Catalytic asymmetric 5-enolexo aldolizations. A computational study.

Area of Science:

• Organic Chemistry
• Computational Chemistry

Background:

• Amine-catalyzed intramolecular 5-enolexo aldolization of 1,6-dicarbonyl compounds is a key reaction.
• Previous models, like Houk's, effectively explain 6-enolexo aldolizations based on sterics and electrostatics.

Purpose of the Study:

• To rationalize the diastereo- and enantioselectivity observed in amine-catalyzed intramolecular 5-enolexo aldolizations.
• To identify the key factors governing selectivity in 5-enolexo aldolization reactions.

Main Methods:

• Density functional theory (DFT) methods were employed to model the reaction.
• A polarizable continuum model (PCM) was used to account for solvent effects.

Main Results:

• Selectivity in 5-enolexo aldolizations is determined by a combination of small electrostatic contacts, unexpected HOMO electronic overlap, and five-membered ring strain.
• Steric effects were found to be unimportant in controlling selectivity for 5-enolexo processes.
• High selectivities are not generally expected for this reaction type, and experimental outcomes are likely condition-dependent.

Conclusions:

• The factors governing selectivity in 5-enolexo aldolizations differ significantly from those in 6-enolexo aldolizations.
• Computational findings suggest that achieving high selectivity in 5-enolexo aldolizations may be challenging and highly sensitive to reaction conditions.
• Differences in reaction rates with various catalysts are likely attributable to catalyst solubility variations.