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.

No abstract

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.

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.

Monoamino and diamino analogues of Tröger's base have been synthesized by palladium-catalyzed aminations of the corresponding dihalo analogues using low catalyst loadings. Depending on the nature of the dihalo analogue (Br or I), catalyst loading and the scale of the reaction, monoamino-monohalo and/or diamino analogues of Tröger's base were obtained. Tröger's base, 2,8-dimethyl-6H, 12H-5,11-methanodibenzo[b,f][1,5]diazocine (1; Figure 1), has drawn the attention of chemists over the years due to the presence of a concave V-shaped aromatic surface and because of its inherent dissymmetry arising from the presence of stereogenic nitrogen atoms in a rigid frame. 1 These properties have rendered the Tröger's base framework an attractive building block for applications in the field of molecular recognition and in supramolecular chemistry, but analogues have also been used as enzyme inhibitors, ligands in asymmetric synthesis, as torsional balances to determine weak intermolecular forces and as functionalized fullerene analogues. 2 To the class of Tröger's base analogues has recently been added metallomacrocycles and a-amino acids. 3 (1) The synthesis of analogues of Tröger's base has been hampered by the lack of a general methodology with which to functionalize the Tröger's base core. In particular, it had been argued that the Tröger's base condensation reaction, the condensation between anilines and formaldehyde under acidic conditions, was hampered by the presence of electron-withdrawing substituents in the corresponding anilines. 4 A few years ago we discovered that halogenated analogues of Tröger's base could be synthesized using trifluoroacetic acid (TFA) and paraformaldehyde under controlled reaction conditions. 5 The reaction has been optimized for larger scale preparation, initially by us 6 and later by Sergeyev and Diederich 7 as well as by Bew. 3b The advent of dihalo-substituted analogues of Tröger's base has allowed further functionalization of the Tröger's base core by two different methodologies. One methodology involves either a single or double halogen-lithium exchange reaction followed by quenching with various electrophiles, producing asymmetric and dissymmetric Tröger's base analogues. 8,9 The second methodology uses the difunctionalization of dihalo analogues of Tröger's base by cross-coupling strategies and was first introduced by us on this system 5a and further developed by us and others. Such approaches include: Corriu-Kumada cross-coupling, 5a the Sonogashira reaction, 10a,b Suzuki, 10b-d Stille, 10c Negishi 10c cross-couplings, and palladium-catalyzed cyanations 10d and coppercatalyzed amidations. 10d Figure 1 Tröger's baseIn a project devoted to the synthesis and study of fused analogues of Tröger's bases as cleft compounds, 11 we became interested in the synthesis of 2-amino-8-bromo analogues of Tröger's base. Thus, following our single halogen-lithium exchange desymmetrization protocol mentioned above, the 2,8-dibromo analogues of Tröger's base 2 11b (0.9 mmol) and 3 5a,6 (3.2 mmol), were...

The 125 th Anniversary of the Troeger's Base Molecule: Synthesis and Applications of Troeger's Base Analogues -[124 refs.]. -(RUNARSSON, O. V.; ARTACHO, J.; WAERNMARK*, K.; Eur. J. Org. Chem. 2012, 36, 7015-7041, http://dx.doi.org/10.1002/ejoc.201201249 ; Dep. Chem., Univ. Lund, S-221 00 Lund, Swed.; Eng.) -Nuesgen 16-222

A Protocol for the exo-Mono and exo,exo-Bis Functionalization of the Diazocine Ring of Troeger's Base. -The direct addition method presented renders possible the access to the desired product types (III) and (IV). Inverse addition allows an increase of moderate yields. -(DAWAIGHER, S.; MAANSSON, K.; ASCIC, E.; ARTACHO, J.; MAARTENSSON, R.; LOGANATHAN, N.; WENDT, O. F.; HARMATA, M.; SNIECKUS, V.; WAERNMARK*, K.; J. Org. Chem. 80 (2015) 24, 12006-12014, http://dx.doi.org/10.1021/acs.joc.5b01921 ; Dep. Chem., Lund Univ., S-221 00 Lund, Swed.; Eng.) -Lehmann 18-176