Synthesis, resolution, and absolute configuration of difunctionalized Tröger's base derivatives

Two racemic derivatives of Tr?ger's base, the 2,8-diboronic acid ester 6 and the 3,9-dibromo-substituted derivative 5, were synthesized and successfully resolved by HPLC on a chiral stationary Whelk-01 phase on a semipreparative scale, thereby giving rise to both enantiomers in a pure form. These functionalized C(2)-symmetric building blocks are valuable precursors for a variety of further applications. Their absolute configurations were determined by comparison of their quantum chemically calculated CD and UV/Vis spectra with the experimental ones and were independently confirmed by X-ray diffraction analysis.     

Synthesis of functionalized chiral carbocyclic cleft molecules complementary to Tröger's base derivatives

The synthesis of optically pure functionalized cleft molecules derived from dibenzobicyclo[b,f][3.3.1]nona-5a,6a-diene-6,12-dione is reported. These clefts are reminiscent of Tr?ger's base but contain clefts with different dimensions and additional carbonyl (or alcohol) groups that may be utilized in molecular recognition studies. The 2,8-dimethyl and 2,8-dibromo derivatives were synthesized via an intramolecular Friedel-Crafts acylation and were resolved by chiral HPLC. The 2,8-dinitro derivative was prepared by regiospecific nitration of dibenzobicyclo[b,f][3.3.1]nona-5a, 6a-diene-6,12-dione. The dibromo and dinitro derivatives allow direct access to a range of functionalized molecular clefts. Palladium-catalyzed coupling of the dibromo derivative afforded the disubstituted phenyl, anisole, and acetylene derivatives, while reduction of the dinitro derivative and acetylation provided amino-dione and amide-hydroxyl derivatives. X-ray crystal structures of the dimethyl 12, dibromo 13, di(p-methoxyphenyl) 16, dinitro 18, and dimethyl dinitro 22 derivatives show cleft angles between the planes between the aromatic rings of 84-104 degrees. The synthetic route, structural features, and potential for molecular recognition studies of this class of clefts are compared with those of the more widely studied Tr?ger's base cleft molecules.     

Theoretical investigation of Raman optical activity signatures of Tröger's base

The Raman and VROA spectra of (S,S)-Tr?ger's base are simulated. We mainly discuss the peaks in the 1140-1400 cm(-1) wavenumber range where an intense VROA signature is found. In this range, nearly all of the Raman-active bands belong to the irreducible representation A (C(2) point group), whereas no such observation is made for the VROA spectrum. The vibrational normal modes associated with the peaks in this range mainly consist of wagging and twisting motions of the hydrogen atoms. From the atomic contribution patterns (ACPs) and the group coupling matrices (GCMs), one finds that the VROA backward-scattering intensities mainly arise from hydrogen and carbon atoms in the vicinity of the two chiral nitrogen atoms. The VROA signatures in the 1140-1400 cm(-1) range are therefore a fingerprint of the local chirality around the two chiral nitrogen centers.     

Charge transfer properties of Tröger base derivatives

Two triarylamine centers bridged through an aliphatic bridge feature unexpected charge transfer properties, bearing an important electronic coupling between them in the absence of a π linker; EPR, electrochemistry, electronic spectroscopy and first principles molecular calculations are combined to study the electronic structure of this compound.     

Metallomacrocycles incorporating a hemilabile Tröger's base derived ligand

Tr?ger's base, a chiral molecule with a rigid 90 degrees backbone, has been incorporated into a novel hemilabile phosphinoalkyl thioether ligand. Using the Weak Link Approach, this ligand has been reacted with Cu(CH3CN)4PF6 and [Rh(COE)2Cl]x (COE = cyclooctene) to form metallomacrocycles. Upon reaction of the ligand with Cu(I), which prefers a tetrahedral coordination geometry, a bimetallic macrocycle was formed. Alternatively, owing to the steric restrictions imposed by the 90 degrees backbone of the ligand and the square-planar geometry of Rh(I), when the ligand was reacted with [Rh(COE)2Cl]x, the formation of bimetallic closed macrocycles was not observed, and instead a mixture of tri- and tetrametallic closed macrocycles is formed. Introducing pyridine to the Cu(I) complex causes the weak thioether-Cu bonds to break, generating a large bimetallic open macrocycle. Upon reaction of the mixture of Rh(I) metallomacrocycles with CO and Cl-, the cyclic structure of these complexes becomes flexible enough that the dimeric bimetallic macrocycle forms, along with tri- and tetrameric open complexes. The mixture of differently sized Rh(I) macrocyclic complexes has been analyzed using gel permeation chromatography, and the tetramer has been characterized by a single-crystal X-ray diffraction study. These are the first examples of metallomacrocycles containing a Tr?ger's base derivative.     

