Elucidating the mechanism of the asymmetric aza-Michael reaction.

The mechanism of the palladium-catalysed asymmetric aza-Michael addition of aniline to alpha,beta-unsaturated N-imide was examined from several aspects using a combination of techniques, including X-ray crystallography, mass spectrometry, NMR, UV/Vis spectroscopy, and kinetic studies. The binding of aniline to the dicationic palladium(II) metal centre was found to occur in two consecutive steps: The binding of the first aniline is fast and reversible, whereas the binding of the second aniline is slower and irreversible. This occurs in competition with the binding of the N-imide, which forms a planar six-membered chelate ring with the metal centre; coordinating through the 1,3-dicarbonyl moiety. Isotopic labelling revealed that the addition of N-H occurs in a highly stereoselective manner, allowing the synthesis of optically active beta(2)- and beta(2,3)-amino acid derivatives. The stereochemistry of the addition is postulated to be syn. In situ kinetic studies provided evidence for product inhibition. The binding of the N-imide to the catalyst was found to be the rate-limiting step. Aniline was found to be an inhibitor of the pre-catalyst. The study culminated in the design of a new reaction protocol. By maintaining a low concentration of the aniline substrate during the course of the reaction, significant enhancement of yield and enantioselectivity can be achieved.

A mechanistic rationalization of unusual kinetic behavior in proline-mediated C-O and C-N bond-forming reactions.

Kinetic evidence supports the role of the reaction product in the catalytic cycle of proline-mediated alpha-aminoxylation and alpha-amination reactions, providing both design principles as well as a model for the evolution of efficiency in catalysis.

Thermodynamic control of asymmetric amplification in amino acid catalysis.

Ever since Pasteur noticed that tartrate crystals exist in two non-superimposable forms that are mirror images of one another--as are left and right hands--the phenomenon of chirality has intrigued scientists. On the molecular level, chirality often has a profound impact on recognition and interaction events and is thus important to biochemistry and pharmacology. In chemical synthesis, much effort has been directed towards developing asymmetric synthesis strategies that yield product molecules with a significant excess of either the left-handed or right-handed enantiomer. This is usually achieved by making use of chiral auxiliaries or catalysts that influence the course of a reaction, with the enantiomeric excess (ee) of the product linearly related to the ee of the auxiliary or catalyst used. In recent years, however, an increasing number of asymmetric reactions have been documented where this relationship is nonlinear, an effect that can lead to asymmetric amplification. Theoretical models have long suggested that autocatalytic processes can result in kinetically controlled asymmetric amplification, a prediction that has now been verified experimentally and rationalized mechanistically for an autocatalytic alkylation reaction. Here we show an alternative mechanism that gives rise to asymmetric amplification based on the equilibrium solid-liquid phase behaviour of amino acids in solution. This amplification mechanism is robust and can operate in aqueous systems, making it an appealing proposition for explaining one of the most tantalizing examples of asymmetric amplification-the development of high enantiomeric excess in biomolecules from a presumably racemic prebiotic world.

Mechanistic insights from reaction progress kinetic analysis of the polypeptide-catalyzed epoxidation of chalcone.

[reaction: see text] Reaction progress kinetic analysis of the poly(L)-leucine (PLL)-catalyzed epoxidation of substituted chalcones 1a-1c helps to refine an earlier mechanistic proposal by demonstrating that the reaction proceeds via reversible addition of chalcone to a PLL-bound hydroperoxide, forming a fleeting hydroperoxy enolate species. Observation of an induction period offers an alternate rationalization for effects formerly attributed to substrate inhibition. Previous clues about the origin of enantioselectivity in this system are supported by this work.

Tuning the enantioselective N-acetylation of racemic amines: a spectacular salt effect.

We have described a spectacular salt effect in the kinetic resolution of (+/-)-1-phenylethylamine, which leads to an increase in reactivity, high levels of selectivity, and a complete reversal of the stereoselectivity. By tuning the reaction conditions, we were able to increase the selectivity factor of (1S,2S)-1 to s = 115.

Probing the active catalyst in product-accelerated proline-mediated reactions.

A new catalytic cycle involving only soluble proline complexes or adducts is proposed for the reactions in eq 1 based on kinetic observations and molecular modeling studies. This reaction pathway circumventing free proline and incorporating hydrogen-bonded reaction product helps to rationalize the observations of accelerating reaction rate in both the alpha-aminooxylation and alpha-amination reactions.

In situ catalyst improvement in the proline-mediated alpha-amination of aldehydes.

Kinetic investigations show that the proline-mediated alpha-amination of aldehydes exhibits autoinductive rate behavior and amplification of product enantiomeric excess. Further experiments highlight the role of product, offering suggestions for the design of catalysts of improved efficiency for such transformations. The unusual characteristics exhibited by these reactions implicate amino acid catalysis in rationalizations of the origin of biological homochirality.