Chiral Phase-transfer Catalysts Research Articles

Synthesis and evaluation of new mono- and binuclear salen complexes for the Cα-alkylation reaction of amino acid substrates as chiral phase transfer catalysts

In this study, we present a series of Zn(II) mono- and Cu(II) binuclear salen complexes synthesized and assessed for their effectiveness in the Cα-alkylation reaction. Through systematic experimentation, it was observed that the introduction of a methoxy group at position 3 of the phenyl group in the salicylidene ligand led to a notable enhancement in asymmetric yield, while an allyl group reduced yield. Computational DFT calculations supported the involvement of the binuclear complex in the transition state of the reaction, elucidating the underlying mechanisms governing the observed catalytic behavior. A newly synthesized binuclear complex exhibited significantly higher catalytic activity compared to its mononuclear counterpart which could potentially be explained by increased intramolecular rigidity. This comprehensive investigation not only advances our understanding of structure-activity relationships in chiral salen complexes but also provides valuable insights for the rational design and optimization of catalysts for the asymmetric Cα-alkylation reaction.

Asymmetric phase-transfer catalysis.

Over the past three decades, chiral phase-transfer catalysts (PTCs) have emerged as highly successful organocatalysts in a diverse range of asymmetric reactions. A substantial number of chiral PTCs have now already been discovered and utilized in dependable routes to enantioenriched products. These extend beyond the classical cationic PTCs with the emergence of anionic phase-transfer catalysis and hydrogen-bonding phase-transfer catalysis providing new asymmetric synthetic approaches. Nevertheless, the application level of chiral PTCs in both academic and industrial processes is below our expectation. This Review highlights the notable advances in chiral PTCs, including challenges, limitations and efforts to overcome them. Following this, the potential for sustainable chiral PTCs is described with a focus on using photocatalysed, flow and electrochemical synthesis.

Catalytic 1,1-Cyanoalkylation of Electron-Deficient Olefins.

A catalytic 1,1-dicarbofunctionalization of electron-deficient olefins was effected on the basis of the three-component coupling reactions involving olefins bearing vicinal electron-withdrawing groups, potassium cyanide, and an alkyl halide, which afforded geminally cyanoalkylated products in high yields via conjugate cyanation, 1,2-proton transfer, and enolate alkylation. The use of suitable chiral phase-transfer catalysts enabled asymmetric induction in this transformation.

Asymmetric Mannich Reaction of Isatin-Derived Ketimines with α-Fluoroindanones Catalyzed by a Chiral Phase-Transfer Catalyst.

A highly enantioselective Mannich reaction of α-fluoroindanones with isatin-derived N-Boc-ketimines catalyzed by a quinine-derived phase-transfer catalyst was developed. A variety of 3-substituted 3-amino-2-oxindoles bearing fluorine-containing, vicinal, tetrasubstituted stereocenters were constructed using this protocol in high yields (83-95%), with moderate to excellent enantioselectivities (66-91%) and high diastereoselectivities (up to >99:1).

Catalytic Enantioselective Nucleophilic Addition to Arynes by a New Quaternary Guanidinium Salt-Based Phase-Transfer Catalyst.

Owing to the mild generation methods, arynes have been widely used in synthetic chemistry. However, achieving asymmetric organocatalytic reactions with arynes remains a formidable and infrequent challenge, primarily because these neutral and transient species tend to spontaneously quench. To address this issue, a solid-liquid phase-transfer strategy is devised in which the generation speed of arynes could be controlled by the in situ generated fluoride-based chiral phase-transfer catalyst. In this study, we present a catalytic enantioselective nucleophilic addition reaction involving arynes, utilizing an amino amide-based guanidinium salt QG•X. Furthermore, we demonstrate the broad compatibility of this reaction with various arynes and cyclic/acyclic β-keto amides, leading to the creation of diverse α-aryl quaternary stereocenters with good stereoselectivity. Mechanistic investigations have uncovered the potential involvement of a chiral intramolecular cationic-anionic pair and HF during the ion exchange between QG•X and CsF for nucleophile activation and aryne generation. Additionally, DFT calculations suggested that the observed high levels of enantioselectivity can be attributed to steric repulsion and the cumulative noncovalent interactions between the catalysts and substrates.

