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 ß-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.

Stereoselective synthesis of quaternary carbons via the dianionic Ireland-Claisen rearrangement.

A dianionic Ireland-Claisen rearrangement of chiral, nonracemic α-methyl-ß-hydroxy allylic esters has been developed that proceeds with high diastereoselectivity and provides products containing three contiguous stereogenic carbons, including a quaternary center. The potential utility of the rearrangement for complex molecule synthesis is also demonstrated.

Asymmetric anti-aldol addition of achiral ketones via chiral N-amino cyclic carbamate hydrazones.

The asymmetric anti-aldol addition of ketone-derived donors and aldehyde acceptors is described. Asymmetric induction is achieved through the use of chiral N-amino cyclic carbamate (ACC) auxiliaries. The transformation exhibits essentially perfect anti-diastereoselectivity and enantioselectivity, and has the unusual feature of proceeding via thermodynamic, rather than kinetic control.

Asymmetric total synthesis of the antimalarial drug (+)-mefloquine hydrochloride via chiral N-amino cyclic carbamate hydrazones.

Mefloquine hydrochloride is an important antimalarial drug. It is currently manufactured and administered in racemic form; however there are indications regarding the biological activity of the two enantiomers that suggest the superiority of the (+)-form. The asymmetric total synthesis of the (+)-enantiomer of mefloquine hydrochloride is described. The key asymmetric transformation utilized is a novel asymmetric Darzens reaction of a chiral α-chloro-N-amino cyclic carbamate hydrazone derived from an N-amino cyclic carbamate (ACC) chiral auxiliary.