Supplementing bicyclic guanidinium anion receptors with four sec-carboxamido groups leads to enhanced affinity for oxoanions, however, for a different reason than originally planned. Calorimetric analysis reveals that better binding is due to higher association entropies rather than more negative enthalpies. Thus, molecular design following geometric and functional complementarity principles may misguide supramolecular constructions aimed at a unique host-guest binding mode, as required, e.g., by self-assembly or catalysis.

[reaction: see text] Supramolecular enantiodifferentiation was studied by isothermal titration calorimetry in an effort to address the order-disorder distinction in the diastereomeric complexes formed from a chiral macrocyclic host and enantiomeric carboxylates. As a result, the association entropy component TDeltaS emerged as an indicator in the enantioselection of tartrate 14 and aspartate 15 by the macrocycle 13 containing two guanidinium anchor groups connected to each other by four urea units. The parent monotopic guanidinium compounds 1 or 2 did not show any enantioselection for chiral carboxylates.

A novel synthetic route to the versatile chiral bicyclic guanidinium building block is described making use of l-methionine as a starting material from the natural chiral pool. Furthermore, the synthetic elaboration of this building block is shown in the construction of macrocyclic and open chain hosts, respectively. The host design employs urea functions as the connecting units and supplementary anchor groups for the complexation of anions. The binding studies of these hosts with various chiral and achiral oxoanions are performed by isothermal titration calorimetry. A trend analysis of the binding energetics in an ensemble of structurally similar guests discloses the importance of geometrical confinement of the guest. Association entropy rather than free energy (affinity) is identified as an indicator of structural uniqueness needed to distinguish configurational isomers in the recognition of enantiomeric carboxylates by the chiral guanidinium hosts.

The bicyclic hexahydropyrimidino[1,2a]pyrimidine cationic scaffold has a well-known capacity to bind a variety of oxoanions (phosphates, carboxylates, squarates, phosphinates). Based on this feature, the parent host was supplemented with sec-carboxamido substituents to generate compounds 1-3 in an effort to improve the anion-binding affinity and selectivity and to learn about the role and magnitude of entropic factors. Bicyclic guanidinium compounds were prepared by a convergent strategy via the corresponding tetraester 22 followed by catalytic amidation. Host-guest binding studies with isothermal titration calorimetry in acetonitrile probed the behavior of artificial hosts 1-3 in comparison with the tetraallylguanidinium compound 4 on binding p-nitrobenzoate, dihydrogenphosphate, and 2,2'-bisphenolcyclophosphate guests that showed enhanced affinities in the 10(5)-10(6) M(-1) range. Contrary to expectation, better binding emerges from more positive association entropies rather than from stronger enthalpic interactions (hydrogen bonding). In an NMR spectroscopy titration in DMSO, o-phthalate was sufficiently basic to abstract a proton from the guanidinium function, as confirmed by an X-ray crystal structure of the product. The novel carboxamide-appended anchor groups also bind carboxylates and phosphates, but not hydrogen sulfate in methanol with affinities in excess of 10(4) M(-1). The energetic signature of the complexation in methanol is inverted with respect to acetonitrile solvent and shows a pattern of general ion pairing with strong positive entropies overcompensating endothermic binding enthalpies. This study provides an example of the fact that bona fide decoration of a parent guanidinium anchor function with an additional binding functionality may provide the desired enhancement of the host-guest affinity, yet for a different reason than that implemented by design as guided by standard molecular modeling.

A synthetic sequence to the benzonaphthyridinone framework is described. The key step is a one-pot, base-catalyzed vicarious nucleophilic substitution followed by ring closure. Additionally, the synthesis represents the application of a vicarious nucleophilic substitution in the total synthesis of a cytotoxic aaptamine derivative.