Enantioselective Henry Reaction Research Articles

Cover Feature: α‐Methylbenzylamine Functionalized Crown‐Ether‐Appended Calix[4]arene Phase Transfer Catalyst for Enantioselective Henry Reaction (Chem. Eur. J. 72/2023)

Cover Feature: <i>α‐Methylbenzylamine</i> Functionalized Crown‐Ether‐Appended Calix[4]arene Phase Transfer Catalyst for Enantioselective Henry Reaction (Chem. Eur. J. 72/2023)

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).

Enantioselective Henry reaction catalysed by Chiral-copper(II) Complexes: Chirality effect derived from ligand backbone and Side-chain

• Two diastereopure camphor-derived iminomethylpyridine ligands were resolved. • Distorted square planar geometry has been featured around the Cu(II) complexes. • Phenyl propionaldehyde and CH 3 NO 2 reaction yields > 99 % 1-nitro-4-phenylbutan-2-ol. • ee > 99 % resulted in opposite configurations with R , R , S and R , R , R -Cu(II) complexes. • The combined backbone and side-chain chirality of the ligand governed the activity. Copper(II) complexes based on two diastereopure camphor-derived iminomethylpyridine ligands were resolved and structurally characterised by single-crystal X-ray diffraction. Each chiral Cu(II) complex was an efficient catalyst for theenantioselective Henry reaction of phenyl propionaldehyde and nitromethane, affording 1-nitro-4-phenylbutan-2-ol in high yields (up to 99%) and excellent enantioselectivities (up to 99%) that were governed by the combined chirality effect of the ligand backbone and side-chain.

Binaphthyl-Proline Hybrid Chiral Ligands: Modular Design, Synthesis, and Enantioswitching in Cu(II)-Catalyzed Enantioselective Henry Reactions.

Chiral O-N-N tridentate ligands were designed from proline and BINOL. Their design strategy and performance were evaluated using a copper(II)-catalyzed asymmetric Henry reaction as a model. The desired β-nitroalcohols were obtained in up to 94% ee's. Preliminary results suggested that the stereofacial selection of the reactions was mainly controlled by the chiral diamine moiety derived from proline, and matching of the central and axial chiralities was essential for the high stereoselectivity of the reaction. Enantioswitching was observed when an appropriate substituent was introduced to the binaphthyl group. Si-selections were found in reactions using 2a without 3-substituents as chiral ligand, and Re-selections were found with the same high enantioselectivities when 2i bearing the 3-trifluoromethyl group was used as the chiral ligand.

Total Synthesis of Marine Alkaloids Cystodytins A-K.

The total synthesis of marine alkaloids cystodytins A-K has been accomplished in five to six steps starting from commercially available compounds. The highlights of the synthesis include an oxidative amination-cyclization of tryptamine and para-hydroquinones to build a tetracyclic pyridoacridinone ring with different side chains and a copper(II)-catalyzed enantioselective Henry reaction to construct an oxygenated stereogenic carbon center. For the first time, the absolute configuration of the stereogenic centers embedded in cystodytins D-I and K was established as R. Moreover, the stereochemistry of the olefin unit in the side chain of cystodytins H and I was revised to the Z configuration from the originally assigned E configuration.

Enantioselective Henry Reaction Catalyzed by Chiral Piperazine Derivatives.

A series of novel tridentate Schiff bases is synthesized from piperazine-amine and substituted salicylaldehydes, and characterized by spectroscopic methods. These chiral ligands were used to catalyze the addition of nitromethane to various aldehydes in the presence of Cu(II) ions under ambient conditions in good yields (98%) and high enantioselectivities (9:91 er).

