The reaction of azoles with 17-chloro-16-formylandrosta-5,16-dien-3ß-yl-acetate: synthesis and structural elucidation of novel 16-azolylmethylene-17-oxoandrostanes.

The synthesis and structural elucidation, by 1D and 2D NMR and X-ray diffraction techniques, of novel E/Z 16-azolylmethylene-17-oxoandrostanes 2-9 prepared from the Vilsmeier-Hack reaction product 17-chloro-16-formylandrosta-5,16-dien-3ß-yl acetate 1 is reported. The reaction proceeds with pyrrole and pyrrole-alike nitrogen heterocycles such as 7-azaindole, indole, and 3-methylindole, in DMF, at 80°C, in the presence of K(2)CO(3), and allowed the attachment of privileged heterocyclic moieties, through the nitrogen atom to the steroid core at C16 via a methine carbon bridge, which is unprecedented in the literature and of potential synthetic and biological interest. Considerations on the possible reaction mechanism are included. All the synthesized compounds are new and are currently being tested for biological activities.

Chiral 6-hydroxymethyl-1H,3H-pyrrolo[1,2-c]thiazoles: novel antitumor DNA monoalkylating agents.

New chiral 1H,3H-pyrrolo[1,2-c]thiazoles were synthesized and screened for their in vitro activity as anti-cancer agents in three human tumor cell lines, colorectal adenocarcinoma, melanoma and breast adenocarcinoma. (R)-6-Hydroxymethyl-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole and the corresponding benzylcarbamate showed selectivity for breast cancer cell lines with IC(50) values of 2.4 microM and 2.2 microM, respectively. The latter also showed significant activity against colorectal adenocarcinoma cancer cell lines (IC(50) = 8.7 microM). In contrast, the 7-hydroxymethyl-5-methyl-3-phenyl-1H,3H-pyrrolo[1,2-c]thiazole gave moderate anti-cancer activity. The performance against breast cancer cell lines (IC(50) = 1.0 microM) of a potential bisalkylating agent, a (3R)-6,7-bis(hydroxymethyl)-1H,3H-pyrrolo[1,2-c]thiazole, wasn't significantly different from the one observed for the monoalkylating derivatives indicating that the main mechanism of action may in fact be the monoalkylation process.

Crystal structure and experimental and theoretical studies of the second-order nonlinear optical properties of salts of triphenylguanidine with carboxylic acids.

N,N',N''-triphenylguanidinium carboxylate salts have been prepared by acid-base reactions of triphenylguanidine with formic, benzoic, and m-methoxybenzoic acids, and their single-crystal X-ray structure analysis has been performed. The salts were found to crystallize into noncentrosymmetric structures with an orthorhombic space group P2(1)2(1)2(1) for the formate and m-methoxybenzoate salts and a monoclinic space group Cc for the benzoate salt. The anions and cations are linked by intermolecular hydrogen bonds with the same motifs in the three salts. By using the molecular structures, the molecular first hyperpolarizabilities of several clusters were determined by semiempirical methods, and the components of the second-order susceptibility tensor, d, of triphenylguanidine and those of the reported crystals were evaluated using the oriented gas model with two different local-field corrections. The efficiency of the second-harmonic generation of triphenylguanidine and that of the reported triphenylguanidinium salts were measured using the Kurtz and Perry powder method.

Bismuth triflate-catalyzed Wagner-Meerwein rearrangement in terpenes. Application to the synthesis of the 18alpha-oleanane core and A-neo-18alpha-oleanene compounds from lupanes.

The use of bismuth(III) salts as catalysts for the Wagner-Meerwein rearrangement of lupane derivatives with expansion of ring E and formation of an additional O-containing ring is reported. This process has also been extended to other terpenes, such as the sesquiterpene (-)-caryophyllene oxide. When the reaction was performed with oleanonic acid, 28,13beta-lactonization occurred, without Wagner-Meerwein rearrangement. Under more vigorous reaction conditions, dehydration of the 3beta-hydroxyl group and subsequent additional Wagner-Meerwein rearrangement led to the selective synthesis of A-neo-18alpha-oleanene compounds, in very high yields.

