Chiral Quaternary Ammonium Salts Research Articles

Chiral Quaternary Ammonium Salt‐Catalyzed Enantioselective Addition Reactions of Hydantoins

AbstractWe herein report a protocol for the asymmetric 1,4‐addition of hydantoins to various Michael acceptors by utilizing Cinchona alkaloid‐based chiral quaternary ammonium salt catalysts. Various products were obtained with moderate to good enantioselectivities and accompanying computational investigations helped to identify key interactions responsible for the observed selectivity. DFT calculations along with non‐covalent interaction plots reveal the presence of numerous stabilizing non‐classical hydrogen bonding interactions along with other non‐covalent interactions between the chiral quaternary ammonium salt and hydantoin molecule in the C−C bond forming transition states leading to the formation of the products. In addition, a first proof‐of‐concept for an analogous a‐sulfanylation reaction, albeit with poor selectivity, is reported as well.

Towards an asymmetric β-selective addition of azlactones to allenoates.

We herein report the asymmetric organocatalytic addition of azlactones to allenoates. Upon using chiral quaternary ammonium salt catalysts, i.e., Maruoka's binaphthyl-based spirocyclic ammonium salts, the addition of various azlactones to allenoates proceeds in a β-selective manner with moderate levels of enantioselectivities (up to 83:17 er). Furthermore, the obtained products can be successfully engaged in nucleophilic ring opening reactions, thus giving highly functionalized α-amino acid derivatives.

Enantioselective synthesis of fluorinated aromatic amino acids catalyzed by SPINOL-derived chiral quaternary ammonium salts†

We report the synthesis of a new class of chiral quaternary ammonium salts featuring a rigid spirobiindane scaffold. These chiral quaternary ammonium salts were employed as catalysts in the phase-transfer catalytic asymmetric alkylation of tert‑butyl glycinate–benzophenone Schiff base with both fluorinated and non-fluorinated benzyl bromides. Under the established reaction conditions, a series of chiral fluorinated aromatic α-amino acid derivatives, some of which are key intermediates for biologically significant compounds, were obtained in high yields and enantioselectivities.

Synthesis and Resolution of an Axially Chiral Spirocyclic Quaternary Ammonium Ion‐Based Phase‐Transfer Catalyst

AbstractWe report the synthesis of a novel spirocyclic quaternary ammonium salt that possesses axial chirality. Enantiopure material was obtained by fractional crystallization of the corresponding (R,R)‐tartrate salt. Application of this chiral quaternary ammonium salt in phase‐transfer catalytic asymmetric alkylation of glycinate Schiff base was examined.

Alkynylation of Isatin Derivatives Catalyzed by a Silver-Chiral Quaternary Ammonium Salt Derived from Quinine.

Asymmetric addition of terminal alkynes catalyzed by a transition metal to isatins obviously is an efficient and economic method for the synthesis of 3-alkynyl-3-hydroxy-2-oxindoles. The new dimeric chiral quaternary ammoniums derived from a natural chiral alkaloid, quinine, can be used as cationic inducers of the enantioselectivity for the Ag(I)-catalyzed alkynylation of isatin derivatives under mild conditions. The desired chiral 3-alkynyl-3-hydroxy-2-oxindoles can be obtained in good to high yields with high to excellent enantioselectivites (≤99% ee). A variety of aryl-substituted terminal alkynes and substituted isatins are tolerated in this reaction.

Enantioselective Molecular Recognition in a Flexible Self-Folding Cavitand.

We report a chiral deep cavitand receptor based on calix[5]arene stabilized by a cooperative network of hydrogen bonds and having a highly flexible structure. The cavitand displays enantioselective molecular recognition with a series of chiral quaternary ammonium salts, providing unprecedented stability ratios between the corresponding diastereomeric host-guest complexes. Molecular dynamics simulations corroborate the higher flexibility of the new host and the emergence of superior induced-fit behavior with regards to resorcin[4]arene derived self-folding cavitands.

Design and catalytic atroposelective synthesis of axially chiral isochromenone-indoles

The catalytic atroposelective synthesis of axially chiral isochromenone-indoles has been established by the strategy of designing homophthalic anhydride-based indole derivatives as a new type of indole-based platform molecules for dynamic kinetic resolution. By this strategy, a wide range of axially chiral isochromenone-indoles were synthesized in high yields with excellent enantioselectivities (up to 98% yield, 97% ee) via the catalytic asymmetric sulfonylation reaction of homophthalic anhydride-based indole derivatives with aryl sulfonyl chlorides under the catalysis of chiral quaternary ammonium salt as a phase-transfer catalyst

Recent Advances in Catalytic Nonenzymatic Kinetic Resolution of Tertiary Alcohols

