Mihaela Gulea

Overview of the Chemistry of 2-Thiazolines

Heterocyclic compounds are of outstanding importance as pharmaceuticals, agrochemicals, fine and bulk chemicals, and ligands for catalysis.1 Among the different heterocycles, 2-oxazolines have been widely studied and reviewed,2 especially chiral oxazolines3 and bis(oxazolines),4 due to their wide application as ligands for asymmetric catalysis. Compared to 2-oxazolines, the sulfur analogues, that is, the 2-thiazolines, have received less attention. To the best of our knowledge, there is only one review, published by Fustero et al. in 2001,5 which focuses on the preparation and to some extent synthetic applications of both 2-alkyl2-thiazolines and 2-alkyl-2-oxazolines. Recently, various groups have paid attention to the chemical properties of 2-thiazolines, mainly because of the unique properties of sulfur. In different reports, a reactivity that often dramatically differs from that of the corresponding oxazoline derivatives was pointed out. In this contribution, we wish to give an overview of the chemistry of 2-thiazolines, including new methodologies for their preparation, and recent applications, such as their growing use in organic synthesis in the biological field and asymmetric catalysis as ligands. The methods enabling access to thiazolines will first be underlined. Then the reactivity and applications in the fields of organic synthesis, biomolecules (natural or not), and catalysis will be documented. The structure of the thiazolines treated in this review is illustrated in Figure 1. Compounds bearing atoms other than carbon at the 2-position, including 2-H-thiazolines, 2-aminothiazolines, or 2-halogenothiazolines, are beyond the scope of this review. Cited references are restricted to journals, reviews, and books. Literature coverage for this review extends up to September 2007.

Mercaptophosphonate Compounds as Broad-Spectrum Inhibitors of the Metallo-β-lactamases

Although commercialized inhibitors of active site serine beta-lactamases are currently used in coadministration with antibiotic therapy, no clinically useful inhibitors of metallo-beta-lactamases (MBLs) have yet been discovered. In this paper, we investigated the inhibitory effect of mercaptophosphonate derivatives against the three subclasses of MBLs (B1, B2, and B3). All 14 tested mercaptophosphonates, with the exception of 1a, behaved as competitive inhibitors for the three subclasses. Apart from 13 and 21, all the mercaptophosphonates tested exhibit a good inhibitory effect on the subclass B2 MBL CphA with low inhibition constants (K(i) < 15 muM). Interestingly, compound 18 turned out to be a potent broad spectrum MBL inhibitor. The crystallographic structures of the CphA-10a and CphA-18 complexes indicated that the sulfur atom of 10a and the phosphonato group of 18 interact with the Zn(2+) ion, respectively. Molecular modeling studies of the interactions between compounds 10a and 18 and the VIM-4 (B1), CphA (B2), and FEZ-1 (B3) enzymes brought to light different binding modes depending on the enzyme and the inhibitor, consistent with the crystallographic structures.

Synthesis of new chiral thiazoline-containing ligands

Abstract New chiral ligands, including bi- and tridentate thiazoline derivatives, analogues of known oxazolines, have been synthesized by a general and convenient procedure, starting from dithioesters and commercial enantiopure 2-aminoalcohols. A preliminary test shows the ability of such ligands to act as asymmetric catalysts in Pd-catalyzed allylic substitution reaction.

Synthesis and properties of thiazoline based ionic liquids derived from the chiral pool

A novel class of chiral ionic liquids derived from amino alcohols is prepared in multi-gram scale. Their potential in chiral recognition is shown in a preliminary example with racemic Moshers acid salt.

Ruthenium–porphyrin-catalyzed carbenoid addition to allylic compounds: application to [2,3]-sigmatropic rearrangements of ylides

Abstract The catalytic effectiveness of ruthenium porphyrins for ylide generation in reactions of ethyl diazoacetate and diisopropyl diazomethylphosphonate with allylic amines, sulfides and iodides is described for the first time. These reactions result mainly in products of the [2,3]-sigmatropic rearrangement of intermediate allylic ylides.

Cyclopropanation of alkenes with diisopropyl diazomethylphosphonate catalysed by ruthenium porphyrin complexes

Stereoselectivities, regioselectivities and yields for cyclopropanation reactions of diisopropyl diazomethylphosphonate (DAMP) with styrene derivatives, catalysed by ruthenium porphyrins, are reported and compared with those observed for cyclopropanation reactions catalysed by other metalloporphyrins. Linear correlations are observed when the rates for competitive cyclopropanation and ratio of the stereoisomers obtained are plotted against Hammet constants of various ring-substituted groups on styrene. Isomeric distribution for the cyclopropanation of 1,3-pentadiene with diisopropyl diazomethylphosphonate is reported. Competition studies between cyclopropanation and diazo insertion into heteroatom-hydrogen bonds and also between cyclopropanation and sigmatropic reaction are reported. A first example of asymmetric cyclopropanation with a chiral catalyst is also described.

Chemo- and enantioselective sulfoxidation of bis(ethylenedithio)-tetrathiafulvalene (BEDT-TTF) into chiral BEDT-TTF-sulfoxide

Selective sulfoxidation of BEDT-TTF (bis(ethylenedithio)-tetrathiafulvalene) with enantiopure (camphoryl-sulfonyl)oxaziridine derivatives provided the inner monosulfoxide, as demonstrated using single crystal X-ray analysis, with an enantiomeric excess of 44% (up to 74% after recrystallization).

Cyclocarbopalladation/Cross-Coupling Cascade Reactions in Sulfide Series: Access to Sulfur Heterocycles

Cyclocarbopalladation/cross-coupling cascade reactions were applied for the first time in a sulfur series and represent an efficient route to access sulfur heterocycles. Stille or Suzuki-Miyaura cross-coupling was successfully used as the final reaction. The products are original benzothiolane and isothiochromane scaffolds with a stereodefined tetrasubstituted exocyclic double bond. To illustrate the application of this method to the synthesis of bioactive molecules, a sulfur analogue of the anticancer agent tamoxifen was prepared as a potential selective estrogen-receptor modulator.

Synthesis of chiral, nonracemic α-sulfanylphosphonates and derivatives

Abstract Optically active α-sulfanylphosphonates and the corresponding methyl sulfides were prepared in three steps starting from chiral, nonracemic (ee 93–97%) α-hydroxyphosphonates obtained by enzymatic resolution. Reaction conditions for the reduction of racemisation-prone substrates were found to preserve the enantiomeric excesses.

Cyclopropyl phosphonate ester synthesis catalyzed by ruthenium porphyrins: first characterization of a phosphonate carbene complex

Abstract Catalytic systems derived from Ru(CO)porphyrins are extremely efficient at converting styrene and diisopropyl diazomethyl phosphonate to cyclopropyl phosphonate esters in high yields and with high stereoselectivity; a monocarbene complex Ru(TPP)(CH{P(O)(O i Pr) 2 }) has been isolated as a possible catalytically active species.