Chiral Phase-transfer Catalysts Research Articles

Sugar-based Crown Ethers in Enantioselective Syntheses

A number of chiral macrocyclic compounds have been prepared that contain a monosaccharide-derived sub-unit. These sugar-based crown ethers were used as chiral phase transfer catalysts in a few asymmetric reactions. A few of them proved to be effective catalysts in Michael additions, a Darzens condensation and an epoxidation of α,β-enones. It was found that the type of the monosaccharide, the substituents on the sugar unit and on the nitrogen atom of the macroring have a significant influence on both the yield and the enantioselectivity.

Organic base-promoted enantioselective electrophilic cyanation of β-keto esters by using chiral phase-transfer catalysts.

Highly enantioselective cyanation of β-keto esters using hypervalent iodine(iii) as the electrophilic cyanating reagent induced by cinchona alkaloid-based chiral quaternary ammonium salt was demonstrated. Organic bases, especially DMAP, in the chiral phase-transfer catalysis were used to obtain high ees.

Highly enantioselective Michael addition reactions with new trimeric chiral phase transfer catalysts

New types of mesitylene based tri-site containing asymmetric quaternary ammonium salts 9 (9a and 9b) were synthesized and their catalytic activities were studied using Michael addition reactions with various chalcones and diethylmalonate under mild basic conditions with very good yields and ee's.

ChemInform Abstract: Catalytic Asymmetric Synthesis of 3,3′‐Diaryloxindoles as Triarylmethanes with a Chiral All‐Carbon Quaternary Center: Phase‐Transfer‐Catalyzed SNAr Reaction.

Catalytic asymmetric synthesis of unsymmetrical triarylmethanes with a chiral all-carbon quaternary center was achieved by using a chiral bifunctional quaternary phosphonium bromide catalyst in the SNAr reaction of 3-aryloxindoles under phase-transfer conditions. The presence of a urea moiety in the chiral phase-transfer catalyst was important for obtaining high enantioselectivity in this reaction.

Phase-transfer-catalyzed asymmetric S(N)Ar reaction of α-amino acid derivatives with arene chromium complexes.

Although phase-transfer-catalyzed asymmetric S(N)Ar reactions provide unique contribution to the catalytic asymmetric α-arylations of carbonyl compounds to produce biologically active α-aryl carbonyl compounds, the electrophiles were limited to arenes bearing strong electron-withdrawing groups, such as a nitro group. To overcome this limitation, we examined the asymmetric S(N)Ar reactions of α-amino acid derivatives with arene chromium complexes derived from fluoroarenes, including those containing electron-donating substituents. The arylation was efficiently promoted by binaphthyl-modified chiral phase-transfer catalysts to give the corresponding α,α-disubstituted α-amino acids containing various aromatic substituents with high enantioselectivities.

ChemInform Abstract: Catalytic Asymmetric Alkylation of 3‐Aryl‐Substituted Oxindoles to Give 3,3‐Disubstituted Oxindoles under Phase‐Transfer Conditions.

An efficient enantioselective method for the construction of all-carbon quaternary stereocenters from 3-aryl-substituted oxindoles via asymmetric phase-transfer alkylation has been developed. The products are obtained in high yields and optical purity of up to 93 % ee by using (S,S)-3,4,5-trifluorophenyl-NAS bromide as a chiral phase-transfer catalyst. The 3,3-disubstituted oxindole products are valuable intermediates for the synthesis of bioactive indole-containing natural products.

Construction of polyheterocyclic spirotetrahydrothiophene derivatives via sulfa-Michael/aldol cascade reaction

A series of polyheterocyclic spirotetrahydrothiophene derivatives were obtained in moderate to excellent yields via a catalyst-free sulfa-Michael/aldol cascade reaction of chalcones 1 and commercially available 1,4-dithiane-2,5-diol 2 under mild conditions. We also present the first asymmetric sulfa-Michael/aldol cascade reaction of chalcones 1 and commercially available 1,4-dithiane-2,5-diol 2 with moderate to good enantioselectivities catalyzed by readily available chiral phase-transfer catalysts (PTCs).

ChemInform Abstract: Cascade Reactions of Glycine Schiff Bases and Chiral Phase Transfer Catalysts in the Synthesis of α‐Amino Acids 3‐Substituted Phthalides or Isoindolinones.

The tuning of aldol/cyclization cascade reactions of glycine Schiff bases with 2-cyano benzaldehydes provides access to non-natural α-amino acid derivatives substituted alternatively with phthalides or isoindolinones, depending on the strength of the used base. Moreover, a preliminary screening of catalysts and conditions for development of asymmetric versions identified chiral bifunctional phase transfer catalysts as particularly promising, leading to the α-amino esters 3-substituted phthalides in high yields and good diastereo- and enantioselectivity.

