Olatz Larrañaga

Phosphoramidite-Cu(OTf)2 complexes as chiral catalysts for 1,3-dipolar cycloaddition of iminoesters and nitroalkenes.

Chiral complexes formed by phosphoramidites such as (Sa,R,R)-9 and Cu(OTf)2 are excellent catalysts for the general 1,3-dipolar cycloaddition between azomethine ylides and nitroalkenes affording the corresponding tetrasubstituted proline esters mainly as exo-cycloadducts in high er at room temperature. The exo-cycloadducts can be obtained in enantiomerically pure form just after simple recrystallization. DFT calculations support the stereochemical results.

Enantioselective Synthesis of Polysubstituted Spiro-nitroprolinates Mediated by a (R,R)-Me-DuPhos·AgF-Catalyzed 1,3-Dipolar Cycloaddition

The synthesis of constrained spirocycles is achieved effectively by means of 1,3-dipolar cyclodditions employing α-imino γ-lactones as azomethine ylide precursors and nitroalkenes as dipolarophiles. The complex formed by (R,R)-Me-DuPhos 18 and AgF is the most efficient bifunctional catalyst. Final spiro-nitroprolinates cycloadducts are obtained in good to moderate yields and both high diastereo- and enantioselectivities. Density functional theory (DFT) calculations supported the expected absolute configuration as well as other stereochemical parameters.

Aggregation and Cooperative Effects in the Aldol Reactions of Lithium Enolates

Density functional theory and Car-Parrinello molecular dynamics simulations have been carried out for model aldol reactions involving aggregates of lithium enolates derived from acetaldehyde and acetone. Formaldehyde and acetone have been used as electrophiles. It is found that the geometries of the enolate aggregates are in general determined by the most favorable arrangements of the point charges within the respective Lin On clusters. The reactivity of the enolates follows the sequence monomer≫dimer>tetramer. In lithium aggregates, the initially formed aldol adducts must rearrange to form more stable structures in which the enolate and alkoxide oxygen atoms are within the respective Lin On clusters. Positive cooperative effects, similar to allosteric effects found in several proteins, are found for the successive aldol reactions in aggregates. The corresponding transition structures show in general sofa geometries.

Synthetic scope and DFT analysis of the chiral binap-gold (I) complex-catalyzed 1,3-dipolar cycloaddition of azlactones with alkenes

Summary The 1,3-dipolar cycloaddition between glycine-derived azlactones with maleimides is efficiently catalyzed by the dimeric chiral complex [(S a)-Binap·AuTFA]2. The alanine-derived oxazolone only reacts with tert-butyl acrylate giving anomalous regiochemistry, which is explained and supported by Natural Resonance Theory and Nucleus Independent Chemical Shifts calculations. The origin of the high enantiodiscrimination observed with maleimides and tert-butyl acrylate is analyzed using DFT computed at M06/Lanl2dz//ONIOM(b3lyp/Lanl2dz:UFF) level. Several applications of these cycloadducts in the synthesis of new proline derivatives with a 2,5-trans-arrangement and in the preparation of complex fused polycyclic molecules are described.

New Insights into the Reactivity of Cisplatin with Free and Restrained Nucleophiles: Microsolvation Effects and Base Selectivity in Cisplatin-DNA Interactions

The reactivity of cisplatin towards different nucleophiles has been studied by using density functional theory (DFT). Water was considered first to analyze the factors that govern the transformation of cisplatin into more electrophilic aquated species by using an activation-strain model. It was found that the selectivity and reactivity of cisplatin is a delicate trade-off between strain and interaction energies and that the second chloride is a worse leaving group than the first. When similar studies were carried out with imidazole, guanine (G), and adenine (A), it was found that in general the second nucleophilic substitution reactions have lower activation barriers than the first ones. Finally, simulations of the structural restrictions imposed by the DNA scaffold in intra- and interstrand processes showed that the geometries of the reaction products are nonoptimal with respect to the unrestrained A and G nucleophiles, although the energetic cost is not considerable under physiological conditions, which thus permits nucleophilic substitution reactions that lead to highly distorted DNA.

