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One of the most active current areas of chemical research is centered on how to synthesize handed (chiral) compounds in a selective manner, rather than as mixtures of mirror-image forms (enantiomers) with different three-dimensional structures (stereochemistries). Nature points the way in this endeavor different enantiomers of a given biomolecule can exhibit dramatically different biological activities, and enzymes have therefore evolved to catalyze reactions with exquisite selectivity for the formation of one enantiomeric form over the other. Drawing inspiration from these natural catalysts, chemists have developed a variety of synthetic smallmolecule catalysts that can achieve levels of selectivity approaching and in some cases matching, those observed in enzymatic reactions.
Although the principles underlying asymmetric catalysis with enzymes and small molecules are fundamentally the same (1), some striking and rather surprising differences have been noted. William S. Knowles, a pioneer in small molecule asymmetric catalysis, made the following key observation in his Nobel address: "When we started this work we expected these man-made systems to have a highly specific match between substrate and ligand, just like enzymes. Generally, in our hands and in the hands of those that followed us, a good candidate has been useful for quite a range of applications" (2). Indeed, the best synthetic catalysts demonstrate useful levels of enantioselectivity for a wide range of substrates. This is very important to synthetic chemists, who must rely on the predictable behavior of reagents and catalysts when planning new syntheses. With a few important exceptions (such as certain lipases), such generality of scope is not observed in enzymatic catalysis.
It is even more surprising that certain classes of synthetic catalysts are enantioselective over a wide range of different reactions. Such catalysts may be called "privileged structures," in much the same manner that the term has been applied in pharmaceutical research to compound classes that are active against a number of different biological targets (3). Privileged chiral catalysts offer much more than one might have imagined, creating effective asymmetric environments for mechanistically unrelated reactions (Fig. 1).
The story behind the discovery of these structures is different in each case. For instance, BINAP and BINOL are completely synthetic molecules developed to exploit the axial dissymmetry induced by the restricted rotation about the biaryl bond (Fig. 1). The...