Directed electrostatic activation in enantioselective organocatalytic cyclopropanation reactions: a computational study.

Cyclopropane rings are versatile building blocks in organic chemistry. Their synthesis, by the reaction of sulfur ylides with α,ß-unsaturated carbonyl compounds, has recently aroused renewed interest after the discovery of efficient catalysis by using (S)-indoline-2-carboxylic acid. In order to rationalize the behavior of this catalyst, MacMillan proposed a directed electrostatic activation (DEA) mechanism, in which the negative carboxylate group interacts with the positive thionium moiety, thus reducing the activation energy and increasing the reaction rate. More recently, Mayr refuted some of MacMillan conclusions, but accepted the DEA mechanism as a justification for the experimental high reaction rates. In contrast, our results indicate that the selectivity obtained in the process seems to result from several strong hydrogen bond interactions between the two reacting species, while no strong evidence for a DEA mechanism was found. We also concluded that the hydrogen bonds don't improve the reaction rate by lowering the activation energy of the rate-determining step, but can do it by promoting efficient reaction trajectories due to long-range complexation of the reagents. Finally, our results confirm that the cyclopropanation reaction occurs by a two-step mechanism, and that the overall enantioselectivity depends on the relative energies of the two steps, averaged by the relative populations of the iminium intermediates that are initially formed in the reaction.

A computational study on the stereoselective organocatalytic epoxidation of α,ß-unsaturated aldehydes with hydrogen peroxide.

The asymmetric synthesis of vicinal diols is a very important process in organic chemistry, as it allows the preparation of a large variety of useful derivatives. One of the most interesting methods to accomplish this synthesis is the asymmetric epoxidation of activated olefins, catalysed by chiral organic or organometallic catalysts. In this paper we study, with computational tools, two possible mechanisms for the asymmetric epoxidation of conjugated aldehydes with hydrogen peroxide, catalysed by chiral pyrrolidine derivatives lacking proton donor groups. Our results indicate that the mechanism that proceeds by the initial formation of an iminium intermediate is more probable than the mechanism proceeding by general base catalysis. We also conclude that besides the oxidant role of hydrogen peroxide, it also has a very important role as a co-catalyst in the initial formation of the iminium intermediates. Moreover, epoxide formation is suggested to be a two-step process that needs the explicit participation of a hydroxyl ion. In the absence of this ion, epoxidation was calculated to be a single step process that does not explain the experimental selectivity. In contrast with the currently accepted idea, the overall calculated selectivity results mainly from the iminium formation steps and from the second step of the epoxidation reaction.

Enantioselective organocatalytic intramolecular Diels-Alder reactions: a computational study.

The diastereo- and enantioselectivity obtained experimentally by Christmann in the amine-catalyzed intramolecular Diels-Alder reaction of α,ß-unsaturated carbonylic compounds were fully rationalized using density functional theory methods at the PBE1PBE/6-311+G** level. A polarizable continuum model was used to describe solvent effects. The selectivity is induced in the cyclization step, and while the enantioselectivity results from the syn/anti orientation around the C-N enamine bond, the diastereoselectivity mainly results from the syn/anti configuration of the substituents in the forming cyclopentane ring. The remarkable reaction rate experimentally observed when an external protic acid is used is attributed to the strong decrease in the activation energy of all steps needed for the enamine formation, while the external acid marginally influences the cyclization step. When hydrogen-bond-donor catalysts are used, the formation of one hydrogen bond in the cyclization step inverts the configuration and reduces the selectivity. The different behavior between dialdehydes and ketoaldehydes is suggested to be resulting from different reaction rates in the catalyst elimination step.

Catalytic asymmetric 5-enolexo aldolizations. A computational study.

The diastereo- and enantioselectivity obtained experimentally by Enders et all. (Enders, D.; Niemeier, O.; Straver, S. Synlett 2006, 3399-3402) in the amine-catalyzed intramolecular 5-enolexo aldolization of 1,6-dicarbonyl compounds were fully rationalized using density functional theory methods. A polarizable continuum model was used to describe solvent effects. While 6-enolexo aldolizations are well described by Houk's model on the basis of steric and electrostatic contacts, the main factors conditioning the final selectivity in 5-enolexo processes are calculated to be quite different. Thus, the selectivity results from the summation of several small electrostatic contacts with an unexpected HOMO electronic overlapping plus the ring strain of the five-membered ring, whereas steric effects seem to be unimportant. Our results indicate, in contrast with 6-enolexo processes, that high selectivities are not expected in this type of reaction and that the experimental selectivity shall be very dependent on the reaction conditions, as known experimental results seem to suggest. 7-enolendo products are not expected, as they are predicted to be formed by higher energetic transition states. Variable reaction rates, experimentally observed with different catalysts, are suggested to be mainly a result of different catalyst solubilities.

