The linear amino acid-catalyzed direct asymmetric intermolecular aldol reaction is presented; simple amino acids such as alanine, valine, isoleucine, aspartate, alanine tetrazole and serine catalyzed the direct catalytic asymmetric intermolecular aldol reactions between unmodified ketones and aldehydes with excellent stereocontrol and furnished the corresponding aldol products in up to 98% yield and with up to > 99% ee.

We would like to point out an error of omission of a citation and present an accurate definition of eutectic in reference [29] in our paper (. We fully agree that the Blackmond group was the first to introduce this concept. Our discussion implied that we measured the eutectics of valine and alanine in this work, which we did not. We would like to clarify the definition of a eutectic with respect to these scalemic amino acid systems. We stated that the eutectic point is the point at which all three phases, (R)-amino acid, (S)-amino acid and DMSO can exist simultaneously. We are grateful to Prof. Donna Blackmond for providing us with the correct definition of a eutectic in the context of these amino acid systems: In an isothermal, three-component system at equilibrium consisting of (R)-amino acid, (S)-amino acid, and solvent, containing two distinct solid phases and one solution phase, the eutectic composition is dictated by the phase rule and is described as a point on the phase diagram where three separate phases intersect. The phase rule also dictates that the solution composition at the eutectic is fixed in this case and hence this composition is identical for any given (R)-and (S)-enantiomeric composition employed. The ee [%] for the (S)-alanine-catalyzed reaction in water given in Table 3, entry 17, should read 0 % ee and not 67 % ee. Editorial Note: D. G. Blackmond and co-workers transmitted their experimental observations prior to A. Cordova et al. The data in the paper by Cordova and co-workers describing nonlinear effects at higher alanine and valine concentrations were obtained during the week December 1-6, 2005. In addition, the experimental data presented in Figure 2 in the paper by Cordova and co-workers (showing striking asymmetric amplification in an asymmetric aldol reaction using scalemic serine as catalyst) were acquired on December 5, 2005. The Nature paper by Blackmond and co-workers referenced above represents, to our knowledge, the first measurement of eutectic points of free amino acids that form racemic compounds and the first comprehensive interpretation of nonlinear effects in asymmetric catalysis using acyclic amino acids as catalysts.

The asymmetric amino acid catalyzed aldol reaction is plausibly an ancient transformation, [1] which enzymes have catalyzed for billions of years. These enzyme-catalyzed stereoselective aldol reactions involve enamine intermediates (type I aldolases) or zinc enolates (type II aldolases) as the reactive nucleophile.[2] The catalytic residue of type I aldolases is the primary amino group of a lysine moiety, which forms enamine intermediates with the help of a proton relay system by neighboring amino acids.[2c]The ability of amino acids to catalyze the asymmetric aldol reaction was discovered in the 1970s by Hajos and Parrish [3] and Wiechert and co-workers, [4] and amino acid mediated stereoselective Robinson annulations were utilized numerous times in natural-product synthesis.[5] In 2000, List and co-workers demonstrated that proline and its derivatives can be used as catalysts for intermolecular asymmetric aldol reactions between ketones and aldehydes with moderate-toexcellent enantioselectivities. [6][7] Both the proline-catalyzed intramolecular and intermolecular aldol reactions involve an enamine mechanism, in which one proline molecule takes part in the transition state, as established by Houk, List, and co-workers. [8] We recently found that acyclic amino acids and their derivatives are able to catalyze asymmetric intermolecular aldol reactions with high stereoselectivity. [1b, 9] For example, simple natural and unnatural primary amino acid derivatives catalyzed the reaction between cyclohexanone 1 and an

It is shown that racemic oxazolones are excellent reagents for the synthesis of chiral quaternary amino acids and its derivatives by the diastereo- and enantioselective nucleophilic addition to alpha,beta-unsaturated aldehydes catalyzed by diarylprolinol silyl ethers. The scope of this new organocatalytic reaction is demonstrated for different oxazolones having aromatic and alkyl groups at the reactive carbon atom and different aromatic and aliphatic substituted alpha,beta-unsaturated aldehydes, for which the stereoselective reaction proceeds with good yield, moderate to good to very high diastereoselectivity, and very high enantioselectivity. The potential of the reaction is shown for the synthesis of optically active alpha,alpha-disubstituted alpha-amino acids, alpha-quaternary proline derivatives, amino alcohols, lactams, and tetrahydropyranes. Furthermore, we have calculated by DFT-methods the transition-state structures that account for both the diastereo- and enantioselectivity observed for the addition of oxazolones to the alpha,beta-unsaturated aldehydes. For one class of compounds, the stereoselectivity is controlled by a hydrogen-bonding interaction of the enolate-form of the oxazolone with an ortho-hydroxy-phenyl substituent of the alpha,beta-unsaturated aldehyde, whereas the benzhydryl-protecting group in the oxazolone determines the diastereo- and enantioselectivity in a more general manner for both aromatic and aliphatic alpha,beta-unsaturated aldehydes.