Optimization of a hybrid chromatography-crystallization process for the separation of Tröger's base enantiomers

This paper presents an analysis of a hybrid process consisting of simulated moving bed (SMB) chromatography and crystallization and studies its performance for the separation of the Tr?ger's base enantiomers. The SMB is simulated using a detailed model including column efficiency, thus, implying a proper evaluation of the effect of column size on column efficiency and separation performance. The crystallization operations are accounted for through material balances, assuming equilibrium between enantiopure crystals and mother liquor. A genetic algorithm is used to optimize the combined process, using proper definitions of objective functions. Multi-objective optimization of this hybrid process for productivity and evaporation cost in terms of operating parameters, column length, and SMB feed concentration shows an optimum SMB purity value as a trade off between increased SMB performance and recycle of the mother liquor.     

The mechanism of Tröger's base formation probed by electrospray ionization mass spectrometry

Using direct infusion electrospray ionization mass and tandem mass spectrometric experiments [ESI-MS(/MS)], we have performed on-line monitoring of some reactions used to form Tr?ger's bases. Key intermediates, either as cationic species or as protonated forms of neutral species, have been intercepted and characterized. The role of urotropine as the methylene source in these reactions has also been accessed. Reaction pathways shown by ESI-MS(/MS) have been probed by gas-phase ion/molecule reactions, and an expanded mechanism for Tr?ger's base formation based on the mass spectrometric data has been elaborated.     

Synthesis and resolution of naphthyl-Tröger's base

A naphthyl analogue of Tröger's base {8H,16H-7,15-methanodinaphtho[2,1-b][2′,1′-f][1,5]-diazocine (NTB)} was prepared and successfully resolved using (−)- and (+)-di-p-toluoyl-tartaric acid. Enantiomers obtained show extremely high specific rotations related to (i) the rigid [1,5]-diazocine skeleton with molecular asymmetry and (ii) the presence of condensed aromatic rings, similar to helicenes.     

Stepwise Replication of a Tröger's Base Analogue

Redox-controlled covalent templating and macrocyclization underlie a novel scheme for stepwise exponential self-replication. This process has been demonstrated by using Tr?ger's base analogue 1 as the template.     

Oligo Tröger's bases--new molecular scaffolds

Oligo Tr?ger's bases are compounds containing two or more Tr?ger's base subunits (1,5-methanodiareno[b,f][1,5]diazocines) sharing one or more arene parts. Due to their interesting molecular shapes, these compounds are studied as chiral molecular tweezers, clips, cavitands, clefts, calixes, etc. This review includes all available data on oligo Tr?ger's bases, and introduces their preparation and properties to a wide audience.     

Intermittent simulated moving bed chromatography: 3. Separation of Tröger's base enantiomers under nonlinear conditions

One of the modified simulated moving bed (SMB) processes, the intermittent SMB (I-SMB) process, has been recently analyzed theoretically [1] and its superior performance compared to the conventional SMB process has been demonstrated at a rather low total feed concentration through experiments and simulations [2]. This work shows that the I-SMB process outperforms the conventional SMB process also at high feed concentration where the species are clearly subject to a nonlinear adsorption isotherm. In the case of the separation of the Tröger's base's enantiomers in ethanol on ChiralPak AD, the two processes operated in a six-column 1-2-2-1 configuration (one column in sections 1 and 4 and two columns in sections 2 and 3) and in a four-column 1-1-1-1 configuration (one column in each section) are compared at high feed concentration through both experiments and simulations. Even under nonlinear conditions the four column I-SMB process can successfully separate the two enantiomers achieving purity levels as high as the two six column processes and exhibiting better productivity.     

Λ-Shaped optoelectronic materials based on Trger's base

Trger's base (TB) is a well-known chiral molecule with rigid concave shape that makes it applicable in different areas such as superamolecular chemistry,molecular recognition,biological labeling,and so on.In this article,we briefly summarize some recent research progress in the optoelectronic properties of novel TB analogues and their applications in optoelectronic field with emphasis on the developments achieved in our group.     

