Content area
Full text
PERSPECTIVES: CHEMISTRY
How small can a highly active and stereoselective catalyst be? And what are the minimal functional and structural features required in a chiral catalyst? A series of recent reports on proline-catalyzed asymmetric reactions may be pointing to the ultimate answer to these practically and fundamentally important questions. The studies are all the more significant because they address some of the most challenging and useful reactions in organic chemistry.
Asymmetric synthesis is dedicated to the preparation of handed (chiral) compounds with defined three-dimensional molecular structure (stereochemistry). The importance of stereochemistry in chemical interactions is probably best appreciated in the context of drug-receptor interactions, because most biological targets are chiral entities. Hence, there is enormous pressure to devise viable and practical methods for preparing chiral compounds in pure form.
Nature is the principal practitioner of asymmetric synthesis. Living systems use enzymes to catalyze stereoselective reactions with very high fidelity. Enzymes exploit hydrogen bonding between the active site and substrate, together with nonbonded dipole-dipole, electrostatic, and steric interactions, to orient the substrate and stabilize the transition state, leading to high levels of stereoselectivity.
The challenge associated with organizing the key transition structure in a catalytic process, such that only a single enantiomer (handedness) of a chiral product is produced, appears formidable. It was therefore long assumed that complex supramolecular structures such as those found in enzymes were required for attaining high enantioselectivity. We now know, however, that synthetic smallmolecule catalysts can approach and sometimes even match the enantioselectivity and reactivity characteristic of enzymes.
Since the first reports appeared in the late 1960s, a wide variety of chiral organometallic complexes have been identified as asymmetric catalysts (1). These catalysts not only effect useful reactions with...