Asymmetric Nitroaldol Reaction Research Articles

The Role of Aromatic Alcohol Additives on Asymmetric Organocatalysis Reactions: Insights from Theory.

The presence of an aromatic additive has been seen to enhance, often significantly, the enantioselectivity and yield in asymmetric organocatalysis. Considering their success across a dizzying range of organocatalysts and organic transformations, it would seem unlikely that a common principle exists for their functioning. However, the current investigations with DFT suggest a general principle: the phenolic additive sandwiches itself, through hydrogen bonding and π⋅⋅⋅π stacking, between the organocatalyst coordinated electrophile and nucleophile. This is seen for a wide range of experimentally reported systems. That such complex formation leads to enhanced stereoselectivity is then demonstrated for two cases: the cinchona alkaloid complex (BzCPD), catalysing thiocyanation (2-naphthol additive employed), as well as for L-pipecolicacid catalysing the asymmetric nitroaldol reaction with a range of nitro-substituted phenol additives. These findings, indicating that dual catalysis takes place when phenolic additives are employed, are likely to have a significant impact on the field of asymmetric organocatalysis.

α-Methylbenzylamine Functionalized Crown-Ether-Appended Calix[4]arene Phase Transfer Catalyst for Enantioselective Henry Reaction.

In this letter, we designed a highly selective α-methylbenzylamine functionalized crown-ether-appended calix[4]arene derived phase transfer catalyst for asymmetric nitroaldol reaction to provide the desired nitroaldol adducts in high yields (up to 99 % yield) with good to excellent enantioselectivities (up to 99.8 % ee).

Porous aromatic frameworks containing binaphthyl-dihydroazepine units (cBAPAFs) as catalytic supports for asymmetric reactions

We present the successfully synthesis of a series of chiral polymeric aromatic frameworks containing novel enantiopure atropoisomeric 1,1′-binaphthyl-dihydroazepine-based compounds as structural building units named cBAPAFs. Three porous materials with amino, pyridinic and amino-alcohol functionalities were successfully obtained from dibrominated monomers by Suzuki-Miyaura couplings. New porous materials present surface areas up to 619 m2 g−1 determined by Brunauer–Emmett–Teller (BET), and high thermal stability. The use of nitrogen-based structural units provides useful functional groups to allow a robust binding site for metal complexes. Thus, after post-synthetic metalation with Cu(OAc)2, these materials have been applied as efficient heterogenized catalysts for the nitroaldol (Henry) reaction and a multicomponent reaction, affording chiral products with comparable enantioselectivity to that of the homogeneous system. The materials were also tested as organocatalysts for the asymmetric addition of diethylzinc to benzaldehyde and the reaction between nitro-styrene and nitroethane. These cBAPAFs could be recycled for the asymmetric nitroaldol reaction for at least 5 cycles without a significant loss in its catalytic efficiency.

Chiral pyridine oxazoline and 1,2,4-triazine oxazoline ligands incorporating electron-withdrawing substituents and their application in the Cu-catalyzed enantioselective nitroaldol reaction

Eight pyridine-containing and four 1,2,4-triazine-containing chiral oxazoline ligands incorporating electron-withdrawing substituents have been synthesized by two-step route including Buchwald–Hartwig amination. Enantio-inducing activity of the ligands has been assessed in the copper-catalyzed asymmetric nitroaldol reactions and the influence of the electron-withdrawing substituents on the ligands' activity has been investigated.Graphical abstract

Stereoselective Synthesis of Protected l-allo-Enduracididine and l-Enduracididine via Asymmetric Nitroaldol Reaction

The diastereoselecetive and scalable synthesis of cyclic guanidine-containing nonproteinoginic amino acids, enduracididines, has been achieved. Both diastereomers, l-allo-enduracididine and l-enduracididine, were prepared via catalyst-controlled asymmetric nitroaldol reaction with the aldehyde precursor derived from l-aspartic acid. The cyclic guanidine of di-Cbz-protected l-allo-enduracididine was fully protected with an allyl group to suppress nucleophilic side reactions. Introduced allyl group was efficiently removed via π-allylpalladium chemistry without attaching the Cbz group on the cyclic guanidine moiety.

