Enantioselective Friedel-Crafts 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, β- hydroxy (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,β- dihydroxy 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.

Enantioselective Friedel-Crafts alkylation of indoles with trifluoropyruvates catalyzed by chiral Cu(II) complex bearing binaphthyl-proline hybrid ligands

A mild and efficient catalyst system for asymmetric Friedel-Crafts alkylation of indoles with trifluoropyruvates was reported. The chiral ligands took the advantages of both the proline and the binaphthyl moieties, and the in situ prepared Cu(II) catalyst showed good substrate tolerance in the reactions. Indoles bearing different substituents could be tolerated, and the desired products could be obtained in up 99 % yields and up to 98 % ee. Especially, the reactions could be carried out in gram scale without the loss of stereoselectivity, and some of products were able to achieve 99 % ee after simple crystallization.

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.

Chiral Phosphoric Acid-Catalyzed Asymmetric Friedel-Crafts Addition of Indolizine to Cyclic N-Sulfonyl Imine.

A highly efficient chiral phosphoric acid-catalyzed enantioselective Friedel-Crafts addition of indolizine to cyclic N-sulfonyl imine has been established. The newly developed protocol, which probably proceeds via a monoactivation reaction pathway, allows the access of enantioenriched sulfonamide functionalized indolizines with excellent yields (up to 99%) and enantioselectivities (up to 99%). Moreover, the synthetic utility of this protocol has been explored with some chemical transformations.

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 Synthesis of an All-Carbon Quaternary Stereocenter by Chiral Brønsted Acid-Catalyzed Friedel-Crafts-Type Reaction between Pyrroles and 3-Indolylmethanols.

We have developed a chiral phosphoric acid-catalyzed enantioselective Friedel-Crafts alkylation reaction between pyrroles and indolylmethanols. Wide substrate scope was observed, and a chiral all-carbon quaternary center was constructed at the 3 position of indoles in high yields with high to excellent enantioselectivities (up to 99% ee).

Asymmetric Synthesis of Triphenylmethanes via Organocatalytic Regio- and Enantioselective Friedel-Crafts Alkylation of Aniline Derivatives.

Herein, we described a highly regio- and enantioselective Friedel-Crafts alkylation of aniline derivatives with in situ generated ortho-quinone methides enabled by chiral phosphoric acid, furnishing a wide range of enantioenriched triarylmethanes bearing three similar benzene rings in high yields (up to 98%) with excellent stereoselectivities (up to 98% ee). Furthermore, the large-scale reactions and diversified transformations of product demonstrate the practicality of the protocol. Density functional theory calculations elucidate the origin of the enantioselectivity.

Enantioselective Friedel–Crafts Alkylation of Indoles with β,γ-Unsaturated α-Ketoesters Catalyzed by New Copper(I) Catalysts

New Cu(I) catalysts are effective in enantioselective Friedel-Crafts alkylation of a variety of indoles with different β,γ-unsaturated α-ketoesters. A control study shows that such a catalyst system is less sensitive to air, and the reactions can be carried out without special cares such as glovebox operation or moisture/oxygen-free conditions. Preliminary computation results suggest that there exists π-π stacking between the substrate and the catalyst, and such an interaction seems to play a role in stabilizing the reaction intermediate and enhancing the stereoselectivity of the reactions. The desired products can be obtained in up to 98% yield at 99% enantiomeric excess. The same high enantioselectivity can be observed when the reaction is carried in a gram scale, indicating a good scalability of the catalyst system in enantioselective Friedel-Crafts alkylation of different indoles with β,γ-unsaturated α-ketoesters.

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.

Asymmetric synthesis of 7-membered-ring-bridged 3,4-fused tricyclic indoles via Friedel–Crafts alkylation/annulation

Regio- and enantioselective Friedel–Crafts alkylation/N-hemiacetalization and dehydration sequence were reported using Ni(ii)-PyBPI complex as catalyst, affording chiral 7-membered-ring-bridged 3,4-fused tricyclic indoles in good results.

Chiral Phosphoric Acid-Catalyzed Enantioselective Aza-Friedel-Crafts Addition of Naphthols with Isatin-Derived Ketimines.

The enantioselective Friedel-Crafts addition of naphthols with isatin-derived ketimines was developed with H8-BINOL-derived chiral biaryl phosphoric acid. A wide range of isatin-derived ketimines and naphthols were successfully applied and gave a series of chiral 3-amino-2-oxindoles in excellent yields with high optical purities.

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.

Enantioselective Friedel-Crafts Alkylation Reaction of Pyrroles with N-Unprotected Alkynyl Trifluoromethyl Ketimines.

Developed herein is an enantioselective Friedel-Crafts alkylation reaction of N-unprotected alkynyl trifluoromethyl ketimines with pyrroles catalyzed by chiral phosphoric acid to furnish chiral primary α-trifluoromethyl-α-(2-pyrrolyl)propargylamines with high enantioselectivity. Transformation of the alkynyl group of the adducts afforded optically active α-trifluoromethylated amines bearing various substituents such as alkyl, alkenyl, enyne, and triazole without loss of optical purity.

Urea derivative organocatalyzed enantioselective Friedel-Crafts alkylation of α-naphthols with isatins.

An organocatalytic enantioselective Friedel-Crafts alkylation of α-naphthols with isatin derivatives was catalyzed by Takemoto-type urea catalyst to give optical active 3-(naphthalen-2-yl)-3-hydroxy-2-oxindoles in 75%-92% yields with up to 95% enantiomeric excess (ee) value. The catalyst type and the substrate scope were broadened in this methodology.

Enantioselective Friedel-Crafts Alkylation of Furans with o-Quinone Methide Using a Chiral Oxazaborolidinium Ion Catalyst.

A chiral Lewis acid-catalyzed enantioselective Friedel-Crafts furan alkylation with in situ-generated o-quinone methides has been developed. In the presence of a chiral oxazaborolidinium ion catalyst, the reaction proceeded in high yield (up to 99%) with excellent enantioselectivity (up to >99% ee).

Chiral Calcium Phosphate Catalyzed Enantioselective Synthesis of All-Carbon Quaternary Center by Friedel–Crafts Alkylation Reaction of Pyrroles and Trifluoromethylated Nitrostyrenes

AbstractA chiral calcium phosphate-catalyzed enantioselective Friedel–Crafts alkylation reaction of pyrroles and α-trifluoromethyl-β-nitrostyrenes has been developed. Pyrroles bearing an all-carbon quaternary center at 2-position were obtained with high to excellent enantioselectivity. Use of 4,7-dihydroindole as a nucleophile and subsequent oxidation resulted in the formation a 2-substituted indole derivative with excellent enantioselectivity. A 3,4-dihydropyrrolo[1,2-c]pyrimidine derivative was successfully synthesized by reduction followed by benzoylation of the product without loss of enantioselectivity. Application to a 1 mmol scale reaction was successfully achieved.

Heterogeneously Organocatalytic, Enantioselective Friedel-Crafts Alkylation of Indole with 3,3,3-Trifluoropyruvate

Heterogeneously Organocatalytic, Enantioselective Friedel-Crafts Alkylation of Indole with 3,3,3-Trifluoropyruvate