Reaction of Tröger’s base analogues with Vilsmeier reagents

As part of a program aimed at introducing functionality onto the Tröger’s base framework post-synthesis, we investigated the formylation reaction of Tröger’s base analogues with Vilsmeier reagents. We found that rather than the anticipated reaction at the aryl rings, these compounds react with Vilsmeier reagents to afford compounds with a modified strap, whereby the apical methylene group is replaced by a methylene strap bearing an N,N-disubstituted amine.     

Selective formation of either Tröger’s base or spiro Tröger’s base derivatives from [2-aminoporphyrinato(2-)]nickel by choice of reaction conditions

The article reports on the unique manipulation of the acid-catalyzed reaction of [2-aminoporphyrinato(2-)]nickel with formaldehyde to form selectively either the symmetric Tröger’s base or the asymmetric spiro Tröger’s base bis(metalloporphyrin) derivative. The reaction is driven by the choice of acid catalyst, formaldehyde source, and particularly, solvent, to give a mixture of both derivatives in preparative yields of about 90%, or to give selectively one of the derivatives in a yield of about 60%.     

Stereoselective Mannich reactions catalyzed by Tröger’s base derivatives in aqueous media

A Tröger’s base derivative (5,12-dimethyl-3,10-diphenyl-1,3,4,8,10,11-hexaazatetracyclo [6.6.1.0^2,6.0^9,13]pentadeca-2(6),4,9(13),11-tetraenes) was used as an efficient catalyst for the three-component Mannich reactions of aromatic aldehydes and aromatic amines with ketones in water at room temperature. This rapid reaction afforded the corresponding β-amino ketones in good yields with excellent stereoselectivity.     

Intermittent simulated moving bed chromatography: 2. Separation of Tröger’s base enantiomers

The intermittent simulated moving bed (I-SMB) process is a modification of the conventional SMB process that has been recently analyzed theoretically [1]. Here, we present a comparative analysis of the two processes, each 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. Experiments are carried out on a properly modified laboratory unit to separate racemic mixtures of the enantiomers of Tröger’s base in ethanol on ChiralPak AD at a total feed concentration of 1 g/L. Simulations are carried out for the same system using the equilibrium dispersive model and a bi-Langmuir isotherm, whose parameters have been preliminarily estimated from pulse and breakthrough experiments. Experiments and simulations are fully consistent and demonstrate that the four-column I-SMB process (but not the four-column SMB process) can separate the two enantiomers at very high purity and achieve a productivity twice as large as that of the six-column I-SMB and conventional SMB processes with the same solvent consumption.     

An efficient access to new Tröger’s bases using superacidic chemistry

In the superacidic media HF/SbF₅, hydroxylation of several Tröger’s bases was performed using sodium persulfate as a hydroperoxonium H₃ precursor. The obtained products are selectively hydroxylated in good yields on unusual positions of the aromatic rings.     

The diastereoisomeric forms of a mononuclear Ru(II) complex bearing a bis-phenanthroline Tröger’s base

The synthesis of a novel completely asymmetric mononuclear complex of ruthenium(II) bearing a chiral bis-phenanthroline Tröger’s base ligand 1 (TBphen₂) is reported. The diastereoisomeric forms of [Ru(phen)₂TBphen₂]²⁺ (ΔS/ΛR=rac-2a and ΛS/ΔR=rac-2b) were separated through crystallization. A complete structure elucidation of the diastereoisomers in solution, including chirality assignment, was achieved by 1D and 2D NMR techniques. Photophysical characterization revealed no significant differences in the emission properties of rac-2a and rac-2b that closely resemble those of [Ru(phen)₃]²⁺.     

Synthesis, structural elucidation and catalytic activity toward a model Mizoroki-Heck C-C coupling reaction of the pyrazolic Tröger’s base Pd4Cl8(PzTB)2 complex

The synthesis of a novel palladium (II) complex Pd₄Cl₈(PzTB)₂, where PzTB is a pyrazole Tröger’s base analogue ligand is reported. A complete structure elucidation of the complex was achieved by spectroscopic and crystallographic data, exhibiting a metallomacrocycle supramolecular structure and a planar-square geometry on each palladium atom. This complex exhibited also a high activity and selectivity toward a model Mizoroki-Heck C-C coupling reaction of styrene with some iodobenzene derivatives.     

Tröger’s bases in the acronycine, benzo[a]acronycine, and benzo[b]acronycine series

Reaction of 11-aminoacronycine, 10-aminobenzo[a]acronycine, and 10-aminobenzo[b]acronycine with paraformaldehyde gave the corresponding Tröger’s bases 11, 14, and 16, respectively. The cytotoxic activity of those three new compounds was determined against L-1210 leukemia and KB-3-1 solid tumor cell lines, in comparison with their parent compounds, acronycine, benzo[a]acronycine, and benzo[b]acronycine.     

Two isolated intermediates of the Tröger's base: synthesis and mechanism

By controlling the amount of catalyst 1-methyl-3-(2-(sulfooxy)ethyl)-1H-imidazol-3-ium chloride, two new intermediates of Tröger's bases (11, 1,6-dimethyl-3-(4-methylphenyl)-1,4-dihydroquinazolin-3-ium tetrafluoroborate and 12, 8-methyl-2,5-bis-(4-methylphenyl)-3,5,6,7-tetrahydropyrimido[5,6,1-ij]quinazoline-2-ium tetrafluoroborate) were simply obtained from the one-pot reaction of aromatic amine and formaldehyde in ionic liquid at ambient temperature. These results support the mechanism for Tröger's base formation supposed by Fernando Coelho and co-workers. However, the crystal structure of 12 and correlative quantum chemistry calculation results are not reconciled with their report.     

