Addressing selectivity challenges by utilizing the xexameric resorcin[4]arene capsule

In recent decades, the development of supramolecular cage and capsule catalysis has allowed impressive deviations in selectivities from the usual solution chemistry. Moreover, examples have been discovered in which artificial catalysts mimic the biosynthetic processes previously unachieved by small-molecule catalysis. A particularly interesting supramolecular assembly for which versatile applications, including catalytic ones, have already been found is the hexameric resorcin[4]arene capsule I.
This thesis contributes to a deeper understanding of the selectivity, mechanism, and limitations of catalysis within I. Specifically, the terpene cyclization of resilphiperfolan-1-β-ol and the proton wire-catalyzed nucleophilic substitution method, which is particularly suited for glycosylation chemistry, were addressed. In addition to the determination of a size limit for this type of terpene synthesis within the capsule, alternative functionalized substrates were tested for the preparation of derivatives of the natural product.
The mechanistic hypothesis for the glycosylation within I was scrutinized specifically with a focus on the different reactivity of the two main electrophile families, the pyranosyl and furanosyl donors. It turns out that, indeed, while pyranosylation occurs by the SN2 mechanism, furanosylation most likely proceeds via the SN1 pathway and therefore yields predominantly good results even with weaker nucleophiles, such as the hydroxyl groups of threonine and serine. In contrast, pyranosylation is more restricted in this respect. Moreover, the remarkably continuous catalyst turnover observed for this bimolecular fusion reaction was attributed to the absence of product inhibition, which is due to the generally very poor binding of glycosides to the capsular catalyst. Furthermore, a sensitivity study on the standard conditions of this methodology was performed and the solvent scope was extended to more sustainable and environmentally friendly variants. Ultimately, the upper limit of the tolerated substrate size was quantified for the capsule-catalyzed glycosylation. Non-glycosylic electrophiles turned out to be less effective substrates for the proton wire-promoted substitution, as only low product yields were obtained with a strong nucleophile.
Another project was dedicated to the induction of regioselectivity in the previously reported Friedel-Crafts benzylation within I. As all selected target nucleophiles are aromatic drug compounds with high annual sales figures, a single example featuring high selectivity could be impactful. Only in one case, benzylation was achieved, and the selectivity was poor. On the other hand, an unusual isomerization process was observed with Tadalafil, and some other acidpromoted side reactions were identified in Tolvaptan and Atorvastatin.
Ultimately, the development of an unprecedented synthetic methodology for macrolactones based on supramolecular capsule chemistry was investigated. The resorcin[4]arene capsule lacked any productive influences on classical esterification methods such as the Steglich, the Mukaiyama, as well as the Corey-Nicolaou approaches. In contrast, I exerted a slightly positive effect for the Brønsted acid-catalyzed attempts, specifically when utilizing p-toluene- and naphthalene-2-sulfonic acid. Nevertheless, only poor product selectivity has generally been observed for the desired macrolactone. It should be noted that the application of this method in the current state is therefore hardly sensible.