Chiral Carboxylate Research Articles

Nickel‐Catalyzed Atroposelective Carbo‐Carboxylation of Alkynes with CO2: En Route to Axially Chiral Carboxylic Acids

AbstractPrecise synthesis of carboxylic acids via catalytic carboxylation with CO2 is highly appealing. Although considerable advancements have been achieved in difunctionalizing carboxylation of unsaturated hydrocarbons, the asymmetric variants are conspicuously underdeveloped, particularly in addressing axially chiral alkenes. Herein, we report the first catalytic atroposelective carboxylation of alkynes with CO2. A variety of valuable axially chiral carboxylic acids are obtained with good yields and high chemo‐, regio‐, Z/E and enantio‐selectivities. Notably, an unexpected anti‐selective carbo‐carboxylation is observed in the sp2‐hybrid carbo‐electrophile‐initiated reductive carboxylation of alkynes. Mechanistic studies including DFT calculation elucidate the origin of chiral induction and anti‐selectivity in vinyl‐carboxylation of alkynes.

Nickel-Catalyzed Atroposelective Carbo-Carboxylation of Alkynes with CO2: En Route to Axially Chiral Carboxylic Acids.

Precise synthesis of carboxylic acids via catalytic carboxylation with CO2 is highly appealing. Although considerable advancements have been achieved in difunctionalizing carboxylation of unsaturated hydrocarbons, the asymmetric variants are conspicuously underdeveloped, particularly in addressing axially chiral alkenes. Herein, we report the first catalytic atroposelective carboxylation of alkynes with CO2. A variety of valuable axially chiral carboxylic acids are obtained with good yields and high chemo-, regio-, E/Z and enantio-selectivities. Notably, an unexpected anti-selective carbo-carboxylation is observed in the sp2-hybrid carbo-electrophile-initiated reductive carboxylation of alkynes. Mechanistic studies including DFT calculation elucidate the origin of chiral induction and anti-selectivity in vinyl-carboxylation of alkynes.

Facile Recovery and Recycling of a Soluble Dirhodium Catalyst in Asymmetric Cyclopropanation via a Catalyst-in-Bag System.

A catalyst-in-bag system facilitates the recovery and recycling of chiral dirhodium carboxylate catalysts used for enantioselective, intermolecular cyclopropanation. The catalyst-in-bag system incorporates a soluble enantioselective dirhodium complex catalyst within a reusable, commercial dialysis membrane. Dirhodium catalysts of different sizes are examined, and two catalysts with molecular weights above 2400 Da are well-retained by the membrane. The catalyst Rh2(S-TPPTTL)4 [TPPTTL = (1,3-dioxo-4,5,6,7-tetraphenylisoindolin-2-yl)-3,3-dimethylbutanoate] is explored in enantioselective cyclopropanation reactions under a variety of conditions. The Rh2(S-TPPTTL)4 catalyst, when contained in the catalyst-in-bag system, provides high yields and enantioselectivities, akin to the homogeneous catalyst in solution, with negligible rhodium permeation out of the bag over five catalytic cycles. The catalyst-in-bag approach facilitates recovery of the expensive rhodium metal and ligand, with only ppm level Rh detected in the reaction products. The flexible and expandable catalyst-in-bag system can be accommodated in vessels of different shapes and dimensions.

Enantioselective Relay Coupling of Perfluoroalkyl and Vinylogous Ketyl Radicals

Abstractβ‐Chiral carboxylic acids and their derivatives are highly valuable structural motifs in the fields of asymmetric synthesis and medicinal chemistry. However, the introduction of a sterically demanding sidechain to the β‐carbon, such as an all‐carbon quaternary center, remains a significant challenge in classical polar processes. Recently, N‐heterocyclic carbene (NHC) mediated coupling reactions involving persistent ketyl radicals have emerged as a promising strategy to assemble highly crowded carbon‐carbon bonds. Nevertheless, achieving enantioselectivity in these reactions remains highly challenging. In this work, we report our recent progress in controlling enantioselectivity for relay coupling of perfluoroalkyl and persistent vinylogous ketyl radicals. We developed a chiral bifunctional NHC‐squaramide catalyst that achieves high facial selectivity in a critical bond‐forming event involving the coupling of a congested tertiary carbon radical and vinylogous ketyl radical. Chiral carboxylates bearing an all‐carbon quaternary center at the β‐position can be prepared in good yield and excellent enantiomeric excess. Results from density functional theory (DFT) calculations and nuclear Overhauser effect (NOE) experiments indicate that the N,N’‐diaryl squaramide motif adopts an unusual syn‐syn conformation, enabling hydrogen bonding interactions with the enolate oxygen, thereby rigidifying the overall conformation of the transition state.

