Overcoming regioselectivity issues inherent in bis-Tröger's base preparation

[structure: see text] Bis-Tr?ger's base derivatives are a new family of molecular tweezers. A major drawback to their study is a lack of commercially available precursors, ortho-nitrocarboxylic acids. A reverse synthetic strategy starting from known dinitrodicarboxylic acids, which circumvents this problem, is presented. Via this methodology regioisomeric bis-TB derivatives can be prepared selectively, using only common aromatic amines that are typically commercially available.     

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.     

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.     

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.     

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.     

The synthesis and characterization of all diastereomers of a linear symmetrically fused Tris-Tröger's base analogue: new chiral cleft compounds

The synthesis and characterization of all diastereomers of a linear symmetrically fused tris-Tr?ger'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-Tr?ger'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 Tr?ger'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 Tr?ger's base condensation to 1 a-c suggesting a templating effect of the ammonium ion.     

Design and synthesis of chiral single-armed molecular tweezers derived fromα-hyodeoxycholic acid

A novel type of molecular tweezers with different chiral center and cleft has been designed and prepared by usingα-hyodeoxycholic acid as spacer and D/L-amino acid methyl ester as chiral arm attached at 3-position.Their structures were elucidated by ~1H NMR,FTIR and elemental analysis.Their recognition properties for various D/L-amino acid methyl esters were also investigated.The preliminary results indicated that these chiral single-armed molecular tweezers exhibited good recognition ability for D/L-ami...     

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.     

Diastereoselective self-assembly of double-stranded helicates from Tröger's base derivatives

[structure: see text]. Several ligands based on the rigid, V-shaped structure of Tr?ger's base bearing 2,2'-bipyridine and 2-pyridylmethanimine moieties have been synthesized. These ligands undergo diastereoselective self-assembly to dinuclear double-stranded D2d-symmetric helicates upon coordination to copper(I) and silver(I) ions as elucidated by NMR techniques and ESI mass spectrometric methods.     

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.     

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.     

Enantioselective Brønsted base catalysis with chiral cyclopropenimines

Cyclopropenimines are shown to be a highly effective new class of enantioselective Br?nsted base catalysts. A chiral 2,3-bis(dialkylamino)cyclopropenimine catalyzes the rapid Michael reaction of a glycine imine substrate with high levels of enantioselectivity. A preparative scale reaction to deliver 25 g of product is demonstrated, and a trivial large scale synthesis of the optimal catalyst is shown. In addition, the basicity of a 2,3-bis(dialkylamino)cyclopropenimine is measured for the first time and shown to be approximately equivalent to the P(1)-tBu phosphazene base. An X-ray crystal structure of the protonated catalyst is shown along with a proposed mechanistic and stereochemical rationale.     

Tröger's Base Derivatives—New Life for Old Compounds

Synthetic Tröger's base derivatives are reviewed, including their properties and applications. The rigid V-shaped Tröger's base framework and its inherent chirality have promoted the preparation of diverse receptor systems. Heterocyclic Tröger's base derivatives exhibit affinity for DNA. Metal complexes of Tröger's base are used as catalysts. New applications continue to emerge as synthetic methods are developed.     

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.     

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, 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.