Asymmetric Cross-aldol Reaction Research Articles

New boro amino amide organocatalysts for asymmetric cross aldol reaction of ketones with carbonyl compounds.

Distinct types of new boron fused primary amino amide organocatalysts were designed and synthesized from commercially available amino acids. Their catalytic activities were investigated in asymmetric crossed aldol reaction of ketones with aromatic aldehydes to afford the corresponding chiral anti-aldol adducts with good chemical yields, moderate diastereoselectivity and good to excellent enantioselectivities (up to 94% yields, up to 90 : 10 dr, up to 94% ee).

Synthetic access to syn-functionalised chiral hydroxy pyrrolidines and pyrrolidones: Evaluation of α-glucosidase inhibition activity, docking studies and pharmacokinetics prediction

A new series of syn-functionalised chiral hydroxy pyrrolidines and pyrrolidones containing α,β-contiguous stereocenters were synthesized via a diphenylprolinol-catalysed asymmetric cross aldol reaction. The synthesized compounds were characterised and evaluated for their α-glucosidase inhibitory potential. The hydroxy pyrrolidine series (9a-9i) was found to be selectively more potent against the α-glucosidase enzyme as compared to the pyrrolidone series (10a-10i). Pyrrolidine 9b was the most efficacious analogue with an IC50 of 48.31 µM. Compounds 9c, 9d, &9f were also found to be more potent than the standard drugs acarbose, miglitol and deoxynojirimycin. Furthermore, these compounds were investigated by computational studies using the GLIDE docking module of the Schrödinger suite 2021-4 in which 9b and 9c showed more promising results than the standard drugs acarbose, miglitol, and deoxynojirimycin.

Diarylprolinol as an Effective Organocatalyst in Asymmetric Cross-Aldol Reactions of Two Different Aldehydes.

The aldol reaction is one of the most important carbon-carbon bond-forming reactions in organic chemistry. Asymmetric direct cross-aldol reaction of two different aldehydes has been regarded as a difficult reaction because of the side reactions such as self-aldol reaction and over reaction. We found that trifluoromethyl-substituted diarylprolinol, α,α-bis[3,5-bis(trifluoromethyl)phenyl]-2-pyrrolidinemethanol (1), is an effective organocatalyst that promotes several cross-aldol reactions of aldehydes with excellent diastereo- and enantioselectivities. Acetaldehyde can be employed as a suitable nucleophilic aldehyde. Successful electrophilic aldehydes are ethyl glyoxylate, chloroacetaldehyde, dichloroacetaldehyde, chloral, α-alkyl-α-oxo aldehyde, trifluoroacetaldehyde, glyoxal, alkenyl aldehyde, alkynyl aldehyde, and formaldehyde. Some of the aldehydes are commercially available as a polymer solution, an aqueous solution, or in the hydrated form. They can be used directly in the asymmetric aldol reaction as a commercially available form, which is a synthetic advantage. Given that the obtained aldol products possess several functional groups along with a formyl moiety, they are synthetically useful chiral building blocks.

A 4-hydroxyproline/trimethyl borate system for asymmetric synthesis of triple aldols from double aldol cyclic hemiacetals

We developed a 4-hydroxyproline-catalyzed asymmetric cross-aldol reaction between aldehydes and cyclic hemiacetals derived from copper-catalyzed asymmetric double aldol reaction reported previously by our group. The addition of trimethyl borate, which acted as a ring-opening reagent for hemiacetals, was critical for producing triple aldol compounds with excellent diastereoselectivity.

Asymmetric cross-aldol reactions of α-keto hydrazones and α,β-unsaturated γ-keto hydrazones with trifluoromethyl ketones.

α-Keto hydrazones and α,β-unsaturated γ-keto hydrazones are suitable pro-nucleophiles for asymmetric cross-aldol reactions with trifluoromethyl ketones via aza-di(tri)enamine-type intermediates. A quinidine-derived primary amine catalyst affords tertiary trifluoromethylated alcohols in good-to-excellent yields and high enantioselectivities. Subsequent transformations of hydrazono moieties yield appealing fluorinated carboxylic acids, 1,4-dicarbonyls and γ-keto acids.

