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

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Abstract

The diastereo- and enantioselectivity obtained experimentally by List on the proline-catalized 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.
Original languageUnknown
Pages (from-to)2546-2555
JournalJournal of Organic Chemistry
Volume75
Issue number8
DOIs
Publication statusPublished - 1 Jan 2010

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