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On the Mechanism of the Asymmetric Aldol Addition of Chiral N‐Amino Cyclic Carbamate Hydrazones: Evidence of Non‐Curtin–Hammett Behavior
Author(s) -
Uddin Md. Nasir,
Knight John D.,
Rastelli Ettore J.,
SoubraGhaoui Chirine,
Albright Thomas A.,
Wu ChiaHua,
Wu Judy I.,
Coltart Don M.
Publication year - 2019
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.201902388
Subject(s) - aldol reaction , chemistry , aldehyde , hydrazone , aldol condensation , diastereomer , lithium (medication) , stereochemistry , medicinal chemistry , organic chemistry , catalysis , medicine , endocrinology
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.