Of 1,327 totally synthetic drugs marketed worldwide in 1990, 528 were chiral. Often only one enantiomer or a chiral drug provides the desired pharmacological action. The opposite enantiomer may have toxic or harmful effects. Thus, syntheses that give racemic drugs are wasteful and potentially dangerous. Surprisingly, only 61 of the 528 synthetic chiral drugs were marketed in non-racemic form in 1990. The most recent FDA policy (1992) allows case-by-case approval of racemates, but absorption/distribution/ metabolism/excretion studies are required on individual enantiomers. Similar considerations apply to chiral inhalation anesthetics and agricultural chemicals. Hence, enantiomeric purity has become a major issue in pharmaceutical synthesis. Transition metal compounds see extensive use in organic synthesis. Accordingly, the objectives of this project are to (1) develop new methods for enantioselective syntheses of organic compounds using chiral transition metal reagents and catalysts, and (2) elucidate mechanisms and underlying general principles of metal-mediated asymmetric induction. The latter includes binding studies that define new paradigms and controlling features in """"""""chiral recognition"""""""" -- a pervasive concept in chemistry and biology. Studies will utilize (1) """"""""chiral-at-metal"""""""" species, such as pseudotetrahedral adducts (pentahapto-C5H5)M(L)(PPh3)(X), and (2) complexes that contain chiral spectator ligands, such as diphosphines. Specific goals include: (A) the development of stereoselective additions of nucleophiles and electrophiles to nitrogen donor ligands with N=C and NC=C linkages, and applications in alkaloid syntheses; (B) studies of other types of nitrogenous ligands as """"""""chiral bases"""""""" for enantioselective deprotonations, alkylations, and related transformations; (C) the generation of new families of more highly acidic chiral transition metal Lewis acids, and their use as catalysts for enantioselective Diels-Alder reactions, condensations of carbonyl compounds and nucleophilic alkenes, and related processes; (D) a detailed characterization of the diverse binding modes possible for selected Lewis bases (e.g., pi/sigma, E/Z and various conformational isomers), including equilibrium measurements and rate studies that will clarify mechanisms of enatioselection; and (E) the development and testing of a model for chiral recognition in dihapto-pi complexes that is based upon the relative steric properties of four quatrants, and enables the enantioface binding selectivities of different classes of ligands to be rationally optimized.