1H-indazole and 2H-indazole derivatives of androsta-5,16-dien-3beta-ol.

The title compounds, 17-(1H-indazol-1-yl)androsta-5,16-dien-3beta-ol, (I), and 17-(2H-indazol-2-yl)androsta-5,16-dien-3beta-ol, (II), both C(26)H(32)N(2)O, have an indazole substituent at the C17 position. The six-membered B ring of each compound assumes a half-chair conformation. A twist of the steroid skeleton is observed and reproduced in quantum-mechanical ab initio calculations of the isolated molecule using a molecular orbital Hartree-Fock method. In the 1H-indazole derivative, (I), the molecules are joined in a head-to-head fashion via O-H...O hydrogen bonds, forming chains along the a axis. In the 2H-indazole derivative, (II), the molecules are joined in a head-to-tail fashion with one of the N atoms of the indazole ring system acting as the acceptor. The hydrogen-bond pattern consists of zigzag chains running along the b axis. Substituted steroids have proven to be effective in inhibiting androgen biosynthesis through coordination of the Fe atoms of some enzymes, and this study shows that indazole-substituted steroids adopt twisted conformations that restrict their intermolecular interactions.

Bismuth(III) salt-catalyzed Westphalen and "backbone" rearrangements of 5 beta,6 beta-epoxysteroids synthesis and structural elucidation of new olefinic 19-nor and 18,19-dinorsteroids.

A new process using the "ecofriendly" bismuth(III) salts as catalysts for the Westphalen and "backbone" rearrangements of 5 beta,6 beta-epoxysteroids is reported. This method is particularly sensitive to changes on solvent, temperature, stereochemistry of starting epoxysteroid, and its substituent at C17. Depending on the reaction conditions, either Westphalen-type or "backbone" rearranged products were obtained, all being 3 beta-acetoxy-6 beta-hydroxy-substituted. Several new olefinic 19-nor and 18,19-dinorsteroids were obtained and their structural elucidation was fully accomplished using 2D NMR and X-ray crystallography techniques.

Chemistry of diazafulvenium methides in the synthesis of functionalized pyrazoles.

The chemistry of diazafulvenium methides generated by the thermal extrusion of sulfur dioxide from 2,2-dioxo-1H,3H-pyrazolo[1,5-c] [1,3]thiazoles is described. The diazafulvenium methides unsubstituted at C-7 participate in [8 pi + 2 pi] cycloadditions giving pyrazolo-annulated heterocycles resulting from the addition across the 1,7-position. 1-Methyl-diazafulvenium methides and 7,7-dimethyl-diazafulvenium methides undergo intramolecular sigmatropic [1,8]H shifts giving vinyl-1H-pyrazoles.

N-Vinyl- and C-vinylpyrroles from azafulvenium methides. flash vacuum pyrolysis route to 5-Oxo-5H-pyrrolizines and 1-azabenzo[f]azulenes.

1-Azafulvenium methides, generated from pyrrolo[1,2-c]thiazole-2,2-dioxides' thermal extrusion of sulfur dioxide, led to the synthesis of functionalized pyrroles. The intramolecular trapping of these transient 8pi 1,7-dipoles in pericyclic reactions, namely sigmatropic [1,8]H shifts and 1,7-electrocyclization, allowed the synthesis of N-vinylpyrroles and C-vinylpyrroles which, under flash vacuum pyrolysis conditions, are converted into 5-oxo-5H-pyrrolizines or 4-oxo-1,4-dihydro-1-aza-benzo[f]azulenes, respectively. These heterocycles can also be obtained directly from FVP of pyrrolo[1,2-c]thiazole 2,2-dioxides. The synthesis and X-ray structure of a new 6-oxocyclopenta[b]pyrrole derivative is also reported.