Bart Roman

Synthesis of isoindoles and related iso-condensed heteroaromatic pyrroles

Over the past few years, isoindoles have found wide application in materials science. Isoindole containing BODIPY dyes are highly fluorescent materials and have been extensively used in various fields of science. Phthalocyanines, metal containing cyclic tetramers of isoindole, form coordination complexes with most elements of the periodic table. These complexes are intensely coloured and are used as pigments and dyes. However, isoindoles are relatively unstable 10π-heteroaromatic systems and few synthetic methods provide these compounds in good yields. This tutorial review will give an overview of the reported synthetic methods towards isoindoles and related heteroaromatic systems over a time span of approximately 10 years (2000 to current), including the applications where they have been reported. The importance of the field will be illustrated and factors influencing product stability will be discussed.

Continuous Synthesis of Peralkylated Imidazoles and their Transformation into Ionic Liquids with Improved (Electro)Chemical Stabilities

A versatile and efficient method to synthesize tetrasubstituted imidazoles via a one-pot modified Debus-Radziszewski reaction and their subsequent transformation into the corresponding imidazolium ionic liquids is reported. The tetrasubstituted imidazoles were also synthesized by means of a continuous flow process. This straightforward synthetic procedure allows for a fast and selective synthesis of tetrasubstituted imidazoles on a large scale. The completely substituted imidazolium dicyanamide and bis(trifluoromethylsulfonyl)imide salts were obtained via a metathesis reaction of the imidazolium iodide salts. The melting points and viscosities are of the same order of magnitude as for their non-substituted analogues. In addition to the superior chemical stability of these novel ionic liquids, which allows them to be applied in strong alkaline media, the improved thermal and electrochemical stabilities of these compounds compared with conventional imidazolium ionic liquids is also demonstrated by thermogravimetrical analysis (TGA) and cyclic voltammetry (CV). Although increased substitution of the ionic liquids does not further increase thermal stability, a definite increase in cathodic stability is observable.

Synthesis of β-, γ-, δ-, ..., ω-halogenated ketones and aldehydes.

2.6. Radical Reactions 5932 2.6.1. Radical Halogenation 5932 2.6.2. Ring-Opening and Expansion 5932 2.6.3. Miscellaneous 5934 2.7. Ring-Opening and Ring Expansion 5934 2.7.1. Cyclic Acetals 5934 2.7.2. Epoxides 5934 2.7.3. Cycloalkanes 5935 2.7.4. Ozonides 5937 2.7.5. Ring Expansion 5938 2.8. Ring Closure and Contraction 5939 2.8.1. Ring Closure 5939 2.8.2. Ring Contraction 5943 2.8.3. Ring Rearrangements 5943 2.9. Oxidation 5943 2.9.1. Oxidation of Halogenated Alcohols 5943 2.9.2. Oxidation of Olefins 5945 2.10. Pericyclic Reactions 5945 2.10.1. Cycloadditions 5945 2.10.2. Sigmatropic Rearrangements 5945 3. Synthesis of γ-Halo Ketones and Aldehydes 5946 3.1. Nucleophilic Substitution 5946 3.1.1. Enolate Alkylation 5946 3.1.2. Conversion of an Alcohol or Ether into an Alkyl Halide 5947

Design, synthesis and structure-activity relationships of some novel, highly potent anti-invasive (E)- and (Z)-stilbenes.

In our ongoing exploration of the structure-activity landscape of anti-invasive chalcones, we have prepared and evaluated a number of structurally related (E)- and (Z)-stilbenes. These molecules exhibited an extraordinary high in vitro potency in the chick heart invasion assay, being active up to 10nmolL(-1), a concentration level a 100-fold lower than the lowest effective doses that have been reported for natural analogues. Furthermore, they possess an interesting pharmacological profile in silico.

Exploration of the SAR of anti-invasive chalcones: Synthesis and biological evaluation of conformationally restricted analogues

In order to get a clearer view on the active geometry of anti-invasive chalcones, we have prepared a number of isoxazoles and related substances as conformationally restrained mimics of 1,3-diarylpropenones, and also of (Z)-stilbenes. In vitro anti-invasive activity data for 3,5-isoxazoles and 4,5-isoxazoles, together with an in silico geometrical comparison, point towards an active conformation for chalcones more resembling their s-trans geometry than the s-cis counterpart.

