Enzymes do amazing things and are Nature’s ultimate catalysts to carry out the chemical reactions of life. They are very complex and not easily duplicated in the lab. A big scientific question is: How does one develop a small molecule catalyst that can carry out the functions of a biological enzyme? Recently, Scientist from NDSU’s Department of Chemistry and Biochemistry have made headway in this direction. A recent paper by University Distinguished Professor Mukund Sibi, postdoctoral research fellow Jun Deng and graduate student Gaoyuan Ma in the journal Angewante Chemie International Edition, is turning heads and making an impact. The paper was featured by the journal as a cover article.
Kinetic resolution is a means of differentiating two enantiomers (left and right handed molecules) in a racemic mixture. In kinetic resolution, two enantiomers react with different reaction rates in a chemical reaction with a chiral catalyst or a reagent, resulting in an enantioenriched sample of the less reactive enantiomer. In the biology world, enzymes do these types of reactions on a routine basis. Organic chemists have adapted enzymes such as lipases to carry out kinetic resolutions. There are several drawbacks for the use of native enzymes in organic reactions: (1) ready availability in pure form, (2) high molecular weight, (3) limited solubility in organic solvents, and (4) stability to degradation. Thus there is significant interest in the development of small organic molecules or organocatalysts that can mimic enzymes.
The paper by Ma, Deng and Sibi details the use of novel fluxionally chiral dimethylaminopyridine (DMAP) organocatalysts. DMAP’s are superbases and form reactive intermediates with anhydrides in situ which can resolve racemic secondary alcohols and axially chiral birayls (atropisomers, handedness from rotation about a single bond). Chiral dihydroxy biaryl derivatives are used extensively as ligands for stereoselective reactions. Thus development of catalysts that can resolve a variety of biaryls efficiently is significant. In organic chemistry, the efficiency of a catalyst to carry out kinetic resolution is denoted by an s factor, the higher the number the better it is. There is only one example of chiral DMAP catalyzed acylative kinetic resolution of 1,1’-binaphthyl derivatives proceeding with only modest selectivities (s = 1-4). The Sibi group has designed useful templates, ligands, and additives that use fluxional groups to control and/or enhance stereoselectivity in a variety of asymmetric transformations. Fluxional substituents are groups that undergo inversion rapidly, for example, a nitrogen with three substituents. A day-to-day analogy is the behavior of an umbrella on a windy day. A key feature of this strategy is that the size of the fluxional substituent can be varied readily and easily. Using this novel concept, several chiral DMAP catalysts containing fluxional chirality have been prepared. These catalysts were found to be highly efficient in promoting kinetic resolution of sec-alcohols and axially chiral binols. Biaryl substrates were resolved with s factors of up to 51 by using the new catalyst system. The selectivities obtained for resolution of biaryl compounds are better than previously reported asymmetric acylation catalysts. These results clearly demonstrate the novelty and utility of the chiral DMAP catalysts.