Enantioselective Friedel Crafts Reaction Research Articles

Enantioselective Zirconium-catalyzed Transformations

Abstract: The cheaper and less-toxic metals of Group 4 compared with common metals used in catalysis are increasingly applied in catalysis, resulting in the development of many novel greener transformations. Zirconium is abundant, non-toxic, and exhibits a remarkably diversified chemical reactivity among these metals. Since the first asymmetric zirconium-catalyzed reaction disclosed by Nugent in 1992, a wide variety of chiral zirconium catalysts have been proven to be capable of promoting many types of highly enantioselective transformations, spanning from standard reactions, such as Friedel‒Crafts reactions, cycloadditions, aldol reactions, Mannich reactions, epoxidations, nucleophilic additions to carbonyl compounds and derivatives, cyanations, ring-opening reactions, hydroxylations, hydroformylations, carboaluminations among others, to more modern and complex domino and tandem processes. This review aims to collect the major progress achieved in the field of enantioselective transformations of all types promoted by chiral zirconium catalysts, covering the literature since the beginning of 2003 and illustrating the power of these non-toxic catalysts to provide high enantioselectivity in almost all kinds of asymmetric organic reactions. It is divided into ten parts, focussing consecutively on enantioselective Friedel‒Crafts reactions, cycloadditions, aldol reactions, Mannich reactions, epoxidations, additions of alkylzinc reagents to imines, cyanations, ring-opening reactions, hydroxylations, and domino/ tandem reactions. The diversity of these transformations well reflects that of the products synthesized. For example, chiral indole and pyrrole derivatives were prepared from Friedel‒Crafts reactions; pyranones, pyridones and pyrazolidines from cycloadditions; β-hydroxy α-diazo carbonyl compounds, βhydroxy (thio)esters and β-hydroxy-α-amino acid derivatives from aldol reactions; β-amino (thio)esters from Mannich reactions; functionalized epoxides from epoxidations; amines from additions of alkylzinc reagents to imines; amino nitriles from cyanations; 1,2-diamines and β-vinyloxy alcohols from ring-opening processes; 2- hydroxy 1-indanones from hydroxylations; various amines, 1,3-anti-diol monoesters, β-amino esters, α,βdihydroxy acid derivatives, α-amino ketones, indoles, cyclopentane and aryl α-aminophosphonates from domino/ tandem reactions. Furthermore, the utility of these novel methodologies was demonstrated in the total synthesis of numerous essential bioactive products, such as (+)-prelactone C, (+)-9-deoxygoniopypyrone, (+)- coniine, vancomycin, (+)-fusarisetin A, mycolipenic acid, onchidin, indoxacarb, tachykinin receptor antagonists, cerebroprotecting agent MS-153, and L-erythro-sphingosine. The advances achieved in the last three decades demonstrate that the non-toxicity, abundance, and efficiency of zirconium make its application in catalysis suiting the growing demand for more environmentally benign processes, offering the real opportunity to replace other toxic and expensive metals in the near future.

Cu(I)-based chiral catalysts bearing binaphthyl-Proline hybrid ligands and their application in enantioselective Friedel-Crafts reactions of indoles with isatins

Highly enantioselective Friedel-Crafts reactions of indoles with isatins were realized using chiral Cu(I) catalyst bearing BINOL and proline-based electronically and sterically tunable chiral O–N–N tridentate ligands. Such catalyst system showed excellent performance in enantioselective Friedel-Crafts alkylation of different indoles, and a series of 3-indolyl-3-hydroxyoxindoles were obtained in high yields (90–98 %) and excellent enantioselectivities (82–98 % ee) under mild reaction conditions.

Enantioselective synthesis of α-tetrasubstituted (1-indolizinyl) (diaryl)-methanamines via chiral phosphoric acid catalysis.

