Enantiomerically pure cyclohexylhemicucurbit[8]uril (cycHC[8]), possessing a barrel-shaped cavity, has been prepared in high yield on a gram scale from either (R,R,N,N')-cyclohex-1,2-diylurea and formaldehyde or cycHC[6]. In either case, a dynamic covalent library is first generated from which the desired cycHC can be amplified using a suitable anion template.

Chiral (all-R)-cyclohexanohemicucurbit[8]uril binds anions in a 1 : 1 ratio in pure methanol like a molecular Pac-Man™ with remarkable selectivity based on the size, shape and charge distribution of the anion.

A computational study of (all-S)-cyclohexylhemicucurbit[6]uril and its complexes with anions (Cl(-), Br(-), I(-) and HCOO(-)), the proton (H(+)) and non-dissociated acid (HCl, HBr, HI and HCOOH) guests was performed. The geometries of guest-host complexes were optimized via density functional theory using the BP86 functional, SV(P) basis set and Stuttgart pseudopotentials for iodide. Binding affinities and their trends were evaluated at the BP86/TZVPD level of theory. In addition, the quantum theory of atoms in molecules was used to gain insight into guest-host interactions. A computational study in the gas phase and ion-mobility mass-spectrometry analysis revealed that the studied macrocycle formed inclusion complexes with anions. Protonation of the macrocycle is preferred at the nitrogen atom pointing inside of the cavity. In the studied conditions, non-dissociated acids formed complexes at the oxygen atom pointing outside of the macrocycle.

3-Chlorooxoindoles have emerged as versatile precursors in the synthesis of spirocyclopropyl oxindoles. High enantio-and diastereoselectivity was attained under conditions of both iminium/enamine and H-bonding catalysis.Keywords: asymmetric synthesis; organocatalysis; oxindoles; spiro compounds Spirocyclic oxindole scaffolds in recent years have continued to draw attention as important and challenging structural motifs featuring in many natural and synthetic compounds. [1][2][3] The core structure can be found in many bioactive molecules exhibiting a diverse range of biological activities. For instance, spirooxindole 1 showed nanomolar activity as an HIV-1 non-nucleoside reverse transcriptase inhibitor, [4,5] whereas compounds of type 2 exhibited promising antitumor activity [6,7] and were also effective for the treatment of obesity and diabetes ( Figure 1). [8] It is worth noting that the compounds in question were tested as racemates, making them highly desirable targets for asymmetric synthesis and subsequent biological evaluation in the enantiopure form. Recently, spiroindolone 3 showed good antimalarial activity at low nanomolar concentrations making this class of compounds potential drug candidates against malaria.[9]Generation of a chiral quaternary center at the 3-position of the oxindole ring remains a major challenge in the synthesis of spirooxindoles. Furthermore, it is often followed by sequential formation of arrays of other quaternary/tertiary centers, adding to the complexity of diastereo-and enantioselective synthesis. In general, the construction of even a single quaternary center is considered a challenge in asymmetric synthesis. [10] Organocatalytic asymmetric cascades represent a promising strategy for the formation of spirooxindoles with efficient diastereo-and enantiocontrol, as the chirality generated in the first step of the sequence further influences the formation of the adjacent centers.Currently, there are two main organocatalytic strategies for setting up a spiro stereocenter at the 3-position of the oxindole ring. The first one relies on Michael addition to exocyclic a,b-unsaturated oxindoles followed by spirocyclization. [11][12][13][14][15] Alternatively, the nucleophilicity of C-3 of oxindoles as enhanced by an electron-withdrawing group at this position, is exploited. The latter approach was recently employed by Melchiorre et al. [16] in a cascade addition of 3-hydroxyoxindoles to unsaturated aldehydes leading to spirolactones, and by us [17] using 3-chlorooxindoles. It is worth noting that 3-hydroxyoxindoles experienced a rather poor diastereocontrol resulting in nearly equimolar quantities of two diastereoisomers. [18] The dual nucleophilic/electrophilic character of C-3 in 3-chlorooxindoles 7 provides an excellent opportunity for constructing an all-carbon quaternary center at this position by organocatalytic cascade reactions.

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