Organocatalytic Asymmetric Direct Aldol Reaction Research Articles

Unraveling and Manipulating the Stereospecific Retro-Aldol Reaction in the Organocatalytic Asymmetric Aldol Reaction of Isatin and Cyclohexanone.

An l-pyroglutamic acid-derived bifunctional organocatalyst was designed and applied in an organocatalytic asymmetric direct aldol reaction between isatins and cyclohexanone, in which an erosion of enantiomeric excess of aldol adduct was unexpectedly observed. Through closely monitoring the reaction and performing extensive control experiments, it was determined that the erosion of ee was attributed to a rare stereospecific retro-aldol process. Moreover, effective manipulation of the retro-aldol process by tuning the use of starting materials was ultimately accomplished, leading to evidently upgraded enantioselectivity and functional group tolerance. This study demonstrates the impact of the hidden reaction pathway on the enantioselectivity in asymmetric transformation.

Ionic liquid supported acid additive stabilizes the transition structure of organocatalytic asymmetric direct aldol reaction by proton donation: A quantum mechanical study

ONIOM studies were performed on the transition structure (TS) of organocatalytic direct aldol reaction by using ionic liquid supported benzoic acid (ILS-PhCO2H) as an additive. Results obtained from this computation suggest direct involvement of ILS-PhCO2H in the TS as a proton donor. It has also come out from the present study that, the counter ion of the ILS-acid additive may also play significant role to maintain the proper TS geometry by holding the organocatalyst and the acid additive close together during the course of reaction.

ChemInform Abstract: A Direct, Concise, and Enantioselective Synthesis of 2‐Substituted 4,4,4‐Trifluorobutane‐1,3‐diols Based on the Organocatalytic in situ Generation of Unstable Trifluoroacetaldehyde.

A direct, concise, and enantioselective synthesis of 2-substituted 4,4,4-trifluorobutane-1,3-diols based on the organocatalytic asymmetric direct aldol reaction of an ethyl hemiacetal of trifluoroacetaldehyde with various aldehydes was examined. A catalytic amount (30 mol %) of commercially available and inexpensive l-prolinamide is quite effective as an organocatalyst for the catalytic in situ generation of gaseous and unstable trifluoroacetaldehyde from its hemiacetal, and a successive asymmetric direct aldol reaction with various aldehydes in dichloromethane at 0 °C, followed by reduction with sodium borohydride, gives 2-substituted 4,4,4-trifluorobutane-1,3-diols in moderate to good yields (31–84 %) with low diastereoselectivities and good to excellent enantioselectivities (64–97 % ee).

A Direct, Concise, and Enantioselective Synthesis of 2-Substituted 4,4,4-Trifluorobutane-1,3-diols Based on the Organocatalytic In Situ Generation of Unstable Trifluoroacetaldehyde.

A direct, concise, and enantioselective synthesis of 2-substituted 4,4,4-trifluorobutane-1,3-diols based on the organocatalytic asymmetric direct aldol reaction of an ethyl hemiacetal of trifluoroacetaldehyde with various aldehydes was examined. A catalytic amount (30 mol %) of commercially available and inexpensive l-prolinamide is quite effective as an organocatalyst for the catalytic in situ generation of gaseous and unstable trifluoroacetaldehyde from its hemiacetal, and a successive asymmetric direct aldol reaction with various aldehydes in dichloromethane at 0 °C, followed by reduction with sodium borohydride, gives 2-substituted 4,4,4-trifluorobutane-1,3-diols in moderate to good yields (31-84%) with low diastereoselectivities and good to excellent enantioselectivities (64-97% ee).

