A theoretical foundation, tools for recognition and control, and recent examples of a class of asymmetric transformation termed dynamic thermodynamic resolution are presented. Enantioselective reaction pathways that involve an induced diastereomeric equilibration to intermediates, which are configurationally stable on the time scale of a subsequent reaction, are illustrated. Dynamic thermodynamic resolution differs from the classic, well-documented pathways of kinetic resolution and dynamic kinetic resolution in that equilibration and resolution can be operative on one system in separate controllable steps. This approach offers a high level of flexibility and provides multiple opportunities for optimization of enantioselectivity.

The reaction pathways for the highly enantioselective, (−)-sparteine-mediated, lithiation−substitution reactions of N-Boc-N-(p-methoxyphenyl)cinnamylamine ((E)-2) have been investigated. The solution structure of the major allyllithium intermediate has been determined by 6Li and 13C NMR to be a monomeric η3 species, endo-syn-anti-8·1. The complexes exo-syn-anti-8·1, endo-syn-syn-8·1, and exo-syn-syn-8·1 are also shown to be present in solution. The enantiodetermining step in the lithiation−silylation or lithiation−alkylation of (E)-2 can involve asymmetric deprotonation, dynamic kinetic resolution, or dynamic thermodynamic resolution. The results reported herein establish that each of these pathways can be operative. This information allows determination of the stereochemical course for each step of these reactions and permits preparation of either epimer at the new stereogenic carbon.