Direct Asymmetric Aldol Reaction Research Articles

Syntheses and Applications of Singh’s Catalyst

Singh’s catalyst has emerged as one of the most promising and valuable catalysts in the field of asymmetric synthesis. Since its discovery, it has proven to be one of the best organocatalysts for asymmetric direct aldol reactions, and is equally efficient in aqueous and organic media. In this Short Review, we summarize reactions utilizing Singh’s catalyst under various conditions.1 Introduction2 Synthesis of Singh’s Catalyst3 Applications in Asymmetric Synthesis4 Conclusion

Asymmetric Aldol Reaction of Pyruvate Promoted by Chiral Tertiary Amines

AbstractThe direct asymmetric aldol reaction of α‐ketoesters catalyzed by chiral tertiary amines is reported. The described methodology is characterized by mild reaction conditions and distinct product selectivity determined by the starting materials. In the developed transformation pyruvates undergo highly selective self‐condensation reaction, whereas cross‐aldol reaction take place predominantly for their carbon chain homologues in presence of aldehyde acceptors. Notably, addition of bulky phenol moiety into pyruvate inhibit the spontaneous lactonization of products and enhance the enantioselectivity.

Enantiodivergent Aldol Condensation in the Presence of Aziridine/Acid/Water Systems

A series of novel chiral imines was synthesized from corresponding aldehydes and 1-(2-aminoalkyl)aziridines with good chemical yields. Such imines were tested as catalysts in the direct asymmetric aldol reaction between aromatic aldehydes and acetone/cyclohexanone in the presence of catalytic amounts of water and an acidic additive. The corresponding aldol products were formed in excellent yields and with very high enantioselectivities (98% and 99% ee, respectively).

Promotion of water in BPL-catalyzed asymmetric cross aldol reaction

Bovine pancreatic lipase (BPL) is reported to catalyze direct asymmetric aldol reactions between aromatic aldehydes and cyclic ketones in water at 50 °C, and water can greatly promote the catalytic activity and selectivity of BPL. A wide range of aromatic aldehydes reacted with cyclic ketones to provide the corresponding aldol products with high yields (up to 93.7%) and moderate to good stereoselectivity (up to 99% ee and 1:99 dr).

L-proline functionalized pH-responsive copolymers as supported organocatalysts for asymmetric aldol reaction in water

pH-Responsive copolymers with reversible transformation ability have been investigated as new effective carriers for L-proline to catalyze asymmetric aldol reaction in water. A series of block copolymers of mPEG-b-P(DEAx-co-L-ProlAy) (mPEG-PDL) bearing L-proline catalytic sites and pH-responsive poly (diethylaminoethyl methacrylate) (PDEA) segments were synthesized by the reversible addition-fragmentation chain transfer (RAFT) polymerization in the presence of methyl polyethylene glycol (mPEG) trithiocarbonate macro-RAFT agent. The pH-induced self-assembly behaviors of three copolymer catalysts with different contents of PDEA were investigated via the combination of UV–visible spectrometer (UV–vis), dynamic light scattering (DLS) and transmission electron microscopy (TEM). Catalytic activity and stereoselectivity of these copolymer catalysts were evaluated by direct asymmetric aldol reaction of p-nitrobenzaldehyde and cyclohexanone in water. The results indicated that catalytic activity and stereoselectivity effected by the pH value of aqueous solution and the structures of copolymer catalyst assemblies. mPEG-PDL-2 give the aldol product with high conv., yield, anti/syn, and ee (92%, 91%, 92/8, 96%), respectively at pH 7.0. Furthermore, these pH-responsive copolymers supported L-proline are easily recycled by a reversible phase transition.

Cover Feature: Practical Synthesis of High‐Performance Amino Tf‐Amide Organocatalysts for Asymmetric Aldol Reactions (Asian J. Org. Chem. 2/2020)

The cover art depicts the direct asymmetric aldol reactions of cycloalkanones and substituted benzaldehydes catalyzed by a secondary-amino aromatic Tf-amide organocatalyst, affording the corresponding aldol adducts in good yield with good to excellent anti-diastereo- and enantioselectivity. The catalyst efficiently “lightens” the diastereo- and enantioselective transformation. The art shows a sky lantern, known as Kongming Light, which is used as a wishing lamp in the traditional Chinese Festivals, such as the Lantern Festival and Mid Autumn Festival. More information can be found in the Communication by Yan Liu, Keiji Maruoka et al. on page 206 in Issue 2, 2020 (DOI: 10.1002/ajoc.201900730).