Diastereoselective [3 + 2] vs [4 + 2] Cycloadditions of Nitroprolinates with α,β-Unsaturated Aldehydes and Electrophilic Alkenes: An Example of Total Periselectivity

Diastereoselective multicomponent reactions of enantioenriched 4-nitroprolinates, obtained by enantiocatalyzed 1,3-dipolar cycloaddition (1,3-DC) of imino esters and nitroalkenes, with α,β-unsaturated aldehydes and electrophilic alkenes proceed with total periselectivity depending on the structure of the aldehyde employed. This process evolves through a [3 + 2] 1,3-DC when cinnamaldehyde is used in the presence of an azomethine ylide, giving the corresponding highly substituted pyrrolizidines with endo selectivity. However, in the case of the α,β-unsaturated aldehyde, which contains a hydrogen atom at the γ position, an amine-aldehyde-dienophile (AAD) [4 + 2] cycloaddition takes place by formation of an intermediate 1-amino-1,3-diene, affording highly functionalized cyclohexenes with high endo diastereoselectivity. This AAD process only occurred when a nitro group is bonded to the 4-position of the initial enantiomerically enriched pyrrolidine ring. DFT calculations have been carried out with the aim of explaining this different behavior between pyrrolidines with or without a nitro group, demonstrating the strong nitro-group-dependent periselectivity. The results of these computational studies also support the experimentally obtained absolute configuration of the final adducts.

Ion-Pair SN2 Reaction of OH− and CH3Cl : Activation Strain Analyses of Counterion and Solvent Effects

We have theoretically studied the non-identity SN 2 reactions of Mn OH(n-1) +CH3 Cl (M+ =Li+ , Na+ , K+ , and MgCl+ ; n=0, 1) in the gas phase and in THF solution at the OLYP/6-31++G(d,p) level using polarizable continuum model (PCM) implicit solvation. We want to explore and understand the effect of the metal counterion M+ and solvation on the reaction profile and the stereoselectivity of these processes. To this end, we have explored the potential energy surfaces of the backside (SN 2-b) and frontside (SN 2-f) pathways. To explain the computed trends, we have carried out analyses with an extended activation strain model (ASM) of chemical reactivity that includes the treatment of solvation effects.

Intramolecular SEAr Reactions of Phosphorus Compounds: Computational Approach to the Synthesis of π-Extended Heterocycles

The reaction mechanism associated with the synthesis of phosphorus-based heteropolyaromatic architectures was investigated by DFT calculations at the B3LYP-D3/6-311+G(D) level of theory. The aim of this study is to provide essential information for the future development of improved polycyclic organophosphorus materials. To that end, the impact of the structure of the initial reactant and/or the intermediates structure on the mechanistic features and energetic profiles of the phosphorus cyclization process was studied. Moreover, the reactivity parameters were analyzed in detail in a conceptual DFT framework and the underlying reactivity trends were extracted. Thus, these findings provide important insights for a rational design of polycyclic phosphorus compounds.

Mono- and Di-Alkylation Processes of DNA Bases by Nitrogen Mustard Mechlorethamine

The reactivity of nitrogen mustard mechlorethamine (mec) with purine bases towards formation of mono- (G-mec and A-mec) and dialkylated (AA-mec, GG-mec and AG-mec) adducts has been studied using density functional theory (DFT). To gain a complete overview of DNA-alkylation processes, direct chloride substitution and formation through activated aziridinium species were considered as possible reaction paths for adduct formation. Our results confirm that DNA alkylation by mec occurs via aziridine intermediates instead of direct substitution. Consideration of explicit water molecules in conjunction with polarizable continuum model (PCM) was shown as an adequate computational method for a proper representation of the system. Moreover, Runge-Kutta numerical kinetic simulations including the possible bisadducts have been performed. These simulations predicted a product ratio of 83:17 of GG-mec and AG-mec diadducts, respectively.