Bohumil Dolenský

Current Tröger's Base Chemistry

Publisher Summary This chapter summarizes Trogers bases (TBs). It describes its historical developments, revival, synthesis and mechanism of formation, reactivity, physicochemical properties, and its uses and applications. The chapter also provides a brief discussion about pseudo-TBs. It is observed that in principle, any aromatic or heteroaromatic amine can serve as a possible precursor of TBs. TB derivatives are generally viewed as anomalous chiral substances with two nitrogen-containing stereogenic centers. TB derivatives are considered highly useful synthetic building blocks. The common properties of TBs include: biomimetic molecular recognition processes and complex interactions with important biomolecules. TBs represent chiral tectons exhibiting a wide range of applications, such as (1) the TB scaffold is used extensively for the construction of molecular receptors, (2) unique geometry of TB is extensively used in preparing macrocycles, (3) TB derivatives are also considered as hosts for cyclic urea and adenine derivatives, and (4) TB analogs promote investigations of second harmonic reflections from chiral surfaces.

In‐Flight Epimerization of a Bis‐Tröger Base

In 1887, Julius Tr ger reported the synthesis of a nitrogen base, whose structure was determined only about 50 years later. In “Tr ger bases”, nitrogen atoms serve as chiral centers because the otherwise rapid nitrogen inversion is prevented by conformational strain. After Prelog and Wieland separated the enantiomers, the chirality and the rigid V-shape of Tr ger bases led to widespread applications in chemistry. A fundamental question in the chemistry of Tr ger bases concerns the mechanism of their pseudoepimerization, for which either a proton-catalyzed ring opening or a retro-Diels–Alder (RDA) sequence has been proposed (Scheme 1).

Methyl 3,3,3-trifluoropyruvate: an improved procedure starting from hexafluoropropene-1,2-oxide; identification of byproducts

Optimized laboratory-scale preparation of methyl 3,3,3-trifluoropyruvate (3, MTFP) has been developed starting from industrial hexafluoropropene-1,2-oxide (1, HFPO) via methyl 2,3,3,3-tetrafluoro-2-methoxypropanoate (2, MTPr), which was transformed to 3 using sulfuric acid with isolated yields up to 81%. Byproducts formed in the transformation of 2 to 3, viz. methyl trifluoroacetate (4, MTAc), methyl 3,3,3-trifluoropyruvate hydrate (5), methyl hemiacetal of trifluoropyruvate (6), a dimer of methyl 3,3,3-trifluoropyruvate hydrate (7, DimMTP), and methyl fluorosulfate (8, Sulf) were identified and their amounts determined under various experimental conditions. Potential reaction pathways leading to the formation of the byproducts are discussed.

One-pot reaction as an efficient method for rigid molecular tweezers.

Rigid molecular tweezers are compounds of increasing scientific interest. As the structural requirements for such compounds are highly specific, few types of these tweezers are thus far known. The preparation of examples of rigid large-pincered molecular tweezers based on bis Trogers bases derived from 1,4-benzenediamine is described. In addition, evidence is presented of the different binding abilities of the diastereoisomers of such compounds.

Synthesis and biological activity evaluation of hydrazone derivatives based on a Tröger’s base skeleton

We report the design and synthesis of novel anticancer agents based on bis-hydrazones separated by a rigid Trögers base skeleton. This novel approach combines a biologically active moiety (hydrazone) with this scaffold (Trögers base) to construct DNA intercalators. Evaluation of the anticancer activity of these agents using seven cancer cell lines and two healthy cell lines found that several derivatives had potent anticancer activity and excellent selectivity indexes toward cancer cells. The antimicrobial activities were tested on a set of thirteen bacterial stains, but the prepared compounds were not active. Complexation studies using biologically important metal ions demonstrated that these compounds are able to bind Cu(2+), Fe(3+), Co(2+), Ni(2+) and Zn(2+). DNA intercalation studies showed that the compounds themselves do not interact with DNA, but their metallocomplexes do interact, most likely via intercalation into DNA.

Caffeine-hydrazones as anticancer agents with pronounced selectivity toward T-lymphoblastic leukaemia cells.

We report design and synthesis of set of novel anticancer agents based on caffeine-hydrazones bearing 2-hydroxyaryl- or 2-N-heteroaryl moiety. Anticancer activity evaluation using seven cancer cell lines and two non-malignant cell lines demonstrated that several derivatives display significant anticancer activity and great selectivity index toward T-lymphoblastic leukaemia cells. In general, hydrazones bearing 2-N-heteroaryl moiety are more active and selective than those with 2-hydroxyaryl moiety. Tested compounds exhibit dose-dependent inhibition of both RNA and DNA synthesis, with some exceptions. Antimicrobial activities were tested on set of twelve bacterial and yeast strains, however prepared compounds were not active, suggesting for a molecular target specific for eukaryotic cells.

Synthesis of Highly Functionalized Fluorinated Porphyrins

Highly functionalized fluorinated porphyrins were synthesized by a convergent strategy. Nucleophilic substitution using fluorinated branched unit and 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin afforded highly functionalized fluorinated porphyrin 8 containing 24 fluorinated chains in the peripheral region.

Spiro Tröger's base derivatives: another structural phoenix?

Recently, naphthalenoide derivatives of Trogers base (TB) have become important as structural compartments of molecular tweezers and compounds with high specific rotation. The formation of TB derivatives and byproducts from naphthalen-2-amine, methyl 6-aminonaphthalene-2-carboxylate, and anthracen-2-amine was studied. It was discovered that the formation of a naphthalenoide TB derivative is followed by the formation of a unique structural isomer of TB: spiroTB.

Identification and interconversion of diastereomeric oligo-Tröger bases probed by ion mobility mass spectrometry

Oligo-Tröger bases are auspicious scaffolds of molecular engineering, which motivates studies on the mechanism of their interconversion and on the facile determination of the relative configuration of their diastereoisomers. Protonated, sodiated, and argentated species of those compounds were therefore studied via ion-mobility mass spectrometry (IM-MS), allowing differentiation on the basis of the shapes of the ions. First, the isomerization was confirmed to be acid-catalyzed as it takes place readily in the case of protonated Tröger bases, whereas the metallated bases are configurationally stable. Second, the corrected arrival times of the various isomers of the cationized bases were found to show distinct differences in IM-MS, and their excellent correlation with the cross sections obtained from quantum chemical calculations paves the way toward the easy identification of diastereoisomers.

Preparation of new trifluoromethyl substituted tri- and tetracyclic heterocycles with Peganin skeleton from a methyl 3,3,3-trifluoropyruvate / 2-aminobenzylamine adduct

Abstract Addition of 2-aminobenzylamine to methyl trifluoropyruvate afforded methyl 2-((2-aminobenzyl)amino)-3,3,3-trifluoro-2-hydroxypropionate, which reacted with various ketones to give new fluorinated tricyclic and tetracyclic heterocycles with the skeleton of the alkaloid Peganin.