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.

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

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.

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.

The cyclobutane scaffold is a structural motif incorporated into a wide range of naturally occurring products, as well as into transiently generated intermediates in primary and secondary metabolism. [1] Moreover, the reactivity pattern shown by cyclobutanes when exploiting ring strain as a driving force to facilitate novel reactivity has also opened the way for their use as intermediates in the synthesis of complex molecules. [2] However, despite their interest, the development of methodologies for the stereocontrolled synthesis of cyclobutanes has received little attention over the years. [3] In this context, the [2+2] cycloaddition represents one of the most straightforward approaches for the stereoselective construction of this structure with several reported and efficient examples, which rely on the use of chiral ligands, [4] auxiliaries, [5] or Lewis acid catalysts. [6] Within this context, we wondered if aminocatalysis could contribute to this field by facing the challenge of setting up an enantioselective version of a [2+2] cycloaddition reaction between a,b-unsaturated aldehydes and nitroalkenes. We were inspired by recent work by Seebach, Hayashi, and coworkers, [7] and Blackmond and co-workers [8] (Scheme 1) in which kinetic and structural studies of O-trimethylsilyldiphenylprolinol-catalyzed Michael addition of aldehydes to nitroolefins led to the detection of an aminonitrocyclobutane intermediate, which was identified as a resting state for the catalyst. Taking this discovery into account, we hypothesized that enolizable enals could undergo a similar reaction based on the dienamine activation mode [9] where the catalyst would be able to undergo turnover, thus furnishing a final nitrocyclobutane product. In fact, literature precedent exists for the related [2+2] cycloaddition of enamines with electronpoor alkenes, thus showing that this process can occur spontaneously without the need of photochemical activation. [10] In contrast, there is also literature precedent which shows that the reaction of nitroalkenes with enolizable a,bunsaturated aldehydes under dienamine catalysis leads to the exclusive formation of Michael-type adducts through the selective a-functionalization of the dienamine intermediate and therefore no opportunity arises for cyclobutane formation. [11] Herein, we wish to present our initial results on a novel chiral secondary amine catalyzed enantioselective formal [2+2] cycloaddition of enolizable a,b-unsaturated aldehydes with a-hydroxymethyl-substituted nitroalkenes which leads to the formation of cyclobutanes in a single step (Scheme 2). This reaction is in sharp contrast with previously published work which, as already mentioned, shows the preference for dienamine intermediates generated from enals to undergo Scheme 1. a) Previous work: addition to nitroolefins throuh enamine catalysis. b) Working hypothesis: formal [2 + 2] cycloaddition through dienamine catalysis. TMS = trimethylsilyl.Scheme 2. One-step synthesis of cyclobutanes by [2+2] cycloaddition/ hemiacetalization under...

Hexose sugars play a fundamental role in vital biochemical processes and their biosynthesis is achieved through enzyme-catalyzed pathways. Herein we disclose the ability of amino acids to catalyze the asymmetric neogenesis of carbohydrates by sequential cross-aldol reactions. The amino acids mediate the asymmetric de novo synthesis of natural L- and D-hexoses and their analogues with excellent stereoselectivity in organic solvents. In some cases, the four new stereocenters are assembled with almost absolute stereocontrol. The unique feature of these results is that, when an amino acid is employed as the catalyst, a single reaction sequence can convert a protected glycol aldehyde into a hexose in one step. For example, proline and its derivatives catalyze the asymmetric neogenesis of allose with >99 % ee in one chemical manipulation. Furthermore, all amino acids tested catalyzed the asymmetric formation of natural sugars under prebiotic conditions, with alanine being the smallest catalyst. The inherent simplicity of this catalytic process suggests that a catalytic prebiotic "gluconeogenesis" may occur, in which amino acids transfer their stereochemical information to sugars. In addition, the amino acid catalyzed stereoselective sequential cross-aldol reactions were performed as a two-step procedure with different aldehydes as acceptors and nucleophiles. The employment of two different amino acids as catalysts for the iterative direct aldol reactions enabled the asymmetric synthesis of deoxysugars with >99 % ee. In addition, the direct amino acid catalyzed C(2)+C(2)+C(2) methodology is a new entry for the short, highly enantioselective de novo synthesis of carbohydrate derivatives, isotope-labeled sugars, and polyketide natural products. The one-pot asymmetric de novo syntheses of deoxy and polyketide carbohydrates involved a novel dynamic kinetic asymmetric transformation (DYKAT) mediated by an amino acid.

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An easy and simple synthetic approach to optically active alpha,alpha-quaternary alpha-amino acids using asymmetric organocatalysis is presented. The addition of oxazolones to nitroalkenes catalyzed by thiourea cinchona derivatives provides the corresponding alpha,alpha-quaternary alpha-amino acid derivatives with good yields, excellent diastereoselectivities (up to 98 % dr), and from moderate to good enantioselectivities (up to 92 % ee). The reaction can be performed on a large scale. The optically active oxazolone-nitroalkene addition products can be opened in a one-pot reaction to the corresponding ester-amide derivatives. Additional transformations are also presented, such as the synthesis of amino esters, amino acids, and transformation into 3,4-disubstituted pyrrolidin-2-ones.