Chiral Enamines Research Articles

Visible-Light-Promoted Enantioselective α-Amidation of Aldehydes by Harnessing Organo-Iron Dual Catalysis.

The strategic integration of organocatalysis with transition-metal catalysis to achieve otherwise unattainable stereoselective transformations may serve as a powerful synthetic tool. Herein, we present a synthetically versatile α-amidation of aldehydes by leveraging dual iron and chiral enamine catalysis in an enantioselective manner (up to >99:1 er). Experimental and computational studies have led us to propose a new mechanistic platform, wherein visible-light-promoted LMCT generates [Fe(II)Cl3-], which effectively activates dioxazolones to form an iron-acylnitrenoid radical that inserts into chiral enamine intermediates.

Development of a Scalable, Stereoselective Second-Generation Route for CXCR7 Antagonist ACT-1004-1239 via Chiral Enamine Reduction and a Novel Telescoped Sequence of Transesterification, cis-to-trans Epimerization, and Saponification

Development of a Scalable, Stereoselective Second-Generation Route for CXCR7 Antagonist ACT-1004-1239 via Chiral Enamine Reduction and a Novel Telescoped Sequence of Transesterification, <i>cis</i>-to-<i>trans</i> Epimerization, and Saponification

Enantioselective organocatalytic strategies to access noncanonical α-amino acids.

Organocatalytic asymmetric synthesis has evolved over the years and continues to attract the interest of many researchers worldwide. Enantiopure noncanonical amino acids (ncAAs) are valuable building blocks in organic synthesis, medicinal chemistry, and chemical biology. They are employed in the elaboration of peptides and proteins with enhanced activities and/or improved properties compared to their natural counterparts, as chiral catalysts, in chiral ligand design, and as chiral building blocks for asymmetric syntheses of complex molecules, including natural products. The linkage of ncAA synthesis and enantioselective organocatalysis, the subject of this perspective, tries to imitate the natural biosynthetic process. Herein, we present contemporary and earlier developments in the field of organocatalytic activation of simple feedstock materials, providing potential ncAAs with diverse side chains, unique three-dimensional structures, and a high degree of functionality. These asymmetric organocatalytic strategies, useful for forging a wide range of C-C, C-H, and C-N bonds and/or combinations thereof, vary from classical name reactions, such as Ugi, Strecker, and Mannich reactions, to the most advanced concepts such as deracemisation, transamination, and carbene N-H insertion. Concurrently, we present some interesting mechanistic studies/models, providing information on the chirality transfer process. Finally, this perspective highlights, through the diversity of the amino acids (AAs) not selected by nature for protein incorporation, the most generic modes of activation, induction, and reactivity commonly used, such as chiral enamine, hydrogen bonding, Brønsted acids/bases, and phase-transfer organocatalysis, reflecting their increasingly important role in organic and applied chemistry.

Stepwise Asymmetric Allylic Substitution‐Isomerization Enabled Mimetic Synthesis of Axially Chiral B,N‐Heterocycles

AbstractAxially chiral molecules bearing multiple stereogenic axes are of great importance in the field of organic chemistry. However, the efficient construction of atropisomers featuring two different types of stereogenic axes has rarely been explored. Herein, we report the novel atroposelective synthesis of configurationally stable axially chiral B,N‐heterocycles. By using stepwise asymmetric allylic substitution‐isomerization (AASI) strategy, diaxially chiral B,N‐heterocycles bearing B−C and C−N axes that are related to the moieties of axially chiral enamines and arylborons were also obtained. In this case, all four stereoisomers of diaxially chiral B,N‐heterocycles were stereodivergently afforded in high enantioselectivities. Density functional theory (DFT) studies demonstrated that the NH⋅⋅⋅π interactions played a unique role in the promotion of stereospecific isomerization, thereby leading to the highly efficient central‐to‐axial chirality transfer.

Stepwise Asymmetric Allylic Substitution-Isomerization Enabled Mimetic Synthesis of Axially Chiral B,N-Heterocycles.