(3S,4S)‐N‐substituted‐3,4‐dihydroxypyrrolidines as ligands for the enantioselective Henry reaction

The enantioselective Henry reaction is a very important and useful carbon–carbon bond forming reaction. The execution of this reaction requires the use of efficient chiral catalysts. In this work, in situ formed complexes of N‐substituted dihydroxypyrrolidines, chiral ligands derived from L‐tartaric acid and amines, were evaluated as catalysts in the enantioselective Henry reaction. The results showed that the nature of the N‐substituent on the ligand significantly influences the outcome of the reaction. Best results were obtained using a Cu (II) complex of (3S,4S)‐N‐benzyl‐3,4‐dihydroxypyrrolidine, in the presence of DIPEA, for the reaction of aromatic aldehydes with nitromethane, at room temperature, originating products with er up to 92:8 (R:S) and conversions up to 96%. The interaction between the pyrrolidine ligand and the copper ion, in isopropanol, was followed by UV‐vis spectrophotometry, showing a 1:1 stoichiometry and a binding constant of 4.4. The results obtained will contribute to the design and development of more efficient chiral catalysts for this type of reaction.

Enantioselective Henry Reaction Catalyzed by Copper(II) Complex of Bis(trans-cyclohexane-1,2-diamine)-Based Ligand

Copper(II) complex of the ligand possessing two enantiomerically pure trans-cyclohexane-1,2-diamine units proved to be an efficient catalyst for the enantioselective Henry reaction of aromatic aldehydes with nitromethane. The effect of various reaction conditions on yield and enantioselectivity of the Henry reaction was studied. The results suggest that only one cyclohexane-1,2-diamine unit is involved in catalysis of the Henry reaction.

Functionalized Magnetic Nanoparticles as Catalysts for Enantioselective Henry Reaction.

With the aim to easily recover and reuse the catalyst, an efficient amino alcohol catalyst previously tested in the asymmetric addition of diethylzinc to several aromatic aldehydes has been immobilized on proper functionalized superparamagnetic core–shell magnetite–silica nanoparticles and employed in the Henry reaction in the semi-homogeneous phase. The nanocatalyst exhibits a promising catalytic activity that remains unchanged in the three catalytic cycles performed. The results prove that highly efficient catalysts, by being immobilized on suitable magnetic nanosupports, can be easily recovered and reused, maintaining their catalytic behavior.

Isosteric expansion of the structural diversity of chiral ligands: Design and application of proline-based N,N′-dioxide ligands for copper-catalyzed enantioselective Henry reactions

Chiral N,N′-dioxide catalysts were designed based on isosteric approach. Using l-Proline as the starting material, a variety of chiral N,N′-dioxide ligands were obtained via conventional functional group transformations and were utilized in asymmetric Henry reactions between nitromethane and aromatic aldehydes. Using the N,N′-dioxide-copper(II) complexes as the catalysts, asymmetric Henry reaction produced the corresponding β-nitroalcohols in up to 66% yields and up to 83% ee's under mild conditions. The reactions were easy to carry out, and special care such as air or moisture-free conditions was not required.

Chiral Cr(III)-salen complex embedded over sulfonic acid functionalized mesoporous SBA-15 material as an efficient catalyst for the asymmetric Henry reaction

Designing novel catalytic system for efficient synthesis of enantiomerically pure β-hydroxy nitroalkanes is a challenging area of research. Herein, we have designed a chiral heterogeneous catalyst through the successful loading of chiral Cr(III)-salen complex over sulfonic acid functionalized SBA-15 material. The catalyst has been thoroughly characterized by powder XRD, N2 adsorption/desorption, XPS, HR-TEM, CHN, AAS analyses and FT-IR spectroscopy. The reactivity of the catalyst has been examined in the enantioselective Henry reaction, where different substituted aromatic, heteroaromatic as well as aliphatic aldehydes produced corresponding β-hydroxy nitroalkanes with excellent product yields (up to 90%) and enantioselectivities (up to 91%). Moreover, this protocol has also been employed as the key-step to prepare enantiomerically pure drug (R)-(-)-isoproterenol from 3,4-dimethoxybenzaldehyde.

Cu(II)-L-prolinamide: First catalytic application of metal-amidoamine complex in enantioselective Henry reaction

For asymmetric Henry reaction, catalysis by chiral metal complexes is often prefered over aminocatalysis. Despite using many complicated L-proline derived ligands, the use of L-prolinamides as ligand in metal catalyzed Henry reaction is conspicuously absent. Here, we report a highly enantioselective Henry reaction catalyzed by N′-phenyl-N-benzyl L-prolinamide and Cu(OAc)2.H2O at room temperature.