Enantioselective Relay Coupling of Perfluoroalkyl and Vinylogous Ketyl Radicals.

β-Chiral carboxylic acids and their derivatives are highly valuable structural motifs in the fields of asymmetric synthesis and medicinal chemistry. However, the introduction of a sterically demanding sidechain to the β-carbon, such as an all-carbon quaternary center, remains a significant challenge in classical polar processes. Recently, N-heterocyclic carbene (NHC) mediated coupling reactions involving persistent ketyl radicals have emerged as a promising strategy to assemble highly crowded carbon-carbon bonds. Nevertheless, achieving enantioselectivity in these reactions remains highly challenging. In this work, we report our recent progress in controlling enantioselectivity for relay coupling of perfluoroalkyl and persistent vinylogous ketyl radicals. We developed a chiral bifunctional NHC-squaramide catalyst that achieves high facial selectivity in a critical bond-forming event involving the coupling of a congested tertiary carbon radical and vinylogous ketyl radical. Chiral carboxylates bearing an all-carbon quaternary center at the β-position can be prepared in good yield and excellent enantiomeric excess. Results from density functional theory (DFT) calculations and nuclear Overhauser effect (NOE) experiments indicate that the N,N'-diaryl squaramide motif adopts an unusual syn-syn conformation, enabling hydrogen bonding interactions with the enolate oxygen, thereby rigidifying the overall conformation of the transition state.

Parallel Chirality Inductions in Möbius Zn(II) Hexaphyrin Transformation Networks.

Networked chemical transformations are key features of biological systems, in which complex multicomponent interactions enable the emergence of sophisticated functions. Being interested in chirality induction phenomena with dynamic Möbius π-systems, we have designed a pair of Möbius [28]hexaphyrin ligands in order to investigate mixtures rather than isolated molecules. Thus, a hexaphyrin bearing a chiral amino arm was first optimized and found to bind a ZnOAc moiety, triggering an impressive quasi-quantitative chirality induction over the Möbius π-system. Second, this amino-type hexaphyrin was mixed with a second hexaphyrin bearing a chiral carboxylate arm, affording at first ill-defined coordination assemblies in the presence of zinc. In contrast, a social self-sorting behavior occurred upon the addition of two exogenous achiral effectors (AcO- and BuNH2), leading to a well-defined 1:1 mixture of two Möbius complexes featuring a sole Möbius twist configuration (parallel chirality inductions). We next successfully achieved compartmentalized switching, i.e., a single-component transformation from such a complex mixture. The BuNH2 effector was selectively protected with Boc2O, owing to a lower reactivity of the arm's NH2 function intramolecularly bound to zinc, and subsequent addition of BuNH2 restored the initial mixture, retaining parallel chirality inductions (five cycles). By changing the nature and twist configuration of only one of the two complexes, at initial state or by switching, this approach enables a "two-channel" tuning of the chiroptical properties of the ensemble. Such multiple dynamic chirality inductions, controlled by selective metal-ligand recognition and chemical reactivity, set down the basis for Möbius-type stereoselective transformation networks with new functions.

Circularly Polarized Luminescence from Uranyl Improves Resolution of Electronic Transitions.