Asymmetric cross-Aldol Reactions between Two Carbonyl Compounds Catalyzed by Chiral Phosphine Oxides

Asymmetric cross-Aldol Reactions between Two Carbonyl Compounds Catalyzed by Chiral Phosphine Oxides

Peptide-Catalyzed Highly Asymmetric Cross-Aldol Reaction of Aldehydes to Biomimetically Synthesize 1,4-Dicarbonyls.

β-Turn tetrapeptides were demonstrated to catalyze asymmetric aldol reaction of α-branched aldehydes and α-carbonyl aldehydes, i.e. glyoxylates and α-ketoaldehydes, to biomimetically synthesize acyclic all-carbon quaternary center-bearing 1,4-dicarbonyls in high yield and excellent enantioselectivity under mild conditions. The spatially restricted environment of the tetrapeptide warrants high enantioselectivity and yield with broad substrates. Using this protocol, (R)-pantolactone, the key intermediate of vitamin B5, was readily accessed in a practical, efficient, and environmentally benign process from inexpensive starting materials.

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).

Pepsin-Catalyzed Asymmetric Cross Aldol Reaction Promoted by Ionic Liquids and Deep Eutectic Solvents

Pepsin was found to catalyze asymmetric cross aldol reactions of aromatic and polycyclicaromatic aldehydes with cyclic ketones in ionic liquids and deep eutectic solvents for the first time. Pepsin exhibited high catalytic activity and excellent stereoselectivity in ionic liquids and deep eutectic solvents in the presence of moderate water. High yields of up to 93.1%, excellent enantioselectivities of up to 96% ee, and good diastereoselectivities of up to 5:95 dr were achieved.

Phosphine Oxide-Catalyzed Asymmetric Aldol Reactions and Double Aldol Reactions.

Chiral phosphine oxides successfully catalyze asymmetric cross-aldol reactions of various carbonyl compounds in a highly enantioselective manner. The phosphine oxide catalysts coordinate to chlorosilanes to form chiral hypervalent silicon complexes in situ, which activate both aldol donors and acceptors, thus realizing cross-aldol reactions between a ketone and an aldehyde, between two aldehydes, between two ketones, and of 2,6-diketones. The use of phosphine oxide catalysis can be further extended to achieve the first catalytic enantioselective double aldol reactions, realizing one-pot stereoselective construction of up to four stereogenic centers.

Organocatalytic asymmetric hydroxymethylation of isoindolinones with paraformaldehyde

Activated 3-substituted isoindolinones have been investigated as nucleophiles in the organocatalytic asymmetric cross-aldol reaction with formaldehyde for the synthesis of derivatives with tetrasubstituted stereocenters. Among the tested catalysts, bifunctional chiral tertiary amines led to the target products in high yields and moderate enantioselectivity, while chiral ammonium salts, tested under phase-transfer conditions, were less effective.

Stereospecific diaza-Cope rearrangement as an efficient tool for the synthesis of DPEDA pyridine analogs and related C2-symmetric organocatalysts.

A simple and efficient synthesis of enantiomerically pure (1S,2S)-1,2-di(pyridin-2-yl)- and (1R,2R)-1,2-di(pyridin-4-yl)-ethane-1,2-diamines from commercial picolinaldehyde or isonicotinaldehyde and 2,2'-((1S,2S)-1,2-diaminoethane-1,2-diyl)diphenol (HPEN) via a stereospecific diaza-Cope rearrangement has been developed. Diamine (R,R)-2b was readily converted to novel diastereomeric ionic group-supported bis-prolinamides (R,S)-1b and (R,R)-1b which appeared to be efficient organocatalysts of asymmetric cross-aldol reactions in aldehyde/aldehyde, ketone/ketone or ketone/aldehyde reagent systems under neat conditions to afford corresponding aldols in high yields and with up to 99% ee. Furthermore, catalyst (R,S)-1b could be reused over 15 times in the same or similar catalytic reactions exhibiting close to original activity and a high level of stereoinduction.

ChemInform Abstract: Asymmetric Aldol Reaction of Dichloroacetaldehyde Catalyzed by Diarylprolinol.

Abstractγ,γ‐Dichloro‐β‐hydroxy aldehydes are generated in the first step.

Enzyme from Daucus carota root catalyzed asymmetric cross aldol reaction

A novel enzyme was isolated from specific variety of Daucus carota root catalyzed asymmetric cross aldol reaction of aromatic aldehydes with acetone to afford cross aldol products with excellent yield (up to 95%) and enantioselectivity (up to 99%). A plausible mechanism of the reaction has also been proposed.