Accessing Phase-Transfer Catalysts and a Phosphoramidite Ligand via the Asymmetric Intramolecular Hydroamination Reaction

Within the last few years, our group has developed the intramolecular, asymmetric hydroamination (HA) reaction to a point where essentially enantiopure products can be obtained. The question then arose as to whether we can apply the reaction in useful ways beyond the synthesis of natural/pharmaceutically relevant products. In the present paper, we incorporate a select few HA products for the production of new chiral phase-transfer catalysts. These species are synthesized in one or two synthetic steps from new spirocyclic HA products and are applied in a classical substitution reaction, showing negligible enantioselectivity. In a second application, we introduce a novel phosphoramidite ligand, obtained by combining BINOL (1,1′-bi-2-naphthol) and an optically pure HA product with phosphorous trichloride. The representative ligand shows high enantioselectivity and activity in the rhodium-catalyzed conjugate addition reaction (Hayashi–Miyaura reaction).

Asymmetric Mannich reaction of N-Boc aminosulfones with 3-methylbenzofuran-2 (3H) - Ones catalyzed by a chiral phase-transfer catalyst

An enantioselective Mannich reaction of N-Boc aminosulfones with 3-methylbenzofuran-2 (3H)-ones catalyzed by a quinine-derived bifunctional phase transfer catalyst was developed, by which a series of chiral benzofuranones bearing adjacent quaternary and tertiary carbon centers were obtained in high yields (up to 96%) with good diastereoselectivities (up to >99:1) and enantioselectivities (up to 98%).

Design of Y-Shaped Trimers of Chiral Phase-Transfer Catalysts for the Asymmetric Alkylation of Amino Acid Derivatives

AbstractA series of soluble Y-shaped trimers of chiral phase-transfer catalysts were synthesized and utilized in the asymmetric alkylation of amino acid Schiff bases. The length of the linker between the ammonium cation of the simplified Maruoka catalyst and a phloroglucinol moiety was varied and excellent yields and enantioselectivity were observed when using the Y-shaped trimer of chiral phase-transfer catalyst with an octamethylene linker. A theoretical study of the most efficient Y-shaped trimer of chiral phase-transfer catalyst suggests the chiral ammonium center of the catalyst is more exposed and thus more available in the reaction.

Photoswitchable Chiral Organocatalysts: Photocontrol of Enantioselective Reactions.

This study presents recent advances in photoswitchable chiral organocatalysts and their applications in the photomodulation of enantioselective reactions. Under irradiation with an appropriate wavelength of light, the E/Z-photoisomerization of the photoresponsive units on the catalysts leads to the control of the catalytic activity and/or selectivity of the enantioselective reactions. Additionally, this study elucidates the design, synthesis, and catalytic application of the fabricated azobenzene BINOL-based photoswitchable chiral phase-transfer catalysts. This account will provide insights into the appropriate design of a photoswitchable chiral organocatalyst that can achieve both good enantioselectivity and photocontrol.

Highly Enantioselective Synthesis of [1,2,4]Triazino[5,4-a]isoquinoline Derivatives via (3 + 3) Cycloaddition Reactions of Diazo Compounds and Isoquinolinium Methylides.

An array of chiral [1,2,4]triazino[5,4-a]isoquinoline derivatives were obtained in excellent yields (up to 98%) and with excellent enantioselectivities (up to 99% ee) via a new highly asymmetric (3 + 3) cycloaddition reaction of diazo compounds and isoquinolinium methylides, with a bifunctional chiral phase-transfer catalyst (PTC). Density functional theory calculations show that PTC has a bridge role in the deprotonation/protonation process. The obtained products were transformed into densely functionalized polycyclic heterocompounds with multiple stereocenters.