Solvent-Dependent Enantiodivergence in anti-Selective Catalytic Asymmetric Nitroaldol Reactions.

anti-Selective catalytic asymmetric nitroaldol reactions of α-keto esters promoted by a heterogeneous Nd/Na heterobimetallic catalyst exhibited a significant, unexpected disparity in enantioselection that was solvent-dependent. This phenomenon exclusively occurred when the stereogenic center of a diamide ligand had the smallest substituent (Me group, derived from l-Ala), which behaved uniquely in comparison with other structurally similar ligands to provide antipodal products under otherwise identical conditions.

Anti-Selective Catalytic Asymmetric Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active Pharmaceutical Ingredients.

A rare-earth metal/alkali metal bimetallic catalyst proved particularly effective for enantioselectively coupling nitroalkanes and α-keto esters in an anti-selective manner to afford synthetically versatile, densely functionalized, and optically active α-nitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solid-phase heterobimetallic catalyst by simple mixing via self-assembly. The advantage of the solid-phase asymmetric catalyst was realized by successful application to the enantio- and diastereoselective reaction in a continuous-flow platform. The use of closely related solvents in terms of structures and polarity parameters, THF and its methylated congener 2-Me-THF, had an unexpectedly large solvent effect both on the reaction rate and the stereoselectivity. The nitroaldol products share a privileged unit for active pharmaceutical ingredients, as demonstrated by the streamlined enantioselective synthesis of the marketed antifungal agents efinaconazole and albaconazole.

Heterogeneous Heterobimetallic Catalysis Enabling Expeditious Access to CF3-Containing vic-Amino Alcohols.

A highly anti-selective catalytic asymmetric nitroaldol reaction of trifluoromethyl ketones based on Nd/Na and Pr/Na heterobimetallic catalysts was developed. These catalysts function as heterogeneous catalysts to engage nitroethane and a range of trifluoromethyl ketones in a stereoselective assembly to afford CF3-appended vic-nitroalkanols that could be readily converted to enantioenriched vic-amino alcohols, which are privileged structural motifs in medicinal chemistry.

Organocatalytic Nitroaldol Reaction Associated with Deuterium‐Labeling

AbstractA deuterium‐labeling reaction of nitroalkanes in deuterium oxide and the subsequent nitroaldol reaction have been accomplished under basic and organocatalytic conditions to provide the deuterium‐labeled β‐nitroalcohols in high yields and high deuterium contents. β‐Deuterated β‐nitroalcohols could be smoothly obtained from the reaction of nitroalkanes and various electrophiles using the easily‐removal basic resin WA30. Furthermore, the asymmetric nitroaldol reaction using nitromethane and α‐keto esters as electrophiles in the presence of a quinine‐derived organocatalyst in deuterium oxide could provide the desired β‐deuterated nitroalcohol derivatives with high enantioselectivities.magnified image

Simple and Effective Catalyst Separation by New CO2 -Induced Switchable Organocatalysts.

CO2 -induced switchable tertiary amine-based organocatalysts were investigated for an efficient catalyst and product separation by its different partitioning between an organic and carbonated water phase. In this case study, the switching ability of eight tertiary amine-based catalysts between the organic and water phase by addition or removal of CO2 was investigated. Here, the catalyst switched both nearly completely (99.9 %) into the aqueous phase by addition of CO2 and effectively back into the organic phase (99.3 %) by expelling CO2 . With this technique, the organocatalyst was successfully recovered and reused twelve times without significant loss of activity (up to 90 % enantiomeric excess) for the asymmetric nitroaldol (Henry) reaction. After the first catalyst switch, evaporation of the solvent affords the product in 98 % purity without any further purification steps.

