Browsing by Author "Bernardo, Carlos E. P."
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- Computational development of rubromycin-based lead compounds for HIV-1 reverse transcriptase inhibitionPublication . Bernardo, Carlos E. P.; Silva, Pedro J.The binding of several rubromycin-based ligands to HIV1-reverse transcriptase was analyzed using molecular docking and molecular dynamics simulations. MM-PBSA analysis and examination of the trajectories allowed the identification of several promising compounds with predicted high affinity towards reverse transcriptase mutants which have proven resistant to current drugs. Important insights on the complex interplay of factors determining the ability of ligands to selectively target each mutant have been obtained.
- Computational exploration of the reaction mechanism of the Cu+- catalysed synthesis of indoles from N-aryl enaminonesPublication . Bernardo, Carlos E. P.; Silva, Pedro J.We have studied the role of Cu+-phenantroline as a catalyst in the cyclization of N-aryl-enaminones using density-functional theory computations. The catalyst was found to bind the substrate upon deprotonation of its eneaminone, and to dramatically increase the acidity of the carbon adjacent to the ketone functionality. The deprotonation of this carbon atom yields a carbanion which attacks the aryl moiety, thereby closing the heterocycle in the rate-determining step. This C–C bond forming reaction was found to proceed much more rapidly when preceded by re-protonation of the substrate N-atom (which had lost H+ in the initial step). Hydride transfer to the catalyst then completes the indole synthesis, in a very fast step. The influence of Li+ and K+ on the regioselectivity of the cyclization of bromo-substituted analogues could not, however, be reproduced by our model. Alternative pathways involving either single-electron transfer from the catalyst to the substrate or ring cyclization without previous carbon α-deprotonation were found to be kinetically or thermodynamically inaccessible.
- Evaluation of density functional methods on the geometric and energetic descriptions of species involved in Cu+-promoted catalysisPublication . Bernardo, Carlos E. P.; Bauman, Nicholas P.; Piecuch, Piotr; Silva, Pedro J.We have evaluated the performance of 15 density functionals of diverse complexity on the geometry optimization and energetic evaluation of model reaction steps present in the proposed reaction mechanisms of Cu(I)-catalyzed indole synthesis and click chemistry of iodoalkynes and azides. The relative effect of the Cu(+) ligand on the relative strength of Cu(+)-alkyne interactions, and the strong preference for a π-bonding mode is captured by all functionals. The best energetic correlations with MP2 are obtained with PBE0, M06-L, and PBE1PW91, which also provide good quality geometries. Furthermore, PBE0 and PBE1PW91 afford the best agreement with the high-level CCSD(T) computations of the deprotonation energies of Cu(+)-coordinated eneamines, where MP2 strongly disagrees with CCSD(T) and the examined DFT functionals. PBE0 also emerged as the most suitable functional for the study of the energetics and geometries of Cu(+) hydrides, while at the same time correctly capturing the influence of the Cu(+) ligands on the metal reactivity.
- Influence of alkyne and azide substituents on the choice of the reaction mechanism of the Cu+-catalyzed addition of azides to iodoalkynesPublication . Silva, Pedro J.; Bernardo, Carlos E. P.The cycloaddition of azides to iodoalkynes is strongly enhanced by some Cu+-complexes. We have studied computationally six reaction pathways for the cycloaddition of 24 combinations of azide and iodoalkyne to identify the dominant pathways and the influence of reactant structure on the evolution of the reaction. Two pathways were found to be operating for distinct sets of reactants. In the first pathway, initial complexation of iodoalkyne by Cu+ is followed by the binding of the azide to the metal through its substituted nitrogen atom, followed by attack of the nonhalogenated alkyne carbon by the terminal nitrogen atom. This pathway is generally followed by aromatic or electron-deficient azides, unless the iodoalkyne bears an electron-withdrawing group. The second pathway is a single-step mechanism similar (apart from the alkyne bond weakening caused by complexation) to that observed in the absence of catalyst. Electron-deficient iodoalkynes and methyl azides strongly prefer this mechanism, regardless of the identity of the reaction partners. The catalytic gain obtained through the use of Cu+ depends only partially on its direct effect on the energy of the transition state (relative to that of the infinitely separated reactants) and may be lost if the iodoalkyne itself strongly interacts with the catalyst through the formation of too strong a π-complex.
- Unveiling the reaction mechanism of the das/chechik/marek synthesis of stereodefined quaternary carbon centersPublication . Silva, Pedro J.; Bernardo, Carlos E. P.The reaction mechanism of the Cu+‐catalyzed introduction of two all‐carbon‐substituted stereocenters in an ynamide system using a Grignard reagent, a zinc carbenoid, and an aldehyde, was investigated using density‐functional theory. In contrast to the formation of an organocopper(I) compound and subsequent carbocupration reaction, previously postulated as the initial step, the reaction proved to instead proceed through an initial complexation of the substrate alkyne bond by the Cu+‐catalyst, which primes this bond for reaction with the Grignard reagent. Subsequent addition of the zinc carbenoid then enables the nucleophilic attack on the incoming aldehyde, which is revealed as the rate‐limiting step. Our computations have also identified the factors governing the regio‐ and setereoselectivity of this interesting reaction, and suggest possible paths forits further development.