AbstractThe kinetic resolution (KR) of racemates is one of the most widely used approaches to access enantiomerically pure compounds. Over the past two decades, catalytic nonenzymatic KR has gained popularity in the field of asymmetric synthesis due to the rapid development of chiral catalysts and ligands in asymmetric catalysis. Chiral tertiary alcohols are prevalent in a variety of natural products, pharmaceuticals, and biologically active chiral compounds. The catalytic nonenzymatic KR of racemic tertiary alcohols is a straightforward strategy to access enantioenriched tertiary alcohols. This short review describes recent advances in catalytic nonenzymatic KR of tertiary alcohols, including organocatalysis and metal catalysis.1 Introduction2 Organocatalysis2.1 Peptide Catalyst2.2 Chiral Phosphoric Acid Catalyst2.3 Chiral Lewis Base Catalyst2.4 Chiral Quaternary Ammonium Salt Catalyst3 Metal Catalysis3.1 Mixed La-Li Heterobimetallic Catalyst3.2 Rh Catalyst3.3 Hf Catalyst3.4 Pd Catalyst3.5 Cu Catalyst3.6 Ag Catalyst4 Conclusion and Outlook

Saucer[n]arenes: Synthesis, Structure, Complexation, and Guest‐Induced Circularly Polarized Luminescence Property

AbstractMacrocycles denoted as saucer[n]arenes (n=4,5) were easily synthesized by the one‐pot condensation of 2,7‐dimethoxynaphthalene (2,7‐DMN) and paraformaldehyde in the presence of TFA or catalytic BF3⋅OEt2. With 1,1‐dimethylpiperidin‐1‐ium as the template, saucer[4]arene was selectively obtained. Crystal structures show that saucer[n]arenes are all composed of 2,7‐DMN moiety bridged by the methylene groups at 1,6‐positions: all of the 7‐methoxy groups lie on one face, and all of the 2‐methoxy groups lie on the other. Saucer[n]arenes exhibit strong fluorescence properties with the quantum yields of 19.6 % and 23.4 %. They form 1:1 complexes with ammonium salts in both solution and solid state (association constant up to 105 M−1 in CDCl3). Chiral quaternary ammonium salts can induce the chirality of the dynamically racemic inherently chiral saucer[n]arenes in solution, and thus show mirror‐imaged circular dichroism signals and circularly polarized luminescence (CPL) properties.

Saucer[n]arenes: Synthesis, Structure, Complexation, and Guest-Induced Circularly Polarized Luminescence Property.

Macrocycles denoted as saucer[n]arenes (n=4,5) were easily synthesized by the one-pot condensation of 2,7-dimethoxynaphthalene (2,7-DMN) and paraformaldehyde in the presence of TFA or catalytic BF3 ⋅OEt2 . With 1,1-dimethylpiperidin-1-ium as the template, saucer[4]arene was selectively obtained. Crystal structures show that saucer[n]arenes are all composed of 2,7-DMN moiety bridged by the methylene groups at 1,6-positions: all of the 7-methoxy groups lie on one face, and all of the 2-methoxy groups lie on the other. Saucer[n]arenes exhibit strong fluorescence properties with the quantum yields of 19.6 % and 23.4 %. They form 1:1 complexes with ammonium salts in both solution and solid state (association constant up to 105 M-1 in CDCl3 ). Chiral quaternary ammonium salts can induce the chirality of the dynamically racemic inherently chiral saucer[n]arenes in solution, and thus show mirror-imaged circular dichroism signals and circularly polarized luminescence (CPL) properties.

Study of Ground State Interactions of Enantiopure Chiral Quaternary Ammonium Salts and Amides, Nitroalkanes, Nitroalkenes, Esters, Heterocycles, Ketones and Fluoroamides.

Chiral phase‐transfer catalysis provides high level of enantiocontrol, however no experimental data showed the interaction of catalysts and substrates. 1H NMR titration was carried out on Cinchona and Maruoka ammonium bromides vs. nitro, carbonyl, heterocycles, and N−F containing compounds. It was found that neutral organic species and quaternary ammonium salts interacted via an ensemble of catalyst +N−C−H and (sp2)C−H, specific for each substrate studied. The correspondent BArF salts interacted with carbonyls via a diverse set of +N−C−H and (sp2)C−H compared to bromides. This data suggests that BArF ammonium salts may display a different enantioselectivity profile. Although not providing quantitative data for the affinity constants, the data reported proofs that chiral ammonium salts coordinate with substrates, prior to transition state, through specific C−H positions in their structures, providing a new rational to rationalize the origin of enantioselectivity in their catalyses.

Enantioselective Construction of C-C Axially Chiral Quinazolinones via Chirality Exchange and Phase-Transfer Catalysis.

