New kinetic resolution glossary

11 july 2008 - Stereochemistry

In chemistry, kinetic resolution is a method used to obtain enantiopure compounds. It has been around since 1899 and new and refined strategies add added regularly even to a point that things are starting to get confusing. Steinreiber, Faber & Griengl to the rescue. They have carefully dissected the jargon in a novel "concepts" article (DOI) so here is the new and improved kinetic resolution glossary.

* Kinetic resolution. Each enantiomer in a racemic mixture reacts at a different reaction rate preferably one very slow and the other fast to 50% chemical yield at which point one enantiomer is converted to enantiopure product while the other substrate enantiomer is left unreacted. Obvious drawback: only 50% conversion

* Parallel kinetic resolution. Both enantiomers of a racemic mixture are converted equally fast to two altogether different compounds.

* Enantiomeric ratio. Ratio of apparent first order reaction rates of enantiomers in above processes. identical to stereoselectivity factor.

* Deracemization. The transformation of a racemate into a single stereoisomeric product. Very general term. Three main methods: dynamic kinetic resolution, enantionconvergent process, cyclic deracemization.

* Dynamic kinetic resolution (DKR). The new and improved kinetic resolution. Because the two substrate enantiomers can rapidly interconvert (or racemize) for example through a common enolate, a 100% yield is possible after all. The less reactive enantiomer is converted to the more reactive one and from there on to product. In kinetic terms krac is equal or greater than kfast

* Crystallization-induced dynamic resolution (CIDR). A subset of DKR when chemical process is crystallization.

* Enantioconvergent processes (ECP). A form of DKR where each enantiomer in a racemic mixture is reacted with a enantiomer-specific reagent. For example the (S)-substrate forms (R)-product with a enzyme A with inversion of configuration while the (R)-substrate with enzyme B form (R)-product with retention of configuration

* Cyclic deracemization (CycD). Applicable to amino acids, this method involves stereoselective conversion (for example oxidaton) of a racemic substrate forming a achiral intermediate (imine) which his reduced back in a non-stereoselective manner to enantiomeric pair in a 1:1 ratio at which point the cycle can repeat itself.

* De-epimerization. The transformation of a mixture of diastereoisomers into a single isomer. Reverse process of epimerization. Difference with deracemerization: favorable enthalpic driving force

* Crystallization induced asymmetric transformation (CIAT). Subset of de-epimerization whereby a mixture of equilibrating epimers is allowed to selectively crystallize.

Dynamic kinetic asymmetric transformation (DYKAT). The desymmetrization of racemic or diastereomeric mixtures involving interconverting diastereomeric intermediates implying different equilibration rates of the stereoisomers. The number of DYKAT methods currently stand at 4.

DYKAT I. Racemic pair (S) and (R) react with chiral catalyst (S)C to form diastereomeric pair (S,S) and (R,S) which can interconvert dynamically through achiral intermediate. Once again the more slowly reacting species is converted to the faster reacting species. The catalyst disengages and enantiopure product forms.

Dynamic thermodynamic resolution (DTR). Really a form of DYKAT and use discouraged. Diastereomeric interconversion strongly temperature dependent (KR will fail in wrong temperature regime) hence the phrase thermodynamic.

DYKAT II Special form of DYKAT, racemic pair with chiral ligand forms single intermediate in which chiral center is lost. Final enantioselectivity depends on remaining chiral centers in this intermediate. Reminiscent of double catalytic enantioselective transformation

DYKAT III The de-epimerization of a diastereomeric mixture of enantiomeric pairs (involves 4 isomers converging to one enantiopure product).

DYKAT IV Epimerization of two diastereomers proceeds through destruction of both centers (not just one as in DYKAT I) yielding two achiral intermediates. Once again all intermediate species equilibrate and a single stereoisomer is formed.