Staudinger ligation towards cyclodextrin dimers in aqueous/organic media. Synthesis, conformations and guest-encapsulation ability

Abstract

Summaryβ-Cyclodextrin (β-CD) dimers have been prepared using the bioorthogonal Staudinger ligation for the first time. In addition to a known linker, methyl 2-(diphenylphosphanyl)terephthalate, a doubly active linker was specifically developed that enabled connection of two β-CD units in a single step and in aqueous/organic media, under mild conditions and with good yields. A three-carbon spacer between the β-CD torus and the azido group was required for facile dimer formation. The products, as studied by NMR spectroscopy, were found to adopt closed conformations by intramolecular self-inclusion. On the other hand, association via intermolecular binding was also observed in aqueous solution, confirmed by DOSY NMR experiments. Despite self-inclusion, the β-CD cavities were capable of guest encapsulation, as shown by titration experiments: the binding constant with 1-adamantylamine was similar to that of natural β-CD. Theoretical calculations for isolated molecules (PM3 level of theory) and in the presence of solvent [water, PM3(COSMO)] as well as DFT calculations suggested that the compounds prefer to adopt conformations which bring the phenyl groups either inside the β-CD cavity (inclusion) or over its narrow side (vicinal). Thus, Staudinger ligation could be the method of choice for linking CDs exhibiting (i) ease of preparation in aqueous media, in short steps, under mild conditions and in good yields, (ii) satisfactory aqueous solubility and independent binding capacity of the cavities.

The Staudinger Ligation

“…In some cases, in particular with anomeric sugar azides, different solvents gave rise to variable diastereomeric ratios . Besides, the pH dependence has been demonstrated in several communications. − , …”

“…274 Besides, the pH dependence has been demonstrated in several communications. [150][151][152][153][154][155][156][157]275 Additives are in general not required for the Staudinger Ligation. It should be mentioned at this point that most aliphatic phosphanes are oxygen-sensitive, hence in nonbiological systems exclusion of oxygen is envisaged.…”

Bioorthogonal Reactions of Triarylphosphines and Related Analogues

“…Gold nanoparticles have also been functionalized with oligopeptide, fluorogenic dyes, and targeting elements via phosphine-azide chemistry. ,, One recent example combined the Staudinger ligation with other bioorthogonal reactions to attach multiple probes to nanoparticle surfaces . Organic azides and phosphine reagents have further been used to craft oligosaccharide drug delivery vectors and other polymers. − …”