In 2012 we celebrate the 125th anniversary of the unique molecule Tröger's base (TB), first synthesized by Julius Tröger in 1887. Being a V‐shaped C2‐symmetric chiral molecule, it possesses many interesting features. The TB field was reopened in 1985, when Craig S. Wilcox published the first crystallographic study of TB and described the synthesis and potential applications of TB analogues in supramolecular chemistry and in ligand design. This led to increasing interest in the development of synthetic methodology for TB analogues, initially for applications in the field of molecular recognition. In this review we give a short historical overview of TB and its chemical properties. In addition, we cover the fast progress in the development of synthetic methodologies to synthesize TB analogues that has taken place during recent decades. The functionalization of TB at almost any position in its skeleton is now possible and we discuss in detail recent developments in the functionalization of TB in the aromatic rings and in the methano bridge. The reopening of the functionalization of the diazocine ring itself is also discussed. In addition, progress in the synthesis of heterocyclic TB analogues and recent developments in the field of fused TB analogues are covered. The improvements in synthetic approaches have resulted in TB analogues with interesting properties that have inspired investigation of TB analogues in new fields of applications, among others as receptors, as molecular torsion balances, as ligands in asymmetric catalysis, as drug candidates, and as new materials for photo‐ and optical applications. The most recent developments in those fields are also discussed.

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The synthesis and characterization of all diastereomers of a linear symmetrically fused tris-Tröger's base analogue are described. The diastereomers are unambiguously assigned as syn-anti 1 a, anti-anti 1 b, and syn-syn 1 c isomers, by using X-ray diffraction analysis and NMR spectroscopy. For the first time, the anti-anti and the syn-syn diastereomers of a linear symmetrically fused tris-Tröger's base analogue have been synthesized. Molecules 1 a and 1 c are new cleft compounds and analysis of compound 1 a in the solid state shows inclusion of one molecule of CH(2)Cl(2) in the larger aromatic cleft, whereas in isomer 1 c disordered solvent molecules are trapped in the extended aromatic cleft. Furthermore, in the solid state, isomer 1 c forms infinite open channels along one of the crystallographic axes and perpendicular to this axis there are infinitely extending "wedged-ravines". Importantly, each of the diastereomers 1 a-c is resistant to inversion at the stereogenic nitrogen atoms under strongly and weakly acidic conditions in the range from room temperature (RT) to 95 degrees C. This observed configurational stability at the stereogenic nitrogens of 1 a-c is unique for analogues of Tröger's base in general to date. Finally, the ratio of cleft compounds 1 a and 1 c significantly increased relative to cavity compound 1 b when ammonium chloride was used as an additive in the Tröger's base condensation to 1 a-c suggesting a templating effect of the ammonium ion.

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.