Abstract: A convenient and efficient procedure for the synthesis of 4-arylchromenes, thiochromenes, and related heterocycles via a four step-sequence has been developed. The first three steps, which involve hydration of alkynes, hydrazones formation, and their Pd-coupling with ortho substituted aryl halides, furnished stereoselectively Z-trisubstituted olefins without any purification of the intermediates generated in each stage. These latter proved to be suitable precursors, in the last step, for the synthesis of the desired heterocycles of biological interest.
Abstract: The cytotoxic activity of a series of 23 new isoerianin derivatives with modifications on both the A and B rings was studied. Several compounds exhibited excellent anti-proliferative activity at nanomolar concentrations against a panel of human cancer cell lines. The most cytotoxic compound, isoerianin (3), strongly inhibits tubulin polymerization in the micromolar range. Moreover, isoerianin leads to G(2)/M phase cell-cycle arrest in H1299 and K562 cancer cells, and strongly induces apoptosis. Isoerianin also disrupts the vessel-like structures formed by human umbilical vein endothelial cells (HUVECs) in vitro, suggesting that this compound may act as a vascular disrupting agent. It clearly appears that in this compound series, the 1,1-ethane bridge encountered in isoerianin derivatives can replace the 1,2-ethane bridge of natural erianin with no loss of activity. This reinforces the bioisosteric replacement approach in the combretastatin series previously reported by our research group.
Abstract: A stereoselective, palladium-catalyzed, cross-coupling reaction between chloroenynes 4 and boronic acids was successfully developed. This procedure is general and provides desired functionalized enynes 1 in high yields. The scope and limitations of this new reaction are described.
Abstract: A series of triarylolefins bearing the combretastatin A-4 and the isocombretastatin A-4 cores were synthesized and evaluated. The cooperative ortho-effect of a labile bromine atom in the regioselective hydrostannation of unsymmetrical diarylalkynes leading to stereodefined triarylolefins is presented.
Abstract: Tributyltin hydride in N-methyl-2-pyrrolidinone (NMP) was used for the partial reduction of various functionalized acid chlorides at room temperature. This transition-metal-free procedure allows the synthesis of a range of (hetero) aromatic- and aliphatic aldehydes in good to excellent yields.
Abstract: A variety of 2-arylbenzo[b]furans are readily prepared in good to excellent yields from the cyclization of o-(1-alkynyl)anisole derivatives under mild reaction conditions using an alcoholic media, p-toluenesulfonic acid under microwave irradiation. Starting from the corresponding o-(1-alkynyl)thioanisole derivatives, this friendly and environmentally free-metal procedure has been successfully extended to the synthesis of benzo[b]thiophenes. Relative to the electronic nature of the substituents, the selectivity of the cyclization reaction from differently o,o′-substituted diarylalkynes is also discussed.
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The palladium-catalyzed hydrostannation of terminal arylalkynes was achieved. The regioselectivity of the H−Sn bond addition across the triple bond was found to be controlled by an ortho substituent on the aromatic ring, whatever its electronic nature, to give exclusively α-branched vinylstannanes 2 in accordance with Markovnikov’s rule. Subsequent Stille cross-coupling reaction of 2 with a variety of aryl halides readily provided, in moderate to good yields, a family of functionalized 1,1-diarylethylenes 1.
Abstract: A quick and efficient entry to 1,1-diarylethylenes via the reaction of polyoxygenated aryl N-tosylhydrazones with aryl triflates is described. The reaction employs the catalytic system Pd(OAc)2/XPhos, tBuOLi as the base and dioxane as the solvent. A variety of substituents on both the coupling partners’ hydrazones and triflates are tolerated. This procedure provides a complementary route to the existing methods for the access to 1,1-diarylethylenes of biological interest.
Abstract: The cytotoxic activities of 23 new isocombretastatin A derivatives with modifications on the B-ring were investigated. Several compounds exhibited excellent antiproliferative activity at nanomolar concentrations against a panel of human cancer cell lines. Compounds isoFCA-4 (2 e), isoCA-4 (2 k) and isoNH2CA-4 (2 s) were the most cytotoxic, and strongly inhibited tubulin polymerization with IC50 values of 4, 2 and 1.5 M, respectively. These derivatives were found to be 10-fold more active than phenstatin and colchicine with respect to growth inhibition but displayed similar activities as tubulin polymerization inhibitors. In addition, cell cycle arrest in the G2/M phase and subsequent apoptosis was observed in three cancer cell lines when treated with these compounds. The disruptive effect of 2 e, 2 k and 2 s on the vessel-like structures formed by human umbilical vein endothelial cells (HUVEC) suggest that these compounds may act as vascular disrupting agents. Both compounds 2 k and 2 s have the potential for further prodrug modification and development as vascular disrupting agents for treatment of solid tumors.
Abstract: Hydrosilylation of functionalized terminal arylalkynes with a variety of silanes catalyzed by PtCl2 or PtO2 in the presence of the air-stable and bulky Xphos ligand was investigated. Regardless of the electronic nature (electron withdrawing or donating group) and the position (o, m, p) of the substituents on the aromatic ring, a single β-(E)-styrylsilanes was obtained in good to excellent yields. The regioselectivity of the H-Si bond addition was found to be governed by steric effects induced by the bulky Xphos ligand. A dramatic regioselectivity was also observed when functionalized terminal aliphatic alkynes were employed as a substrate and in these cases regioisomeric β-(E)-vinylsilanes were generated with excellent selectivity.
Abstract: Various 3-substituted chiral 1,2,4-oxadiazole-containing Fmoc-3- and --amino acids were synthesized from Fmoc-(L or D)-Asp(OtBu)-OH and Fmoc-L-Asp-OtBu, respectively, in three steps (i.e., condensation of an aspartyl derivative with differentially substituted amidoximes, formation of the 1,2,4-oxadiazole, and cleavage of the tert-butyl ester). These compounds represent new series of nonnatural amino acids, which could be used in combinatorial synthesis. A simple protocol has been developed to generate the 1,2,4-oxadiazole ring. Indeed, common methods resulted in cleavage of the Fmoc group or required long reaction times. We found that sodium acetate in refluxing ethanol/water (86 C) was a convenient and efficient catalyst to promote conversion of Fmoc-amino acyl amidoximes to 1,2,4-oxadiazoles, and this procedure proved to be compatible with Fmoc protection. It is shown that these compounds can be prepared without significant loss of enantiomerical purity. Furthermore, the alkaline conditions used to cleave the Fmoc protecting group from these compounds did not induce epimerization of their chiral center.
Abstract: Palladium-catalyzed hydrostannation of substituted Z- and E-enynols is controlled by the geometry of the double bond (Z- or syn-directing effect) rather than the nature of its substituents. Exclusively α-vinyl stannanes were obtained from Z-enynols having various substituents on the double bond regardless of their electronic, steric, or chelating natures.