An enantioselective Friedel-Crafts reaction of cyclic α-diaryl N-acyl imines with indolizines catalyzed by a chiral spirocyclic phosphoric acid has been developed. The asymmetric transformation proceeds smoothly to afford α-tetrasubstituted (1-indolizinyl) (diaryl)methanamines in good yields with up to 98% ee under mild conditions.

Using BpyAla to generate copper artificial metalloenzymes: a catalytic and structural study.

Artificial metalloenzymes (ArMs) have emerged as a promising avenue in the field of biocatalysis, offering new reactivity. However, their design remains challenging due to the limited understanding of their protein dynamics and how the introduced cofactors alter the protein scaffold structure. Here we present the structures and catalytic activity of novel copper ArMs capable of (R)- or (S)-stereoselective control, utilizing a steroid carrier protein (SCP) scaffold. To incorporate 2,2'-bipyridine (Bpy) into SCP, two distinct strategies were employed: either Bpy was introduced as an unnatural amino acid (2,2'-bipyridin-5-yl)alanine (BpyAla) using amber stop codon expression or via bioconjugation of bromomethyl-Bpy to cysteine residues. The resulting ArMs proved to be effective at catalysing an enantioselective Friedel-Crafts reaction with SCP_Q111BpyAla achieving the best selectivity with an enantioselectivity of 72% ee (S). Interestingly, despite using the same protein scaffold, different attachment strategies for Bpy at the same residue (Q111) led to a switch in the enantiopreference of the ArM. X-ray crystal structures of SCP_Q111CBpy and SCP_Q111BpyAla ArMs with bound Cu(ii) ions unveiled crucial differences in the orientation of the catalytic centre. Combining structural information, alanine scanning studies, and computational analysis shed light on the distinct active sites of the ArMs, clarifying that these active sites stabilise the nucleophilic substrate on different sides of the electrophile leading to the observed switch in enantioselectivity. This work underscores the importance of integrating structural studies with catalytic screening to unravel the intricacies of ArM behaviour and facilitate their development for targeted applications in biocatalysis.

Enantioselective Friedel-Crafts Reaction of Heteroaromatic Compounds with Glyoxals Catalyzed by Chiral Oxazaborolidinium Ion Catalyst.

A catalytic enantioselective Friedel-Crafts reaction of various heteroaromatic compounds with glyoxals has been developed. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction provided chiral α-hydroxyketones in high yield (up to 96%) with excellent enantioselectivity (up to >99% ee). The synthetic utility of this method was illustrated by conversion of the products to various derivatives such as 1,2-diol and β-amino alcohol.

Enantioselective organocatalytic Friedel-Crafts reaction of electron-rich phenols and isatins by Takemoto's thiourea catalyst.

Takemoto's catalysts were used to organocatalyze the enantioselective Friedel-Crafts reaction with different electron-rich phenols and substituted isatins. The resulting 3-aryl-3-hydroxyl-2-oxindoles were obtained in good yields (85-96%) with up to 99% ee. The substrate scope was broadened with this methodology compared to reported examples catalyzed by cinchonidine thiourea.

Enantioselective Friedel-Crafts reaction between indoles and α,β-unsaturated aldehydes catalyzed by recyclable α,α-diarylprolinol derived chiral ionic liquids

Imidazolium-based chiral ionic liquid containing α,α-diaryl-(S)-prolinol trimethylsilyl ether acts as an efficient and reusable organocatalyst for the enantioselective Friedel-Crafts reaction between indoles and α, β-unsaturated aldehydes. 3-Alkylated indoles were obtained in 62–89 % yields with 47–88 % enantiomeric excesses using α,α-diphenyl-(S)-prolinol trimethylsilyl ether having hexafluorophosphate anion [PF6]− (20 mol%) and triethylamine (40 mol%) as a base additive in 1,4‑dioxane at 25 °C. The α,α-diphenyl-(S)-prolinol trimethylsilyl ether having hexafluorophosphate anion [PF6]− was recycled and reused for FC reaction up to seven recycles with consistent enantioselectivity, but a considerable loss in yield of the product was observed after the third recycling. The energies of possible conformers (iminium intermediates) were calculated by DFT.

