This review showcases various coupling reagents which have been implemented specifically for large-scale amide synthesis via the condensation of an acid and amine, while highlighting the benefits and drawbacks of each reagent on an industrial scale.

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.

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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.

The (-)-sparteine-mediated asymmetric lithiation-substitution of (E)-N-Boc-N-(p-methoxyphenyl)-3-cyclohexylallylamine ((E)-5) to afford gamma-substituted enantiomerically enriched products 6 is reported. The solution structure for the lithiated intermediate 8.1 in these reactions was determined by heteronuclear NMR to be a configurationally stable, alpha-lithio, eta(1)-coordinated monomer. This intermediate is proposed to exist as two rotamers that are rapidly equilibrating on the NMR time scale; competitive electrophilic substitution of each conformation results in the formation of Z or E products. Kinetic measurements of the lithiation by in situ infrared spectroscopy provide pseudo-first-order rate constants for reactions with a variety of concentrations of amine, (-)-sparteine, and n-BuLi. The reaction is first order in amine and zero order in 1:1 base--ligand complex. When the concentration of n-BuLi is varied independently of (-)-sparteine concentration, the reaction rate exhibits an inverse dependence on n-BuLi concentration. The deuterium isotope effect for the reaction was determined to be 86 at -75 degrees C, a result consistent with C--H bond breaking in the rate-determining step and indicative of tunneling. A reaction pathway involving a prelithiation complex is supported by kinetic simulations.