Susana M. M. Lopes

Reactions of Nitrosoalkenes with Dipyrromethanes and Pyrroles: Insight into the Mechanistic Pathway

The reactivity of nitrosoalkenes toward dipyrromethanes, pyrrole, and 2,5-dimethylpyrrole is described. 1-(p-Bromophenyl)nitrosoethylene shows a different chemical behavior with these heterocycles than the previously reported reactions of ethyl nitrosoacrylate, which proceeds via a Diels-Alder reaction. 1-(p-Bromophenyl)nitrosoethylene reacts with dipyrromethanes and pyrrole to afford two isomeric oximes via conjugate addition followed by rearomatization of the pyrrole unit. On the other hand, this nitrosoalkene reacts with 2,5-dimethylpyrrole through an initial conjugate addition followed by intramolecular O- and N-nucleophilic addition with the formation of the corresponding bicyclic oxazine and five-membered cyclic nitrone, respectively. Quantum chemical calculations, at the DFT level of theory, indicate that the barriers associated with the Diels-Alder reactions of ethyl nitrosoacrylate are over 30 kJ/mol lower than those that would be required for the cycloadditions of 1-(p-bromophenyl)nitrosoethylene. Thus, calculations predict that the Diels-Alder reaction is privileged in the case of ethyl nitrosoacrylate and point to a different reaction pathway for 1-(p-bromophenyl)nitrosoethylene, corroborating the experimental findings.

Synthesis and anti-cancer activity of chiral tetrahydropyrazolo[1,5-a]pyridine-fused steroids

HIGHLIGHTSSynthesis novel chiral heterocycle‐fused steroids based on [8&pgr; + 2&pgr;] cycloadditions.Biological evaluation of a new family of hexacyclic steroids as anti‐cancer agents.Conclusions regarding structure‐activity relationships could be withdrawn.A benzyl group at C24 is important to ensure cytotoxicity against EL4. ABSTRACT Regio‐ and stereoselective synthesis of novel chiral 4,5,6,7‐tetrahydropyrazolo[1,5‐a]pyridine–fused steroids via [8&pgr; + 2&pgr;] cycloaddition of diazafulvenium methides with steroidal scaffolds is reported. The biological evaluation of the new family of hexacyclic steroids as anti‐cancer agents was also carried out. Hexacyclic steroids bearing a benzyl group at C‐22, derived from 16‐dehydropregnenolone and 16‐dehydroprogesterone, show considerable cytotoxicity against EL4 (murine T‐lymphoma) in contrast with the corresponding C‐22‐unsubstituted derivatives showing low cytotoxicity. Thus, results indicate that the presence of the benzyl group is important to ensure cytotoxicity.

Hexahydro-Pyrrolo(1',2',5':3,4,5)Thiazolo(3,4-c)Oxazol-1-ones: New Chiral Tricyclic L-Cysteine and D-Penicillamine Derivatives

A simple and efficient approach to the synthesis of the new chiral hexahydropyrrolo [1’,2’,5’:3,4,5]thiazolo[3,4-c]oxazol-1-one ring system is reported. Infrared spectroscopy, quantum-chemical calculations and X-ray analysis allowed the stereochemistry assignment of (2aS,4aR,6aR)-2a,3,4,4a,6,6ahexahydropyrrolo-[1’,2’,5’:3,4,5]thiazolo[3,4-c]oxazol-1-one.

Reactivity of 1-arylnitrosoethylenes towards indole derivatives

The reactivity of 1-arylnitrosoalkenes toward indole, 1-methylindole, and 3-methylindole is described. In contrast with the previously observed chemical behaviour of 1-(p-bromophenyl)nitrosoethylene towards pyrrole, the studied heterodienes reacted with indole and 1-methylindole to afford E-oximes via hetero-Diels–Alder reactions. The reaction with 3-methylindole also proceeds via cycloaddition giving the corresponding 1,2-oxazine. Quantum chemical calculations, at the DFT level, indicate that the energy barriers associated with the reactions between 1-(p-bromophenyl)nitrosoethylene and indole and its derivatives are similar to those observed for the reaction between this nitrosoalkene and pyrrole. However, the calculated energy of the theoretical Diels–Alder cycloadducts involving indole and pyrrole clearly suggests that the Diels–Alder reaction is privileged in the case of indole. Furthermore, in the case of the indole, the energy difference between reactants and products clearly favors the regiochemistry observed experimentally.Graphical abstract

Biological Evaluation of Dipyrromethanes in Cancer Cell Lines: Antiproliferative and Pro‐apoptotic Properties

Functionalized dipyrromethanes were synthesized by hetero‐Diels–Alder reactions of nitroso‐ and azoalkenes and screened for their in vitro activity as anticancer agents. The studied dipyrromethanes were tested against leukemia and lymphoma cell lines, and showed GI50 values in the mid‐micromolar range. The pro‐apoptotic activities of two candidates, (E)‐1‐(2′‐ethoxycarbonylhydrazono‐1′‐benzyl‐1H‐tetrazol‐5‐yl)‐5,5′‐diethyldipyrromethane and (E)‐1‐(2′‐p‐nitrophenyl‐2′‐hydroxyiminoethyl)‐5‐phenyldipyrromethane, and their effects on the cell cycle are described. The latter compound was found to decrease the S‐phase cell population in a dose‐dependent manner and to irreversibly block cells in the G2/M phase.

Synthesis of chiral thiazolo[3,4-a]pyrazine-5,8-diones

A synthetic approach to chiral (3R,8aR)-3-phenyltetrahydrothiazolo[3,4-a]pyrazine-5,8-diones starting from a (2S,4R)- and (2R,4R)-diastereoisomeric mixture of 2-phenylthiazolidine is described. The diastereoselective N-acylation of the thiazolidine followed by condensation with amines affords the chiral 1,3-thiazolidine-annulated system. The structure of (3R,8aR)-7-(methoxycarbonylmethyl)-3-phenyltetrahydrothiazolo[3,4-a]pyrazine-5,8-dione was determined by X-Ray crystallography.

Reactivity of Steroidal 1-Azadienes toward Carbonyl Compounds under Enamine Catalysis: Chiral Penta- and Hexacyclic Steroids

The synthesis and reactivity of a steroidal N-sulfonyl-1-azadiene, derived from 16-dehydropregnenolone acetate, toward carbonyl compounds under enamine catalysis is disclosed. An unexpected annulation reaction was observed involving an initial stereoselective conjugate addition of the in situ generated enamine to the steroidal 1-azadiene. The developed diastereoselective synthetic methodology is a novel approach to a new class of chiral pentacyclic and hexacyclic steroids.