Asymmetric Intermolecular Aldol Reaction Research Articles

Amino oxazolines as a new class of organocatalyst for the direct intermolecular asymmetric aldol reaction between acetone and aromatic aldehydes

A series of chiral amino oxazolines were synthesized and screened as organocatalysts for asymmetric intermolecular aldol reactions between acetone and aromatic aldehydes. The reaction works well with a range of aromatic aldehydes showing good to high selectivity. The present new system of the organocatalyst was effective for the asymmetric aldol reaction for a wide range of aromatic aldehydes and isatin to carry out an asymmetric carbon–carbon bond forming reaction with a high enantioselectivity of up to 91%.

Various Polar Tripeptides as Asymmetric Organocatalyst in Direct Aldol Reactions in Aqueous Media

A series of tripeptide organocatalysts containing a secondary amine group and two amino acids with polar side chain units were developed and evaluated in the direct asymmetric intermolecular aldol reaction of 4-nitrobenzaldehyde and cyclohexanone. The effectiveness of short polar peptides as asymmetric catalysts in aldol reactions to attain high yields of enantio- and diastereoselective isomers were investigated. In a comparison, glutamic acid and histidine produced higher % ee and yields when they were applied as the second amino acid in short trimeric peptides. These short polar peptides were found to be efficient organocatalysts for the asymmetric aldol addition reaction in aqueous media.

Direct Asymmetric Aldol Reactions Inspired by Two Types of Natural Aldolases: Water-Compatible Organocatalysts and ZnIIComplexes

In this article the utility of water-compatible amino-acid-based catalysts was explored in the development of diastereo- and enantioselective direct aldol reactions of a broad range of substrates. Chiral C(2)-symmetrical proline- and valine-based amides and their Zn(II) complexes were designed for use as efficient and flexible chiral catalysts for enantioselective aldol reactions in water, on water, and in the presence of water. The presence of 5 mol % of the prolinamide-based catalyst affords asymmetric intermolecular aldol reactions between unmodified ketones and various aldehydes to give anti products with excellent enantioselectivities. We also demonstrate aldol reactions of more demanding substrates with high affinity to water (i.e., acetone and formaldehyde). Newly designed serine-based organocatalyst promoted aldol reaction of hydroxyacetone leading to syn-diols. For presented catalytic systems organic solvent-free conditions are also acceptable, making the elaborated methodology interesting from a green chemistry perspectives.

Organocatalytic Direct Asymmetric Aldol Reactions of 3-Isothiocyanato Oxindoles to Ketones: Stereocontrolled Synthesis of Spirooxindoles Bearing Highly Congested Contiguous Tetrasubstituted Stereocenters

The first example of a direct catalytic asymmetric intermolecular aldol reaction of 3-isothiocyanato oxindoles to simple ketones with bifunctional thiourea-tertiary amine as catalyst is reported. This strategy provides a promising approach for the asymmetric synthesis of a range of enantioenriched spirocyclic oxindoles bearing two highly congested contiguous tetrasubstituted carbon stereocenters. Versatile transformations of the spirocyclic oxindole products into other structurally diverse spirocyclic oxindoles have also been demonstrated.

L-Valine Dipeptide Organocatalysts with Two Amide Units for the Direct Asymmetric Aldol Reaction in Brine

A series of valine dipeptide organocatalysts containing a primary amine group and two amide units have been developed and evaluated in the direct asymmetric intermolecular aldol reaction of 4-nitrobenzaldehyde and cyclohexanone. When 2,4-dinitrophenol (DNP) was used as an acidic additive, the catalyzed reactions of various aldehydes and ketones gave the corresponding aldol products with moderate to high enantioselectivities (up to 95%) and diastereoselectivities (up to >99/1, anti/syn) in the presence of 3c in brine. .

Novel Primary Amine Organocatalysts Derived from Cinchona Alkaloids for Asymmetric Direct Aldol Reactions in Brine

A series of Cinchona alkaloids derived organocatalysts have been developed and evaluated in the direct asymmetric intermolecular aldol reaction of 4-nitrobenzaldehyde and cyclohexanone. The catalyzed reactions of various aldehydes and ketones gave the corresponding aldol products with moderate to high enantioselectivities (up to 92%) and diastereoselectivities (up to >99/1, anti/syn) in the presence of 3e in brine.

Thiazolidine-based organocatalysts for a highly enantioselective direct aldol reaction

A set of enantiopure thiazolidine-based organocatalysts have been synthesized from l-cysteine, in a straightforward manner allowing numerous structural variations. In particular, organocatalyst 3a exhibits the highest catalytic performance working in an aqueous medium. It catalyzed the direct catalytic asymmetric intermolecular aldol reaction between unmodified ketones and an aldehyde with excellent stereocontrol and furnished the corresponding aldol products in up to 99% ee. Compound 3a also showed excellent asymmetric catalytic activity in the asymmetric Michael reaction (up to 99% ee).

(2R,3R)-2-[(4-Chlorophenyl)hydroxymethyl]cyclopentanone

The title compound, C12H13ClO2, was prepared by the direct asymmetric inter­molecular aldol reaction of cyclo­penta­none and 4-chloro­benzaldehyde catalysed by l-tryptophan in water. The absolute mol­ecular structure was determined to be a racemic twin with 91% (2R,3R) isomer and 9% of the (2S,3S) form. In the crystal structure, the mol­ecules are connected into a one-dimensional chain along the a axis through the formation of inter­molecular O—H⋯O hydrogen bonds. Further, non-conventional C—H⋯O and C—H⋯π contacts are observed in the structure, which consolidate the crystal packing.

