Bifunctional Lewis acid-nucleophile-based asymmetric catalysis: mechanistic evidence for imine activation working in tandem with chiral enolate formation in the synthesis of beta-lactams.

We report a mechanistically based study of bifunctional catalyst systems in which chiral nucleophiles work in conjunction with Lewis acids to produce beta-lactams in high chemical yield, diastereoselectivity, and enantioselectivity. Chiral cinchona alkaloid derivatives work best when paired with Lewis acids based on Al(III), Zn(II), Sc(III), and, most notably, In(III). Homogeneous bifunctional catalysts, in which the catalyst contains both Lewis acidic and Lewis basic sites, were also studied in detail. Mechanistic evidence allows us to conclude that the chiral nucleophiles form zwitterionic enolates that react with metal-coordinated imines. Alternative scenarios, which postulated metal-bound enolates, were disfavored on the basis of our observations.

Development of a new dimeric cyclophane ligand: application to enhanced diastereo- and enantioselectivity in the catalytic synthesis of beta-lactams.

We detail the synthesis of a new C(2)-symmetric bis(cyclophane) ligand system that can be thought of as electronically analogous to binol, but which possesses the added "third dimension" of cyclophane chirality. The ligand synthesis involves a spontaneous (but unexpected) atropisomerization to the desired product. We have employed this ligand to form a metal complex that is an effective cocatalyst for the highly enantio- and diastereoselective catalytic asymmetric synthesis of a beta-lactam.

Catalytic, asymmetric alpha-chlorination of acid halides.

We present a full account of a tandem catalytic, asymmetric chlorination/esterification process that produces highly optically enriched alpha-chloroesters from inexpensive, commercially available acid halides using cinchona alkaloid derivatives as catalysts and polychlorinated quinones as halogenating agents. We have performed kinetics and control experiments to investigate the reaction mechanism and establish conditions under which the reactions can be best performed. We have developed NaH and NaHCO3 shuttle base systems as the easiest and most cost-effective ways of conducting the reactions, rendering the methodology economically competitive with known chiral halogenation procedures. We have also demonstrated the utility of our reactions by converting the products to synthetically useful derivatives.

The development of the first catalyzed reaction of ketenes and imines: catalytic, asymmetric synthesis of beta-lactams.

We report practical methodology for the catalytic, asymmetric synthesis of beta-lactams resulting from the development of a catalyzed reaction of ketenes (or their derived zwitterionic enolates) and imines. The products of these asymmetric reactions can serve as precursors to a number of enzyme inhibitors and drug candidates as well as valuable synthetic intermediates. We present a detailed study of the mechanism of the beta-lactam forming reaction with proton sponge as the stoichiometric base, including kinetics and isotopic labeling studies. Stereochemical models based on molecular mechanics (MM) calculations are also presented to account for the observed stereoregular sense of induction in our reactions and to provide a guidepost for the design of other catalyst systems.

Bifunctional asymmetric catalysis: a tandem nucleophile/Lewis acid promoted synthesis of beta-lactams.

[reaction: see text]. We describe a superior procedure for the catalytic, asymmetric synthesis of beta-lactams using a bifunctional catalyst system consisting of a chiral nucleophile and an achiral Lewis acid.

Generation of ketenes from acid chlorides using NaH/crown ether shuttle-deprotonation for use in asymmetric catalysis.

[reaction: see text] We describe methodology for the in situ generation of reactive monosubstituted ketenes from acid chlorides through a shuttle deprotonation process using NaH as an inexpensive stoichiometric base and a crown ether cocatalyst. We have successfully applied this new procedure to the catalytic, asymmetric synthesis of beta-lactams and alpha-haloesters.

Strong Hydrogen Bonding to the Amide Nitrogen Atom in an "Amide Proton Sponge": Consequences for Structure and Reactivity.

N-Protonated amides have been proposed as intermediates in several biologically important reactions, but they have yet to be identified spectroscopically. The first step toward this goal is now reported in the form of spectroscopic and crystallographic proof of a strong intramolecular hydrogen bond between a charged proton donor and an amide nitrogen atom in the "proton sponge" derivative 1; novel reactivity results from this interaction. TfO-= trifluoromethanesulfonate.