Assessment of the Antineoplastic Potential of Chalcones in Animal Models

One part of chemical space that is endowed with interesting biological properties is the area of the chalcones. With this review, we provide a comprehensive overview of the numerous in vivo animal studies on the antineoplastic potential of both natural and synthetic members of this flavonoid subclass (covering: up to mid-2011). The thus far identified modes of action of these compounds are also discussed. We hope that this overview may stimulate deeper investigations into the biochemical mechanisms by which chalcones exert their antineoplastic action. As a result, in the foreseeable future, chalcones may prove suitable lead molecules or early drug candidates for the prevention or treatment of various neoplastic diseases.

Experimental and computational study of the ring opening of tricyclic oxanorbornenes to polyhydro isoindole phosphonates

Phosphonylated azaheterocycles are an important class of compounds with high biological potential as conformationally restricted bioisosteres of amino acids. Therefore, it is of interest to synthesize conformationally constrained amino phosphonates. We wanted to investigate possible routes via ring opening of alpha-amino phosphonates with an oxanorbornene skeleton, as these can be synthesized with high stereoselectivity. This was achieved using different Lewis acids, leading to a range of products. The reaction with TiCl(4) and FeCl(3) was modelled at a DFT level of theory to get insight in the pathways towards the corresponding products. To ease the work up, the Fe(iii) catalyst was coated on montmorillonite clay, but this accelerated aromatization after ring opening. Quenching the FeCl(3) catalyzed reaction mixture on celite caused complete aromatization.

A new class of antimicrobial biosurfactants: quaternary ammonium sophorolipids

New synthetic pathways are proposed for the production of a broad range of innovative sophorolipid amines and sophorolipid quaternary ammonium salts starting from microbially produced sophorolipids. The selective formation of an intermediate sophorolipid aldehyde proved to be a key synthetic step of the new derivatives. The sophorolipid quaternary ammonium salts were evaluated for their antimicrobial activity against Gram-negative and Gram-positive test strains. Minimum inhibitory concentration (MIC) values were determined for the active compounds. Derivatives with an octadecyl group on the nitrogen atom proved to be more active than the antibiotic gentamicin sulfate against all tested Gram-positive strains. The results show great promise for modified sophorolipids in the medical sector.

Synthesis of tricyclic phosphonopyrrolidines via IMDAF: Experimental and theoretical investigation of the observed stereoselectivity

During the synthesis of tricyclic phosphonopyrrolidines via intramolecular Diels-Alder reactions of 1-acylamino(furan-2-yl)methyl phosphonates, two isomers are formed in most cases. The presence of a short three-atom tether together with spectroscopic data, including difference NOE, revealed that the cycloaddition occurred exo, but the phosphonate substituent on the tether had an exo or endo orientation. This was confirmed via X-ray analysis. A thermodynamic preference for the product with the phosphonate function in the endo position was observed experimentally and was confirmed theoretically. Density functional theory methods and several high-level post Hartree-Fock procedures were used to rationalize the observed isomer ratio of the IMDAF-reactions. This was done for two different types of reagents: with the activating carbonyl group in the tether or as a substituent on the tether. For the first type of molecules there is a large steric hindrance of the bulky tether substituents that disfavors the exo-isomer. In the latter case, there was a very small energy difference between the transition states causing a mixture of epimers being formed.

Further studies on anti-invasive chemotypes: An excursion from chalcones to curcuminoids.

In our ongoing search for new anti-invasive chemotypes, we have made an excursion from previously reported potent 1,3-diarylpropenones (chalcones) to congeners bearing longer linkers between the aromatic moieties. Nine 1,ω-diarylalkenones, including curcumin and bisdemethoxycurcumin, were evaluated in the chick heart invasion assay. Unfortunately, these compounds proved less potent and more toxic than earlier evaluated chemotypes. In the 1,3-diarylpenta-2,4-dien-1-one series, fluoro and/or trimethoxy substitution caused an increase in potency. This agrees with observations made earlier for the chalcone class.