Access to Versatile β‐Cyclodextrin Scaffolds through Guest‐Mediated Monoacylation

Abstract

Herein, we report the selective mono-derivatization of heptakis[6-deoxy-6-(2-aminoethylsulfanyl)]-β-CD (1) through a guest-mediated covalent capture strategy. The use of guests functionalized with cleavable linkers enables the installation of an amine-orthogonal thiol group on the primary rim of 1 as a handle for further transformations to the β-CD scaffold. Applying this methodology, two novel monoderivatized β-CDs were obtained in good yield and high purity. Both of these monoacylated CDs were amenable to facile linker cleavage and further modification at the resulting thiol group. This methodology can be applied towards the synthesis heterofunctionalized β-CD constructs for analyte sensing, drug delivery, and other applications.

Highly Functionalized β‐Cyclodextrins by Solid‐Supported Synthesis

“…Comparison of the initial rates of release of 4‐hydroxybenzoic acid (A 280 ) in the presence of CD‐ 1 or ethylenediamine, at an equivalent concentration to the amines of CD‐ 1 , gave an effective amine concentration of 60 m m for the CD– 1:5 complex (Figure S6, Table S3). Although this effective concentration is lower than that of the CD‐ 1:2 complex (540 m m ) it is evidently sufficient to allow for selective acylation . In the presence of competing guests (adamantane carboxylate, DEAC, or phenylacetic acid) the reaction rate was reduced, consistent with complex formation prior to acylation (Figures S7, S8, Table S4, S5).…”

“…We previously reported the application of DEAC guest 2 for the mono‐acylation of CD 1 . Although the strategy was highly selective, the low stability of guest 2 presented a challenge.…”

“…CD 1 also features an extended hydrophobic cavity with improved guest binding over native β‐CD . The high affinity interaction of CD 1 with N , N ‐4‐diethylaminocoumarin‐3‐carboxylic acid (DEAC) ( K a =2.7×10 6 m −1 , 50 m m phosphate, pH 7.5) served as the basis of a covalent capture strategy to mono‐functionalize an amine of CD 1 . We established that this route could be used to install a thiol group on CD 1 with exquisite selectivity and good yield.…”

“… Previously reported synthesis of mono‐acylated CD 4 . Proposed SPS methodology to functionalize the primary rim amines and thiol of CD 4 .…”

Modular core-shell polymeric nanoparticles mimicking viral structures for vaccination

“…The synthesis procedure of 3-((2-azidoethyl)disulfanyl)propanoic acid was based on a previous study (Scheme S2) [27]. In detail, 1,2-bis (2-azidoethyl) disulfane (1.9 g, 9.3 mmol) was dissolved in methanol (100 mL) and cooled in an ice bath.…”