Enantioselective Friedel-Crafts Reaction of 2-Alkynyphenols with Aromatic Ethers by Chiral Brønsted Acid Catalysis.

Herein, we report chiral strong Brønsted acid-catalyzed enantioselective Friedel-Crafts reaction of 2-alkynyphenols with aromatic ethers. The reaction affords the corresponding axially chiral styrenes in up to 91% yield and 97% ee.

O-Tms-Α , Α -Diaryl-(S)-Prolinol Tagged with Imidazolium Ionic Liquids as Recyclable and Recoverable Organocatalysts for the Enantioselective Friedel-Crafts Reaction between Indoles and Α , Β -Unsaturated Aldehydes

O-Tms-Α , Α -Diaryl-(S)-Prolinol Tagged with Imidazolium Ionic Liquids as Recyclable and Recoverable Organocatalysts for the Enantioselective Friedel-Crafts Reaction between Indoles and Α , Β -Unsaturated Aldehydes

Lewis acid-catalyzed enantioselective Friedel-Crafts reaction of pyrazole-4,5-diones with β-naphthol

A series of pyrazolone derivatives bearing a tetrasubstituted chiral center were prepared by virtue of a Lewis acid-catalyzed Friedel-Crafts reaction, in which a chiral copper complex was employed as the catalyst. This reaction can be carried out smoothly under mild condition to afford the pyrazolone derivatives with high yields (up to 85%) and excellent enantioselectivities (up to 99%). In addition, the gram scale synthesis proved the practicality of this reaction. A series of pyrazolone derivatives bearing a tetrasubstituted chiral center were prepared by virtue of a Lewis acid-catalyzed Friedel-Crafts reaction, in which a chiral copper complexes was employed as the catalyst. This reaction can be carried out smoothly under mild condition to afford the pyrazolone derivatives with high yields (up to 85%) and excellent enantioselectivities (up to 99%).

Chiral Heterogeneous Scandium Lewis Acid Catalysts for Continuous‐Flow Enantioselective Friedel–Crafts Carbon–Carbon Bond‐Forming Reactions

AbstractWhile continuous‐flow reactions with chiral heterogeneous catalysts provide a highly efficient method to synthesize optically active compounds, chiral heterogeneous Lewis acid catalysis has been less extensively explored. We have developed the first example of chiral heterogeneous Sc catalysts, which demonstrated excellent activity and selectivity for continuous‐flow enantioselective Friedel–Crafts reactions of isatins with indoles. Noncovalent interactions between chiral Sc complexes and heteropoly acid‐anchored amine‐functionalized SiO2 as support were utilized for the synthesis. The heteropoly acid was found to be crucial for the preparation, activity, and selectivity of the catalysts. The chiral ligand could be easily tuned without chemical modification and the continuous‐flow synthesis of a biologically active compound was achieved.

Chiral Heterogeneous Scandium Lewis Acid Catalysts for Continuous-Flow Enantioselective Friedel-Crafts Carbon-Carbon Bond-Forming Reactions.

While continuous-flow reactions with chiral heterogeneous catalysts provide a highly efficient method to synthesize optically active compounds, chiral heterogeneous Lewis acid catalysis has been less extensively explored. We have developed the first example of chiral heterogeneous Sc catalysts, which demonstrated excellent activity and selectivity for continuous-flow enantioselective Friedel-Crafts reactions of isatins with indoles. Noncovalent interactions between chiral Sc complexes and heteropoly acid-anchored amine-functionalized SiO2 as support were utilized for the synthesis. The heteropoly acid was found to be crucial for the preparation, activity, and selectivity of the catalysts. The chiral ligand could be easily tuned without chemical modification and the continuous-flow synthesis of a biologically active compound was achieved.