Synthesis of symmetrical amino and aminomethyl derivatives of Tröger's base via Pd-catalyzed C-C and C-N bond formation

In this paper, we report the synthesis of amino and aminomethyl derivatives of Tröger's base (±)-1 and (±)-2. The key steps in the synthesis of (±)-1 and (±)-2 are Pd-catalyzed amination and cyanation, respectively, of the easily accessible dihalo derivatives (±)-3. These compounds are important intermediates in the synthesis of new ligands and building blocks for H-bonded supramolecular architectures.     

Changing the shape of Tröger’s base

The first synthesis of Tröger’s base analogues bearing three and four atoms in the apical strap is reported, leading to a dramatic change in the shape of the aromatic scaffold with respect to the Tröger’s base framework.     

Functionalized analogues of Tröger's base: scope and limitations of a general synthetic procedure and facile, predictable method for the separation of enantiomers

A major stumbling block in the applications of enantiomerically pure Tröger's base analogues is their poor availability. We have therefore developed a facile method for the enantioseparation of functionalized Tröger's base analogues possessing various substitution patterns. The systematic separation of a library comprising 36 representatives on the commercially available Whelk O1 chiral stationary phase provided valuable information on structure-enantioselectivity relationships. A mechanistic explanation of observed relationships allows one to predict whether or not enantioseparation of a given, perhaps yet unknown derivative of Tröger's base will be feasible. In addition, we provide a detailed report on the scope and limitations of the general synthetic protocol employing anilines and paraformaldehyde in CF₃COOH, as well as some considerations concerning the mechanism of formation of Tröger's base analogues.     

Synthesis and fluorescence properties of naphthalimide-containing Tröger’s bases

Tröger’s bases based on the naphthalimide fluorophore have been prepared from N-alkyl-4-amino-1,8-naphthalimides. The fluorescence emission intensity of these dyes is highly medium dependent. In cyclohexane, these dyes emit near 440 nm with high quantum yields; addition of cosolvents reduces the fluorescence intensity near 440 nm and leads to increased fluorescence intensity around 480 nm.     

Tröger's base scaffold in racemic and chiral fashion as a spacer for bisdistamycin formation. Synthesis and DNA binding study

‘Head-to-head’ oligo-N-methylpyrrole peptide dimers linked by a methano[1,5]diazocin scaffold are presented in racemic as well as chiral fashion. Their DNA binding activities were assayed on calf thymus DNA, poly(dA-dT)₂, and poly(dC-dG)₂ by NMR and ECD spectroscopies, and fluorescence probe displacement assay. The presented dimers prefer AT sequences, but show higher affinity to poly(dC-dG)₂ than distamycin A. The (4R,9R) configuration of methanodiazocin bridge was found to be better suited for interaction with ct-DNA and poly(dA-dT)₂ than (4S,9S) configuration.     

Novel heterocyclic Tröger's base derivatives containing N-methylpyrrole units

Novel analogues of Tröger's base were prepared regioselectively from 4-amino-N-methylpyrrole carboxylates in good yield. Catalytic hydrogenation of dibenzyl-4,9-methano-1,6-dimethyl-4,5,9,10-tetrahydro-1H,6H-dipyrrolo-[3,2-b:3′,2′-f][1,5]diazocin-2,7-dicarboxylate 2b led to 4,9-methano-1,6-dimethyl-4,5,9,10-tetrahydro-1H,6H-dipyrrolo-[3,2-b:3′,2′-f][1,5]diazocin-2,7-dicarboxylic acid 3 which was used for the preparation of Tröger's base derivatives of natural antibiotics via an amide protocol. The novel heterocyclic Tröger's bases were characterized by a variety of spectroscopic techniques and compound 2b by X-ray crystallography. Incorporation of guanidine as the terminal group in the N-methylpyrrole Tröger's base skeleton opens the possibility for preparation of water soluble derivatives.     

Regio/diastereo-controls of the Bingel-type biscyclopropanation of [60]fullerene by using bismalonates with a Tröger base analogue-derived tether

Four kinds of bismalonates tethered with a Tröger base derivative were synthesized and used for the double Bingel reaction of [60]fullerene. The regio/diastereoselectivities of the reaction were highly influenced by the structure of the Tröger base derivatives. Heteroaromatic analogues of the Tröger base were found to be applicable as the core of the tether.     

Palladium-catalyzed direct intramolecular double α-C–H arylation of 1,5-diketone: a strategy for synthesis of Tröger’s base analogues

9-Aryl-2,3:6,7-dibenzobicyclo[3.3.1]nona-2,6-diene-4,8-diones were straightforwardly prepared via a tandem reaction of easily available ortho-chloroacetophenone and ortho-chlorochalcone catalyzed by PdCl₂(PCy₃)₂.     

Absolute configuration of Tröger bases: an X-ray diffraction and circular dichroism study

Bis-ortho-methyl-bis-meta-bromo Tröger base (TB) 2 and bis-ortho-methyl TB 3 were prepared in enantiopure form. The absolute configuration for (5S,11S)-(−)-2 was determined by X-ray diffraction. The sign of the longest wavelength band in the electronic CD spectrum is negative for both (5S,11S)-(−)-2 and (5S,11S)-(−)-3, as well as for the parent para-methyl TB (5S,11S)-(+)-1, which is in agreement with TD DFT B3LYP/6-31G(d,p) calculations.