Practical Synthesis of High‐Performance Amino Tf‐Amide Organocatalysts for Asymmetric Aldol Reactions

AbstractA type of optically pure secondary‐amino aromatic Tf‐amide organocatalysts can be easily prepared from commercially available L‐hydroxyproline. The chemical behavior of these organocatalysts was investigated by the application to asymmetric aldol reactions. Among these, catalyst 2 a efficiently catalyzed direct asymmetric aldol reactions of cycloalkanones and substituted benzaldehydes, which afforded the corresponding aldol adducts in good yield with good to excellent anti‐diastereo and enantioselectivity.

Construction of Chiral 2,3-Allenols through a Copper(I)-Catalyzed Asymmetric Direct Alkynylogous Aldol Reaction.

Chiral 2,3-allenols were constructed through copper(I)-catalyzed asymmetric direct alkynylogous aldol reaction. With aromatic and heteroaromatic aldehydes, the alkynylogous aldol reaction with (R)-DTBM-SEGPHOS as the ligand proceeded smoothly to furnish the products in excellent regioselectivity with good to high diastereoselectivity and excellent enantioselectivity. In the cases of aliphatic aldehydes, esters of but-2-yn-1-ol as the substrates and (R,R)-Ph-BPE as the ligand were found to be crucial to get good to high regio- and diastereoselectivity. The produced chiral 2,3-allenols are easily transformed into synthetically useful 2-furanones through cyclization. Finally, the developed method was successfully applied in the rapid synthesis of two chiral intermediates toward the synthesis of two pharmaceutically active compounds that have been proposed for the treatment of neurological disorders.

Asymmetric Direct Aldol Reaction in Confined Space: Molecular Conformations of Organocatalyst Affect Chiral Induction

AbstractWe have demonstrated that chiral induction in the aldol product is possible by generating an enzyme‐like cavity in molecular framework of the amphiphlic catalyst. The esters of trans‐4‐hydroxy‐L‐proline and long chain fatty acids have been synthesized by O‐acylation. Synthesized molecules were used as organocatalysts for asymmetric direct aldol reaction between 4‐nitrobenzaldehyde and cyclohexanone. The molecular framework of the catalyst not only induces the amphiphilicity but also acquires specific conformation leads to formation of catalytic cavity facilitating stereo‐induction in the aldol product. Systematic addition of olefinic bonds in the long hydrocarbon chain makes this cavity more robust stabilizing transition state of the aldol product. By proper tuning of the water content and % loading of the catalyst in aldol reaction, o/w or w/o type emulsion is formed due to aggregation of catalyst molecules. Performance based evaluation of catalytic activity suggests that aldol reaction proceeds with ∼ 99% yield, 84% dr and 97.94% ee in presence of 10% catalyst (having three π bonds), in an o/w emulsion (85 equiv. of water) within 12 h. The stereoselectivity of the catalyst is almost maintained up to 2.5% loading. The high stereoselectivity of the aldol reaction is maintained even on increasing the amount of water to 300 equiv. A plausible reason has been proposed for retaining the high stereoselectivity and corroborated by computational analysis.

Construction of Chiral 2,3‐Allenols through a Copper(I)‐Catalyzed Asymmetric Direct Alkynylogous Aldol Reaction

AbstractChiral 2,3‐allenols were constructed through copper(I)‐catalyzed asymmetric direct alkynylogous aldol reaction. With aromatic and heteroaromatic aldehydes, the alkynylogous aldol reaction with (R)‐DTBM‐SEGPHOS as the ligand proceeded smoothly to furnish the products in excellent regioselectivity with good to high diastereoselectivity and excellent enantioselectivity. In the cases of aliphatic aldehydes, esters of but‐2‐yn‐1‐ol as the substrates and (R,R)‐Ph‐BPE as the ligand were found to be crucial to get good to high regio‐ and diastereoselectivity. The produced chiral 2,3‐allenols are easily transformed into synthetically useful 2‐furanones through cyclization. Finally, the developed method was successfully applied in the rapid synthesis of two chiral intermediates toward the synthesis of two pharmaceutically active compounds that have been proposed for the treatment of neurological disorders.