Crystal structures of anhydrous and hydrated N-benzyl-cinchonidinium bromide.

N-benzyl-cinchonidinium bromide, C26H29N2O+·Br-, with the systematic name (R)-[(2S,4S,5R)-1-benzyl-5-ethenyl-1-azoniabi-cyclo-[2.2.2]octan-2-yl](quinolin-4-yl)-methanol bromide, is a quaternary ammonium salt of the cinchona alkaloid cinchonidine. This salt is widely used as a chiral phase-transfer catalyst and chiral resolution agent. Both classical and non-classical hydrogen-bonding inter-actions, as well as anion effects have been shown to play key mechanistic roles in the catalysis of cinchona alkaloids. In an effort to understand the effects of water on these inter-molecular inter-actions, the structures of anhydrous N-benzyl-cinchonidinium bromide, (I), and the sesquihydrate, C26H29N2O+·Br-·1.5H2O, (II), were determined.

Phase-Transfer-Catalyzed Alkylation of Hydantoins.

A highly efficient, cost-effective, and environmentally friendly protocol is reported for the C5-selective alkylation of hydantoins under phase-transfer catalysis. The reactions are scalable and only require a catalytic amount of tetrabutylammonium bromide (TBAB) to achieve high yields under mild reaction conditions. Moreover, the method is applicable to a wide range of electrophiles, including alkyl-, allyl-, propargyl-, and benzyl halides, as well as acrylates and dibromoalkanes, but also to virtually any hydantoin precursor. We also highlight the potential for an enantioselective adaptation using a chiral phase-transfer catalyst.

Aymmetric Aza-Friedel-Crafts Reaction of Isatin-Derived Ketimines with Indoles Catalyzed by a Chiral Phase-Transfer Catalyst.

A highly enantioselective aza-Friedel-Crafts reaction of 1H-indoles with isatin-derived N-Cbz-ketimines catalyzed by quinine-derived phase-transfer catalysts was developed. A series of chiral 3-aminobisindole compounds containing a tetrasubstituted stereocenter were constructed by this protocol in high yields (82-91%) and moderate to excellent enantioselectivities (46-94% ee).

Investigation of [MSalen/salophen] (M = Cr3+, Fe3+ or Co3+) capped dinuclear complexes of two novel tetraoxocalix[2](m-hydroxymethyl)arene[2]triazine compounds

In this work, (3,5-bis((4,6-dichloro-1,3,5-triazine-2-yl)oxy)phenyl)methanol was obtained by reacting cyanuric chloride with 3,5-dihydroxybenzyl alcohol at 0 °C. Then, s-triazine bridged calixarene codded as L1 was obtained by reacting the compounds with 3,5-dihydroxybenzyl alcohol. Targed ligands, which we code as L2 and L3, were obtained from the reaction of the L1 coded compound with 4-aminobenzoic acid or 4-hydroxybenzoic acid, respectively. [MSalen/Saloph] capped s-triazine bridged calixarene complexes were obtained from the reaction of the L2 or L3 codded ligand and the [(MSalen/Saloph)2O] (M = Cr3+, Fe3+, Co3+) starting complexes in 1,4-dioxane media. The ligands and complexes were characterized by using 1H-NMR, FT-IR spectroscopy, UV-Vis spectroscopies, magnetic susceptibility, TGA-DTA and elemental analysis techniques. Metal contents of the complexes were determined by using ICP-AES spectroscopy. Calixarenes can be used in many areas such as chiral phase transfer catalyst, recognition of enantiomers, stationary phase in chromatography, recovery of heavy and precious metals molecules or ions from environmental wastes.

Phase-Transfer Catalyzed Asymmetric [4 + 1] Annulations for the Synthesis of Chiral 2,2-Disubstituted Tetrahydrothiophenes.