A family of axially chiral quinazolinone-based heterobiaryls were constructed with high levels of enantiocontrol (up to 94% ee). Convergently, three different synthetic methods have been realized to prepare these valuable compounds including central-to-axial chirality transfer, dynamic kinetic resolution, and phase-transfer catalysis. Importantly, novel P,N-ligands with a π-π stacking can be derived from heterobiaryls by chirality exchange strategy or synthesized directly from complementary phase-transfer catalysis by using the inexpensive chiral quaternary ammonium salt.

A Remarkably Efficient Phase-Transfer Catalyzed Amination of α-Bromo-α, β-Unsaturated Ketones in Water

Tandem conjugate addition–alkylation reaction of various amines with α-bromo-α, β-unsaturated ketones resulted in near-quantitative conversions into the corresponding aziridines when the reaction was carried out in the presence of 10 mol% of phase-transfer, PT catalysts in water. Some chiral quaternary ammonium salts derived from Cinchona alkaloids were investigated as water-stable PT catalysts. The scope and limitations of the reaction have also been investigated. The catalytic performances were significantly improved in comparison with the corresponding ordinary quaternary ammonium salt catalysts, and excellent yields (81%–96%) were obtained. Although an increase in the rate of aziridination has been accomplished, no stereoselectivity was observed. The positive values of the protocol have been confirmed.

Synthesis, characterization and physicochemical properties of new chiral quinuclidinol quaternary ammonium salts

A new series of chiral quaternary ammonium salts (QASs) were successfully synthesized and characterized by FT-IR, NMR and MS. The thermal stability and melting point (mp) of the chiral QASs were measured. Moreover, basic physicochemical properties of the QAS solutions including density, viscosity, conductivity and specific optical rotation were investigated. The solution properties such as dissociation equilibrium constant (k) and critical micelle concentration (CMC) were deduced with theoretical methods. All QASs exhibited good thermal stability (decomposition temperature > 470 K) and large specific optical rotations (−228.12 to −156.83).

A flexible strategy for the synthesis of bifunctional 6′-(thio)-urea containing Cinchona alkaloid ammonium salts

A flexible and functional group tolerant synthesis route to access a structurally diverse collection of bifunctional 6′-(thio)-urea containing Cinchona alkaloid-based chiral quaternary ammonium salts has been developed. This route gives access to more than 25 different novel urea- and thiourea-containing ammonium salt derivatives, which were not accessible so far.

Dipeptide-Based Phosphonium Salt Catalysis: Application to Enantioselective Synthesis of Fused Tri- and Tetrasubstituted Aziridines

Over the past decades, phase-transfer catalysis (PTC), generally based on numerous chiral quaternary ammonium salts, has been recognized as a powerful and versatile tool for organic synthesis in both industry and academia. In sharp contrast, PTC involving chiral phosphonium salts as the catalysts is insufficiently developed. Recently, our group realized the first enantioselective aza-Darzens reaction for preparing tri- and tetrasubstituted aziridine derivatives under bifunctional phosphonium salt catalysis. This article briefly discusses the recent development in asymmetric reactions (mainly including nucleophilic additions and cyclizations) promoted by chiral quaternary phosphonium salt catalysts. We expect that more catalytic asymmetric reactions will be developed on the basis of such new phase-transfer catalytic systems in the near future.

Macrocyclic Hosts in Asymmetric Phase-Transfer Catalyzed Reactions

The introduction and development of neutral macrocyclic hosts capable of complexing ions within their pre-organized cavity, has been of utmost importance in supramolecular chemistry. Their ability to form stable organic-soluble metal–macrocycle complexes opened up the way to their application in phase-transfer catalysis (PTC) as a viable alternative to quaternary onium salts. In particular, their conformationally rigid preorganized backbone, accommodating organic substrates in defined orientations, promotes highly efficient stereoselective reactions. This short review summarizes the applications of neutral macrocyclic hosts in stereoselective PTC, highlighting the difference and possible complementarity with quaternary ammonium salts.1 Introduction2 Crown Ethers and Related Coronands2.1 Enantioselective PTC with Chiral Macrocyclic Coronands2.2 Enantioselective PTC Reactions Catalyzed by Chiral Quaternary Ammonium Salts with Achiral Crown Ether Co-catalysts3 Cyclic Peptoids4 Miscellaneous Chiral Macrocyclic Hosts5 Summary and Outlook

Design, Synthesis, and Antitobacco Mosaic Virus Activity of Water-Soluble Chiral Quaternary Ammonium Salts of Phenanthroindolizidines Alkaloids.

To study the influence of the substituent at the N-10 position on antiviral activity, the chiral quaternary ammonium salt derivatives of R- and S-tylophorine were designed, synthesized, and evaluated for antiviral activity against tobacco mosaic virus (TMV). The bioassay results indicated that most of the designed structural analogues showed good in vivo anti-TMV activity, among which propargyl quaternary ammonium salt compound S-7b showed the best anti-TMV activities (80.5%, 77.6%, 76.6%, 82.1%) at 500 μg/mL both in vitro and in vivo in the laboratory. In the field trials of antiviral efficacy against TMV, S-7b as well exhibited better activities than control plant virus inhibitors. The stability of compound S-7b was obviously increased, and its solubility was more than 500-times higher than that of S-tylophorine. Therefore, chiral quaternary ammonium salt S-7b was expected to be developed as a promising candidate as an inhibitor of plant virus.