Axially chiral molecules bearing multiple stereogenic axes are of great importance in the field of organic chemistry. However, the efficient construction of atropisomers featuring two different types of stereogenic axes has rarely been explored. Herein, we report the novel atroposelective synthesis of configurationally stable axially chiral B,N-heterocycles. By using stepwise asymmetric allylic substitution-isomerization (AASI) strategy, diaxially chiral B,N-heterocycles bearing B-C and C-N axes that are related to the moieties of axially chiral enamines and arylborons were also obtained. In this case, all four stereoisomers of diaxially chiral B,N-heterocycles were stereodivergently afforded in high enantioselectivities. Density functional theory (DFT) studies demonstrated that the NH⋅⋅⋅π interactions played a unique role in the promotion of stereospecific isomerization, thereby leading to the highly efficient central-to-axial chirality transfer.

Stereo‐ and Regioselective [3+3] Annulation Reaction Catalyzed by Ytterbium: Synthesis of Bicyclic 1,4‐Dihydropyridines

AbstractAn ytterbium catalyzed formal [3+3] cycloaddition of cyclic enamines and α,β‐unsaturated ketones catalyzed is reported. The reaction proceeds with a ‘head to tail’ regioselectivity through a conjugate addition of the enamine moiety followed by an amine‐carbonyl condensation. In addition the use of chiral enamines provided a high degree of stereoselectivity, driven by a possible balance between steric and π‐stacking effects. The resulting bicyclic 1,4‐dihydropyridines were evaluated as antiproliferative agents against A549 (carcinomic human alveolar basal epithelial cell) and SKOV3 (human ovarian carcinoma) human tumor cell lines. Good toxicities were found for some of the compounds against A549 and SKOV3 cell lines, with best IC50 values of 0.89 μM for A549 and 6.69 μM for SKOV3, and a very good selectivity was observed towards MRC5 (non‐malignant) cell lines.magnified image

Intramolecular asymmetric oxidopyrylium-based [5 + 2] cycloadditions

Intramolecular oxidopyrylium-based [5 + 2] cycloadditions utilizing chiral auxiliaries were investigated. Both acetoxypyranones and silyloxypyrones were employed and sulfinimines, oxazolidinones, hydrazones, and chiral enamines were explored. Carbonyl-based auxiliaries gave low selectivity, but enamines afforded excellent diastereoselectivity. Overall, facial selectivity varied significantly providing insight regarding the scope and limitation of chiral auxiliary-based oxidopyrylium-alkene [5 + 2] cycloadditions.

Enantioselective 1,4‐Addition Reaction of α,β‐Unsaturated Carboxylic Acids with Cycloalkanones Using Cooperative Chiral Amine–Boronic Acid Catalysts

AbstractAn enantioselective 1,4‐addition of α,β‐unsaturated carboxylic acids with cycloalkanones has been developed by using chiral amine–boronic acid cooperative catalysts. In the presence of a chiral amine and boronic acid, cycloalkanones and carboxylic acids are activated as chiral enamines and mixed anhydrides, respectively. The corresponding 1,4‐adducts are obtained in high yield with high enantioselectivity. Furthermore, subsequent oxylactonization of the 1,4‐adducts gives spirolactones with high diastereoselectivity.

Enantioselective 1,4-Addition Reaction of α,β-Unsaturated Carboxylic Acids with Cycloalkanones Using Cooperative Chiral Amine-Boronic Acid Catalysts.

An enantioselective 1,4-addition of α,β-unsaturated carboxylic acids with cycloalkanones has been developed by using chiral amine-boronic acid cooperative catalysts. In the presence of a chiral amine and boronic acid, cycloalkanones and carboxylic acids are activated as chiral enamines and mixed anhydrides, respectively. The corresponding 1,4-adducts are obtained in high yield with high enantioselectivity. Furthermore, subsequent oxylactonization of the 1,4-adducts gives spirolactones with high diastereoselectivity.

