Chiral Imines Research Articles

Novel Synthesis of rac- and Enantiomerically Enriched Dimethyl α-Methyl-phosphoserinate

The novel synthesis of racemic and enantiomerically enriched (S)- and dimethyl (R)-α-methylphosphoserinate is described. The racemic synthesis involves a three-component reaction of hydroxyacetone, benzylamine, dimethyl phosphite and catalytic amounts of phenylphosphonic acid or alternatively, the reaction of ethyl pyruvate with NH4OAc, dimethyl phosphite in the presence of SiO2 under solvent-free conditions, followed by the reduction of ethyl ester with NaBH4 in a THF/MeOH. On the other hand, the stereoselective synthesis involve the phosphonylation of chiral cyclic imines obtained by reaction of ethyl pyruvate with (S)- or (R)-phenylglycinol, followed by the reduction of the cyclic ester with NaBH4 and cleavage of the phenylglycinol fragment under hydrogenolysis. The absolute configuration was established by 2D NOESY experiments. All synthesized compounds were fully characterized.

Asymmetric organocatalytic synthesis of chiral homoallylic amines.

In recent decades, the chiral allylation of imines emerged as a key methodology in the synthesis of alkaloids and natural products with 4-, 5- and 6-membered cyclic amine motifs. Initially reliant on stoichiometric reagents, synthetic chemists predominantly used N-substituted chiral imines, organometallic chiral reagents and achiral reagents with an equimolar chiral controller. However, recent years have witnessed the rise of asymmetric transition-metal catalysts and, importantly, organocatalytic allylation, reshaping the landscape of modern synthetic chemistry. This review explores the latest developments in the asymmetric allylation of imines, encompassing cutting-edge advances in hydrogen-bond catalysis and non-classical approaches. Furthermore, practical examples showcasing the application of these innovative methodologies in total synthesis are presented.

Synthesis of Nitrones and Nitroalkanes via Chiral Cyclic Imines.

A series of structurally chiral cyclic imines efficiently yields chiral nitrones and nitroalkanes. This is the first report of the synthesis of nitro groups by C═N bond cleavage of imines through a nitrone intermediate.

Efficient Asymmetric Syntheses of Chiral Imines with Multi-Stereocenters

Efficient Asymmetric Syntheses of Chiral Imines with Multi-Stereocenters

Synthesis of Vicinal anti-Amino Alcohols from N-tert-Butanesulfinyl Aldimines and Cyclopropanols.

The stereoselective synthesis of vicinal amino alcohols derivatives from 1-substituted cyclopropanols and chiral N-tert-butanesulfinyl imines is described. Cyclopropanols are easily prepared from carboxylic esters upon reaction with ethylmagnesium bromide in the presence of titanium tetraisopropoxide and undergo carbon-carbon bond cleavage by means of diethylzinc to produce, upon base deprotonation, enolized zinc homoenolates, which react with chiral sulfinyl imines in a highly regio- and stereoselective manner.

TBADT-Mediated Photocatalytic Stereoselective Radical Alkylation of Chiral N-Sulfinyl Imines: Towards Efficient Synthesis of Diverse Chiral Amines.

Herein we describe a sustainable and efficient photocatalytic method for the stereoselective radical alkylation of chiral sulfinyl imines. By employing readily available non-prefunctionalized radical precursors and the cost-effective TBADT as a direct HAT photocatalyst, we successfully obtain diverse chiral amines with high yields and excellent diastereoselectivity under mild conditions. This method provides an efficient approach for accessing a diverse array of medicinally relevant compounds, including both natural and synthetic α-amino acids, aryl ethyl amines, and other structural motifs commonly found in approved pharmaceuticals and natural product.

