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.     

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%.     

The selective mono and difunctionalization of carbocyclic cleft molecules with pyridyl groups and X-ray crystallographic analysis

The diesterification and selective mono and dialkylation of carbocyclic analogues of Tröger’s base with pyridyl groups has been achieved in high yield and good selectivity giving access to a novel range of cleft molecules capable of binding events. Reaction conditions for the selective functionalization of this carbocyclic cleft molecule are discussed as well as the solid state structures of these newly synthesized ligands.     

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.     

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.     

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 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.     

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.     

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.     

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.     

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.     

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.     

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⁺.     

Adducts of Tröger bases and activated acetylenes: synthesis and structure

It was found by X-ray diffraction and NMR studies that the structure of the adduct of bis-ortho-methyl-bis-para-methyl substituted Tröger base and dimethyl acetylenedicarboxylate is a [3.3.1]bicyclic compound corresponding to the methyl 13-[1-(methoxycarbonyl)vinyl]-13-carboxylate. Chemical and NMR evidence supported similar structures for all other reported adducts of Tröger bases and activated acetylenes.     

Characterizing the Memory Effect on the amylose tris(3,5-dimethylphenyl) carbamate stationary phase

Acid/base modifiers are sometimes used as additives in normal phase elution on columns packed with CHIRALPAK^® AD^®. They affect enantioseparations in ways that are not understood for the lack of systematic studies, which makes the scale-up of preparative separations difficult to predict. Once a column has been exposed to these modifiers, the selectivity of certain pairs of enantiomers may change, for the better or the worse. Numerous molecules that are affected by this phenomenon are listed in the literature. We selected five of them, the selectivity of which changes as more acidic or basic solutions are percolated through the column. The selectivity of ketoprofen, 4-chlorophenylalanine methyl and ethyl esters improves as a solution of Ethanesulfonic Acid is percolated through the column. The selectivity of Propranolol HCl and Tröger’s base increases as a solution of diisopropylamine is percolated through the column. Each one of these five compounds is inversely affected by the percolation of the opposite acid/base solution. We used trans-Stilbene Oxide (tso) as a “standard” to determine the columns stability because no Memory Effect is observed for it (its retention, enantioselectivity, and resolution remain constant). Karl Fisher titrations showed that only slight changes in the water content of the mobile phase occurred, and that a unique water to polymer moiety ratio is important. Analytical studies of the stationary phase suggest that slow protonation/deprotonation of water attached to the carbamate moiety may be responsible for the acid/base Memory Effect. Finally, we showed that the Memory Effect can be minimized by percolating through the column a sufficiently concentrated solution of the appropriate acid or base. Thus, columns that were unreliable for method development, due to the Memory Effect, can now be used. As a result, the need to store several CHIRALPAK AD columns, specific for each condition of the Memory Effect, is eliminated.     

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.     

Tröger's base analogs. New structural units for the preparation of chiral hosts and metal ligands.

Several Tröger's base analogs are prepared and presented as practical, structurally well defined and unique “folded” armatures for the preparation of chelating or macrocyclic host molecules.     

Synthesis of acrimarins from 1,3,5‐trioxygenated‐9‐acridone derivatives

1,3,5‐Trihydroxy‐9(10H)‐acridinone (1) was prepared from 3‐hydroxyanthranillic acid with phloroglucinol. 1,3‐Dihydroxy‐5‐methoxy‐9(10H)‐acridinone (2) was prepared from 3‐methoxyanthranillic acid and phloroglucinol. Methylation of 1 under different conditions gave 1‐hydroxy‐3,5‐dimethoxy (3), 1‐hydroxy‐3,5‐dimethoxy‐10‐methyl (4), 1‐hydroxy‐3,5‐dimethoxy‐4‐methyl (5), 1,3,5‐trimethoxy‐10‐methyl (6) and 1,3,5‐trimethoxy‐4,10‐dimethyl (7) analogues. Demethylation of 4 afforded the 1,3,5‐trihydroxy‐10‐methyl analogue 8. Condensation of acridones 1, 2, 3 and 4 individually with E‐suberenol (9) gave four novel acrimarins (acridone‐coumarin dimers) 10, 11, 12 and 13 respectively, while the acridone 8 gave previously reported acrimarin‐G (14).     

Synthesen neuer Phosphono-Analoga von Pantethein-derivaten

Syntheses of New Phosphono Analogues of Pantetheine Derivatives The phosphono analogues 5 and 13 of pantothenate 4′-(dibenzyl phosphate) and pantetheine 4′-(dibenzyl phosphate), respectively, are prepared as intermediates for the synthesis of a coenzyme-A phosphono analogue (Schemes 1 and 2). The synthesis of phosphono analogues 20 and 21 of oxapantetheine, which are structurally similar compounds to the phosphono analogue of pantetheine, is also described (Scheme 3).