Chiral Dicarboxylates Research Articles

Dearomative enantio- and diastereoselective difluorination of resorcinol derivatives

We herein report enantio- and diastereoselective fluorination of naphthoresorcinol and resorcinol derivatives for the first time using a dicarboxylate phase-transfer catalyst. Stereoselective oxidative transformation of resorcinol derivatives is considered to be difficult because of their high reactivity, multiple reaction sites, and multiple hydrogen bond interactions due to the presence of the two hydroxy groups. Even though resorcinol and its oxidized frameworks are widely found in bioactive natural compounds, dearomative asymmetric fluorination of resorcinol derivatives remains unexplored. We found that our chiral dicarboxylate phase-transfer catalyst could serve as an effective catalyst for the purpose. Interestingly, naphthoresorcinols and resorcinols were converted to difluorination products preferentially rather than monofluorinated products. It is noteworthy that asymmetric desymmetrization of symmetrically substituted resorcinols occurred with up to 95% ee and the reaction was tolerant of various functional groups.

Neutral Chiral Tetrakis-Iodo-Triazole Halogen-Bond Donor for Chiral Recognition and Enantioselective Catalysis.

Halogen bonding represents a powerful tool in the field of noncovalent interactions. However, applications in enantioselective recognition and catalysis remain almost nonexistent, due in part to the distinct features of halogen bonds, including long covalent and noncovalent bond distances and high directionality. Herein, this work presents a novel chiral tetrakis‐iodo‐triazole structure as a neutral halogen bond donor for both chiral anion‐recognition and enantioinduction in ion‐pair organocatalysis. NMR‐titration studies revealed significant differences in anion affinity between the halogen bonding receptor and its hydrogen bonding parent. Selective recognition of chiral dicarboxylates and asymmetric induction in a benchmark organocatalytic reaction were demonstrated using the halogen bond donor. Inversions in the absolute sense of chiral recognition, enantioselectivity, and chiroptical properties relative to the related hydrogen donor were observed. Computational modeling suggested that these effects were the result of distinct anion‐binding modes for the halogen‐ versus hydrogen‐bond donors.

Enabling Homochirality and Hydrothermal Stability in Zn4O-Based Porous Crystals.

The [Zn4O]6+ cluster is well-known to form the archetypal MOF-5 topology with dicarboxylate ligands. Here we report two new materials (CPM-300 and -301) that show dramatic alteration of topological and chemical behaviors of [Zn4O]6+ clusters. In CPM-300, [Zn4O]6+ untypically forms the MIL-88/MOF-235 type framework with a small pentane-ring-based chiral dicarboxylate. In contrast, in CPM-301, when mediated by [Zn9(btz)12]6+ clusters (btz = benzotriazolate), the MOF-5 topology is regenerated with the same chiral ligand, albeit with alternating [Zn4O]6+ and [Zn9(btz)12]6+ clusters. Importantly, both CPM-300 and CPM-301 are homochiral, hydrothermally stable in boiling water and alcohol, and thermally stable to 440 °C or higher. It is concluded that small methyl groups on the chiral ligand is sufficiently powerful to shield [Zn4O]6+ clusters from degradation by water, even at high temperatures. These results reveal a promising platform for the development of a new class of cluster-based homochiral and hydrothermally stable porous materials.

Synthesis of the homochiral metal–organic framework DUT-129 based on a chiral dicarboxylate linker with 6 stereocenters

A dicarboxylate linker with an exceptionally high density of stereogenic centers for the development of new chiral metal–organic frameworks (MOFs) was synthesized. A bicyclic functionality forms the backbone of the linker, creating a linear structural analogue of terephthalic acid. The linker includes two side chains bearing secondary amine functionalities, which could induce catalytic activity of the resulting MOF structures for nucleophilic organocatalysis. The new chiral linker was used to synthesize a zinc-based MOF structure, named DUT-129. Single crystal X-ray analysis identified the porous framework with a sodalite (sod) topology. The bulky side groups of the chiral linker limit the pore accessibility of DUT-129, which was proven by liquid phase adsorption experiments. The calculated pore limiting diameter of 5.2 A indicates pore accessibility exclusive for small molecules, such as linear and branched alkanes. Therefore, the new MOF DUT-129 is expected to show high size selectivity in adsorption and separation applications in combination with high enantiomeric discrimination.

Practical Synthesis of Axially Chiral Dicarboxylates via Pd-Catalyzed External-CO-Free Carbonylation.

We have developed a safe and practical synthetic method for preparing axially chiral diphenyl dicarboxylates using Pd-catalyzed external-CO-free carbonylation with phenyl formate as a CO surrogate. Optimized conditions consisted of axially chiral [1,1'-binaphthalene]-2,2'-diyl ditriflate and its congeners, each easily prepared from commercially available enantiomerically pure diols, Pd(OAc)2, 1,3-bis(diphenylphosphino)propane, ethyldiisopropylamine, and no solvent. To demonstrate the potential utility of these products, this method was conducted on gram-scale and the phenyl ester products were converted to other useful compounds, and both processes were carried out without difficulty.

Self-Assembly of Chiral Metallacycles and Metallacages from a Directionally Adaptable BINOL-Derived Donor.

We present the formation of a series of chiral metallacycles and metallacages by the use of a BINOL-derived dicarboxylate as a donor that is capable of affording a variety of coordination angles between its two Lewis basic sites. Two squares, two rhomboids, two tetragonal prisms, and one hexagonal prism were successfully formed when the chiral dicarboxylate donor self-assembled with one of four ditopic Pt(II) complexes, including two bimetallic 180° Pt-based acceptors, a 120° bimetallic Pt-based acceptor, and a 90° mononuclear Pt-based acceptor. Their structures were well characterized by (31)P{(1)H} NMR, ESI-MS, CD, and optical rotation analyses.

