Dynamic Thermodynamic Resolution: Advantage by Separation of Equilibration and Resolution

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• 作者：Won Koo Lee† ; Yong Sun Park‡ ; Peter Beak*§
• 刊名：Accounts of Chemical Research
• 出版年：2009
• 出版时间：February 17, 2009
• 年：2009
• 卷：42
• 期：2
• 页码：224-234
• 全文大小：396K
• 年卷期：v.42,no.2(February 17, 2009)
• ISSN：1520-4898

文摘

In the investigation of a chemical reaction, researchers typically survey variables such as time, temperature, and stoichiometry to optimize yields. This Account demonstrates how control of these variables, often in nontraditional ways, can provide significant improvements in enantiomeric ratios for asymmetric reactions. Dynamic thermodynamic resolution (DTR) offers a convenient method for the resolution of enantiomeric products in the course of a reaction. This process depends on an essential requirement: the equilibration of the penultimate diastereomers must be subject to external control. As a general case, the reaction of A_R, A_S with B under the influence of the chiral species, L*, gives resolved products C_R and C_S.

In the first step of dynamic resolution under thermodynamic control, the enantiomeric reactants A_R and A_S and L* form the diastereomers A_R/L* and A_S/L*. The equilibrium between A_R and A_S can be rapid, slow, or not operative, and L* can represent a ligand, an auxiliary, or a crystallization process that provides a chiral environment. Second, the populations of the diastereomers are controlled, usually by thermal equilibration. Finally, the reaction of the diastereomers with a reagent B provides the enantiomeric products C_R and C_S. The control of the diastereomeric equilibrium distinguishes DTR from other resolution techniques. By contrast, physical resolutions separate thermodynamically stable, nonequilibrating diastereomers, and dynamic kinetic resolutions utilize kinetic control for reactions of rapidly equilibrating diastereomers.

The dynamic thermodynamic resolutions discussed in this Account illustrate cases of significantly improved enantioselectivities using this technique. Although many of the well-recognized cases come from organolithium chemistry, the principles are general, and we also present cases facilitated by other chemistries. This approach has been used to control enantioselectivities in a number of different reactions, with improvements in enantiomeric ratios up to 99% from essentially racemic reactants.