The first reported example of circularly polarized luminescence from a chiral, molecular uranyl (UO22+) complex in solution is presented. This uranyl chiroptical activity is enabled by complexation with ibuprofen, an enantiopure chiral carboxylate ligand. Salt metathesis between [UO2Cl2(thf)2]2 and the sodium ibuprofenate salts results in the formation of the anionic tris complexes; these complexes are found to be luminescent in solution, both under visible excitation, directly targeting the metal, and through sensitization by UV absorption and energy transfer from the ligand. Each enantiomer displays both circular dichroism and circularly polarized luminescence (CPL) with |gabs| ≤ 8.1 × 10-2 and |glum| ≤ 8.0 × 10-3 under UV excitation, comparable to chiral transition metal complexes or purely organic emitters. The strength of the CPL emission is found to be comparable following excitation of either the ligand or metal directly. Further, use of CPL allows for resolution of subcomponents of the emission spectrum not previously possible at room temperature using standard fluorescence techniques. Observation of CPL following direct uranyl excitation presents a new tool for probing speciation of uranyl complexes when chiral ligands are used, without the need for synthetic modification to incorporate a suitable chromophore, and could enable the design of improved ligands for uranyl extraction from wastewater.

Ni/Chiral Sodium Carboxylate Dual Catalyzed Asymmetric O-Propargylation.

A highly enantioselective O-propargylation catalyzed by combining a phosphine-nickel complex and an axially chiral sodium dicarboxylate has been developed. The transformation features mild reaction conditions, a broad substrate scope, and excellent functional group tolerance, offering an efficient approach to an array of enantioenriched O-propargyl hydroxylamines. Mechanistic studies support the presumed role of the chiral carboxylate as a counterion for nickel catalysis enabling the discovery of highly stereoselective transformations. The power of this reaction is illustrated by its application in the asymmetric total synthesis of potent firefly luciferase inhibitors and (S)-dihydroyashabushiketol.

Recognition of Chiral Carboxylates by Synthetic Receptors.

Recognition of anionic species plays a fundamental role in many essential chemical, biological, and environmental processes. Numerous monographs and review papers on molecular recognition of anions by synthetic receptors reflect the continuing and growing interest in this area of supramolecular chemistry. However, despite the enormous progress made over the last 20 years in the design of these molecules, the design of receptors for chiral anions is much less developed. Chiral recognition is one of the most subtle types of selectivity, and it requires very precise spatial organization of the receptor framework. At the same time, this phenomenon commonly occurs in many processes present in nature, often being their fundamental step. For these reasons, research directed toward understanding the chiral anion recognition phenomenon may lead to the identification of structural patterns that enable increasingly efficient receptor design. In this review, we present the recent progress made in the area of synthetic receptors for biologically relevant chiral carboxylates.

Rhodium-Catalyzed and Chiral Zinc Carboxylate-Assisted Allenylation of Benzamides via Kinetic Resolution.

Enantioenriched allenes are important building blocks. While they have been accessed by other coupling methodologies, enantioenriched allenes have been rarely obtained via C-H activation. In this work, kinetic resolution of tertiary propargyl alcohols as an allenylating reagent has been realized via rhodium(III)-catalyzed C-H allenylation of benzamides. The reaction proceeded efficiently under mild conditions, and both the allenylated products and the propargyl alcohols were obtained in high enantioselectivities with an s-factor of up to 139. The resolution results from bias of the two propargylic substituents and is assisted by a chiral zinc carboxylate additive.

A chiral spirobifluorene-based bis(salen) zinc(ii) receptor towards highly enantioselective binding of chiral carboxylates.

We have designed a new chiral receptor based on two salen zinc(ii) complex units connected with a spirobifluorene framework. The chiral receptor is proven to enantioselectively bind chiral carboxylate guests and the differences between the binding constants of enantiomeric guests were up to more than one order of magnitude.

