Organolanthanides are highly efficient catalysts for inter- and intramolecular hydroamination of various C-C unsaturations such as alkenes, alkynes, allenes, and dienes. Attractive features of organolanthanide catalysts include very high turnover frequencies and excellent stereoselectivities, rendering this methodology applicable to concise synthesis of naturally occurring alkaloids and other polycyclic azacycles. The general hydroamination mechanism involves turnover-limiting C-C multiple bond insertion into the Ln-N bond, followed by rapid protonolysis by other amine substrates. Sterically less encumbered ligand designs have been developed to improve reaction rates, and metallocene and nonmetallocene chiral lanthanide complexes have been synthesized for enantioselective hydroamination.

C(2)-symmetric bis(oxazolinato)lanthanide complexes of the type [(4R,5S)-Ph(2)Box]La[N(TMS)(2)](2), [(4S,5R)-Ar(2)Box]La[N(TMS)(2)](2), and [(4S)-Ph-5,5-Me(2)Box]La[N(TMS)(2)](2) (Box = 2,2'-bis(2-oxazoline)methylenyl; Ar = 4-tert-butylphenyl, 1-naphthyl; TMS = SiMe(3)) serve as precatalysts for the efficient enantioselective intramolecular hydroamination/cyclization of aminoalkenes and aminodienes. These new catalyst systems are conveniently generated in situ from the known metal precursors Ln[N(TMS)(2)](3) or Ln[CH(TMS)(2)](3) (Ln = La, Nd, Sm, Y, Lu) and 1.2 equiv of commercially available or readily prepared bis(oxazoline) ligands such as (4R,5S)-Ph(2)BoxH, (4S,5R)-Ar(2)BoxH, and (4S)-Ph-5,5-Me(2)BoxH. The X-ray crystal structure of [(4S)-(t)BuBox]Lu[CH(TMS)(2)](2) provides insight into the structure of the in situ generated precatalyst species. Lanthanides having the largest ionic radii exhibit the highest turnover frequencies as well as enantioselectivities. Reaction rates maximize near 1:1 BoxH:Ln ratio (ligand acceleration); however, increasing the ratio to 2:1 BoxH:Ln decreases the reaction rate, while affording enantiomeric excesses similar to the 1:1 BoxH:Ln case. A screening study of bis(oxazoline) ligands reveals that aryl stereodirecting groups at the oxazoline ring 4 position and additional substitution (geminal dimethyl or aryl) at the 5 position are crucial for high turnover frequencies and good enantioselectivities. The optimized precatalyst, in situ generated [(4R,5S)-Ph(2)Box]La[N(TMS)(2)](2), exhibits good rates and enantioselectivities, comparable to or greater than those achieved with chiral C(1)-symmetric organolanthanocene catalysts, even for poorly responsive substrates (up to 67% ee at 23 degrees C). Kinetic studies reveal that hydroamination rates are zero order in [amine substrate] and first order in [catalyst], implicating the same general mechanism for organolanthanide-catalyzed hydroamination/cyclizations (intramolecular turnover-limiting olefin insertion followed by the rapid protonolysis of an Ln-C bond by amine substrate) and implying that the active catalytic species is monomeric.

The efficient synthesis of enantioenriched compounds is becoming increasingly important in modern organic, pharmaceutical, and materials chemistry. Recently, chiral cooperative bimetallic catalysts have emerged as a powerful tool to achieve high efficiency and selectivity in asymmetric transformations. This tutorial review highlights strategies and recent advances in cooperative bimetallic catalysts which have been developed for a variety of asymmetric transformations.

Among the agents classified as “Category A” by the U.S. Centers for Disease Control and Prevention, botulinum neurotoxin (BoNT) is the most toxic protein known, with microgram quantities of the protein causing severe morbidity and mortality by oral or i.v. routes. Given that this toxin easily could be used in a potential bioterrorist attack, countermeasures urgently are needed to counteract the pathophysiology of BoNT. At a molecular level, BoNT exerts its paralytic effects through intracellular cleavage of vesicle docking proteins and subsequent organism-wide autonomic dysfunction. In an effort to identify small molecules that would disrupt the interaction between the light-chain metalloprotease of BoNT serotype A and its cognate substrate, a multifaceted screening effort was undertaken. Through the combination of in vitro screening against an optimized variant of the light chain involving kinetic analysis, cellular protection assays, and in vivo mouse toxicity assays, molecules that prevent BoNT/A-induced intracellular substrate cleavage and extend the time to death of animals challenged with lethal toxin doses were identified. Significantly, the two most efficacious compounds in vivo showed less effective activity in cellular assays intended to mimic BoNT exposure; indeed, one of these compounds was cytotoxic at concentrations three orders of magnitude below its effective dose in animals. These two lead compounds have surprisingly simple molecular structures and are readily amenable to optimization efforts for improvements in their biological activity. The findings validate the use of high-throughput screening protocols to define previously unrecognized chemical scaffolds for the development of therapeutic agents to treat BoNT exposure.

-The design and solution-phase synthesis of an α-helix mimetic library as an integral component of a small molecule library targeting protein-protein interactions are described. The iterative design, synthesis, and evaluation of the candidate α-helix mimetic was initiated from a precedented triaryl template and refined by screening the designs for inhibition of MDM2/p53 binding. Upon identifying a chemically and biologically satisfactory design and consistent with the screening capabilities of academic collaborators, the corresponding complete library was assembled as 400 mixtures of 20 compounds (20 × 20 × 20-mix), where the added subunits are designed to mimic all possible permutations of the naturally occurring i, i+4, i+7 amino acid side chains of an α-helix. The library (8000 compounds) was prepared using a solution-phase synthetic protocol enlisting acid/base liquid-liquid extractions for purification on a scale that insures its long term availability for screening campaigns. Screening of the library for inhibition of MDM2/p53 binding not only identified the lead α-helix mimetic upon which the library was based, but also suggests that a digestion of the initial screening results that accompany the use of such a comprehensive library can provide insights into the nature of the interaction (e.g., an α-helix mediated protein-protein interaction) and define the key residues and their characteristics responsible for recognition.