Kinetic resolution

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In kinetic resolution two enantiomers show different reaction rates in a chemical reaction thereby creating an excess of the less reactive enantiomer [1]. This excess goes through a maximum and disappears on full completion of the reaction. Kinetic resolution is a very old concept in organic chemistry and can be used in the organic synthesis of chiral molecules. It has been surpassed by other methods.

Kinetic resolution was first observed by Marckwald and McKenzie in 1899 [2] in the esterification reaction of racemic mandelic acid with optically active (-)-menthol to a pair of diastereomeric esters.

Kinetic resolution Marckwald

In this reaction the (R)-enantiomer of mandelic acid displays the higher reaction rate and with incomplete conversion the reaction mixture gets enriched in (S)-mandelic acid. Full hydrolysis of the incomplete mixture of esters gives an excess of (R)-mandelic acid. Taking the reaction to 100% completion will again produce equal amounts of both esters.

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[edit] Dynamic kinetic resolution

An important extension of kinetic resolution is called dynamic kinetic resolution or DKR for short. It tackles the obvious drawbacks of the above described system that the maximum conversion in the reaction is only 50% and that the product has to be separated from the reactants. In DKR it is possible to convert the achiral reactant with 100% completion because both (reactant) enantiomers form a chemical equilibrium and exchange. In this way the faster reacting enantiomer is replenished in the course of the reaction at the expense of the slower reacting enantiomer. The observed dynamics are based on the Curtin-Hammett principle. In order to separate this process from classic resolution (which strictly speaking it is not) the term dynamic kinetic asymmetric transformation (DYKAT) has been introduced [3].

One of the earliest demonstrations of this method[4] is an adaptation of the Noyori asymmetric hydrogenation by Ryoji Noyori:

Dynamic Kinetic Resolution Noyori 1989

The enantiomers interconvert through their common enol. The ultimate reaction product is the protected syn adduct l-threonine (2S,3R) with 99% diastereomeric excess (preference for the syn diastereomeric pair and not the anti pair) and 99% enantiomeric excess (preference for 3R product within syn-pair).

One study examined the biocatalytic acetylation of a racemic 8-amino-tetrahydroquinoline (1) with Candida antarctica [5] Lipase B:

Dynamic Kinetic Resolution Crawford 2007

The enzyme only converts the R-enantiomer and in regular kinetic resolution a 50:50 mixture of (S)-amine (2) is retained and (R)-acetamide (3) obtained. It turns out that the amine is racemized thus increasing the yield of the acetamide beyond 50% and turning the process into a DKR one. The compound believed to be responsible for the racemization path is the ketone A formed in catalytic quantities from the amine by action of the same enzyme and a catalytic amount of water. The ketone is able to form the racemic enamine 3 which can be hydrolyzed back to the amine.

In a second DKR method both enantiomers of a racemic pair form a prochiral intermediate or a meso compound. An example is the allylic asymmetric alkylation depicted below which proceeds through a pseudo-meso palladium - allyl complex [3] [6].

DYKAT AAA application Trost 2007

[edit] Mutual and Parallel Kinetic resolution

Mutual kinetic resolution (MKR) is the reaction between two sets of racemic compounds via a kinetic pathway. The reason for the kinetic resolution to be described as a "mutual" kinetic resolution is due to the mutual reaction between the two sets of racemates.

Parallel kinetic resolution (PKR) is much the same as mutual kinetic resolution except that, instead of using two sets of racemates, only one set of racemates is used and resolved using a pseudo-enantiomeric mixture of reagents.

[edit] See also

v • d • e
Concepts in asymmetric synthesis
Nomenclature
Analysis
Chiral resolution
Reactions

[edit] External links

  • Dynamic chiral resolutions A MacMillan Group Meeting Jake Wiener Link
  • Dynamic Kinetic Resolution:A Powerful Approach to Asymmetric Synthesis Erik Alexanian Supergroup Meeting March 30, 2005 Link
  • Dynamic Kinetic Resolution: Practical Applications in Synthesis Valerie Keller 3rd Year Seminar November 1, 2001 Link

[edit] References

  1. ^ Asymmetric Synthesis of Natural Products, Ari Koskinen ISBN 0-471-93848-3
  2. ^ W. Marckwald, A. McKenzie, Ber. Dtsch. Chem. Ges. 1899
  3. ^ a b Palladium-Catalyzed Dynamic Kinetic Asymmetric Allylic Alkylation with the DPPBA Ligands Barry M. Trost and Daniel R. Fandrick Aldrichimica Acta 40, 3 , 2007 [1]
  4. ^ Stereoselective hydrogenation via dynamic kinetic resolution R. Noyori, T. Ikeda, T. Ohkuma, M. Widhalm, M. Kitamura, H. Takaya, S. Akutagawa, N. Sayo, T. Saito, and et al. J. Am. Chem. Soc.; 1989; 111(25) pp 9134 - 9135; doi:10.1021/ja00207a038
  5. ^ Spontaneous Enzymatically Mediated Dynamic Kinetic Resolution of 8-Amino-5,6,7,8-tetrahydroquinoline Jason B. Crawford, Renato T. Skerlj, and Gary J. Bridger J. Org. Chem.; 2007; 72(2) pp 669 - 671; (Note) doi:10.1021/jo062037t
  6. ^ Reagents: DACH ligand, Allylpalladium chloride dimer, Caesium carbonate and Dimethyl malonate