Organocatalytic Asymmetric Aldol Reaction Research Articles

Synthesis and Evaluation of N-Diaminophosphoryl Aminothioureas as Bifunctional Catalysts for Vinylogous Aldol Reactions of Isatins and 2(3H)-Furanones.

The organocatalytic asymmetric direct vinylogous aldol reaction of N-methylisatins 1 and γ-butenolides 2 to provide 3-hydroxy-2-oxindole derivatives 3 was investigated. A series of N-diaminophosphoryl aminothiourea catalysts 4 was synthesized, and their utility for the stereoselective formation of 3 was examined.

Organocatalytic asymmetric nitroso aldol reaction of α-substituted malonamates.

A practical enantioselective N-selective nitroso aldol reaction of α-methylmalonamates with a nitrosoarene is reported. The reaction employs the Takemoto thiourea catalyst for the induction of enantioselectivity, and the corresponding optically active oxyaminated malonamates were obtained in reasonably good yields.

Organocatalytic asymmetric aldol reaction using protonated chiral 1,2-diamines

Organic-catalyzed stereoselective reactions have gained attention because they avoid the problems associated with metal catalysts, but existing catalysts based on proline have limitations. Therefore, (R,R)-(+)-1,2-diphenylethylenediamine (DPEN) was selectively mono-N-alkylated through reductive alkylation and used as an organic catalyst for the aldol reaction. Using a variety of aldehydes in the catalytic aldol reaction, the N-alkylated DPEN catalyst proceeded from primary amine to enamine and iminium intermediates and achieved both a high yield (80%) and enantioselectivity (90%). It was found that the steric hindrance of the N-alkyl substituent of the chiral diamine and the hydrogen bond between the ammonium moiety and the oxygen of the aromatic aldehyde determine the enantioselectivity. Various aromatic aldehydes were tested, and electron-withdrawing substituents led to good yields, whereas electron-donating substituents led to poor yields via the deactivation of the carbonyl group of the aldehyde. Further, ortho substituents resulted in higher stereoselectivities than para substituents because the stereoscopic effect was enhanced.

Organocatalytic Asymmetric Aldol Reaction of Arylglyoxals and Hydroxyacetone: Enantioselective Synthesis of 2,3-Dihydroxy-1,4-diones.

A highly efficient quinine-derived primary-amine-catalyzed asymmetric aldol addition of hydroxyacetone to arylglyoxals is described. Structurally diverse anti-2,3-dihydroxy-1,4-diones were generated in high yields, with good diastereoselectivities and enantioselectivities.

β-Ketoesters as Mono- or Bisnucleophiles: A Concise Enantioselective Total Synthesis of (-)-Englerin A and B.

A short enantioselective total synthesis of englerin A, a guaiane sesquiterpene with significant in vitro antitumor activity, is reported. Key features of this total synthesis are an organocatalytic asymmetric decarboxylative aldol reaction, a neighboring-group-participating [4+3] cycloaddition, a novel one-pot Heck coupling/regioselective 1,4-hydrosilylation/Tamao-Fleming oxidation cascade, and a kinetic CBS reduction, generating the optically pure natural product in 6.7 % overall yield over twelve steps starting from methylglyoxal. Selective saponification of the more reactive glycolic ester moiety of englerin A also gave (-)-englerin B.

β‐Ketoesters as Mono‐ or Bisnucleophiles: A Concise Enantioselective Total Synthesis of (−)‐Englerin A and B

AbstractA short enantioselective total synthesis of englerin A, a guaiane sesquiterpene with significant in vitro antitumor activity, is reported. Key features of this total synthesis are an organocatalytic asymmetric decarboxylative aldol reaction, a neighboring‐group‐participating [4+3] cycloaddition, a novel one‐pot Heck coupling/regioselective 1,4‐hydrosilylation/Tamao–Fleming oxidation cascade, and a kinetic CBS reduction, generating the optically pure natural product in 6.7 % overall yield over twelve steps starting from methylglyoxal. Selective saponification of the more reactive glycolic ester moiety of englerin A also gave (−)‐englerin B.