Discovery of Novel Potent Muscarinic M3 Receptor Antagonists with Proper Plasma Stability by Structural Recombination of Marketed M3 Antagonists.

The marketed long-acting M3 antagonists for treatment of chronic obstructive pulmonary disease have inappropriate plasma stability (either overstable or excessively unstable), which causes substantial systemic exposure or poor patient compliance. To discover novel M3 antagonists with proper plasma stability, we synthesized and biologically evaluated a series of chiral quaternary ammonium salts of pyrrolidinol esters, which were designed by structural recombination of the marketed M3 antagonists. As a result, two novel potent M3 antagonists, (R/S)-3-[2-hydroxy-2,2-di(thiophen-2-yl)acetoxy]-1,1-dimethylpyrrolidinium bromides (1 a: Ki =0.16 nm, IC50 =0.38 nm, t1/2 =9.34 min; 1 b: Ki =0.32 nm, IC50 =1.01 nm, t1/2 =19.2 min) with proper plasma stability were identified, which (particularly 1 a) hold great promise as clinical drug candidates to overcome the drawbacks caused by the inappropriate stability of the currently marketed M3 antagonists. In addition, structure-activity relationship studies revealed that the R configuration of the pyrrolidinyl C3 atom was clearly better than the S configuration.

Phase-Transfer and Ion-Pairing Catalysis of Pentanidiums and Bisguanidiniums.

Catalysts accelerate biological processes and organic reactions in a controlled and selective fashion. There are continuing efforts in asymmetric catalysis to develop efficient catalysts with broad reaction scope and industrial practicability. Among the various modes of asymmetric catalysis, phase-transfer catalysis has attracted intense interest due to its facile scale up and low catalyst loading. Chiral quaternary ammonium and phosphonium salts are well-studied classes of chiral phase-transfer catalysts, and they are typically composed of sp3-hybridized quaternary onium salts. In this Account, we describe our recent attempts to develop N-sp2-hybridized guanidinium-type salts as efficient phase-transfer catalysts as well as ion-pair catalysis based on N-sp2 hybridized bisguanidinium-type salts. The sp2-quaternized ammonium salts, pentanidiums, which contain five nitrogen atoms in conjugation, displayed remarkable phase-transfer catalytic efficiency. We have shown that pentanidium can catalyze Michael additions of tert-butyl glycinate-benzophenone Schiff bases with various α,β-unsaturated acceptors, such as vinyl ketones, acrylates, and chalcones, in high enantioselectivities. The structurally amendable pentanidium phase-transfer catalysts supply diverse reactivity and selectivity to various other organic transformations, such as α-hydroxylation of 3-substituted-2-oxindoles, Michael addition of 3-alkyloxindoles with vinyl sulfone, and alkylation reactions of sulfenate anions and dihydrocoumarins. Pentanidium salts are applicable to enantioselective transformations on a preparative scale at low catalyst loading, allowing for the synthesis of a broad range of enantiopure compounds. From computational and experimental results, we also proposed that the halogenated pentanidium catalysts participated in halogen bonding and that this contributed to the excellent stereocontrol in alkylation reactions. Subsequently, we determined that chiral cations can direct functional anions besides basic anions in traditional Brønsted basic phase-transfer reactions, including metal-centered anions. We identified dicationic bisguanidinium as an excellent ion-pairing catalyst, first demonstrating that bisguanidinium formed an ion pair with permanganate and directed the anion in enantioselective dihydroxylation and oxohydroxylation of a,β-unsaturated esters. This initial success led us to explore chiral cationic ion-pairing catalysis as a general mode of catalysis. This mode of catalysis is at the interphase between organocatalysis, phase-transfer catalysis and organometallic catalysis. We then identified bisguanidinium diphosphatobisperoxotungstate and bisguanidinium dinuclear oxodiperoxomolybdosulfate ion pairs as the active catalysts in enantioselective sulfoxidations using aqueous H2O2 as the oxidant. The structure of the bisguanidinium dinuclear oxodiperoxomolybdosulfate ion pair was elucidated using single-crystal X-ray analysis. Bisguanidinium-catalyzed sulfoxidations emerged as a practical methodology for the synthesis of enantioenriched sulfoxides including armodafinil and lansoprazole, which are commercial drugs. Finally, we are also able to show that pentanidium and bisguanidinium hypervalent silicates are intermediates in enantioselective alkylations using silylamide as a Brønsted probase.