Development of novel C2-symmetrical [5]oxahelicenoid diols

Novel C2-symmetric [5]oxahelicenoid diols were synthesized via dehydroaromatization from the previous reported [5]oxahelicenoid dione 7 starting from 2-diazocyclohexane-1,3-dione and furan. The key dehydroaromatization reaction can be realized either by DDQ mediated or Pd/C catalyzed dehydrogenative aromatization. Optical resolution of (rac)-8 with N-benzylquininium chloride 9 and N-benzylquinidinium chloride 10 afforded the enantiomerically pure (P)-8 and (M)-8, respectively. In addition, six chiral phosphoric acids 13a ~ 13f were synthesized from (P)-8 and subjected to an enantioselective Friedel-Crafts reaction to afford the desired product 16 in up to great yield and moderate er value (94% yield, 76:24 er). The result indicates that these readily synthesized [5]oxahelicenoid diol based catalysts have comparable catalytic activity albeit lower enantioselectivity as BINOL-based and SPINOL-based ones. We believe that this work as the first try to introduce the helical diols-based chiral phosphoric acids as catalysts would draw the attention and interest of chemists.

Enantioselective Friedel-Crafts reaction of hydroxyarenes with nitroenynes to access chiral heterocycles via sequential catalysis.

Naphthols, hydroxyindoles and an activated phenol are reacted with differently substituted (E)-nitrobut-1-en-3-ynes using the commercially available Rawal's chiral squaramide. The corresponding β-nitroalkynes were obtained with good yields and excellent enantioselectivities. Moreover, dihydronaphthofurans can be accessed via silver catalysed cyclization in a tandem one-pot procedure, with high preservation of the optical purity.

Enantioselective Friedel-Crafts Reaction of Indoles with Isatins Catalyzed by Cinchona Alkaloid Silyl Ether Derivative

Enantioselective Friedel-Crafts Reaction of Indoles with Isatins Catalyzed by Cinchona Alkaloid Silyl Ether Derivative

Covalently Functionalized DNA Duplexes and Quadruplexes as Hybrid Catalysts in an Enantioselective Friedel-Crafts Reaction.

The precise site-specific positioning of metal–ligand complexes on various DNA structures through covalent linkages has gained importance in the development of hybrid catalysts for aqueous-phase homogeneous catalysis. Covalently modified double-stranded and G-quadruplex DNA-based hybrid catalysts have been investigated separately. To understand the role of different DNA secondary structures in enantioselective Friedel–Crafts alkylation, a well-known G-quadruplex-forming sequence was covalently modified at different positions. The catalytic performance of this modified DNA strand was studied in the presence and absence of a complementary DNA sequence, resulting in the formation of two different secondary structures, namely duplex and G-quadruplex. Indeed, the secondary structures had a tremendous effect on both the yield and stereoselectivity of the catalyzed reaction. In addition, the position of the modification, the topology of the DNA, the nature of the ligand, and the length of the linker between ligand and DNA were found to modulate the catalytic performance of the hybrid catalysts. Using the optimal linker length, the quadruplexes formed the (−)-enantiomer with up to 65% ee, while the duplex yielded the (+)-enantiomer with up to 62% ee. This study unveils a new and simple way to control the stereochemical outcome of a Friedel–Crafts reaction.

Mechanism Change of (+)-Nonlinear Effect in a Phase Separation System in a CuII-Catalyzed Asymmetric Friedel-Crafts Reaction Using a C2-Chiral Dioxolane-Containing-Bisamidine Ligand, Naph-diPIM-dioxo-iPr

