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The reaction of C60 with pregnen-20-carboxaldehyde, a biologically active synthetic steroid, by using a 1,3-dipolar cycloaddition reaction (Prato's protocol) results in the formation of pyrrolidine rings bearing a new stereogenic center on the C2 of the five-membered ring. The formation of the fullerene-steroid hybrids proceeds with preference for the Re face of the 1,3-dipole, with formation of a diastereomeric mixture in 73:15 ratio. The investigation of the chiroptical properties of these conjugates allowed determining the absolute configuration of the new fulleropyrrolidines. In addition, a thorough spectroscopical study permitted to determine the structure of the two mono-cycloadducts. The electrochemical properties of the new hybrids were also evaluated by cyclic voltammetry, both systems exhibit three quasi-reversible reduction waves which are cathodically shifted in regard to the parent C60. Theoretical calculations help supporting the experimental data. A conformational study combining semiempirical methods and density functional theory has predicted the most stable diastereomer. On the basis of this agreement, a possible reaction mechanism is presented. Additionally, a molecular docking simulation has been carried out using the HIV-1 protease as receptor, thus paving the way to study the possible application of these stereoisomers in biomedicine.

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The diastereoselective synthesis of cis and trans steroid-fulleropyrrolidines hybrids by reaction of N-metalated azomethine ylides [Cu(II) or Ag(I)] with the appropriate chiral ligand and C60 is described. The experimental findings reveal that the azomethine ylide stabilized by an allylic group cycloadds to [60]fullerene in an efficient manner and with a good diastereomeric excess. Furthermore, the new generated stereocenters are fully controlled by the catalytic systems used without being influenced by the chirality of the steroid. Interestingly, by this synthetic methodology the each one of the four possible stereoisomers have efficiently been obtained and characterized by CD spectra.

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The retro-cycloaddition thermal reaction of isoxazolino[4,5:1,2][60]fullerenes to pristine fullerene seems to be guided by the electronic nature of the substituted nitrile oxide 1,3-dipole in the isoxazoline ring. Trapping experiments proved that the reaction mechanism occurs by thermal removal of the nitrile oxide 1,3-dipole in a process that is favored in the presence of a big excess of a highly efficient dipolarophile such as maleic anhydride. Theoretical gas phase calculations carried out at the B3LYP/6-31G(d) and M06-2X/6-31G(d) levels of theory underpin the experimental findings and predict that compound 1c, bearing the p-(CH3)2N-Ph substituent on the isoxazoline ring and with a remarkable experimental conversion efficiency in just 12 h, showed the lowest activation energy. Solvent calculations have predicted the same behavior in gas phase. Different approaches such as electrostatic natural population analysis and Houk's distortion/interaction model have been applied to understand how the electronic nature of these substituents affects the retro-cycloaddition reaction process. Analysis of the values of the condensed Fukui functions and dual descriptor shed light on the mechanism of the retro-cycloaddition reaction.

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RATIONALE: We have investigated the fragmentation reactions of ions from bis-adducts containing isoxazolino-, pyrrolidino- and methanofullerene moieties. METHODS: The fragmentation reactions induced by collision-induced dissociation (CID) of ions generated under electrospray ionization (ESI) in positive and negative modes of detection using an ion-trap spectrometer have been investigated. RESULTS: The competitive retro-cycloaddition process between isoxazoline and pyrrolidine rings fused to [60]fullerene reveals that it is strongly dependent on the experimental negative or positive ESI experimental conditions. Thus, whereas retro-cycloaddition reaction is favored in the pyrrolidine ring under negative conditions, the protonation occurring on the nitrogen atom of the pyrrolidine ring under positive conditions precludes its retro-cycloaddition and, therefore, only the isoxazoline ring undergoes the retro-cycloaddition process. The obtained experimental results are different from those reported when the reaction is carried out under thermal conditions. Competitive retro-cycloaddition reactions of isoxazolino- and methanofullerenes show that the heterocyclic ring undergoes cycloelimination, leaving the methanofullerene moiety unchanged. In this case, the same selectivity is observed under thermal and gas-phase conditions. CONCLUSIONS: The observed selectivity in the heterocyclic removal in these [60]fullerene derivatives is reversed from negative conditions (radical anions) to positive conditions (protonated molecules). Moreover, the retro-cycloaddition reaction behaves differently under spectrometric and thermal conditions.

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New [60]fullerene-steroid conjugates (4-6) have been synthesized by 1,3-dipolar cycloaddition and Bingel-Hirsch cyclopropanation reactions from suitably functionalized epiandrosterone and [60]fullerene. Since a new stereocenter is created in the formation of the Prato monoaduct, two different diastereomers were isolated by HPLC (4, 5) whose absolute configurations were assigned according to the highly reliable "sector rule" on fullerenes. A further reaction of the malonate-containing diastereomer 5 with a second C60 molecule has afforded dumbbell fullerene 6 in which the two fullerene units are covalently connected through an epiandrosterone moiety. The new compounds have been spectroscopically characterized and their redox potentials, determined by cyclic voltametry, reveal three reversible reduction waves for hybrids 4 and 5, whereas these signals are split in dumbbell 6. Theoretical calculations at semiempirical (AM1) and single point B3LYP/6-31G(d) levels have predicted the most stable conformations for the hybrid compounds (4-6), showing the importance of the chlorine atom on the D ring of the steroid. Furthermore, TDDFT calculations have allowed assignments of the experimentally determined circular dichroism (CD) of the [60]fullerene-steroid hybrids based on the sign and position of the Cotton effects, despite the exceptionally large systems under study.

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The design and synthesis of fullerene-steroid hybrids by using Prato's protocol has afforded new fullerene derivatives endowed with epiandrosterone, an important naturally occurring steroid hormone. Since the formation of the pyrrolidine ring resulting from the 1,3-dipolar cyloaddition reaction takes place with generation of a new stereogenic center on the C2 of the five-membered ring, the reaction proceeds with formation of a diastereomeric mixture [compounds 6 and 7 in 70:30 ratio, 8 and 9 in 26:74 ratio (HPLC)] in which the formation of the major diasteroisomers 6 and 9 is consistent with an electrophilic attack of [60]fullerene on the Re face of the azomethine ylide directed by the steroidic unit. The chiroptical properties of these conjugates reveal typical Cotton effects in CD spectra that have been used to assign the absolute configuration of the new fulleropyrrolidines. The electrochemical study of the new compounds reveals the presence of four quasi-reversible reduction waves which are cathodically shifted in comparison with the parent C60, thus ascertaining the proposed structures.

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A facile, efficient and environment-friendly protocol for the synthesis of 6-chloro-5-formyl-1,4-dihydropyridine derivatives has been developed by the convenient ultrasound-mediated reaction of 2(1H)pyridone derivatives with the Vilsmeier-Haack reagent. This method provides several advantages over current reaction methodologies including a simpler work-up procedure, shorter reaction times and higher yields.

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The condensation of Meldrum's acid, aromatic aldehydes, alkyl acetoacetates and ammonium acetate in glacial acetic acid under ultrasound irradiation at room temperature results in the formation of 3,4-dihydropyridone derivatives (4a-p) in 85-96% yields. Compared with conventional methods, the main advantages of the present procedure are milder conditions, shorter reaction times and higher yields.

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The 1H and 13C NMR spectroscopic data for 4-aryl-1,4,5,6,7,8-hexahydro-2,7,7,5-oxo-quinoline 3-substituted derivatives have been fully assigned by the combination of one- and two dimensional experiments (DEPT, HMBC, HMQC, COSY, NOE).

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