Side‐Arm Effect of a Methyl α‐d‐Glucopyranoside Based Lariat Ether Catalysts in Asymmetric Syntheses

ABSTRACTMethyl α‐d‐glucopyranoside based monoaza‐15‐crown‐5 type lariat ethers with different heteroatom‐containing side arm attached to the nitrogen of the macrocyclic ring have been synthesized. These compounds were used as chiral phase transfer catalysts in a few asymmetric reactions, such as Michael additions, Darzens condensation, and epoxidation of chalcone. The side arms of the macrocycles had a significant impact on the chemical yields and the enantioselectivity. The effect of the lariat ethers with side arms having heteroatom (O, N, and S) was compared with the effect of the analogues having substituents without a heteroatom. The terminal allyl group also generated a significant enantioselectivity (79% enantiomeric excess) in one of the Michael additions. The application of crown ethers with substituents (CH2)3OH or (CH2)3OCH3 leads to the best enantioselectivities 85% and 99%, respectively.

Quaternary ammonium derivatives of natural terpenoids. Synthesis and properties

In this review, we summarized and analyzed the literature data (from 1963 to March, 2014) on the synthesis and properties of quaternary ammonium derivatives of citronellal, menthol, camphor, lambertian acid, dehydroabietic acid, levopimaric acid, isosteviol, steviol, betulinic acid, dihydrobetulinic acid, platanic acid, oleanolic acid, ursolic acid, and polyprenols. Functionalization of terpenoids with ammnoium groups offers them new properties, such as cholinotropic, antiviral, and antimicrobial activities, or transforms them into chiral ionic liquids having a practical potential for application as chiral phasetransfer catalysts. The synthesis of ammonium derivatives of terpenoids possessing properties of cationic lipids or dimeric bis-quaternary ammonium surfactants was proved to have a promising outlook. A specific attention was paid to the method developed for transformation of any hydrophobic terpenoid or steroid into an amphiphilic water-soluble compound self-organized in the aqueous medium into vesicles (liposomes) forming cell-penetrating complexes with DNA.

Chiral Phase Transfer Catalysts for the Synthesis of Chiral N‐Heterocycles viaAsymmetric Cascade Reactions

The effectiveness of a series of chiral phase transfer catalysts in cascade reactions of active methylene compounds with 2‐cyanobenzaldehyde leading to chiral 3‐substituted isoindolinones and fused benzoindolizidinones has been investigated. High yields and moderate enantiomeric excesses (e.e.s) were achieved employing a chiral phase‐transfer catalyst derived from bifunctional urea–quinine. Moreover, an efficient process of heterochiral crystallization, performed on moderately enantioenriched compounds, led to an impressive increase of the enantiopurity up to 93% e.e.s.

Catalytic asymmetric synthesis of 3,3'-diaryloxindoles as triarylmethanes with a chiral all-carbon quaternary center: phase-transfer-catalyzed S(N)Ar reaction.

Catalytic asymmetric synthesis of unsymmetrical triarylmethanes with a chiral all-carbon quaternary center was achieved by using a chiral bifunctional quaternary phosphonium bromide catalyst in the S(N)Ar reaction of 3-aryloxindoles under phase-transfer conditions. The presence of a urea moiety in the chiral phase-transfer catalyst was important for obtaining high enantioselectivity in this reaction.

ChemInform Abstract: Enantioselective Alkylation by Binaphthyl Chiral Phase‐Transfer Catalysts: A DFT‐Based Conformational Analysis.

A conformational search method based on the density functional theory (DFT) was successfully applied to explore a mechanism for the highly enantioselective alkylation by binaphthyl-modifed chiral phase-transfer catalysts. Key interactions that govern the enantioselectivity were analyzed. The computational results are encouraging for further application of the DFT-based conformational search toward the rational design of next-generation asymmetric phase transfer catalysts.

Phase‐Transfer‐Catalysed Synthesis of Pyrroloindolines and Pyridoindolines by a Hydrogen‐Bond‐Assisted Isocyanide Cyclization Cascade

A cascade reaction that generates pyrrolo- and pyridoindoline motifs from isocyanide precursors under phase-transfer conditions is described. This transformation proceeds at room temperature in the presence of a quaternary ammonium catalyst and base to generate functionalized products containing an all-carbon quaternary stereocentre. Quantum chemical calculations demonstrated that intramolecular general acid catalysis plays a key accelerating role through stabilization of developing charge in the transition state, and that the reaction is best described as a 5-endo dig cyclization, rather than an anionic 6π electrocyclization. Investigations employing chiral phase-transfer catalysts have given promising selectivities to date.