Abstract A CuII complex of bisamidine ligand LS, chirally modified naphtho[1,2-b:7,8-b′]dipyrroloimidazole (Naph-diPIM), catalyzes the enantioselective Friedel-Crafts (FC) reaction of indole (1a) with ethyl trifluoropyruvate (2) to give quantitatively the FC adduct 3a with a 98:2 S/R enantiomer ratio (er). The reaction shows no nonlinear effect (NLE) under the standard conditions of [1a] = [2] = 100 mM; [Cu(OTf)2] = [LS + LR] = 0.10 mM; CPME; and 0 °C irrespective of the catalyst aging temperature. A five-fold increase in the catalyst concentration (0.50 mM) changes the situation, leading to a strong (+)-NLE with phase separation of a white solid. The NLE is expressed by the Noyori-type mechanism: Aggregate of heterochiral dimer CuLSCuLR is separated from the reaction system (Khetero > 1 > Khomo). Furthermore, a strong (+)-NLE is observed via a purple solid liberation even with [CuII] = 0.10 mM after the catalyst aging at 100 °C in the presence of an excess amount of chiral ligand. A mechanistic study has revealed i) that the sterically disfavored homochiral 1:2 complex CuLSLS is more stabilized by an intramolecular n-π* interaction than the sterically favored heterochiral 1:2 complex CuLSLR and ii) that the (+)-NLE originates from the phase separation of heterochirally interacted (CuLSLSCuLRLR).

Highly Efficient Cyclic Dinucleotide Based Artificial Metalloribozymes for Enantioselective Friedel-Crafts Reactions in Water.

The diverse secondary structures of nucleic acids are emerging as attractive chiral scaffolds to construct artificial metalloenzymes (ArMs) for enantioselective catalysis. DNA-based ArMs containing duplex and G-quadruplex scaffolds have been widely investigated, yet RNA-based ArMs are scarce. Here we report that a cyclic dinucleotide of c-di-AMP and Cu2+ ions assemble into an artificial metalloribozyme (c-di-AMP⋅Cu2+ ) that enables catalysis of enantioselective Friedel-Crafts reactions in aqueous media with high reactivity and excellent enantioselectivity of up to 97 % ee. The assembly of c-di-AMP⋅Cu2+ gives rise to a 20-fold rate acceleration compared to Cu2+ ions. Based on various biophysical techniques and density function theory (DFT) calculations, a fine coordination structure of c-di-AMP⋅Cu2+ metalloribozyme is suggested in which two c-di-AMP form a dimer scaffold and the Cu2+ ion is located in the center of an adenine-adenine plane through binding to two N7 nitrogen atoms and one phosphate oxygen atom.

Highly Efficient Cyclic Dinucleotide Based Artificial Metalloribozymes for Enantioselective Friedel–Crafts Reactions in Water

AbstractThe diverse secondary structures of nucleic acids are emerging as attractive chiral scaffolds to construct artificial metalloenzymes (ArMs) for enantioselective catalysis. DNA‐based ArMs containing duplex and G‐quadruplex scaffolds have been widely investigated, yet RNA‐based ArMs are scarce. Here we report that a cyclic dinucleotide of c‐di‐AMP and Cu2+ ions assemble into an artificial metalloribozyme (c‐di‐AMP⋅Cu2+) that enables catalysis of enantioselective Friedel–Crafts reactions in aqueous media with high reactivity and excellent enantioselectivity of up to 97 % ee. The assembly of c‐di‐AMP⋅Cu2+ gives rise to a 20‐fold rate acceleration compared to Cu2+ ions. Based on various biophysical techniques and density function theory (DFT) calculations, a fine coordination structure of c‐di‐AMP⋅Cu2+ metalloribozyme is suggested in which two c‐di‐AMP form a dimer scaffold and the Cu2+ ion is located in the center of an adenine‐adenine plane through binding to two N7 nitrogen atoms and one phosphate oxygen atom.

Mechanistic insights into Cu-catalyzed enantioselective Friedel–Crafts reaction between indoles and 2-aryl-N-sulfonylaziridines

Computational studies were successfully carried out to provide mechanistic insights into LCu-catalyzed (L = (S)-Segphos ligand) Friedel–Crafts (F–C) reaction between indoles and 2-aryl-N-sulfonylaziridines.