Stereoselective synergystic organo photoredox catalysis with enamines and iminiums

Graphical Abstract Application of small chiral organic molecules in catalysis has been dominated by formation of chiral enamines or iminium ions. Nucleophiles – electrophiles reactivity has been exploited in many papers. Now, the possibility to combine organocatalysis with photochemistry open new “exciting” possibilities and opportunities, in reactions that are mediated by radicals.

An approach to new chiral bicyclic imines and amines via Horner-Wadsworth-Emmons reaction.

New chiral bicyclic imines, enamines and amines were prepared via Horner–Wadsworth–Emmons reaction of hexahydroquinoxalin-2(1H)-one-derived phosphonate, as the source of a phosphonate carbanion, and a wide range of structurally diverse carbonyl substrates. The simplicity of the synthetic protocol, high selectivity, and broad substrate scope are the main advantages of the presented methodology.

Arynes and Cyclic Alkynes as Synthetic Building Blocks for Stereodefined Quaternary Centers.

We report a facile method to synthesize stereodefined quaternary centers from reactions of arynes and related strained intermediates using β-ketoester-derived substrates. The conversion of β-ketoesters to chiral enamines is followed by reaction with in situ generated strained arynes or cyclic alkynes. Hydrolytic workup provides the arylated or alkenylated products in enantiomeric excesses as high as 96%. We also describe the one-pot conversion of a β-ketoester substrate to the corresponding enantioenriched α-arylated product. Computations show how chirality is transferred from the N-bound chiral auxiliary to the final products. These are the first theoretical studies of aryne trapping by chiral nucleophiles to set new stereocenters. Our approach provides a solution to the challenging problem of stereoselective β-ketoester arylation/alkenylation, with formation of a quaternary center.

Cooperative Catalysis-Enabled Asymmetric α-Arylation of Aldehydes Using 2-Indolylmethanols as Arylation Reagents

A catalytic asymmetric α-arylation of aldehydes using 2-indolylmethanols as arylation reagents has been established. This reaction was enabled by a cooperative catalytic system consisting of a gold complex, a Brønsted acid, and a chiral amine, which have a synergistic effect in the reaction process. By using this strategy, a series of α-arylation products of aldehydes were generated in overall acceptable yields and good enantioselectivities (up to 69%, 91:9 er). The control experiments demonstrated that the addition of PPh3AuCl as a gold complex was helpful to improve the yield, and trifluoroacetic acid as a Brønsted acid played a crucial role in the reaction by promoting the generation of carbocation and chiral enamine intermediates, which are two key intermediates of the asymmetric α-arylation reaction. In addition, the enantioselectivity of the reaction was mainly controlled by the chiral amine catalyst via forming a chiral enamine intermediate. This reaction has not only provided a useful protocol for catalytic asymmetric α-arylation of aldehydes but also enriched the research contents of 2-indolylmethanol-involved reactions and asymmetric cooperative catalysis.

Asymmetric α-Allylation of Aldehydes with Alkynes by Integrating Chiral Hydridopalladium and Enamine Catalysis.

A palladium-catalyzed asymmetric α-allylation of aldehydes with alkynes has been established by integrating the catalysis of enamine and chiral hydridopalladium complex that is reversibly formed from the oxidative addition of Pd(0) to chiral phosphoric acid. The ternary catalyst system, consisting of an achiral palladium complex, a primary amine, and a chiral phosphoric acid allows the reaction to tolerate a wide scope of α,α-disubstituted aldehydes and alkynes, affording the corresponding allylation products in high yields and with excellent levels of enantioselectivity.

An Adverse Effect of Higher Catalyst Loading and Longer Reaction Time on Enantioselectivity in an Organocatalytic Multicomponent Reaction.

An enantioselective organocatalytic multicomponent reaction of aldehydes, ketones, and Meldrum's acid has been developed. A cinchona-based primary amine (1 mol %) catalyses the multicomponent reaction via the formation of the Knoevenagel product and a chiral enamine to form enantiopure δ-keto Meldrum's acids in a tandem catalytic pathway. An adverse effect of higher catalyst loading and longer reaction time on enantioselectivity was studied. This mild protocol provides an easy access to enantiopure carboxylic acids, esters and amides and the method is scalable on a gram quantity. DFT calculations were carried out on the proposed reaction mechanism and they were in close agreement with the experimental results.