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.

Organocatalytic Enantioselective Vinylogous Aldol Reaction of 5-Alkyl-4-Nitroisoxazoles to Paraformaldehyde.

An organocatalytic asymmetric aldol reaction of 5-alkyl-4-nitroisoxazoles to paraformaldehyde has been developed. By using a chiral dipeptide-based urea-amide-guanidinium as the phase-transfer catalyst, the transformations were promoted by sodium acetate, leading to a range of enantio-enriched isoxazole derivatives in high yields with moderate to excellent enantioselectivities. This work represents the first example of constructing chiral C-C bonds at the α-position of 5-alkyl-4-nitroisoxazoles. The viability of readily accessing chiral fungicides from the obtained aldol products demonstrates the important utility of this method.

Organocatalytic Asymmetric Vinylogous Aldol Reaction of Allyl Aryl Ketones to Silyl Glyoxylates.

A direct organocatalytic asymmetric vinylogous aldol reaction of allyl aryl ketones to silyl glyoxylates has been developed through the bifunctional catalyst, giving the α-hydroxysilanes with excellent enantioselectivity (up to 95% ee) and in high yields (up to 96%). The success of this catalytic methodology offers an opportunity to tackle the problems in the nucleophilic addition to acylsilanes. To activate both allyl aryl ketones and acylsilanes, the utilized bifunctional catalyst was an ideal organocatalyst in this unprecedented transformation.

Synthesis of (–)-Muricatacin and (–)-(R,R)-L-Factor Involving an Organocatalytic Direct Vinylogous Aldol Reaction

Concise syntheses of the polyketide natural product (–)-muricatacin and (–)-(R,R)-L-factor (natural product enantiomer) were achieved in four steps by employing an organocatalytic asymmetric direct vinylogous aldol reaction of γ-crotonolactone and suitable aliphatic aldehydes as the key step.

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 Aldol Reactions in Aqueous or Neat Conditions: Review of Data Published in 2009‐2013

AbstractReview: 94 refs.

ChemInform Abstract: Asymmetric Synthesis of Chiral β‐Hydroxy‐α‐amino Acid Derivatives by Organocatalytic Aldol Reactions of Isocyanoesters with β,γ‐Unsaturated α‐Ketoesters.

Abstract The first organocatalytic asymmetric aldol reaction of isocyanoesters with various β,γ-unsaturated α-ketoesters has been described. Using cinchona alkaloid-derived bifunctional thiourea as the catalyst, chiral β-hydroxy-α-amino acid derivatives can be obtained in excellent yields and enantioselectivities (up to 95% yield and 92% ee) after acidic hydrolysis. This protocol provides a straightforward method to access multiple substituted β-hydroxy-α-amino acid derivatives with high enantiomeric purity.

Asymmetric synthesis of chiral β-hydroxy-α-amino acid derivatives by organocatalytic aldol reactions of isocyanoesters with β,γ-unsaturated α-ketoesters

The first organocatalytic asymmetric aldol reaction of isocyanoesters with various β,γ-unsaturated α-ketoesters has been described. Using cinchona alkaloid-derived bifunctional thiourea as the catalyst, chiral β-hydroxy-α-amino acid derivatives can be obtained in excellent yields and enantioselectivities (up to 95% yield and 92% ee) after acidic hydrolysis. This protocol provides a straightforward method to access multiple substituted β-hydroxy-α-amino acid derivatives with high enantiomeric purity.

Organocatalytic Asymmetric Aldol Reactions in Aqueous or Neat Conditions: Review of Data Published in 2009-2013

Organocatalytic Asymmetric Aldol Reactions in Aqueous or Neat Conditions: Review of Data Published in 2009-2013

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.

ChemInform Abstract: Regioselectivity‐Reversed Asymmetric Aldol Reaction of 1,3‐Dicarbonyl Compounds.

AbstractThe first organocatalytic asymmetric C1 aldol reaction of 1,3‐dicarbonyl compounds to isatins and dihydrofurandiones is presented.