Experimental and Computational Models for Side Chain Discrimination in Peptide-Protein Interactions.

A bis(18-crown-6) Tröger's base receptor and 4-substituted hepta-1,7-diyl bisammonium salt ligands have been used as a model system to study the interactions between non-polar side chains of peptides and an aromatic cavity of a protein. NMR titrations and NOESY/ROESY NMR spectroscopy were used to analyze the discrimination of the ligands by the receptor based on the substituent of the ligand, both quantitatively (free binding energies) and qualitatively (conformations). The analysis showed that an all-anti conformation of the heptane chain was preferred for most of the ligands, both free and when bound to the receptor, and that for all of the receptor-ligand complexes, the substituent was located inside or partly inside of the aromatic cavity of the receptor. We estimated the free binding energy of a methyl- and a phenyl group to an aromatic cavity, via CH-π, and combined aromatic CH-π and π-π interactions to be -1.7 and -3.3 kJ mol-1 , respectively. The experimental results were used to assess the accuracy of different computational methods, including molecular mechanics (MM) and density functional theory (DFT) methods, showing that MM was superior.

A Protocol for the exo-Mono and exo,exo-Bis Functionalization of the Diazocine Ring of Tröger's Base.

An efficient protocol has been developed for the exo-mono and exo,exo-bis functionalization of Tröger's base in the benzylic 6 and 12 positions of the diazocine ring. The lithiation of Tröger's base using s-BuLi/TMEDA followed by electrophilic quench affords exo-mono- and exo,exo-bis-substituted derivatives of Tröger's base in good to excellent yields. The variation of the number of equivalents of s-BuLi/TMEDA and the order of addition of the electrophile strongly govern the outcome of the reaction for each electrophile.

Substrate-selective catalysis.

Substrate selectivity is an important output function for the validation of different enzyme models, catalytic cavity compounds, and reaction mechanisms as demonstrated in this review. In contrast to stereo-, regio-, and chemoselective catalysis, the field of substrate-selective catalysis is under-researched and has to date generated only a few, but important, industrial applications. This review points out the broad spectrum of different reaction types that have been investigated in substrate-selective catalysis. The present review is the first one covering substrate-selective catalysis and deals with reactions in which the substrates involved have the same reacting functionality and the catalysts is used in catalytic or in stoichiometric amounts. The review covers real substrate-selective catalysis, thus only including cases in which substrate-selective catalysis has been observed in competition between substrates.

Tröger's base twisted amides: endo functionalization and synthesis of an inverted crown ether.

Taking advantage of the unconventional reactivity of twisted mono- and bis-amides of Tröger's base (TB), rac-6 and rac-7, respectively, the first synthesis of a 6-endo-monosubstituted TB analogue, rac-9, and the first rational synthesis of a 6,12-endo,endo-disubstituted TB analogue, rac-11, have been achieved. The bis-TB crown ether, meso-13, was prepared starting from rac-7. Meso-13 constitutes a rare example of a crown ether with an inverted methylene bridge-to-bridge bis-TB conformation both in solution and in the solid state, resulting in a reluctance to act as a receptor for cations.