On the Mechanism of the Asymmetric Aldol Addition of Chiral N-Amino Cyclic Carbamate Hydrazones: Evidence of Non-Curtin-Hammett Behavior.

he mechanistic details of the aldol addition of N-amino cyclic carbamate (ACC) hydrazones is provided herein from both an experimental and computational perspective. When the transformation is carried out at room temperature the anti-aldol product is formed exclusively. Under these conditions the anti- and syn-aldolate intermediates are in equilibrium and the transformation is under thermodynamic control. The anti-aldolate that leads to the anti-aldol product was calculated to be 3.7 kcal mol-1 lower in energy at room temperature than that leading to the syn-aldol product, which sufficiently accounts for the exclusive formation of the anti-aldol product. When the reaction is conducted at -78 °C it is under kinetic control and favors formation of the syn-aldol addition product. In this case, it was found that a solvent separated aza-enolate anion and aldehyde form a σ-intermediate in which the lithium cation is coordinated to the aldehyde. The σ-intermediate collapses with a very small activation barrier to form the β-alkoxy hydrazone intermediate. The chiral nonracemic lithium aza-enolate discriminates between the two diastereotopic faces of the pro-chiral aldehyde, and there is no rapid direct pathway that interconverts the two diastereomeric intermediates. Consequently, the reaction does not follow the Curtin-Hammett principle and the stereochemical outcome at low temperature instead depends on the relative energies of the two σ-intermediates.