In Situ Chiral Template Approach to Synthesize Homochiral Lead Iodides for Second‐Harmonic Generation

AbstractHomochiral halide perovskites have gained increasing attention because of their fascinating optoelectronic properties and prospective applications in laser technologies. However, the limited choice of chiral organic templates severely restricts their structural diversity and second‐harmonic generation (SHG) effects. Here, we present an in situ chiral template approach for the synthesis of one‐dimensional (1D) homochiral lead iodides. A chiral imine (L‐ipp) template was generated in situ by reacting L‐proline (L‐pro) and acetone under ambient conditions. Notably, L‐ipp can cooperate with L‐pro to direct the formation of a homochiral lead iodide with dual chiral templates, which is unprecedented in crystalline metal halides. The homochiral lead iodide containing both L‐ipp and L‐pro shows a strong SHG response of 8.0 times that of KH2PO4 (8.0×KDP). The SHG efficiency is one of the largest values reported to date for any homochiral lead halides under 1064 nm laser irradiation. A comparative study shows that homochiral 1D lead iodides containing either L‐ipp or L‐pro exhibit relatively weak SHG responses (≤1.0×KDP). This work demonstrates the advantage of using two different chiral templates over a single chiral template in enhancing the SHG responses of halide materials.

In Situ Chiral Template Approach to Synthesize Homochiral Lead Iodides for Second-Harmonic Generation.

Homochiral halide perovskites have gained increasing attention because of their fascinating optoelectronic properties and prospective applications in laser technologies. However, the limited choice of chiral organic templates severely restricts their structural diversity and second-harmonic generation (SHG) effects. Here, we present an in situ chiral template approach for the synthesis of one-dimensional (1D) homochiral lead iodides. A chiral imine (L-ipp) template was generated in situ by reacting L-proline (L-pro) and acetone under ambient conditions. Notably, L-ipp can cooperate with L-pro to direct the formation of a homochiral lead iodide with dual chiral templates, which is unprecedented in crystalline metal halides. The homochiral lead iodide containing both L-ipp and L-pro shows a strong SHG response of 8.0 times that of KH2 PO4 (8.0×KDP). The SHG efficiency is one of the largest values reported to date for any homochiral lead halides under 1064 nm laser irradiation. A comparative study shows that homochiral 1D lead iodides containing either L-ipp or L-pro exhibit relatively weak SHG responses (≤1.0×KDP). This work demonstrates the advantage of using two different chiral templates over a single chiral template in enhancing the SHG responses of halide materials.

Inside Back Cover: Catalytic Atroposelective Synthesis of Axially Chiral Azomethine Imines and Neuroprotective Activity Evaluation (Angew. Chem. Int. Ed. 5/2024)

Inside Back Cover: Catalytic Atroposelective Synthesis of Axially Chiral Azomethine Imines and Neuroprotective Activity Evaluation (Angew. Chem. Int. Ed. 5/2024)

Innenrücktitelbild: Catalytic Atroposelective Synthesis of Axially Chiral Azomethine Imines and Neuroprotective Activity Evaluation (Angew. Chem. 5/2024)

Innenrücktitelbild: Catalytic Atroposelective Synthesis of Axially Chiral Azomethine Imines and Neuroprotective Activity Evaluation (Angew. Chem. 5/2024)

Iron-catalyzed decarboxylative radical addition to chiral azomethine imines upon visible light.

Herein, we disclose an eco-efficient redox-neutral iron-catalyzed decarboxylative radical addition to chiral azomethine imines upon visible light (427 nm) giving cyclic hydrazine derivatives with dr ranging from 82 : 18 to >96 : 4. This earth-abundant metal promoted sequence proceeds efficiently under ligand-free conditions based on a LMCT process and opens a route to new chiral heterocycles.

Catalytic Atroposelective Synthesis of Axially Chiral Azomethine Imines and Neuroprotective Activity Evaluation

AbstractAzomethine imines, as a prominent class of 1,3‐dipolar species, hold great significance and potential in organic and medicinal chemistry. However, the reported synthesis of centrally chiral azomethine imines relies on kinetic resolution, and the construction of axially chiral azomethine imines remains unexplored. Herein, we present the synthesis of axially chiral azomethine imines through copper‐ or chiral phosphoric acid catalyzed ring‐closure reactions of N′‐(2‐alkynylbenzylidene)hydrazides, showcasing high efficiency, mild conditions, broad substrate scope, and excellent enantioselectivity. Furthermore, the biological evaluation revealed that the synthesized axially chiral azomethine imines effectively protect dorsal root ganglia (DRG) neurons by inhibiting apoptosis induced by oxaliplatin, offering a promising therapeutic approach for chemotherapy‐induced peripheral neuropathy (CIPN). Remarkably, the (S)‐ and (R)‐atropisomers displayed distinct neuroprotective activities, underscoring the significance of axial stereochemistry.