Computer-Aided Insight into the Relative Stability of Enamines

Venerable aldol, Michael, and Mannich reactions have undergone a renaissance in the past fifteen years, as a consequence of the development of direct organocatalytic versions, mediated by chiral amines. Chiral enamines are key intermediates in these reactions. This review focuses on the formation of enamines from secondary amines and their relative thermodynamic stability, as well as on the reverse reactions (hydrolysis). Experimental results and predictions based on MO calculations are reviewed to show which enamine forms may predominate in the reaction medium and to compare several secondary amines as organocatalysts.1 Introduction2 Relative Stability of Enamines as Determined Experimentally3 Pyrrolidine Enamines4 Enamines of the Jørgensen–Hayashi Catalyst5 Proline Enamines6 Free Enthalpies and Polar Solvent Effects7 Comparison of Organocatalysts8 Summary and Outlook9 Appendix

Asymmetric Dual Chiral Catalysis using Iridium Phosphoramidites and Diarylprolinol Silyl Ethers: Insights into Stereodivergence

Recent examples of asymmetric dual chiral catalysis (ADCC), where two chiral catalysts are employed under one-pot reaction conditions, have demonstrated how all stereoisomers of a product could be effectively accomplished through changes in the catalyst chirality. Insufficient mechanistic details on the action of two chiral catalysts and molecular insights into the origin of stereodivergence prompted us to undertake a comprehensive density functional theory (B3LYP-D3) investigation on an α-allylation reaction of an aldehyde by using an allyl alcohol, resulting in two new chiral centers in the product. The structural and energetic features of the stereocontrolling transition states helped us delineate how all four product stereoisomers could be accessed by using suitable combinations of chiral iridium phosphoramide and diarylprolinol silyl ether in this ADCC reaction. The covalent activation of the pronucleophile (aldehyde) by the organocatalyst furnishes a chiral enamine, whereas the action of the transit...

Chiral Phosphinyl Enamines and Their Asymmetric Reduction through Group-Assisted Purification Chemistry Leading to Enantiopure β-Amino Esters/Amides

A series of new chiral N-phosphinyl β-enamino esters and amides were successfully prepared with excellent Z-stereoselectivity (Z/E &gt; 99:1 in nearly all cases). Group-assisted purification chemistry proved to be an efficient method for the asymmetric reduction of the resulting β-enamino esters/amides to give enantiopure β-amino esters/amides. The asymmetric reduction can be controlled efficiently by using a combination of sodium cyanoborohydride and acetic acid.

Enantioselective Formal α‐Methylation and α‐Benzylation of Aldehydes by Means of Photo‐organocatalysis

AbstractDetailed herein is the photochemical organocatalytic enantioselective α‐alkylation of aldehydes with (phenylsulfonyl)alkyl iodides. The chemistry relies on the direct photoexcitation of enamines to trigger the formation of reactive carbon‐centered radicals from iodosulfones, while the ground‐state chiral enamines provide effective stereochemical control over the radical trapping process. The phenylsulfonyl moiety, acting as a redox auxiliary group, facilitates the generation of radicals. In addition, it can eventually be removed under mild reducing conditions to reveal methyl and benzyl groups.

Enantioselective Formal α-Methylation and α-Benzylation of Aldehydes by Means of Photo-organocatalysis.

Detailed herein is the photochemical organocatalytic enantioselective α‐alkylation of aldehydes with (phenylsulfonyl)alkyl iodides. The chemistry relies on the direct photoexcitation of enamines to trigger the formation of reactive carbon‐centered radicals from iodosulfones, while the ground‐state chiral enamines provide effective stereochemical control over the radical trapping process. The phenylsulfonyl moiety, acting as a redox auxiliary group, facilitates the generation of radicals. In addition, it can eventually be removed under mild reducing conditions to reveal methyl and benzyl groups.