Asymmetric aldol reactions catalyzed by efficient and recyclable silica‐supported proline‐based peptides

A series of silica-supported proline-based peptides were synthesized and applied as catalysts for direct asymmetric intermolecular aldol reactions. Among these, a peptide with two L-proline units was found to be the most efficient one for the asymmetric aldol reactions between acetone and aromatic aldehydes. The reactions generated the corresponding products with satisfactory isolated yields (up to 97%) and enantiomeric excesses (up to 96%) in the presence of this catalyst (5 mol %). Furthermore, the silica-supported organocatalyst could be recovered and recycled by a simple filtration of the reaction solution and used for five consecutive trials without loss of its reactivity.

Communicating Chemistry in “Chemistry”

Communicating Chemistry in “Chemistry”

Direct Catalytic Asymmetric Aldol Reactions Assisted by Zinc Complex in the Presence of Water

AbstractA combination of zinc triflate and chiral C2‐symmetrical prolinamide ligand leads to high enantioselectivities in direct aldol reactions essentially assisted by water. The presence of 5 mol % of the catalyst affords an asymmetric intermolecular aldol reaction between unmodified ketones and aldehydes to give anti‐products with excellent enantioselectivities ranging from 86–98 % ee. The same bis(prolinamide) ligand is found to catalyze the direct aldol reactions in the presence of water (or in water) with excellent stereocontrol and furnish the corresponding aldols in up to 99 % ee. For the demonstrated catalytic systems organic solvent‐free conditions are applied.

Direct Asymmetric Intermolecular Aldol Reactions Catalyzed by Amino Acids and Small Peptides.

AbstractChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.

Non-linear effects in acyclic amino acid-catalyzed direct asymmetric aldol reactions

Non-linear effects were observed in acyclic amino acid-catalyzed direct asymmetric intermolecular aldol reactions. The non-linear effects are due to the equilibrium solid–liquid phase behavior of amino acids. The results suggest that the phase behavior of amino acids linked to asymmetric catalysis may have implications to the evolution of homochirality.

Direct Asymmetric Intermolecular Aldol Reactions Catalyzed by Amino Acids and Small Peptides

In nature there are at least nineteen different acyclic amino acids that act as the building blocks of polypeptides and proteins with different functions. Here we report that alpha-amino acids, beta-amino acids, and chiral amines containing primary amine functions catalyze direct asymmetric intermolecular aldol reactions with high enantioselectivities. Moreover, the amino acids can be combined into highly modular natural and unusual small peptides that also catalyze direct asymmetric intermolecular aldol reactions with high stereoselectivities, to furnish the corresponding aldol products with up to >99 % ee. Simple amino acids and small peptides can thus catalyze asymmetric aldol reactions with stereoselectivities matching those of natural enzymes that have evolved over billions of years. A small amount of water accelerates the asymmetric aldol reactions catalyzed by amino acids and small peptides, and also increases their stereoselectivities. Notably, small peptides and amino acid tetrazoles were able to catalyze direct asymmetric aldol reactions with high enantioselectivities in water, while the parent amino acids, in stark contrast, furnished nearly racemic products. These results suggest that the prebiotic oligomerization of amino acids to peptides may plausibly have been a link in the evolution of the homochirality of sugars. The mechanism and stereochemistry of the reactions are also discussed.

Direct Asymmetric Intermolecular Aldol Reactions Catalyzed by Amino Acids and Small Peptides

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 (DOI: 10.1002/chem.200501639; submitted: December 29, 2005, published online: April 25, 2005). We were remiss not to state that the concept relating eutectics of amino acids to nonlinear effects in asymmetric catalysis had previously been presented at the Erdtman Lecture at KTH Stockholm by Prof. D. G. Blackmond on November 29, 2005. This work is now published (see M. Klussmann, H. Iwamura, S. P. Matthew, D. H. Wells, U. Pandya, A. Armstrong, D. G. Blackmond, Nature 2006, 441, 621; submitted November 21, 2005). 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.

Acyclic Amino Acid‐Catalyzed Direct Asymmetric Aldol Reactions: Alanine, the Simplest Stereoselective Organocatalyst.

AbstractFor Abstract see ChemInform Abstract in Full Text.

Acyclic amino acid-catalyzed direct asymmetric aldol reactions: alanine, the simplest stereoselective organocatalyst

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.

Small peptides as modular catalysts for the direct asymmetric aldol reaction: ancient peptides with aldolase enzyme activity

Simple peptides and their analogues having a primary amino group as the catalytic residue mediate the direct asymmetric intermolecular aldol reaction with high stereoselectivity and furnish the corresponding aldol products with up to 99% ee; this intrinsic ability of highly modular peptides may explain the initial molecular evolution of aldolase enzymes.

Quantum mechanical predictions of the stereoselectivities of proline-catalyzed asymmetric intermolecular aldol reactions.

Quantum mechanical calculations were employed to predict the ratio of four stereoisomeric products expected from two complex reactions involving the aldol reactions of cyclohexanone with benzaldehyde or with isobutyraldehyde catalyzed by (S)-proline. Experimental tests of these predictions provide an assessment of the state-of-the-art in quantum mechanical prediction of products of complex organic reactions in solution.