Synthesis and conformational analysis of a novel carbohydrate-fused bis-crown ether: crown-CyPLOS

doi:10.1016/j.tet.2009.09.100

Tetrahedron

Volume 65, Issue 47, 21 November 2009, Pages 9694-9701

https://doi.org/10.1016/j.tet.2009.09.100 Get rights and content

Abstract

A novel sugar-based macrocycle consisting of a phosphate-linked 12-membered disaccharide ring (cyclic phosphate-linked oligosaccharide, CyPLOS), fused to two 18-crown-6 ether residues, is here described. The synthesis of the target compound has been accomplished in 23% overall yield for 11 reaction steps, exploiting phosphoramidite chemistry for the dimerization and a classical phosphotriester methodology for the cyclization reaction. NMR-based conformational analysis studies have been carried out on the fully deprotected macrocycle, showing a characteristic arched-structure with C₂-symmetry.

Graphical abstract

Introduction

In order to achieve efficient recognition of a specific guest, most host agents in supramolecular chemistry exhibit pre-organized conformations, ensured by a well-defined three-dimensional presentation of the interacting moieties.1, 1(a), 1(b) In the design of effective artificial hosts, the presence of chiral, amphiphilic and cyclic structural motifs is highly desirable, and cyclodextrins, calixarenes, cyclic peptides are typical examples in this frame. Among the most efficient and selective receptors for cations are crown ethers, which, in contrast, exhibit an achiral, rather simple backbone. Since the pioneering work of Pedersen,2, 2(a), 2(b) crown ethers have attracted a great deal of attention over the last three decades, and a large number of diverse derivatives have been designed and synthesized for a variety of supramolecular applications. Bis- or poly-crown ether compounds have proven to be much more effective extraction agents - and more active transmembrane ion channels or mobile carriers - than their monomeric counterparts.3, 3(a), 3(b), 3(c), 3(d) Relevant examples are, among others, crown ether-modified cyclodextrins,4, 4(a), 4(b) calixarenes5, 5(a), 5(b), 5(c), 5(d), 5(e), 5(f) and resorcinarenes,6, 6(a), 6(b), 6(c), 6(d), 6(e) as well as the synthetic ionophores developed by Gokel and co-workers.⁷

In a previous paper,⁸ we have showed that cyclic phosphodiester-linked disaccharide 1 (Fig. 1), as the first member of a family of compounds we named CyPLOS (Cyclic Phosphate-Linked OligoSaccharides), preferentially adopts a concave conformation, potentially able to bind metal ions.

It was originally envisaged that 1 would provide a useful synthetic platform for the construction of new artificial receptors for transmembrane ion transport: the hydroxy groups at C-2 and C-3 of each saccharide residue can in fact be exploited as synthetic handles for the attachment of suitable lipophilic appendages assuring the insertion into the hydrophobic core of lipid systems. Following this design, by covalently linking alkyl or polyether linear tentacles onto the disaccharide macrocycle, a series of amphiphilic, jellyfish-shaped CyPLOS derivatives endowed with good ion transport activity have been prepared (2a–c, Fig. 2). It was also demonstrated that the presence of the disaccharide macrocycle was essential for the ionophore activity, probably furnishing a portal entry for ions at the water-membrane interface.9, 9(a), 9(b)

These promising results prompted us to explore other variants of functionalized CyPLOS, exhibiting diverse structural motifs useful for ion recognition. We here describe novel polycyclic derivative 3 (Fig. 3), carrying a cyclic phosphate-linked disaccharide skeleton fused to two 18-crown-6 units, which potentially offer additional complexing sites, thus contributing to the ionophore properties of the macrocycle.10, 10(a), 10(b) Attachment of these moieties to the vicinal OH groups of a glucoside scaffold was considered to introduce only marginal rigidification into the crown ether backbone, thus leaving the six oxygen atoms in the cavity of each 18-crown-6 unit with optimal orientation to host cations.

Under the assumption that the binding abilities of the crown ether residues in derivative 3 are preserved, if two monopositive ions are bound, this compound results in an electrically neutral, internal salt, which could be spatially organized into a peculiar molecular architecture.

Section snippets

Synthesis

We reasoned that treatment of 4,6-benzylidene protected glucoside 4 ⁸ with a small excess of penta(ethylene glycol) ditosylate in the presence of a strong base as sodium or potassium hydride, i.e. under classical Williamson reaction conditions, would preferentially lead to the formation of the desired 18-crown-6 containing derivative. In fact, assuming the alkylation on the 2-OH group as the first event, the close proximity of the 3-OH associated with the template effect of the metal ion (Na⁺

Conclusions

A novel C₂-symmetric basket-shaped macrocycle with a central phosphate-linked disaccharide skeleton, decorated with two 18-crown-6 ether moieties (crown-CyPLOS), has been prepared in 11 steps with 23% yields. Conformational preferences in solution of the bis-crown ether-fused compound have been investigated by a detailed NMR analysis, suggesting that the supramolecular capacities of the crown ethers into this macrocycle can be dramatically enhanced by the close interaction with negatively

Materials and methods

TLC analyses were carried out on silica gel plates from Merck (60, F254). Reaction products on TLC plates were visualized by UV light and then by treatment with a 10% Ce(SO₄)₂/H₂SO₄ aqueous solution. For column chromatography, silica gel from Merck (Kieselgel 40, 0.063–0.200 mm) was used. HPLC analyses were performed on a Beckman System Gold instrument equipped with a UV detector module 166 and a Shimadzu Chromatopac C-R6A integrator. By HPLC analysis on a Nucleosil 100–5C18 Supelco analytical

Acknowledgements

We thank MIUR (PRIN) for grants in support of this investigation and Centro di Metodologie Chimico-Fisiche (CIMCF), Università di Napoli ‘Federico II’, for the MS and NMR facilities. We also thank prof. Paolo Tecilla, from Università di Trieste, Italy, for the transmembrane ion transport assays.

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Synthesis and conformational analysis of a novel carbohydrate-fused bis-crown ether: crown-CyPLOS

Abstract

Graphical abstract

Introduction

Section snippets

Synthesis

Conclusions

Materials and methods

Acknowledgements

Chem.—Eur. J.

Org. Lett.

Angew. Chem., Int. Ed.

Biochem. Biophys. Res. Commun.

J. Am. Chem. Soc.

J. Am. Chem. Soc.

J. Org. Chem.

Tetrahedron

Chem. Rev.

J. Chem. Soc., Perkin Trans. 2

Org. Biomol. Chem.

J. Chem. Soc., Perkin Trans. 2

New J. Chem.

J. Incl. Phenom. Macrocycl. Chem.

Tetrahedron

Tetrahedron Lett.

J. Chem. Soc., Perkin Trans. 2

Tetrahedron Lett.

Chem.—Eur. J.

Tetrahedron Lett.

Org. Lett.

Chem.—Eur. J.

J. Org. Chem.