Cascade reactions of glycine Schiff bases and chiral phase transfer catalysts in the synthesis of α-amino acids 3-substituted phthalides or isoindolinones

The tuning of aldol/cyclization cascade reactions of glycine Schiff bases with 2-cyano benzaldehydes provides access to non-natural α-amino acid derivatives substituted alternatively with phthalides or isoindolinones, depending on the strength of the used base. Moreover, a preliminary screening of catalysts and conditions for development of asymmetric versions identified chiral bifunctional phase transfer catalysts as particularly promising, leading to the α-amino esters 3-substituted phthalides in high yields and good diastereo- and enantioselectivity.

Ultrasonic assisted dimeric cinchona based chiral phase transfer catalysts for highly enanatioselective synthesis of epoxidation of α,β-unsaturated ketones

New types of bis-quaternary ammonium bromide as chiral multisite phase transfer catalysts derived from cinchona alkaloids have been developed and evaluated for the enantioselective epoxidation of chalcones in the presence of lower concentrations of various oxidants, bases and ultrasonic irradiation conditions.

9-Amino-(9-deoxy)cinchona alkaloid-derived new chiral phase-transfer catalysts

A new class of 9-amino-(9-deoxy)cinchona alkaloid-derived chiral phase-transfer catalysts bearing amino groups was developed by using known cinchona alkaloids as the starting materials. Due to the transformation of the 9-hydroxyl group into a 9-amino functional group, the catalytic performances were significantly improved in comparison with the corresponding first generation phase-transfer catalysts, and excellent yields (92-99%) and high enantioselectivities (87-96% ee) were achieved in the benchmark asymmetric α-alkylation of glycine Schiff base. Based on the special contribution of the amino group to the high yield and enantioselectivity, the possible catalytic mechanism was conjectured.

Enantioselective Alkylation by Binaphthyl Chiral Phase-Transfer Catalysts: A DFT-Based Conformational Analysis

A conformational search method based on the density functional theory (DFT) was successfully applied to explore a mechanism for the highly enantioselective alkylation by binaphthyl-modifed chiral phase-transfer catalysts. Key interactions that govern the enantioselectivity were analyzed. The computational results are encouraging for further application of the DFT-based conformational search toward the rational design of next-generation asymmetric phase transfer catalysts.

Highly Enantioselective Bromocyclization of Tryptamines and Its Application in the Synthesis of (−)‐Chimonanthine

A shorter path: A highly enantioselective bromocyclization of tryptamine has been developed using an anionic chiral phase-transfer catalyst. This method provides a direct approach for preparing chiral 3-bromopyrroloindoline from tryptamine, which enables a four-step enantioselective synthesis of (-)-chimonanthine. PG=protecting group.

Production at the Curie Level of No-Carrier-Added 6-18F-Fluoro-l-Dopa

6-(18)F-fluoro-L-dopa ((18)F-FDOPA) has proven to be a useful radiopharmaceutical for the evaluation of presynaptic dopaminergic function using PET. In comparison to electrophilic synthesis, the no-carrier-added (NCA) nucleophilic method has several advantages. These include much higher available activity and specific activity. Recently, we have described an NCA enantioselective synthesis using a chiral phase-transfer catalyst. However, some chemicals were difficult to implement into a commercially available synthesizer, restricting access to this radiopharmaceutical to only a few PET centers. In this paper, 2 important chemical improvements are proposed to simplify production of (18)F-FDOPA, resulting in straightforward automation of the synthesis in a commercially available module. First, a fast, simple, and reliable synthesis of 2-(18)F-fluoro-4,5-dimethoxybenzyl iodide on a solid-phase support was developed. Second, a phase-transfer catalyst alkylation of a glycine derivative at room temperature was used to enable enantioselective carbon-carbon bond formation. After hydrolysis and high-performance liquid chromatography purification, a high enantiomeric excess of (18)F-FDOPA (≈ 97%) was obtained using a chiral catalyst available from a biphenyl 3 substrate. The total synthesis time was 63 min, and the decay-corrected radiochemical yield was 36% ± 3% (n = 8). By exploiting the advantages of this NCA approach, using a starting activity of 185 GBq of NCA (18)F-fluoride, high activities of (18)F-FDOPA (>45 GBq) with high specific activity (≥ 753 GBq/μmol) are now available at the end of synthesis for use in clinical investigations.