Graphene-based recyclable and bifunctional heterogeneous chiral catalyst for direct asymmetric aldol reaction

Application of metal-free heterogeneous asymmetric catalysis is of great interest in the field of asymmetric synthesis. Herein, two novel graphene-supported proline-based bifunctional carbocatalysts were prepared by post-grafting l-proline onto graphene oxide sheets via organoamine-functionalized graphene oxide (GO-NH2) and reduced graphene oxide (rGO-NH2). Different methods such as Fourier-transform infrared spectroscopy (FT-IR), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and transmission electron spectroscopy (TEM) were employed to examine the surface functionalization of GO. The catalytic properties of these materials were investigated in the direct asymmetric aldol reaction. l-proline grafted heterogeneous catalyst, GO-Pro, was found to be an efficient and powerful organocatalyst for the enantioselective aldol reaction under mild conditions in hexane and afforded the corresponding aldol adducts with satisfactory isolated yields (up to 88%) and enantiomeric excesses (up to 85%). Furthermore, graphene-based carbocatalyst could be recovered and recycled easily by a simple washing procedure and re-used for several times without substantial reduction in its catalytic activity.

Synthesis of 1,2-Diamine Bifunctional Catalysts for the Direct Aldol Reaction Through Probing the Remote Amide Hydrogen

Background: While proline can catalyze the asymmetric direct aldol reactions, its catalytic activity and catalyst turnover are both low. To improve the catalytic efficiency, many prolinebased organocatalysts have been developed. In this regard, prolinamide-based bifunctional catalysts have been demonstrated by us and others to be highly efficient catalysts for the direct aldol reactions. Results: Using the β-acetamido- and β-tosylamidoprolinamide catalysts, the highly enantio- and diastereoselective direct aldol reactions between enolizable ketones and aldehydes were achieved (up to >99% ee, 98:2 dr). A low catalyst loading of only 2-5 mol % of the β-tosylamidoprolinamide catalyst was needed to obtain the desired aldol products in good to high yields and high stereoselectivities. Methods: By carefully adjusting the hydrogen bonding ability of the remote β-amide hydrogen of the 1,2-diamine-based prolinamide bifunctional catalysts, the catalytic activity and the asymmetric induction of these catalysts were significantly improved for the direct aldol reaction between aldehydes and enolizable ketones. Conclusion: Some highly efficient 1,2-diamine-based bifunctional prolinamide catalysts have been developed through probing the remote β-amide hydrogen for its hydrogen bonding capability. These catalysts are easy to synthesize and high enantioselectivities may be achieved at very low catalyst loadings.

Asymmetric Direct Aldol Reaction Catalyzed by (1R, 2R)-(+)-1, 2- Diammonium Cyclohexane-L-tartrate in Water

Background: A cheap and commercially available organocatalyst, (1R, 2R)-(+)-1, 2- diammonium cyclohexane-L-tartrate 1 was applied in direct aldol reaction in water. The organocatalyst 1 afforded aldol products from cyclohexanone and substituted aromatic aldehydes with high yield (up to 90%) and good stereoselectivity (up to 99% ee and up to 11.5:1 dr) in large volume of water (10 ml). Methods: The same aldol reaction when carried out in the presence of more expensive organocatalyst e.g. (1R, 2R)-(+)-1,2-diaminocyclohexane and 1,6-hexanediaoic acid as acid additive furnished the aldol products with only 20% yield, 2:1 anti/syn ratio and 92% ee. Results and Conclusion: In summary, we have applied a reasonably cheap and commercially available organocatalyst 1 for highly enantioselective direct aldol reaction in water at room temperature.

Prolinamide‐Catalysed Asymmetric Organic Transformations

AbstractProline was reported as an enantioselective organocatalyst for direct asymmetric aldol reaction in the early 1971 s by two independent groups of researchers and the reaction was called the Hajos‐Parrish‐Eder‐ Sauer Wiechert reaction. The breakthrough of enantioselective organocatalysis was demonstrated by List and co‐workers in 2000 for intermolecular aldol reaction between benzaldehydes and ketone using proline as a catalyst. After this report many researchers were applied the proline as a catalyst for other organic transformation. The proline has a carboxylic functional group which can easily convert to the amide and known as prolinamide. Prolinamides were found to be a better catalyst compared to proline in the most of cases. In this review article we are compiling the results of the prolinamides catalyzed asymmetric organic transformation with insight of the mechanism of catalysis.