Measurement and modeling of the equilibrium behavior of the Tröger's base enantiomers on an amylose-based chiral stationary phase

The binary isotherms of the two enantiomers of Tr?ger's base were measured on a system made of pure 2-propanol as the mobile phase and of Chiralpak AD, a chiral stationary phase (CSP) based on amylose tri-(3,5-dimethylphenyl carbamate). The experimental data were acquired using both frontal analysis and the perturbation method. The results obtained are most unusual. The adsorption of the more-retained (-)-enantiomer is not competitive: the amount adsorbed onto the CSP at equilibrium with a constant concentration of the (-)-enantiomer is independent of the concentration of the (+) enantiomer. On the other hand, the adsorption of the less-retained enantiomer is cooperative: the amount of this (+)-enantiomer adsorbed by the CSP at equilibrium with a constant concentration of this enantiomer increases with increasing concentration of the (-)-enantiomer. Such a phenomenon has hardly ever been reported. A model equation is proposed that accounts well for all these isotherm data.     

Alpha-amino acid Tröger base derivatives, possible conformationally restricted scaffolds?

The first synthesis of innovative alpha-amino acid conjugates of Tr?ger base is reported; their potential application as conformationally restricted scaffolds is proposed and has been investigated using high level ab initio calculations.     

Probing the stereointegrity of Tröger's base--a dynamic electrokinetic chromatographic study

Under acidic conditions the enantiomers of Tr?ger's base 1 (2,8-dimethyl-6 H,12 H-5,11-methanodibenzo[b,f][1,5]diazozine) are subject to enantiomerization. During enantioselective dynamic electrokinetic chromatography using 10 mM hydroxypropyl-beta-cyclodextrin as the chiral mobile phase additive in 50 mM tris/phosphate buffer at pH 2.2, enantiomerization of Tr?ger's base gives rise to characteristic elution profiles featuring plateau formation and peak broadening. Introduction of a permanent positive charge attributed to quaternization in the monobenzylated derivative of Tr?ger's base 2 (5-benzyl-2,8-dimethyl-6 H,12 H-5,11-methanodibenzo[b,f][1,5]diazozinium bromide) decreases the enantiomerization barrier significantly. To determine the rate constants of enantiomerization the experimental chromatograms were evaluated by a direct calculation method and by using the computer simulation program ChromWin. From temperature-dependent measurements the Eyring activation parameters for 1 and 2 were determined: 1: DeltaG( not equal ) (298 K)=100.9+/-0.5 kJ mol(-1), DeltaH( not equal )=89.5+/-2.0 kJ mol(-1), DeltaS( not equal )=-42+/-10 J K(-1) mol(-1); 2: DeltaG( not equal ) (298 K)=90.2+/-0.5 kJ mol(-1), DeltaH( not equal )=91.4+/-2.0 kJ mol(-1), DeltaS( not equal )=9.8+/-10 J K(-1) mol(-1).     

Synthesis and Properties of Chiral Molecular Clefts Related to Tröger's Base

The chiral cavities present in 2,3:6,7-dibenzo-9-oxabicyclonona-2,6-diene, dibenzobicyclo[b,f][3.3.1]nona-5a, 6a-diene-6,12-dione, bicyclo[3.3.1]nonane and dibenzobicyclo[b,f],diazocines are reminiscent of Tröger's base, which has been widely used as a molecular cleft in supramolecular chemistry. The synthetic methodology to provide key derivatives for elaboration into new supramolecular structures, efficient resolution methods, the introduction of additional recognition groups and applications in supramolecular chemistry of these structurally related molecular clefts are reviewed.     

Innovative Multipodal Ligands Derived from Tröger's Bases for the Sensitization of Lanthanide(III) Luminescence

Herein, the synthesis and characterization of the first family of multipodal ligands with a Tröger's base framework designed for the preparation of luminescent lanthanide(III) complexes are reported. Eight ligands were designed and synthesized using different strategies, including alkylation reactions, amide couplings, and Ugi multicomponent reactions. All the ligands bear carboxylate groups for the coordination of the lanthanide(III) ions, with the lanthanide(III)-sensitizing units consisting of the Tröger's base framework itself or attached benzamides. Upon irradiation of the chromophoric ligands, green terbium(III) emission was efficiently generated, whereas europium(III) emission was negligible. The geometry and substitution pattern of the ligands allow control of the stoichiometry of the species formed and the Tb^III luminescence sensitization efficiency, showing that para-substitution patterns are more efficient than meta substitution for the formation of coordination compounds with lower Tb^III/ligand ratio. We propose that the species formed are self-assembled 2:2 or 2:4 metallosupramolecular structures.