Maria I. L. Soares

Chiral 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles with anti-breast cancer properties.

The synthesis and biological evaluation of 6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazoles as anticancer agents against MCF7 breast cancer cell lines is reported. The design of the new compounds has been guided considering (3R)-6,7-bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole as the lead compound due to its good performance against MCF7 breast cancer cell lines (IC(50) = 1.0 μM). The structural changes included the removal of the phenyl group at C-3, the replacement of this group by a 3,4,5-trimethoxyphenyl group, the removal of the methyl group at C-5 from the lead scaffold and the replacement of this group by a phenyl substituent. Overall, these studies showed that the combined presence of a phenyl group at C-3 and a methyl group at C-5 in the 1H,3H-pyrrolo[1,2-c]thiazole ring system is essential to ensure high cytotoxicty against MCF7 breast cancer cell lines. To probe whether the absolute configuration of the lead compound might affect the anticancer activity, its enantiomer was prepared and the activity against MCF7 cells was evaluated. (3S)-6,7-Bis(hydroxymethyl)-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole proved to be the most active compound so far studied, with IC(50) value of 0.5 μM.

Intermolecular Dipolar Cycloaddition Reactions of 5H,7H-Thiazolo[3,4-c]oxazol-4-ium-1-olates

Abstract (5R)-3-Methyl-5-phenyl-5H,7H-thiazolo[3,4-c]oxazol-4-ium-1-olate was generated in the presence of a range of dipolarophiles. The intermolecular 1,3-dipolar cycloaddition of this mesoionic species led to the synthesis of chiral 1H-pyrrolo[1,2-c]thiazole derivatives 7a, 7b, 8, 14, 18, 19 and 20. In the reaction with methyl and ethyl vinyl ketone, spiro compounds 9 and 15 were also obtained. The structure of compound 15 was determined by X-ray crystallography.

Microwave-induced Pericyclic Reactions of Aza- and Diazafulvenium Methides

The pericyclic reactions of 4,5-dimethoxycarbonyl-substituted aza- and diazafulvenium methides generated un- der microwave-induced thermolysis conditions have been described. The 7,7-dimethyl-substituted derivatives undergo al- lowed suprafacial sigmatropic (1,8)-hydrogen shifts leading to the efficient synthesis of C-vinylpyrroles and C- vinylpyrazoles. These intermediates could not be trapped in (8� +2� ) cycloaddition in the presence of dipolarophiles. Aza- and diazafulvenium methides unsubstituted at C-1 and C-7 behave as 8� 1,7-dipoles in the presence of dipolarophiles un- der microwave irradiation, leading to a range of pyrrolo and pyrazolo annulated heterocycles resulting from addition across positions 1 and 7. Aza- and diazafulvenium methide derivatives bearing only one methyl group at C-7 are inter- cepted in sigmatropic hydrogen shifts to give functionalized pyrroles and pyrazoles, respectively. In the presence of elec- tron-deficient dipolarophiles, these 7-methyl-substituted derivatives act as 1,7-dipoles in (8� +2�) cycloadditions, how- ever, competitive formation of the corresponding vinyl pyrroles and vinylpyrazoles is also observed.

Conformational behaviour, photochemistry and flash vacuum pyrolysis of a 2-(1H-tetrazol-1-yl)thiophene

The conformational properties and the photochemical behaviour of a 2-(1H-tetrazol-1-yl)thiophene were studied using low-temperature matrix isolation (argon; 16 K) coupled with infrared spectroscopy. The experimental results were supported by theoretical calculations carried out at the B3LYP/6-311++G(d,p) level. The calculations predicted two conformers for the studied compound in the gas phase that differ in energy by 3.2 kJ mol−1. Accordingly, two conformers were observed in the low-temperature matrix. UV-laser irradiation at 245 nm of the studied compound isolated in the argon matrix led to photocleavage of the tetrazole ring, with elimination of N2 and formation of the corresponding thiophen-2-ylcarbodiimide, most likely via the corresponding imidoylnitrene intermediate. The flash vacuum pyrolysis of 2-(1H-tetrazol-1-yl)thiophene gave methyl 1H-thieno[2,3-d]imidazole-1-carboxylate via intramolecular formal insertion into a C–C bond of the corresponding imidoylnitrene intermediate and the unexpected 2-methoxythieno[2,3-d]pyrimidin-4(3H)-one. The synthesis of this heterocycle was rationalized considering the initial N2 elimination to generate an imidoylnitrene followed by rearrangement to the corresponding thiophen-2-ylcarbodiimide, [1,5] sigmatropic shift of the methoxyl group and electrocyclic ring closure.

(R)-Spiro[(2R)-N-acetyl-2-phenyl-1,3-thiazolidine-4,3'-(3a'R,6a'S)-5',6a'-dimethyl-3a',-6a'-dihydro-3H-furo[2,3-b]furan-2-one]

In the title compound, C 18 H 19 NO 4 S, the two furan rings are fused cis. The dihydrofuran ring is practically planar and the saturated furan-2-one ring is only slightly puckered. The thiazolidine ring has a twisted conformation about the C4-S1 bond. The environment around the spiro atom is nearly tetrahedral.