Lewis acid catalyzed reactions of chiral imidazolidinones and oxazolidinones: insights on the role of the catalyst.

The mechanism proposed by Evans to justify the selectivity obtained in Lewis acid catalyzed Diels-Alder reactions of cyclopentadiene with acyloxazolidinones has been generalized and used in the rationalization of selectivities obtained in many other systems. However, we recently proposed an alternative mechanism, on the basis of open-chain mono- and bicomplexes, that avoids the need for chelates and explains the selectivity obtained by Evans. In this manuscript we apply our proposal to the catalyzed conjugated addition of amines to acylimidazolidinones, reported by Cardillo, and we clearly show that aluminum chelates are not involved in the reaction, as they induce no selectivity, while Cardillo observed high experimental selectivities. Our data equally show that bicomplexes with carbonyl parallel orientation, proposed by Cardillo to justify the experimental selectivity with nonchelating Lewis acids, indeed induce the opposite selectivity and have also to be dismissed. On the other hand, our mechanistic proposal allows for the full rationalization of the data obtained by Cardillo with aluminum, boron, or zinc Lewis acids and supports our previous proposal on DA cycloadditions of dienes to Evans chiral auxiliary derivatives.

Density functional study of proline-catalyzed intramolecular Baylis-Hillman reactions.

The mechanisms of proline-catalyzed and imidazole-co-catalyzed intramolecular Baylis-Hillman reactions have been studied by using density functional theory methods at the B3LYP/6-31G(d,p) level of theory. A polarizable continuum model (PCM B3LYP/6-31++G(d,p)//B3LYP/6-31G(d,p)) was used to describe solvent effects. Different reaction pathways were investigated, which indicated that water is an important catalyst in the imine/enamine conversion step in the absence of imidazole. When imidazole is used as a co-catalyst, water is still important in the imidazole addition step, but is not present in the Baylis-Hillman cyclization step. The computational data has allowed us to rationalize the experimental outcome of the intramolecular Baylis-Hillman reaction, validating some of the mechanistic steps proposed in the literature, as well as to propose new ones that considerably change and improve our understanding of the full reaction path.

An alternative mechanism for Diels-Alder reactions of Evans auxiliary derivatives.

The mechanism proposed by Evans for the dialkylaluminum chloride promoted Diels-Alder reaction of cyclopentadiene with alpha,beta-unsaturated N-acyloxazolidinones has been widely used as a basis for the rationalization of the experimental selectivities observed in many different types of reactions in which oxazolidinones or imidazolidinones are used as chiral auxiliaries. In this manuscript we introduce a new and more general model based on molecular modeling and NMR spectroscopy data that avoids several ambiguous concepts raised by the Evans model and fully explains all available experimental data. While the Evans proposal relies on the formation of high-energetic ionic chelates that promote the rotation of the amide bond in the N-acyloxazolidinone molecule, our model is based on the catalysis by means of low-energetic mono- or bicomplexes at the chain and the ring carbonyl groups that are easily observed by NMR spectroscopy measurements. The observed selectivities are explained by a chirality-transfer concept, in which an achiral Lewis acid works as a bridge for the transfer of chirality between a chiral auxiliary and a prochiral reactive center. Different to the Evans proposal, this mechanism fully explains the experimental selectivities for low Lewis acid concentrations, based on the catalysis by means of concurrent monocomplexes at the chain or the ring carbonyl groups, as well as the increased reaction rates and selectivities experimentally observed for high Lewis acid concentrations. The model can be extrapolated to nonchelating and other chelating Lewis acids, thereby allowing for the rationalization of much experimental data that were never explained by the Evans proposal.

Opening the Way to Catalytic Aminopalladation/Proxicyclic Dehydropalladation: Access to Methylidene γ-Lactams.

A new aerobic intramolecular palladium(II)-based catalytic system that triggers aminopalladation/dehydropalladation of N-sulfonylalkenylamides to give the corresponding methylidene γ-lactams has been identified. Use of triphenylphosphine and chloride anion as ligands is mandatory for optimal yields, and molecular oxygen can be used as the sole terminal oxidant. Scope and limitations of the methods are described. A mechanism is proposed on the basis of experimental results as well as density functional theory calculations.