Filipe J. S. Duarte

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.

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,β-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.

Asymmetric Intramolecular Aldol Reactions of Substituted 1,7-Dicarbonylic Compounds. A Mechanistic Study

The diastereo- and enantioselectivity obtained experimentally by List on the proline-catalyzed intramolecular aldol reaction of substituted 1,7-dicarbonylic compounds was accurately predicted using density functional theory methods at the B3LYP/6-31++G** level. A polarizable continuum model was used to describe solvent effects. The theoretical data agree in good extension with Lists experimental results, both in enantioselectivity and diastereoselectivity, and allow for the confirmation of our previous rationalization of the main factors contributing to the reaction selectivity. While the enantioselectivity results from an important electrostatic contact between the forming alkoxyde group and the proline moiety, the calculated diasteroselectivity results from several steric contacts that can be established between the different substituents and from their relative orientation in respect to the ring conformation. However, for dialdehydes that can originate two diastereomeric enamine intermediates, the proline attack and the immonium formation steps can also be of major importance in the rationalization of the final reaction selectivity, as is the case in two of the six studied systems. The obtained data allows for a full rationalization of the known experimental systems as well as for the extrapolation to new ones with variable substitution at the carbonylic chain.

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.