Asymmetric synthesis of trisubstituted oxazolidinones by the thiourea-catalyzed aldol reaction of 2-isocyanatomalonate diester.

A new method has been developed for the synthesis of chiral 4-carboxyl oxazolidinones by the catalytic asymmetric aldol reaction of an isocyanatomalonate diester with an aldehyde in the presence of a thiourea catalyst. The resulting chiral 4-carboxyl oxazolidinones are the equivalent of ß-hydroxy-α-amino acids bearing a tri- or tetrasubstituted carbon center at their α position. With this in mind, this procedure was successfully applied to the first total synthesis of mycestericin C, which was completed in 12 steps and represents one of the shortest reported sequences for the construction of natural products of this type.

Self-assembly of long chain fatty acids: effect of a methyl branch.

The morphology and molecular conformation of Langmuir-Blodgett deposited and floating monolayers of a selection of straight chain (eicosanoic acid, EA), iso (19-methyl eicosanoic acid, 19-MEA), and anteiso (18-methyl eicosanoic acid, 18-MEA) fatty acids have been investigated by Vibrational Sum Frequency Spectroscopy (VSFS), AFM imaging, and the Langmuir trough. While the straight chain fatty acid forms smooth, featureless monolayers, all the branched chain fatty acids display 10-50 nm sized domains (larger for 19-MEA than the 18-MEA) with a homogeneous size distribution. A model is suggested to explain the domain formation and size in terms of the branched fatty acid packing properties and the formation of hemispherical caps at the liquid-air interface. No difference between the chiral (S) form and the racemic mixture of the 18-MEA is observed with any of the utilized techniques. The aliphatic chains of the straight chain fatty acids appear to be oriented perpendicular to the sample surface, based on an orientational analysis of VSFS data and the odd/even effect. In addition, the selection of the subphase (neat water or CdCl2 containing water buffered to pH 6.0) used for the LB-deposition has a profound influence on the monolayer morphology, packing density, compressibility, and conformational order. Finally, the orientation of the 19-MEA dimethyl moiety is estimated, and a strategy for performing an orientational analysis to determine the complete molecular orientation of the aliphatic chains of 19-MEA and 18-MEA is outlined and discussed.

Asymmetric synthesis of the stereoisomers of 11,12,15(S)-trihydroxyeicosa-5(Z),8(Z),13(E)-trienoic acid, a potent endothelium-derived vasodilator.

The four stereoisomers of the endothelial-derived vasorelaxant 11,12,15(S)-trihydroxyeicosatrienoic acid [1, 11,12,15(S)-THETA] were prepared by a triply convergent, asymmetric route that exploited the stereospecific, copper mediated cross-coupling of alpha,beta-dialkoxystannanes with organic electrophiles and the utility of dialkylthionocarbamates as orthogonal alcohol protective groups. Only 11(R),12(S),15(S)-THETA was comparable to natural material by HPLC, GC/MS, and in vitro bioassay.

Stereoselective synthesis of (6Z,10E,12Z)-octadeca-6,10,12-trienoic acid, (8Z,12E,14Z)-eicosa-8,12,14-trienoic acid, and their [1-14C]-radiolabeled analogs.

To study the metabolic fate of conjugated linoleic acid isomers, we synthesized, in seven steps, from 1-heptyne, (6Z,10E,12Z)-octadeca-6,10,12-trienoic acid, (8Z,12E,14Z)-eicosa-8,12,14-trienoic acid, and their [1-(14)C]-analogs. In the case of (6Z,10E,12Z)-octadecatrienoic acid, a series of palladium-catalyzed cross-coupling reactions between 1-heptyne and (E)-1,2-dichloro-ethene, a coupling reaction with a Grignard reagent and cleavage of the dioxolane gave (E)-dodec-4-en-6-ynal 3. Stereoselective Wittig reaction between aldehyde 3 and triphenyl-[5-(tetrahydro-pyran-2-yloxy)-pentyl]-phosphonium provided a dienyne. Stereocontrolled reduction of the triple bond and replacement of the tetrahydropyranyl group by a bromine gave (5Z,9E,11Z)-1-bromo-heptadeca-5,9,11-triene 10. Formation of the alkenyl lithium derivative and carbonation with CO(2) furnished (6Z,10E,12Z)-octadecatrienoic acid. (8Z,12E,14Z)-eicosa-8,12,14-trienoic acid was obtained by the same route but using triphenyl-[5-(tetrahydro-pyran-2-yloxy)-heptyl]-phosphonium iodide for the Wittig reaction. [1-(14)C]-analogs were obtained from the bromides by carbonation with (14)CO2. In all cases, chemical or radiochemical purities were found to be better than 95% after purification by flash chromatography on silica gel (>99% after additional purification by RP-HPLC). Metabolism studies in animals are in progress.

Non-peptidic, non-prenylic bisubstrate farnesyltransferase inhibitors. Part 3: structural requirements of the central moiety for farnesyltransferase inhibitory activity.

Recently, we have described non-peptidic, non-prenylic bisubstrate analogues as a novel type of farnesyltransferase inhibitor composed of a farnesyl-mimetic, a linker and an AAX-peptidomimetic substructure. With this study, we showed that the amide function connecting the farnesyl-mimetic and the linking substructures of our inhibitors is crucial for their activity. We suggest that the amide is bound to the essential zinc ion in the farnesyltransferases active center. We identified succinic and glutaric acid, respectively, in addition to the initially used 1-alanyl moiety as suitable linking structures. Glycine can also be used in this function provided the distance between the alpha-amide group and the center of the peptidomimetic substructure is enlarged by introduction of an additional methylene unit into the peptidomimetic substructure.

5-Oxo-eicosanoids are potent eosinophil chemotactic factors. Functional characterization and structural requirements.

Human eosinophils produce upon treatment with 5-oxo-eicosatetraenoic acid or (5S,15S)-dihydroxyeicosatetraenoic acid a potent eosinophil-chemotactic eicosanoid, 5-oxo-15-hydroxy-(6E,8Z,11Z,13E)-eicosatetraenoi c acid (5-oxo-15-HETE). 5-Oxo-15-HETE induces human eosinophil (Eo) chemotaxis at nanomolar concentrations with an efficacy in vitro comparable to that seen for platelet activating factor. Comparison of Eo chemotactic activities of several structurally related eicosanoids with different substituents and/or double bound geometry led to the conclusion that maximal potency and efficacy of eosinophil-chemotactic and chemokinetic activity is present in 5-oxo-(6E,8Z,11Z,14Z)-eicosatetraenoic acid (5-oxo-ETE). The presence of a hydroxyl group at position C-15 is not necessary for potent chemotactic activity, whereas a geometric isomer having trans instead of cis double bond at C-atom 8, as well as esterified 5-oxo-ETE usually show a 5-10-fold lower potency. 5-Oxo-eicosanoids elicit a dose-dependent transient rise of intracellular Ca2+ levels in human Eos, however, in contrast to some other Eo chemotaxins do not induce degranulation. Cross-desensitization of Ca2+ mobilization and Eo chemotaxis revealed that the geometric isomers of 5-oxo-eicosanoids, 5(S)-HETE, and (5S,15S)-di-HETE cross-deactivate Eo responses to each other, whereas other, unrelated stimuli did not interfere with these lipids indicating that 5-oxo-eicosanoids activate Eos via a separate receptor.