Anion-π interactions have been systematically studied using tetraoxacalix[2]arene[2]triazine 1, an electron-deficient and cavity self-tunable macrocyclic host, as an electron-neutral molecular probe. As revealed by electrospray ionization mass spectrometry (ESI-MS), fluorescence titration and X-ray crystallography, tetraoxacalix[2]arene[2]triazine has been found to form 1:1 complexes with four typical polyatomic anions of different geometries and shapes in the gaseous phase, in solution, and in the solid state. The association constants for the formation of anion-π complexes in acetonitrile are in the range of 239 to 16950 M(-1), following the order of 1·NO(3)(-) > 1·BF(4)(-) > 1·PF(6)(-) > 1·SCN(-). X-ray molecular structures of the complexes showed that two opposing triazine rings of tetraoxacalix[2]arene[2]triazine act as a pair of tweezers to interact with the included anions through cooperative anion-π and lone-pair electron-π interactions. The generality of anion-π interactions and diverse anion-π interaction motifs can provide a new dimension in the study of molecular recognition and self-assembly. Moreover, this study potentiates the effect of anion-π interactions in chemical and biological systems, especially those involving anion and electron-deficient aromatic species.

The Passerini three-component (P-3CR) and the Ugi four-component (U-4CR) are two of the most prominent isocyanide-based multicomponent reactions (IMCRs). The P-3CR transforms isocyanides, aldehydes (ketones), and carboxylic acids to α-acyloxy carboxamides, while the U-4CR converts isocyanides, aldehydes (ketones), amines, and carboxylic acids to α-acetamido carboxamides. Conversion of the high energy formal divalent isocyano carbon into a tetravalent amide carbonyl carbon provides the driving force for these reactions. While the prototypical P-3CR and U-4CR provide linear adducts, many heterocycles and macrocycles are now readily synthesized by modifying these truly versatile reactions. As one stereocenter is generated by the nucleophilic addition of the isocyanide to the carbonyl and imine functions, the search for enantioselective versions of these reactions has become a much sought after goal among synthetic chemists. This seemingly trivial endeavor turns out to be extremely difficult to achieve, in sharp contrast to the remarkable progress documented in the field of asymmetric synthesis in general and catalytic enantioselective nucleophilic addition to C═X bond in particular. Since Denmark's first report in 2003 on the catalytic enantioselective Passerini two-component reaction of isocyanides with aldehydes, several Lewis acid (LA) and Brønsted acid-catalyzed enantioselective protocols have been developed. However, it is fair to say that truly catalytic enantioselective P-3CR and U-4CR with wide application scope remain elusive. In this Account, we summarize the progress recorded in this field over the past 15 years. We entered the field by investigating the enantioselective reaction of α-isocyanoacetamides with aldehydes and imines, which was previously developed in our lab for the synthesis of functionalized 5-aminooxazoles. Our initial experimental results, in conjunction with Dömling's and Schreiber's earlier findings, prompted us to assume that the low turnover number in LA-catalyzed asymmetric IMCRs is a main hurdle for enantioselectivity. We speculated that the LA incapable of forming chelates would be the catalyst of choice for enantioselectivity, the rational being that the P-3CR and the U-4CR afforded bidentate intermediates (α-hydroxy imidates, α-amino imidates) and products (α-acyloxy carboxamides, α-acetamido carboxamides) from nonchelating inputs. Therefore, the transfer of catalyst from these chelating intermediates or products to the monocoordinating starting materials would be difficult, hence the problem with catalyst turnover. This working hypothesis turned out to be a valuable guide that allowed us to develop Al-salen and Al-phosphate-catalyzed enantioselective P-3CR and enantioselective construction of chiral heterocycles such as oxazoles and tetrazoles. Nevertheless, all our attempts to apply these LA catalysts to the Ugi reaction failed. Indeed, to date, no reports on the successful LA-catalyzed asymmetric Ugi-type reactions exist in the literature. However, significant progress has bee...