A Neodymium/Sodium-Based Catalyst for Asymmetric Flow Nitroaldol Reaction

A Neodymium/Sodium-Based Catalyst for Asymmetric Flow Nitroaldol Reaction

Asymmetric flow catalysis: Mix-and-go solid-phase Nd/Na catalyst for expeditious enantioselective access to a key intermediate of AZD7594

An anti-selective catalytic asymmetric nitroaldol reaction was implemented in a continuous-flow reaction platform for the synthesis of a key intermediate of a drug candidate. The requisite solid-phase catalyst was readily prepared by mixing an amide-based chiral ligand and inexpensive inorganic salts, NdCl3•6H2O and NaOtBu, without covalent bond linkages. The flow system was operated with 2-Me-THF as the eluent for ca. 400 h to provide a crude nitroaldol adduct in a highly stereoselective manner with no work-up procedure, reaching turnover number over 1600. Facile reduction of the nitro group of the product afforded a key intermediate of AZD7594, a therapeutic candidate for asthma and chronic obstructive pulmonary disease.

ChemInform Abstract: Copper Complex of Pinene Based Schiff Base [CuSBADBH]2: Synthesis and Its Application in Catalytic Asymmetric Nitroaldol (Henry) Reaction.

Eight new pinene based tridentate Schiff bases of (+)-(1S,2R,3S,5S)-3-amino-6,6-dimethylbicyclo[3.1.1]heptan-2-ol were synthesized from (+)-(α)-pinene. Copper complexes of these Schiff bases were prepared for asymmetric nitroaldol (Henry) reaction. Among the eight copper complexes, 3-methylsalicylaldehyde-derived [CuSBADBH-4]2 32 showed high chiral induction (85 % ee) for the catalytic asymmetric Henry reaction of 4-nitrobenzaldehyde. Under optimal reaction conditions, 1 mol% [CuSBADBH-4]2 32 catalyzed enantioselective Henry reaction of various aromatic and poly aromatic aldehydes afforded the corresponding (R)-β-hydroxy nitroalkanes with high ee (up to 92 %) and yield (up to 99 %).

Enantio- and Diastereoselective Synthesis of β-Nitroalcohol via Henry Reaction Catalyzed by Cu(II), Ni(II), Zn(II) Complexes of Chiral BINIM Ligands

Enantiopure Cu(II), Ni(II) and Zn(II) chiral complexes CuLR, CuLS, NiLR, NiLS, ZnLR and ZnLS were synthesised by using ligands LR and LS, which were derived from the (R)-(+)-1,1’-Binaphthyl-2,2′-diamine or (S)-(−)-1,1’-Binaphthyl-2,2’-diamine with pyridine-2-aldehyde. These six complexes are characterised and applied as a catalyst for asymmetric nitroaldol reaction. The enantiopure chiral ligand upon complexation transfers its chirality from ligand to metal and generate “Δ or Λ” chirality at the metal centre. All these associated chiral responses were monitored using circular dichroism. Ensuring the enantiopure nature of the complexes they have been demonstrated as an efficient enantioselective catalyst for nitroaldol reaction. Further, this asymmetric catalytic study has been extended to various nitroalkanes such as nitromethane, nitroethane and nitropropane with substituted benzaldehydes leading to the synthesis of various diastereoselective β-nitroalcohols.

ChemInform Abstract: Preparation of Nd/Na Heterogeneous Catalyst from Bench‐Stable and Inexpensive Nd Salt for an anti‐Selective Catalytic Asymmetric Nitroaldol Reaction.

Abstract A Nd/Na heterobimetallic complex prepared from an amide-based chiral ligand, Nd alkoxide, and NaHMDS is a highly efficient heterogeneous catalyst for an anti-selective catalytic asymmetric nitroaldol reaction. Nd alkoxide is sensitive to moisture, expensive, and scarce, making it difficult to use the Nd/Na catalyst in large-scale applications. Herein we describe a new protocol that allows for catalyst preparation from bench-stable and inexpensive NdCl3·6H2O with comparable catalytic activity.