Chiral Photoresponsive Liquid Crystalline Materials Derived from Cyanoazobenzene Central Core: Effect of UV Light Illumination on Mesomorphic Behavior

One of the most frequently utilized liquid crystalline (LC) materials is a rod-like (calamitic) compound 4-cyano-4′-pentylbiphenyl (5-CB). The main objective of this work is to enhance its functionality by introducing a photoresponsive diazenyl spacer in the aromatic core and replace the non-chiral pentyl chain with various chiral alkyl carboxylate units. The mesomorphic properties of the prepared materials have been studied using polarizing optical microscopy and differential scanning calorimetry. It has been found that materials with an extended aromatic system possess the liquid crystalline behavior. The studied LC materials have shown mesophases at lower temperatures than previously reported analogous substances. Furthermore, one of them exhibits a chiral orthogonal frustrated twist grain boundary smectic phase, which has not been previously observed for this structural type of materials. We also investigated photoresponse of the mesophases under illumination with UV-light (365 nm) using a polarizing optical microscope. A non-conventional photoresponse of the prepared materials in a crystalline phase is presented and discussed.

The Impact of Solvent and the Receptor Structure on Chiral Recognition Using Model Acyclic Bisamides Decorated with Glucosamine Pendant Arms.

We investigated the influence of various factors (including solvent mixtures) on chiral recognition of chiral carboxylates, using the titration method under 1H NMR control. We found that strong binding carboxylates (geometrical matching) is not enough for the satisfactory differentiation of enantiomers. Moreover, solvent mixture studies indicate a significant influence of environment on the formation of diastereomeric complexes and variations among them. Our findings offer insights into the complementarity of chiral recognition processes.

Functionalized Chiral Bambusurils: Synthesis and Host-Guest Interactions with Chiral Carboxylates.

Bambusurils are a class of macrocyclic anion receptors that exhibit notable anion recognition properties, able to bind various inorganic anions as well the carboxylates or sulfonates. Recently, we reported enantioselective recognition of chiral carboxylates using non-functionalized chiral bambusuril derivatives. Herein, we report the synthesis and host-guest properties of two new representatives of chiral bambusuril macrocycles bearing ester functional groups, differing by the substituents attached to their portals. Their supramolecular properties in terms of carboxylate binding were studied by means of NMR in DMSO-d6 . The reported bambusurils bind selected chiral carboxylates with enantioselectivity factors up to 3.1. The results indicated that the selectivity towards different carboxylates is governed by the steric constraint of the substituents surrounding bambusuril portals. No clear trend in the binding affinities and their enantioselectivities was found.

Molecular Recognition by Zn(II)-Capped Dynamic Foldamers.

Two α‐aminoisobutyric acid (Aib) foldamers bearing Zn(II)‐chelating N‐termini have been synthesized and compared with a reported Aib foldamer that has a bis(quinolinyl)/mono(pyridyl) cap (BQPA group). Replacement of the quinolinyl arms of the BQPA‐capped foldamer with pyridyl gave a BPPA‐capped foldamer, then further replacement of the linking pyridyl with a 1,2,3‐triazole gave a BPTA‐capped foldamer. Their ability to relay chiral information from carboxylate bound to Zn(II) at the N‐terminus to a glycinamide‐based NMR reporter of conformational preference at the C‐terminus was measured. The importance of the quinolinyl arms became readily apparent, as the foldamers with pyridyl arms were unable to report on the presence of chiral carboxylate in acetonitrile. Low solubility, X‐ray crystallography and 1H NMR spectroscopy suggested that interfoldamer interactions inhibited carboxylate binding. However changing solvent to methanol revealed that the end‐to‐end relay of chiral information could be observed for the Zn(II) complex of the BPTA‐capped foldamer at low temperature.

Induced Circular Dichroism of Achiral Cyclic Bisurea via Hydrogen Bonds with Chiral Carboxylates.

Chiral induction properties of achiral bisurea derivatives by binding tetrabutylammonium salts of N-acetylated chiral carboxylates (Ac-AlaO-, Ac-ValO-, Ac-LeuO-, and Ac-PheO-) was studied. Ultraviolet-visible titrations showed 1:1 complex formation between the bisureas and the carboxylates. The calculated association constants of cyclic bisurea (1a) were 5-10 times larger than those of the acyclic derivative (2), and 1a showed the highest binding affinity for Ac-LeuO-. While circular dichroism (CD) of both 1a and 2 was induced upon the addition of chiral carboxylates, the CD intensity of 1a was greater than that of 2. Especially, the intensity induced by chiral Ac-LeuO- was the greatest. 1H nuclear magnetic resonance titrations and density functional theory (DFT) calculations showed the cooperative hydrogen bonds of four urea N-Hs and the carboxylate group and the CH-π interactions between a naphthyl unit of 1a and the methyl moieties of Ac-LeuO-. Furthermore, DFT calculations suggested that the twisted anticlockwise conformation of 1a would be dominantly induced by Ac-d-LeuO-. The CD intensity changes of 1a showed a good linear relationship with the enantiomeric excess (ee) values of Ac-LeuO-; therefore, 1a could be utilized as a stereodynamic chiral probe for determining the ee of chiral anions.

