative assembly of diastereoisomeric epoxide 1α with benzyl glycoside initiator 3α, which unlocks easy access to d-Mannose-based 1,4-linear oligosaccharides (Scheme 4).

Scheme 4. Reiterative Assembly of Vinyl Epoxide 1α with Initiator 3α.

Scheme 4

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Following the new protocol for the vinyl epoxide assembly, we successfully obtained a pool of oligomers, with a molar distribution of oligosaccharides centered on the trimer (33%) with a conversion of 52%. The four main isolated oligomers were characterized by NMR (tetra-3α also by MALDI). In particular, tetra-3α was investigated in detail (see SI), and as previously stated, taking advantage of known absolute configurations on C1, C4, and C5 of the initiator, the NOE correlations between protons H1 (5.07–5.21 ppm) and H4 (4.03–4.10 and 4.19–4.26 ppm) of the adjacent unit (Figure S68) unequivocally confirmed the oligomers as 2,3-unsaturated-α-1,4-oligosaccharides.

The remarkably complete α-stereoselectivity obtained by using vinyl epoxide 1α clearly demonstrated that the process is stereospecific: the oligomerization of 1α will form 2,3-unsaturated-α-1,4-oligosaccharides, while epoxide 2β will always give rise to 2,3-unsaturated-β-1,4-oligosaccharides.

Moreover, the 2,3 unsaturated α-1,4 trisaccharide tri-3α was submitted to a cis-dihydroxylation with OsO4/NMMO (Scheme 5), and in this case, the β-stereoselective attack of the electrophile is directed by the allyl substituents at C4 and C1, now located in the α-face.23,33 Therefore, the corresponding dihydroxylated derivative 7, which represents a 1,4-trisaccharide with a manno configuration, was the only stereoisomer obtained (65% yield).

Scheme 5. Dihydroxylation of tri-3α.

Scheme 5

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To highlight the versatility of this procedure, which allows fast reactivity of relatively unreactive nucleophiles, we synthesized disaccharide 10α, which represents, for example, an epitope to better understand the carbohydrate recognition process by lectins34 and a key Mannobioside to elucidate the mechanism of the interaction mode between antibiotic BMY-28864 (Pm) and mannose residues as well as the biological action of this antibiotic.35 Using a 1:3 ratio between the glycosyl donor 1α and the glycosyl acceptor 8α,16 the microwave activated process is centered on the production of disaccharide di-8α, obtained only together with trisaccharide tri-8α (ratio di-8α/tri-8α 80:20 (Scheme 6). Di- and trisaccharide were separated by chromatography, and di-8α was subjected to a cis-dihydroxylation with the typical OsO4/NMMO protocol, to afford manno-derivative 9α. Debenzylation of 9α under palladium-catalyzed hydrogenation afforded the desired, fully deprotected, disaccharide 10α.36

Scheme 6. Synthesis of Disaccharide 10α.

Scheme 6

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Conclusions

In conclusion, we have successfully realized a new, fast, and versatile one-pot stereospecific reiterative glycal-derived vinyl epoxide assembly for the preparation of linear β-1,4-d-Gulo and α-1,4-d-Manno oligosaccharides (2–6 units). It is noteworthy that the access to 2,3-unsaturated-1,4 oligosaccharides reinforce the interest for this methodology, especially considering that these structures are rather appealing in Medicinal Chemistry as unnatural sugars,24,37−39 and also emphasizing a rare complete control over the desired degree of lipophilicity/hydrophilicity of the oligosaccharides synthesized. Moreover, the possibility of constructing the first unit bearing different functionalities opens several chances of easy glycoconjugation reactions of these products with various molecular/supramolecular entities such as proteins, synthetic polymers, nanoparticles, and metal complexes. Studies are in progress to synthesize long and branched polysaccharides exploiting this versatile new methodology.

Acknowledgments

We thank Giulia Corsi, Silvia Disperati, Sofia Lepri, Chiara Mangini, and Giusy Laura Fratello for their help in producing the preliminary results. This work is supported by the Università di Pisa under the “PRA Progetti di Ricerca di Ateneo” (Institutional Research Grants) PRA_2020-2021_58 “Agenti innovativi e nanosistemi per target molecolari nell’ambito dell’oncologia di precisione”.

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acsomega.4c05247.

  • Full computational and experimental details and characterization data for all products (PDF)

Author Present Address

§ GSK, Technical Research and Development (TRD), Via Fiorentina 1, 53100, Siena, Italy

Author Contributions

The manuscript was written through contributions of all authors. All authors have given approval to the final version of the manuscript.

The authors declare no competing financial interest.

Supplementary Material

ao4c05247_si_001.pdf (7.8MB, pdf)

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ao4c05247_si_001.pdf (7.8MB, pdf)

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