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.     

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.     

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.     

A Convenient Method for the Synthesis Of Tröger's Base Analogues

Para substituted anilines have been converted to Tröger's base analogues by refluxing with a mixture of methylal and methanesulfonic acid.     

Chiral selection of Tröger's base-based macrocycles with different ethylene glycol chains length in crystallization

In the present work, two Trӧger's base-based macrocycles (TBBMs) with different bridging ethylene glycol chains (T1, n = 1; T3, n = 3) were successfully synthesized and studied via the crystal analysis. These two TBBMs possess rare rectangular-like cavities and show chiral selection during the crystallization. T1 with short glycol chain (n = 1) crystallized as racemates, while T3 with long glycol chain (n = 3) was found as meso isomer. In contrast to T1 and T3, for T2 (n = 2) both rac-T2 and meso isomer R_2NS_2N-T2 has been observed in our previous report. Thus, the synthesis of new TBBMs T1 and T3 with different bridging ethylene glycol chains not only makes the study of TBBMs more systematically, but also helps to understand the relationship between the size of the rectangular cavity and the chiral selection of Tröger's base-based macrocycles during their crystallization.     

The Synthesis of New Sulfur-containing Chiral Macrocyclic Ligands

Chiralrecognitionphenomenaplayanimportantroleinavarietyofchemical,physicalandbiologicalprocesses-SinceCramandhiscoworkerspublishedtheirfirstpioneeringstudiesontheuseofchiralmacrocyclicligandsinenantiomericrecognition,manychiralmacrocycleshavebeensynthesizedandusedinchiralrecognition'~'-Sulfuratomissoftbase.Thesulfur-containingchiralmacrocyclicligandscanformcomplexwithtransitionmetalsandhavepotentialapplicationinasymmetricsynthesisandchiralrecognition,butlittlestudyofsynthesisandapplicationhasb…     

Synthesis of Chiral Sulfamide–Amine Alcohol Ligands for Enantioselective Alkylation of Aldehydes

A series of chiral sulfamide–amine alcohols (SAA) (1–6) has been easily synthesized from commercially available chiral amino alcohols. In the absence of Ti(O ⁱ Pr)₄, ligand 4 catalyzed the asymmetric addition of diethylzinc to aromatic aldehydes with moderate to good yields and enantioselectivities.     

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.     

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.     

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.     

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.     

New Chiral Ligands: From Fundamental Research to Potential Industrial Applications

Asymmetric catalysis is one of the most extensively studied areas in chemistry over the past three decades. In this presentation we will discuss the new advancements in the design, synthesis, and application of chiral ligands used for catalytic reactions in our laboratory. Particular emphasis will be placed on new, highly efficient synthetic methodologies and their potential industrial applications.New Chiral Ligands: From Fundamental Research to Potential Industrial Applications@Albert S.…     

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).     

Peptide Deravatives as New Chiral Ligands for Enantioselective Phenylacetylene Addition to Aldehydes

The asymmetric addition of alkynylzinc to aldehydes is an important method of synthesizing chiral propargyl alcohols, which are important precursors to many chiral organic compounds. Recently, many significant chiral ligands in this area have been disclosed.[1] Use of a short peptide as a catalyst would allow expansion beyond the (still uncharted) repertoire of single amino acids, while conserving the advantages of a small molecule catalyst. To the best of our knowledge,no results of peptide derivatives as chiral ligands in this reaction has been disclosed to date.[2] Herein, we report the initial results of peptide derivatives, which have been used directly as a chiral ligand in this reaction (Scheme 1).     

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.     

New Chiral N,S—Ligands with Thiophenyl at Benzylic Position.Palladium（Ⅱ）—catalyzed Enantioselective Allylic Alkylation

New chiral N,S-ligands with oxazoline and thiophenyl sub-stituents at benzene ring and benzylic postition have been pre-pared and applied in palladium-catalyzed asymmetric allylic alkylation reaction to provide the product with high yield and entantioselectivity (82%-93%)ee.     

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.     

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.