Catalytic Atroposelective Synthesis of Axially Chiral Azomethine Imines and Neuroprotective Activity Evaluation.

Azomethine imines, as a prominent class of 1,3-dipolar species, hold great significance and potential in organic and medicinal chemistry. However, the reported synthesis of centrally chiral azomethine imines relies on kinetic resolution, and the construction of axially chiral azomethine imines remains unexplored. Herein, we present the synthesis of axially chiral azomethine imines through copper- or chiral phosphoric acid catalyzed ring-closure reactions of N'-(2-alkynylbenzylidene)hydrazides, showcasing high efficiency, mild conditions, broad substrate scope, and excellent enantioselectivity. Furthermore, the biological evaluation revealed that the synthesized axially chiral azomethine imines effectively protect dorsal root ganglia (DRG) neurons by inhibiting apoptosis induced by oxaliplatin, offering a promising therapeutic approach for chemotherapy-induced peripheral neuropathy (CIPN). Remarkably, the (S)- and (R)-atropisomers displayed distinct neuroprotective activities, underscoring the significance of axial stereochemistry.

Biomimetic asymmetric transamination reactions catalyzed by axial pyroxamine organocatalysts: Mechanism and origin of stereoselectivity

Biomimetic asymmetric transamination reactions have emerged as a focal point within the organocatalysis domain, generating substantial interest. However, the detailed mechanism and origin of stereoselectivity are remains elusive. Within this context, we present an exhaustive theoretical investigation into the detailed mechanism and origin of stereoselectivity governing such reactions between α-keto acids and amines catalyzed by axial pyroxamine. The fundamental reaction pathway can be divided into two stages, i.e. amino transfer stage to form chiral amine product and imine hydration stage for the generation of ketone product. To uncover the mystery of the chiral center produced by protonation in the amino transfer stage, five possible pathways were investigated and compared. This thorough examination unequivocally identifies the HOAc-assisted [1,3]-proton transfer as the pivotal step dictating stereoselectivity within the most energetically advantageous route. Further atoms-in-molecules (AIM) analysis was carried out to predict the origin of stereoselectivity. Notably, the N–H⋯O hydrogen bond interaction occurring between the pyridoxamine catalyst and α-keto acid of substrate has been pinointed as the driving force responsible for the energetical favorability of S-configurational pathway. These insights will be of great value for understanding and rational design of biomimetic organocatalysts for transamination reactions.

A Nitrogen Out-of-Plane (NOOP) Mechanism for Imine-Based Light-Driven Molecular Motors

Light-driven molecular motors have generated considerable interest due to their potential applications in material and biological systems. Recently, Greb and Lehn reported a new class of molecular motors, chiral N-alkyl imines, which undergo unidirectional rotation induced by light and heat. The mechanism of unidirectional motion in molecular motors containing a C═N group has been assumed to consist of photoinduced torsion about the double bond. In this work, we present a computational study of the photoisomerization dynamics of a chiral N-alkyl imine motor. We find that the location and energetics of minimal energy conical intersections (MECIs) alone are insufficient to understand the mechanism of the motor. Furthermore, a key part of the mechanism consists of out-of-plane distortions of the N atom (followed by isomerization about the double bond). Dynamic effects and out-of-plane distortions are critical to understand the observed (rather low) quantum yield for photoisomerization. Our results provide hints as to how the photoisomerization quantum yield might be increased, improving the efficiency of this class of molecular motors.

Fluorinated Imines in Tandem and Cycloaddition Reactions.