Two chiral cadmium carboxylate framework isomers generated by spontaneous resolution: synthesis, structures and properties

Two three-dimensional (3-D) chiral coordination polymers, [Cd(NDC)(DMF)]n (1L and 1D: H2NDC = 1,4-naphthalenedicarboxylic acid and DMF = N,N′-dimethylformamide), have been synthesized by introducing the rigid achiral dicarboxylic acid ligand under solvo-thermal conditions, without chiral template or additives. Both chiral Cd-CPs were characterized by single crystal X-ray crystallography, and structural analysis indicates that 1L and 1D are enantiomers based on the zigzag [Cd(COO)2(DMF)]n rod secondary building units, featuring the left- or right-hand 21 Cd-O-C-O-Cd helix chains and left- or right-hand 41 screw [Cd(NDC)]n columns, respectively. The FT-IR, TGA, powder X-ray diffraction and solid-state luminescence of 1 have been investigated. It is intriguing that the evidence from the circular dichroism spectroscopies confirms enantiomeric excess in the whole spontaneous resolution crystallization.

Phenanthroline-based fluorescence sensors for Eu3+ ion and subsequent enantioselective discriminating of malate

ABSTRACTA pair of novel chiral fluorescent and colorimetric sensors L1 and D1 had been designed and synthesized, which were based on phenanthroline as the fluorophore and mandelohydrazide as the binding site. They showed selective recognition toward Eu3+ ion as ‘turn-off’ mode in DMSO-H2O solution (v/v = 1:5, 10 mM HEPES, pH = 7.4). The fluorescence discrimination towards chiral carboxylate anions had been studied for L1-Eu3+ and D1-Eu3+ complex and they showed good enantioselective recognition ability towards malate as ‘turn-on’ mode. The interaction of sensor L1, D1 with Eu3+ and L1-Eu3+, D1-Eu3+ towards malate caused different color changes in the naked eye.

Chiral Bambusurils for Enantioselective Recognition of Carboxylate Anion Guests.

Synthesis of the first enantiomerically pure chiral bambusurils is reported. The bambusurils were prepared on the gram scale without using any chromatography techniques. The bambusurils formed supramolecular complexes with all tested chiral carboxylates including amino acids and drug molecules with the enantioselectivity ranging from 1.1 to 3.2.

Dynamic Helicity Control of Oligo(salamo)-Based Metal Helicates

Much attention has recently focused on helical structures that can change their helicity in response to external stimuli. The requirements for the invertible helical structures are a dynamic feature and well-defined structures. In this context, helical metal complexes with a labile coordination sphere have a great advantage. There are several types of dynamic helicity controls, including the responsive helicity inversion. In this review article, dynamic helical structures based on oligo(salamo) metal complexes are described as one of the possible designs. The introduction of chiral carboxylate ions into Zn3La tetranuclear structures as an additive is effective to control the P/M ratio of the helix. The dynamic helicity inversion can be achieved by chemical modification, such as protonation/deprotonation or desilylation with fluoride ion. When (S)-2-hydroxypropyl groups are introduced into the oligo(salamo) ligand, the helicity of the resultant complexes is sensitively influenced by the metal ions. The replacement of the metal ions based on the affinity trend resulted in a sequential multistep helicity inversion. Chiral salen derivatives are also effective to bias the helicity; by incorporating the gauche/anti transformation of a 1,2-disubstituted ethylene unit, a fully predictable helicity inversion system was achieved, in which the helicity can be controlled by the molecular lengths of the diammonium guests.