Bioinspired Polymer-Bound Organocatalysts for Direct Asymmetric Aldol Reaction: Experimental and Computational Studies

A series of poly(2-oxazoline) (POX) derivatives bearing prolinamide pendants were designed as organocatalysts and evaluated in the direct asymmetric aldol reaction between aromatic aldehydes and cyclic ketones. The structural variation of the alkyl spacer connecting the polymer backbone with the catalytic unit was applied so as to deduce structure–performance relationships combined with comparable experiments from model catalysts. Results showed that the POX-bound prolinamides can promote the aldol reaction more effectively as compared to their small-molecular and non-POX-bound analogs. The catalyst P3 containing the pyrrolidine moiety closer to the tertiary amide backbone exhibited the overall best catalytic efficiency, affording anti-products in 84% yield with 89% ee in the representative aldol addition of cyclohexanone to 4-nitrobenzaldehyde at a 10 mol.% catalyst loading. Furthermore, the influence of trifluoroacetic acid as an additive on the asymmetric transformation was investigated. Theoretical calculations revealed that the protonation of the aldehyde carbonyl group switched the activation mode of the aldol acceptor through hydrogen bond interactions, thereby changing the relative energy barrier of the enamine/aldehyde reaction transition states, which accounted well for the significant improvement in the enantioselectivity of the acidic additives observed experimentally.

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.

Probing the Synergistic Catalytic Model: A Rationally Designed Urea-Tagged Proline Catalyst for the Direct Asymmetric Aldol Reaction.

A urea tag was incorporated at the C-4 position of proline, cis to its COOH group, in order to explore the prospect of a synergistic effect between the two functional groups in the transition state of the enamine route to the asymmetric aldol reaction. The catalyst proved to be an excellent performer, delivering aldols in high yields and with excellent enantio- and diastereoselectivities using just 2 mol % loading in the presence of water; it also exhibited good levels of recyclability under aqueous conditions. The favorable results reveal the interesting possibility of an intramolecular host-guest interaction between the urea and the amino acid moieties, exerting a beneficial effect on catalysis. The concept could certainly offer a new direction toward more efficient catalyst design.

Theoretical Investigation on Direct Vinylogous Aldol Reaction of Isatin Catalyzed by Chiral-N, N'-dioxide Sc(III) Complex

The mechanism and enantio- as well as diastereo-selectivity of asymmetric direct aldol reaction of isatin with α-angelica lactone catalyzed by chiral N, N'-dioxide-Sc(OTf)3 were studied at the B3LYP(SMD, THF)/6-31G(d,p) level. The calculations indicated that the reaction occurred along stepwise mechanism, that is, CC bond formation followed by H-transfer from α-angelica lactone to carbonyl group of isatin. The H-transfer step was predicted to be the rate-determining step(RDS), with the energy barrier of 23.3 ∼ 26.2 kcal mol−1 for four stereoisomeric products. The ortho-isopropyl groups of amide in ligand blocked the reacting site from re-face of isatin and induced the re-face of α-angelica lactone to approach to the si-face of isatin, leading to the predominant product with 3S, 2′S-configuration. In this asymmetric catalysis, the interaction energy term (ΔEint), especially stabilizing orbital energy (ΔEoi) and electrostatic energy (ΔVelstat), were the main contributors to the enantioselectivity of the reaction, while the activation strain energy (ΔEstrain) of α-angelica substrate enhanced the diastereodifferentiation of the two competing pathways, contributing to high diastereomeric ratio (d.r.). The turnover frequency (TOF) along the favorable si-face pathway was predicted to be 2.76 × 10−21 s−1, with the rate constant of k(T) = 7.5 × 10−2 exp(-108390/RT) dm3 mol−1 s−1 over 258.15 K ∼ 358.15 K temperature range. These results provided explanation for the good reactivity as well as excellent asymmetric induction of chiral N, N'-dioxide-Sc(OTf)3 in direct aldol reaction of isatin.

New Prolinamides with Isosteviol Skeleton as Efficient Organocatalysts for the Direct Asymmetric Aldol Reaction

New Prolinamides with Isosteviol Skeleton as Efficient Organocatalysts for the Direct Asymmetric Aldol Reaction

Two-Pot Synthesis of Chiral 1,3-syn-Diols through Asymmetric Organocatalytic Aldol and Wittig Reactions Followed by Domino Hemiacetal/Oxy-Michael Reactions.

A two-pot synthetic method to construct the chiral syn-1,3-diol unit has been developed from three aldehydes and either Wittig or Horner-Wadsworth-Emmons reagents. In the first pot, chiral δ-hydroxy α,β-unsaturated ketones are synthesized with excellent enantioselectivity by the organocatalyst-mediated asymmetric direct aldol reaction of two different aldehydes, followed by either Wittig or Horner-Wadsworth-Emmons reactions. In the second pot, domino acetalization with an aldehyde and subsequent oxy-Michael reaction proceeds in the presence of NaClO4 and a catalytic amount of Bi(OTf)3 (OTf=trifluoromethanesulfonate) to provide the chiral 1,3-syn-diol derivative with excellent diastereoselectivity. Diospongin C and yashabushidiol A have been synthesized efficiently by using the present method as a key step.