ChemInform Abstract: Catalytic Asymmetric Iterative/Domino Aldehyde Cross‐Aldol Reactions for the Rapid and Flexible Synthesis of 1,3‐Polyols.

We report here catalytic asymmetric iterative and domino cross-aldol reactions between aldehydes, endowed with a high level of robustness, flexibility, and generality. A Cu(I)-DTBM-SEGPHOS complex catalyzes an asymmetric cross-aldol reaction between acceptor aldehydes and boron enolates derived from donor aldehydes, which are generated through Ir-catalyzed isomerization of allyloxyboronates. The unit process can be repeated using the aldol products in turn as acceptor substrates for the subsequent asymmetric aldol reaction. The donor aldehydes and stereoselectivity can be flexibly switched in a stepwise manner for the double-aldol reaction. Furthermore, asymmetric triple- and quadruple-aldol reactions are possible in one-pot using the appropriate amounts of donors and amine additives, rapidly elongating the carbon skeleton with controlling up to eight stereocenters. The method should be useful for straightforward synthesis of enantiomerically and diastereomerically enriched 1,3-polyols.

Copper-Catalyzed Asymmetric Cross-Aldol Reactions

Copper-Catalyzed Asymmetric Cross-Aldol Reactions

Tertiary amino thiourea-catalyzed asymmetric cross aldol reaction of aryl methyl ketones with aryl trifluoromethyl ketones

An enantioselective aldol reaction of aryl methyl ketones with aryl trifluoromethyl ketones catalyzed by tertiary amino thiourea has been established. Under mild conditions, the corresponding β-trifluoromethyl-β-hydroxy ketone products were obtained with up to 89% ee.

Catalytic Asymmetric Iterative/Domino Aldehyde Cross-Aldol Reactions for the Rapid and Flexible Synthesis of 1,3-Polyols.

We report here catalytic asymmetric iterative and domino cross-aldol reactions between aldehydes, endowed with a high level of robustness, flexibility, and generality. A Cu(I)-DTBM-SEGPHOS complex catalyzes an asymmetric cross-aldol reaction between acceptor aldehydes and boron enolates derived from donor aldehydes, which are generated through Ir-catalyzed isomerization of allyloxyboronates. The unit process can be repeated using the aldol products in turn as acceptor substrates for the subsequent asymmetric aldol reaction. The donor aldehydes and stereoselectivity can be flexibly switched in a stepwise manner for the double-aldol reaction. Furthermore, asymmetric triple- and quadruple-aldol reactions are possible in one-pot using the appropriate amounts of donors and amine additives, rapidly elongating the carbon skeleton with controlling up to eight stereocenters. The method should be useful for straightforward synthesis of enantiomerically and diastereomerically enriched 1,3-polyols.

(1,2-Diaminoethane-1,2-diyl)bis(N-methylpyridinium) Salts as a Prospective Platform for Designing Recyclable Prolinamide-Based Organocatalysts.

A new efficient and highly recyclable organocatalyst has been developed for asymmetric cross-aldol reactions under neat conditions in ketone-ketone, ketone-aldehyde, and aldehyde-aldehyde systems. The catalyst features two prolinamide fragments and a C2-symmetrical (1,2-diaminoethane-1,2-diyl)bis(N-methylpyridinium) group. The catalyst retained high activity and excellent stereoselection over the operating period of more than 830 h (25 cycles). An ab initio theoretical investigation explained the absolute configuration of the products and different stereoinduction levels for designed diastereomeric organocatalysts.

Ionic liquid as a recyclable and efficient medium for lipase-catalyzed asymmetric cross aldol reaction

PPL (lipase from porcine pancreas) was found to catalyze asymmetric cross aldol reactions of aromatic and heteroaromatic aldehydes with various ketones in ionic liquid ([BMIM][PF6]) for the first time. Interestingly, PPL exhibited high catalytic activity and excellent stereoselectivity in this efficient and recyclable room temperature ionic liquid in the presence of moderate water, similar to the results obtained in organic solvents. High yields of up to 99%, excellent enantioselectivities of up to 90% ee, and good diastereoselectivities of up to >99:1 dr were achieved.