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

Abstract

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 List's 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.

Catalytic Asymmetric 5-enolexo Aldolizations. A Computational Study

“…On the other hand, with the exception of catalyst 11, the rate-limiting step is the dehydration step (TS-2), in agreement with previous results. 32,34 With catalyst 11, the rate-limiting step is the enamine formation (but almost isoenergetic with TS-2), which correlates with the relative acidities of the different tested catalysts (see the Supporting Information). The acid strength of the catalyst is mainly important in TS-2 and TS-6, as the acid has to protonate the oxygen atom, reducing its negative charge.…”

“…All structures were calculated with the pyrrolidine ring of the catalyst in its lower-energy conformation. 26,32 The inclusion of the other possible TSs does not change the calculated selectivities, as seen in the Supporting Information when the catalyst is proline.…”

“…34 However, proline and other proline derivatives with small substituent groups do not induce any important energy difference between the two enamine conformers, in enamines resulting from either aldehydes or ketones (Scheme 3). 32 Thus, in Figure 1, the steric effects result from the equatorial versus axial conformation of the catalyst moiety and not from the syn/anti orientation of the enamine bond. In the structures in Figure 2, there is also the possibility of equatorial/axial orientations (see the Supporting Information for a different perspective of the four TSs).…”

“…Recently, we reported that the rate-limiting step in catalytic 6enolexo aldol condensations of 1,7-dicarbonylic compounds can be either the initial attack of the catalyst to the carbonyl group or the iminium formation step, 32 a result that is in full agreement with kinetic studies reported by Meyer et al 33 Thus, in order to rationalize the large variation of the reaction rates reported by Enders et al, it is necessary to evaluate not only the activation energies of the cyclization TSs but also the activation energies of the enamine formation steps. As these types of structures were already discussed in detail, 32,34 only a general scheme is presented (Scheme 4), the main values being compiled in Table 2 (full data are given in the Supporting Information). For an easy comparison with the experimental results, the calculated selectivities for the cyclization step are already given in Table 1.…”

Enantioselective Organocatalytic Intramolecular Diels–Alder Reactions: A Computational Study

“…It is accepted that the amine-catalyzed IMDA reaction of dialdehydes follows an enamine pathway, as described in Scheme . The enamine formation steps have been intensely studied over the last years, when the catalyst is proline, and it is now accepted that its carboxylic acid plays an important role in the catalytic process. − However, the work from Christmann is mainly based on catalysts that do not allow for intramolecular acid catalysis, used alone or assisted by external protic acids, a situation that was not previously studied by computational methods.…”