Chiral iminophosphorane catalyzed asymmetric Henry reaction of α,β-alkynyl ketoesters

α,β-Alkynyl ketoesters were introduced to the enantioselective Henry reaction (nitroaldol condensation) with nitromethane catalyzed by tartaric acid derived chiral iminophosphoranes. As such, a variety of optically active β-nitro-substituted tertiary alcohols bearing alkyne moieties were obtained in good to excellent yields (42%–99%) and moderate to good level of enantiomeric excess (up to 87% ee).

Synthesis and Investigations of Chiral NNO Type Copper(II) Coordination Polymers

AbstractHerein, we report the synthesis and characterizations of chiral copper(II) coordination polymers (CPs) based on Schiff base of (S)‐2‐aminomethylpyrrolidine and salicylaldehyde derivatives. Single crystal X‐ray analysis showed that copper(II) complex is 1D CP, with the repeating units LCu‐OAc (L=ligand) organized in a perpendicular manner, where the copper(II) atoms are six‐coordinated and have a distorted octahedral geometry. Also complex with chlorine counter ion having unusual dimeric structure was synthesized and characterized. It was demonstrated that CPs catalyze the enantioselective Henry reaction with up to 78% ee.

Copper-Catalyzed Enantioselective Henry Reaction of β,γ-Unsaturated α-Ketoesters with Nitromethane in Water.

A highly enantioselective Henry reaction of β,γ-unsaturated α-ketoesters with nitromethane in water by virtue of chiral copper complexes has been developed. A series of unsaturated β-nitro-α-hydroxy esters bearing tetrasubstituted carbon stereocenters were obtained exclusively with high yields and excellent enantioselectivities. This method could avoid tedious anaerobic anhydrous manipulation and reduce the environmental pollution caused by organic solvents.

The synthesis of chiral tridentate ligands from l-proline and their application in the copper(II)-catalyzed enantioselective Henry reaction

A series of chiral tridentate ligands derived from readily available enantiopure l-proline were designed and synthesized. The ligands together with Cu(OAc)2 were successfully used in asymmetric Henry reactions. Various structurally divergent aldehydes and nitromethane were converted into versatile β-nitro alcohols in MeOH at room temperature with very good yields (up to 85%) and enantioselectivities (up to 86%).

ChemInform Abstract: Synthesis of Chiral Tetrahydroisoquinoline and C2‐Symmetric Bistetrahydroisoquinoline Ligands and Their Application in the Enantioselective Henry Reaction.

Application of chiral tetrahydroisoquinoline and bistetrahydroisoquinoline scaffolds in asymmetric reactions is limited by the inefficient synthesis of their chiral structural variants. We have conveniently synthesized 24 such variants and applied them as ligands in the enantioselective Henry reaction. The conformational rigidity of these ligands and the size of the coordination sphere control the enantioselectivity of the products. The conformationally rigid chiral tetrahydroisoquinoline THIQ–Cu(OAc) 2 ·H 2 O complex successfully catalyzed the enantioselective Henry reaction between various aldehydes and nitromethane and gives the β-nitro alcohol adducts in up to 96% yield and 80% ee.

Enantioselective nitromethane addition to brominated and fluorinated benzaldehydes (Henry reaction) catalyzed by chiral bisoxazoline–copper(II) complexes

The successful enantioselective Henry reaction of nitromethane to brominated and fluorinated benzaldehydes was achieved using a chiral bisoxazoline (unbridged)–Cu(II) complex as a catalyst. Nitroalcohols were obtained in excellent yields (up to 99%) and with enantioselectivities up to >99%. Theoretical calculations support the idea that the unbridged bisoxazoline–Cu(II) complex behaves similarly to the privileged bisoxazolines as catalysts in the Henry reaction.

ChemInform Abstract: The Development of New Amine—Amide Ligands for Application in Cu(II)‐Catalyzed Enantioselective Henry Reactions.

AbstractCombined with Cu(II) acetate, novel BINOL‐derived chiral tertiary amine ligands are developed as catalysts for the asymmetric Henry reaction of aromatic, heteroaromatic, and aliphatic aldehyde substrates.

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 %).