Stabilization of the transition structures of organocatalytic asymmetric direct aldol reaction in wet solvent free condition by the formation of water assisted supramolecular network: A DFT study

Organocatalytic asymmetric direct aldol reaction in wet solvent free medium has been studied by DFT quantum mechanical (QM) method, using l-proline hydrazide as catalyst. Present study has revealed for the first time, the direct involvement of two water molecules in the aldol transition structures (TSs). In the TS, the enamine and the aldehyde is connected through hydrogen bonding by the assistance of two intervening water molecules forming a supramolecular network. Formation of this type of supramolecular assembly is possible due to the presence of protonated –NH2 group in the l-proline hydrazide moiety, which is responsible for the favorable entropic contribution to the aldol reaction. It is also revealed from the present study that, water assisted TS is energetically more favorable than the TS without involving any water molecule. It can be concluded from this study that, insertion of polar group capable of hydrogen bond formation in the l-proline skeleton can lead to a favorable aldol reaction with significantly high enantiomeric excess (ee) in wet solvent free condition by reducing the activation barrier of this reaction.

ChemInform Abstract: Organocatalytic Asymmetric Direct Aldol Reaction of Pyruvic Aldehyde Dimethyl Acetal with Isatin Derivatives.

AbstractA highly enantioselective approach for the synthesis of the compounds (III) and (V) by the title reaction is developed.

Organocatalytic Asymmetric Direct Aldol Reaction of Pyruvic Aldehyde Dimethyl Acetal with Isatin Derivatives

AbstractCinchona‐derived primary amine catalysts in combination with a trichloroacetic acid (TCA) additive catalysed the aldol reaction of pyruvic aldehyde dimethyl acetal with isatins in highly enantioselective manner. Both enantiomers of 3‐substituted 3‐hydroxy‐2‐oxindoles were obtained using pseudo‐enantiomeric organocatalysts. Mild reaction conditions, excellent stereocontrol, the accessibility of both enantiomers of the 3‐substituted 3‐hydroxy‐2‐oxindole products, and the additional functionality (masked aldehyde) that may be used for the further elaboration of the products, are important features of the catalytic protocol.

Organocatalytic Asymmetric Direct Aldol Reactions of Trifluoroacetaldehyde Ethyl Hemiacetal with Aromatic Methyl Ketones

The organocatalytic asymmetric direct aldol reaction of trifluoroacetaldehyde ethyl hemiacetal with aromatic methyl ketones in the presence of a catalytic amount of (S)-5-(pyrrolidin-2-yl)-1H-tetrazole in dichloroethane at 40 °C proceeds smoothly to produce (R)-4,4,4-trifluoro-1-aryl-3-hydroxy-1-butanones in high yields with up to 90% ee.

Asymmetric Direct Stoichiometric Aldol Reactions in Water

The authors report an organocatalytic asymmetric direct aldol reaction that only requires stoichiometric amounts of the substrates, in water mediated by sulfated β-cyclodextrin (β-CD). tert-Butylphenoxy proline catalyst 1 was found to be effective for this reaction. The sulfated β-CD binds with the catalyst 1 and acts as an inverse phase-transfer reagent (i.e., it allows water-insoluble molecules to react in aqueous medium). With 2 mol% of catalyst 1 and 10 mol% of sulfated β-CD good to high diastereoselectivities (dr = 84:16 to >99:1) and excellent enantioselectivities (er = 98:2 to >99:1) are obtained for different aldehydes.

Direct Aldol-Type Reaction of Oxindoles with Ethyl Trifluoropyruvate

The authors report an organocatalytic asymmetric direct aldol reaction of oxindoles with ethyl 3,3,3-trifluoropyruvate. Cinchona alkaloid catalyst (DHQD)2PHAL (1) was found to be effective for this reaction. Its pseudoenantiomer (DHQ)2PHAL (2) gave the opposite enantiomer of the trifluoromethylated oxindole product. With 10 mol% of catalyst 1 or 2, good to high dia­stereoselectivities (dr = 71:29 to 97:3) and excellent enantioselectivities (er = 90:10 to >99:1) are obtained for different substituted oxindoles.

Asymmetric organocatalytic direct aldol reactions of cyclohexanone with aldehydes in brine

Organocatalytic asymmetric direct aldol reactions in brine with high diastereo- and enantioselectivities, using a readily available bifunctional amide catalyst, were developed.Key words: aldol reaction, organocatalyst, asymmetric catalysis, water.