Cobalt(II)-Salen-Linked Complementary Double-Stranded Helical Catalysts for Asymmetric Nitro-Aldol Reaction

Double-helical, bimetallic chiral Co(II)-salen complexes stabilized by chiral amidinium–carboxylate salt bridges efficiently catalyzed the asymmetric nitro-aldol (Henry) reaction, producing products with up to an 89% enantiomeric excess (ee); the reactivity and enantioselectivity were higher than those catalyzed by the corresponding single strands. The key role of the chiral double-helical framework for the supramolecular bimetallic catalysis has been revealed by a double-helical catalyst carrying achiral Co(II)-salen units that promoted the Henry reaction, yielding the product with a 50%–45% ee, while the corresponding single strands showed poor or no enantioselectivity.

Copper Complex of Pinene based Schiff base [CuSBADBH]2: Synthesis and its Application in Catalytic Asymmetric Nitroaldol (Henry) Reaction

AbstractEight new pinene based tridentate Schiff bases of (+)‐(1S,2R,3S,5S)‐3‐amino‐6,6‐dimethylbicyclo[3.1.1]heptan‐2‐ol were synthesized from (+)‐(α)‐pinene. Copper complexes of these Schiff bases were prepared for asymmetric nitroaldol (Henry) reaction. Among the eight copper complexes, 3‐methylsalicylaldehyde‐derived [CuSBADBH‐4]2 32 showed high chiral induction (85 % ee) for the catalytic asymmetric Henry reaction of 4‐nitrobenzaldehyde. Under optimal reaction conditions, 1 mol% [CuSBADBH‐4]2 32 catalyzed enantioselective Henry reaction of various aromatic and poly aromatic aldehydes afforded the corresponding (R)‐β‐hydroxy nitroalkanes with high ee (up to 92 %) and yield (up to 99 %).

ChemInform Abstract: Binuclear Cu(II) Chiral Complexes: Synthesis, Characterization and Application in Enantioselective Nitroaldol (Henry) Reaction.

Enantiopure macrocyclic ligands were synthesized from (1R,2R)-(+)- and (1S,2S)-(−)-diphenylethylenediamine with 3,3'-methylenebis(5-(tert-butyl)-2-hydroxybenzaldehyde) and characterized. The chirality transfer and chiral inversion from ligand to copper(II) metal centre were studied using circular dichroism spectroscopy. The enantiopure binuclear copper(II) complexes (ΔΔ and ΛΛ) were used as catalysts for asymmetric nitroaldol reaction to generate β-nitroalcohol with 88% yield and 67% enantioselectivity. Copyright © 2015 John Wiley & Sons, Ltd.

Preparation of Nd/Na heterogeneous catalyst from bench-stable and inexpensive Nd salt for an anti-selective catalytic asymmetric nitroaldol reaction

A Nd/Na heterobimetallic complex prepared from an amide-based chiral ligand, Nd alkoxide, and NaHMDS is a highly efficient heterogeneous catalyst for an anti-selective catalytic asymmetric nitroaldol reaction. Nd alkoxide is sensitive to moisture, expensive, and scarce, making it difficult to use the Nd/Na catalyst in large-scale applications. Herein we describe a new protocol that allows for catalyst preparation from bench-stable and inexpensive NdCl3·6H2O with comparable catalytic activity.

Binuclear Cu(II) chiral complexes: synthesis, characterization and application in enantioselective nitroaldol (Henry) reaction

Enantiopure macrocyclic ligands were synthesized from (1R,2R)‐(+)‐ and (1S,2S)‐(−)‐diphenylethylenediamine with 3,3'‐methylenebis(5‐(tert‐butyl)‐2‐hydroxybenzaldehyde) and characterized. The chirality transfer and chiral inversion from ligand to copper(II) metal centre were studied using circular dichroism spectroscopy. The enantiopure binuclear copper(II) complexes (ΔΔ and ΛΛ) were used as catalysts for asymmetric nitroaldol reaction to generate β‐nitroalcohol with 88% yield and 67% enantioselectivity. Copyright © 2015 John Wiley & Sons, Ltd.