An efficient catalytic asymmetric [4 + 1] reaction, which features the use of simple β-keto esters as one-carbon nucleophiles and 5-succinimidothio-pent-2-enoates as four-atom bielectrophiles, has been developed in the presence of a bifunctional chiral phase-transfer catalyst. The new annulation provides a distinct protocol to access the functionalized 2-acyl-2-carboxyl tetrahydrothiophenes bearing consecutive quaternary and tertiary carbon stereocenters in high diastereoselectivities and enantioselectivities. Moreover, the prepared products could be readily transformed into the chiral 2-alkyl-2-carboxyl tetrahydrothiophenes via two steps of debenzoylation and alkylation reactions.

Carbohydrate-Based Azacrown Ethers in Asymmetric Syntheses

Carbohydrate-based crown ethers represent a special group of chiral phase transfer catalysts. Several derivatives of these macrocycles have been synthesized in our research group. Among these compounds, monoaza-15-crown-5 lariat ethers proved to be effective phase transfer and enantioselective catalysts in certain reactions. Those chiral azacrown ethers incorporating various carbohydrate moieties in the macrocyclic structure are reviewed, which generated asymmetric induction in reactions, such as Michael addition, epoxidation of enones, Darzens condensation and Michael-initiated ring-closure (MIRC) reaction. Effects on the catalytic activity of the structural changes are the focus.

Photoswitchable Chiral Phase Transfer Catalyst

Azo-crown ether-based photoswitching chiral phase transfer catalysts have been developed to control the catalytic activity by photoirradiation. Azobenzene binaphthyl crown ether (ABCE) can switch i...

Ring-Strain-Enabled Catalytic Asymmetric Umpolung C-O Bond-Forming Reactions of 1,2-Oxazetidines for the Synthesis of Functionalized Chiral Ethers.

An unprecedented catalytic asymmetric umpolung C-O bond-forming reaction of N-nosyl 1,2-oxazetidines with β-keto esters has been achieved in the presence of a chiral phase-transfer catalyst, allowing access to a range of highly functionalized chiral ethers bearing quaternary and no adjacent stereogenic centers with high yields, excellent enantioselectivities, and diastereoselectivities (up to 97% ee and 20:1 dr). These versatile products could be flexibly transformed into biologically important chiral fused and spiro morpholines in two steps.

Quaternary β2,2-amino acid derivatives by asymmetric addition of isoxazolidin-5-ones to para-quinone methides.

The highly enantioselective (>99.5% ee) synthesis of a new class of densely functionalized β2,2-amino acid derivatives by reacting isoxazolidin-5-ones with para-quinone methides in the presence of chiral ammonium salt phase-transfer catalysts was developed. The reaction proceeds with exceptionally low catalyst loadings down to 20 ppm on gram scale and the utilization of the primary addition products towards further manipulations was demonstrated for selected examples.

Review on Asymmetric Transformations with Chiral Phase-Transfer Catalysts

This review focuses onasymmetric transformations with Chiral Phase-Transfer Catalysts and its application. Phase-transfer catalysis is practical methodology for organic synthesis. It is possible to achieve highly enantio selective transformations under phase-transfer conditions for a variety of ─C─C─ ─C─O─ and ─C─N─ bond-forming reactions. The asymmetric transformations using modified cinchona alkaloids, chiral spiro ammonium salts and crown ether are among the primary source of effective chiral phase-transfer catalyst, which allows access to enantiomerically pure unnatural amino acids and synthetically useful adducts containing quaternary stereogenic centers. The advantage of this method is its simple experimental procedure, large chiral pool, mild reaction condition, inexpensive, environmentally benign reagent and use of simple and inexpensive reactants. Nowadays, it appears to be the most important synthetic method used in various fields of organic chemistry, and also found widespread industrial applications. This review summarizes the synthesis application, enantio selective transformation of some selected reaction, biological activities and catalytic activities of Phase-transfer catalysis and especial emphasis is given for organo catalysis. In asymmetric organo catalyst, it is possible to obtain chiral organic products in high enantio enriched form by steric hindrance approach method. The advantage of organic molecules as chiral catalysts complements the traditional organo-metallic and biological approaches to asymmetric catalysis.