Michał Wierzbicki

Dynamic Formation of Hybrid Peptidic Capsules by Chiral Self‐Sorting and Self‐Assembly

Owing to their versatility and biocompatibility, peptide-based self-assembled structures constitute valuable targets for complex functional designs. It is now shown that artificial capsules based on β-barrel binding motifs can be obtained by means of dynamic covalent chemistry (DCC) and self-assembly. Short peptides (up to tetrapeptides) are reversibly attached to resorcinarene scaffolds. Peptidic capsules are thus selectively formed in either a heterochiral or a homochiral way by simultaneous and spontaneous processes, involving chiral sorting, tautomerization, diastereoselective induction of inherent chirality, and chiral self-assembly. Self-assembly is shown to direct the regioselectivity of reversible chemical reactions. It is also responsible for shifting the tautomeric equilibrium for one of the homochiral capsules. Two different tautomers (keto-enamine hemisphere and enol-imine hemisphere) are observed in this capsule, allowing the structure to adapt for self-assembly.

Mechanochemical Encapsulation of Fullerenes in Peptidic Containers Prepared by Dynamic Chiral Self‐Sorting and Self‐Assembly

Molecular capsules composed of amino acid or peptide derivatives connected to resorcin[4]arene scaffolds through acylhydrazone linkers have been synthesized using dynamic covalent chemistry (DCC) and hydrogen-bond-based self-assembly. The dynamic character of the linkers and the preference of the peptides towards self-assembly into β-barrel-type motifs lead to the spontaneous amplification of formation of homochiral capsules from mixtures of different substrates. The capsules have cavities of around 800 Å(3) and exhibit good kinetic stability. Although they retain their dynamic character, which allows processes such as chiral self-sorting and chiral self-assembly to operate with high fidelity, guest complexation is hindered in solution. However, the quantitative complexation of even very large guests, such as fullerene C60 or C70 , is possible through the utilization of reversible covalent bonds or the application of mechanochemical methods. The NMR spectra show the influence of the chiral environment on the symmetry of the fullerene molecules, which results in the differentiation of diastereotopic carbon atoms for C70 , and the X-ray structures provide unique information on the modes of peptide-fullerene interactions.

Inherently Chiral Iminoresorcinarenes through Regioselective Unidirectional Tautomerization

Tetraformylresorcin[4]arene is obtained in 48% yield via a chromatography-free Duff reaction. The formylated resorcinarene reacts easily with primary aliphatic and aromatic amines. The resulting imines exist exclusively in keto-enamine forms. Owing to a system of intramolecular hydrogen bonds, the reaction selectively leads to regioisomers with C4 symmetry. They possess an inherent chirality due to a propeller-like skeleton. For chiral amines, inherently chiral diastereoisomers are observed.

Enantioselective Diels–Alder reaction in the confined space of homochiral metal–organic frameworks

A novel homochiral porous metal–organic framework (MOF) has been synthesized using (R)-2,2′-dihydroxy-1,1′-binaphthyl-4,4′-dibenzoic acid as the chiral ligand. This MOF acts as an effective heterogeneous catalyst for the enantioselective Diels–Alder reaction between isoprene and N-ethyl maleimide.

Inherently chiral heterocyclic resorcinarenes using a Diels–Alder reaction

This paper presents a novel approach to highly diastereoselective synthesis of resorcinarenes having enlarged cavities. Inherently chiral heterocyclic resorcinarenes have been obtained with unusually high diastereoselecivity by a “one pot” sequence involving thermal generation of o-quinomethide resorcinarene derivatives and the subsequent Diels–Alder reaction with dienophiles (exemplified by α-methylstyrene). The diastereoselectivity of this reaction is explained based on the thermodynamic stability of the products. The enantiomers of rac-4 have been separated by HPLC and their absolute configuration was assigned by comparison of their experimental and theoretical CD spectra.

Experiences with applications of macromolecular tools in supramolecular crystallography

Supramolecular structures, with ever increasing size ranging from a few up to tens of nanometres, represent an intermediate stage between small molecules and biological macromolecules. Many crystal structures of these large supramolecular assemblies have been solved using dual space algorithms. However, supramolecular assemblies with a capsular shape present a particular challenge for crystallography, especially when they are chiral and composed of only light atoms. In this paper, we show that the application of “routine” macromolecular tools may be of great help in solving the crystal structures of supramolecular assemblies that are otherwise refractory to the routine methods of small molecule crystallography. Specifically, we have applied the method of molecular replacement as implemented in PHASER in order to solve the crystal structure of a chiral organic capsule, which could not be determined using direct or dual space methods. By utilizing various models consisting of well-defined supramolecular “bricks” or modelled structures, we show how model size (fraction of the asymmetric unit) and quality (root mean square deviation from target) influence the success rate of medium sized non-protein structures. The results indicate that supramolecular structures, that are still “small molecules” for macromolecular standards, can be successfully solved using even very small models, down to 25% by weight of the contents of the asymmetric unit.

Chiral Calixarenes and Resorcinarenes

Since the first synthesis of chiral calixarenes in 1979 by Gutsche enormous progress has been made in preparation techniques and applications. Many chiral calixarenes (including resorcinarenes and homocalixarenes) modified with peptides, carbohydrates, chiral amines or axially chiral groups are known. Due to their diverse conformational features, introduction of chirality into a calixarene platform is not only limited to classical chirality based on carbon stereogenic centers but also can be introduced by asymmetric/dissymmetric substitution pattern or in a non-covalent way. The main driving force for the development of chiral calixarenes is the possibility to use them as enantioselective synthetic receptors. Effective chiral receptors based on calixarenes have found applications in recognition of chiral guests in solution, as chromatography stationary phases, enantioselective membrane carriers and catalysts. Their potential has also been demonstrated in interactions with biological molecules, including protein recognition, formation of gels and antimicrobial activity. The chapter summarizes the current achievements in the field with the special emphasis on unique features of calixarenes and resorcinarenes leading to “non-classical” chirality and functionality based on chiral recognition.

The Inverse Demand Oxa-Diels–Alder Reaction of Resorcinarenes: An Experimental and Theoretical Analysis of Regioselectivity and Diastereoselectivity

The Diels-Alder reaction enables introduction of new functionalities onto the resorcinarene skeleton with simultaneous generation of new stereogenic centers and expansion of the internal cavity. We present highly regio- and diastereoselective inverse electron demand oxa-Diels-Alder reactions of resorcinarene ortho-quinone methide with benzofuran and indene, each generating 12 new stereogenic centers. The mechanism and reasons for regioselectivity and diastereoselectivity were analyzed using theoretical calculations (NBO charges, Fukui functions, transition state energies, and thermodynamic stability of the products). Enantiomers were separated, and their configurations were determined by comparison of experimental and theoretical electronic circular dichroism spectra.