Enantioselective Friedel-Crafts Alkylation Research Articles

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.

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 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.

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

Enantioselective Friedel-Crafts alkylation of indole with nitroalkenes in the presence of bifunctional squaramide organocatalysts

A series of chiral bifunctional quinine and 2-aminoDMAP based squaramide organocatalysts are evaluated in Friedel-Crafts alkylation of indoles with nitroolefins. These 3-substituted indole derivatives are synthesized in the presence of sterically encumbered tert-butyl squaramide/quinine with high enantioselectivity (up to >99% ee) and moderate chemical yields (up to 80%) by representing as chiral precursors for very important biologically active molecules. Besides, this asymmetric transformation provides a very simple, efficient, clean and environmental friendly route. In addition, this process has very mild reaction conditions such as ambient temperature and usage of only 2 mol% catalyst loading compared to previous studies in literature.

In Vivo Assembly of Artificial Metalloenzymes and Application in Whole-Cell Biocatalysis*.

We report the supramolecular assembly of artificial metalloenzymes (ArMs), based on the Lactococcal multidrug resistance regulator (LmrR) and an exogeneous copper(II)–phenanthroline complex, in the cytoplasm of E. coli cells. A combination of catalysis, cell‐fractionation, and inhibitor experiments, supplemented with in‐cell solid‐state NMR spectroscopy, confirmed the in‐cell assembly. The ArM‐containing whole cells were active in the catalysis of the enantioselective Friedel–Crafts alkylation of indoles and the Diels–Alder reaction of azachalcone with cyclopentadiene. Directed evolution resulted in two different improved mutants for both reactions, LmrR_A92E_M8D and LmrR_A92E_V15A, respectively. The whole‐cell ArM system required no engineering of the microbial host, the protein scaffold, or the cofactor to achieve ArM assembly and catalysis. We consider this a key step towards integrating abiological catalysis with biosynthesis to generate a hybrid metabolism.

In Vivo Assembly of Artificial Metalloenzymes and Application in Whole‐Cell Biocatalysis**

AbstractWe report the supramolecular assembly of artificial metalloenzymes (ArMs), based on the Lactococcal multidrug resistance regulator (LmrR) and an exogeneous copper(II)–phenanthroline complex, in the cytoplasm of E. coli cells. A combination of catalysis, cell‐fractionation, and inhibitor experiments, supplemented with in‐cell solid‐state NMR spectroscopy, confirmed the in‐cell assembly. The ArM‐containing whole cells were active in the catalysis of the enantioselective Friedel–Crafts alkylation of indoles and the Diels–Alder reaction of azachalcone with cyclopentadiene. Directed evolution resulted in two different improved mutants for both reactions, LmrR_A92E_M8D and LmrR_A92E_V15A, respectively. The whole‐cell ArM system required no engineering of the microbial host, the protein scaffold, or the cofactor to achieve ArM assembly and catalysis. We consider this a key step towards integrating abiological catalysis with biosynthesis to generate a hybrid metabolism.

Cofactor Binding Dynamics Influence the Catalytic Activity and Selectivity of an Artificial Metalloenzyme.

We present an artificial metalloenzyme based on the transcriptional regulator LmrR that exhibits dynamics involving the positioning of its abiological metal cofactor. The position of the cofactor, in turn, was found to be related to the preferred catalytic reactivity, which is either the enantioselective Friedel–Crafts alkylation of indoles with β-substituted enones or the tandem Friedel–Crafts alkylation/enantioselective protonation of indoles with α-substituted enones. The artificial metalloenzyme could be specialized for one of these catalytic reactions introducing a single mutation in the protein. The relation between cofactor dynamics and activity and selectivity in catalysis has not been described for natural enzymes and, to date, appears to be particular for artificial metalloenzymes.

Asymmetric Friedel–Crafts Alkylation of Indoles Catalyzed by Chiral Aziridine-Phosphines

Over the course of the present studies, a series of optically pure phosphines functionalized by chiral aziridines was synthesized in reasonable/good chemical yields. Their catalytic activity was checked in the enantioselective Friedel–Crafts alkylation of indoles by β-nitrostyrene in the presence of a copper(I) trifluoromethanesulfonate benzene complex. The corresponding Friedel–Crafts products were achieved efficiently in terms of chemical yield and enantioselectivity (up to 85% in some cases).

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.

Lewis Acid-Catalyzed Enantioselective Friedel-Crafts Alkylation of Pyrrole in Water.

Highly enantioselective Friedel–Crafts alkylation of pyrroles with 2-enoyl-pyridine N-oxides in water/chloroform (10:1) was developed under catalysis of Lewis acid. The Friedel–Crafts alkylation products can be obtained in high yields and excellent enantioselectivities. Moreover, several control experiments were carried out to study the reaction mechanism.

Calcium-Catalyzed Enantioselective Friedel–Crafts Alkylation of Indoles

Calcium-Catalyzed Enantioselective Friedel–Crafts Alkylation of Indoles

Enantioselective Friedel–Crafts Alkylation Reaction of Indoles with α-Trifluoromethylated β-Nitrostyrenes Catalyzed by Chiral BINOL Metal Phosphate

An efficient enantioselective Friedel–Crafts alkylation reaction of indoles with α-CF3-substituted β-nitrostyrenes is disclosed. The key to success is the use of a chiral calcium BINOL bis(phosphat...

Enantioselective Friedel-Crafts Alkylation Reaction of Heteroarenes with N-Unprotected Trifluoromethyl Ketimines by Means of Chiral Phosphoric Acid.

An enantioselective Friedel-Crafts alkylation reaction of pyrroles and indoles with N-unprotected trifluoromethyl ketimines by use of chiral phosphoric acid provided α-trifluoromethylated primary amines bearing chiral tetrasubstituted carbon centers in high yields and with high to excellent enantioselectivities. The present reaction is unique to N-unprotected trifluoromethyl ketimines. No reaction took place with N-p-methoxyphenyl (PMP)-substituted ketimine. Corresponding α-trifluoromethylated amines were transformed without loss of enantioselectivity.

A chiral bicyclic skeleton-tethered bipyridine-Zn(OTf)2 complex as a Lewis acid: enantioselective Friedel-Crafts alkylation of indoles with nitroalkenes.

A conformationally rigid chiral bicyclic skeleton tethered bipyridine-Zn(OTf)2 complex facilitated the enantioselective Friedel-Crafts alkylation of indoles with trans-β-nitroarylalkenes in an enantioselective manner at elevated temperature. Indoles reacted smoothly with β-nitroarylalkenes to generate the corresponding 3-(2-nitroalkyl)indoles in good to excellent yields (up to 94%) with moderate to excellent enantioselectivities (up to 91%). The stereochemical outcome of the product from indole and trans-β-nitrostyrene in the presence of the CRCB tethered bipyridine-Zn(OTf)2 complex and the DFT calculation of the CRCB tethered bipyridine-Zn:trans-β-nitrostyrene complex support the si-face attack of indole on trans-β-nitrostyrene.

Organocatalytic enantioselective direct alkylation of phloroglucinol derivatives: asymmetric total synthesis of (+)-aflatoxin B2.

The organocatalytic enantioselective Friedel-Crafts alkylation of phloroglucinol derivatives with enals is reported, providing general access to the benzylic chiral centers shown in a variety of phloroglucinol natural products. The synthetic utility is demonstrated by the very concise asymmetric total synthesis of aflatoxins B2.