The chemistry of fluorinated compounds has experienced extraordinary growth in recent decades due to the many and varied properties which many of the compounds that contain fluorinated groups possess. Among all of them, fluorinated chiral imines, in particular the Ellman's imines, are of great importance since they are some of the most interesting building blocks for the synthesis of a large number of enantioenriched carbocycles and heterocycles with extraordinary biological and synthetic properties. This personal account covers the most significant results obtained in our research group in the last two decades concerning asymmetric tandem reactions, paying special attention to the intramolecular aza-Michael reaction (IMAMR), diversity oriented synthesis (DOS), asymmetric tandem reactions involving a p-tolylsulfinyl group as chiral inducer and cycloaddition processes, in particular, the Pauson-Khand reaction, [2+2+2]-cycloadditions and metathesis reactions, starting mainly from enyne compounds and through the use of fluorinated chiral N-sulfinyl imines and their derivatives as starting materials.

One Step Selective Counterion Dependent Formation of Conjugated Chiral N-Sulfinylimines from Aldehydes.

We report a detailed study on the synthesis and aldehyde vinylogation applications of chiral N-sulfinyl imine phosphonate reagents. Two complementary scalable reagent routes, from trialkyl phosphites and methyl phosphonates, respectively, are presented. This reagent class enables significant streamlining in synthesis of conjugated Ellman imines from aldehydes, which can now be accomplished in a single step compared to a more classic 4-step redox-based approach. Aldehyde vinylogation optimizations have revealed significant counterion effects and unexpected competing reaction challenges that needed to be addressed to achieve high yields.

Soluble porous organic cages as homogenizers and electron-acceptors for homogenization of heterogeneous alloy nanoparticle catalysts with enhanced catalytic activity

The creation of ultrafine alloy nanoparticles (<5 nm) that can maintain surface activity and avoid aggregation for heterogeneous catalysis has received much attention and is extremely challenging. Here, ultrafine PtRh alloy nanoparticles imprisoned by the cavities of reduced chiral covalent imine cage (PtRh@RCC3) are prepared successfully by an organic molecular cage (OMC) confinement strategy, while the soluble RCC3 can act as a homogenizer to homogenize the heterogeneous PtRh alloy in solution. Moreover, the X-ray absorption near-edge structure (XANES) results show that the RCC3 can act as an electron-acceptor to withdraw electrons from Pt, leading to the formation of higher valence Pt atoms, which is beneficial to improving the catalytic activity for the reduction of 4-nitrophenol. Attributed to the synergistic effect of Pt/Rh atoms and the unique function of the RCC3, the reaction rate constants of Pt1Rh16@RCC3 are 49.6, 8.2, and 5.5 times than those of the Pt1Rh16 bulk, Pt@RCC3 and Rh@RCC3, respectively. This work provides a feasible strategy to homogenize heterogeneous alloy nanoparticle catalysts in solution, showing huge potential for advanced catalytic application.

Synthesis of Chiral β,β-Disubstituted Ketones via CuH-Catalyzed Coupling of Aryl Alkenes and 3-Aryl-2H-azirines.

A CuH-catalyzed coupling of aryl alkenes with 3-aryl-2H-azirines has been developed to synthesize optically active β,β-disubstituted ketones. We propose that this protocol occurs through a sequence in which a chiral alkylcopper complex regioselectively attacks the N-C2 bonds of azirines to generate chiral β-aryl imines, which additionally afford ketones upon hydrolysis. This method provides a novel complementary approach for synthesizing chiral β,β-disubstituted ketones in good yields with high levels of enantioselectivity under mild conditions.

Ten-Step Total Synthesis of (-)-Andranginine.

The total synthesis of the indole alkaloid (-)-andranginine has been achieved in 10 steps. Key reactions of the synthesis include a nucleophilic addition of acetylenyl anion to chiral N-sulfinyl imine, an intramolecular N-alkylation reaction to close the C ring, and a dienyne metathesis cascade reaction to construct the DE rings. Meanwhile, 16-epi-(-)-andranginine was also obtained with the developed strategy.