Application of optically active chiral bis(imidazolium) salts as potential receptors of chiral dicarboxylate salts of biological relevance.

A family of chiral bis(imidazolium) salts derived from natural amino acids has been synthesized by a simple synthetic approach and the corresponding bis(trifluoromethylsulfonyl)imide salts have been shown to be room temperature chiral ionic liquids (RTCILs). The structures and self-assembling properties of the resulting salts have been studied by (1)HNMR, ATR-FTIR, DSC, SEM and theoretical calculations. Moreover, these receptors have been applied to the enantiomeric recognition of dicarboxylic amino acids. The supramolecular complexes formed have been studied by (1)HNMR titration experiments, ATR-FTIR and DSC.

Chirality Sensing and Size Discrimination of Anions by Macrotricyclic Cyclen-Disodium Complexes

Two macrotricyclic ligands composed of two face-to-face octadentate metal chelates were synthesized. These cage-shaped disodium complexes had special recognition ability for various counter anions. Specific chiral dicarboxylates bound to the complexes within the cavity and exhibited chirality induction properties. For instance, N-Boc-Asp dianion strongly induced circular dichroism (CD) signals, but N-Boc-Glu dianion, which is one carbon longer, did not.

ChemInform Abstract: Enantioselective Formal Alkenylations of Imines Catalyzed by Axially Chiral Dicarboxylic Acid Using Vinylogous Aza‐Enamines.

AbstractCompounds (III) and (V) are obtained as mixtures of E‐ and Z‐isomers with the internal E‐isomer predominating except for (Vb).

Enantioselective Formal Alkenylations of Imines Catalyzed by Axially Chiral Dicarboxylic Acid Using Vinylogous Aza‐Enamines

Enantioselective Formal Alkenylations of Imines Catalyzed by Axially Chiral Dicarboxylic Acid Using Vinylogous Aza‐Enamines

Enantioselective Formal Alkenylations of Imines Catalyzed by Axially Chiral Dicarboxylic Acid Using Vinylogous Aza‐Enamines

In the zone: The use of vinylogous aza-enamaines (hydrazones) as a source of an alkenyl group has been achieved (see scheme). Unmasking of the aza-enamine moiety opens up a novel approach for the preparation of chiral allylic amines bearing an electron-withdrawing alkene moiety functionalized at the electron-deficient β position.

Enantioselective sensing of dicarboxylates. Influence of the stoichiometry of the complexes on the sensing mechanism

Two new cyclohexane-based thiourea chiral ligands have been synthesized in their enantiomerically pure forms. Both the ability of these ligands in the complexation of chiral dicarboxylates and their sensing properties have been studied. The influence of the stoichiometry of the formed complexes on the fluorescent properties of the systems has been established. The effect of additional substitution in the cyclohexyl moiety was considered by comparing the properties of the newly prepared ligands with those of similar compounds previously described.

Chiral cyclohexane based fluorescent chemosensors for enantiomeric discrimination of aspartate

Some new chiral cyclohexyl based fluorescent anion receptors have been synthesized and their absolute configuration has been determined by using circular dichroism (CD). Complexation experiments have been carried out with several dicarboxylates, and stoichiometries and complexation constants for the corresponding complexes have been determined. The chiral discrimination ability of these ligands for chiral dicarboxylates has been studied and the best results have been obtained with TMA aspartate.

A Simple Helical Macrocyclic Polyazapyridinophane as a Stereoselective Receptor of Biologically Important Dicarboxylates under Physiological Conditions

The interaction of a synthetic enantiopure azamacrocyclic receptor (L) with biologically important chiral dicarboxylates (A, 1-7) has been studied by means of potentiometric titrations in 0.15 M NaCl aqueous solution in a wide pH range. This macrocycle forms strong complexes of the type [HnLA](n-2) (with n = 0-5). As a general trend, the binding is much tighter at basic or neutral pH than in acidic medium. Interestingly, nonprotected excitatory amino acids (Asp and Glu) are strongly bound even at acidic pH. Regarding selectivity, the receptor showed stereoselective binding toward those substrates bearing an H-bonding donor at Calpha, being S-selective in most of the cases, except for glutamic acid. Thus, L displayed an excellent enantioselectivity for (S)-malate dianion (KS/KR = 11.50 at pH 10.0 and KS/KR = 6.86 at pH 7.0) and exhibited moderate enantiopreference for (S,S)-tartrate (KSS/KRR = 3.01 at pH 10 and KSS/KRR = 1.70 at pH 7.0). For this last anion, a very good diastereopreference was also observed (KSS/KRS = 8.46 at pH 10 and KSS/KRS = 4.99 at pH 7.0). On the contrary, L is smoothly R-selective toward (R)-Glu (KR/KS = 3.22 at pH 10 and KR/KS = 2.05 at pH 7.0) due to its longer and more flexible molecular structure. The stereoselectivity of the corresponding complexes decreased when decreasing pH values. For the hydroxy derivatives, mass spectrometry also reflected the trends observed by potentiometry and confirmed the receptor:dicarboxylate 1:1 stoichiometry of the supramolecular complexes. Additional experimental techniques were used to study the most stereoselective example. Solution studies by NMR suggested a good geometrical complementarity between the malate dianion and the receptor, which showed a predominant helical conformation in solution. Besides, self-diffusion rates (PGSE) of the diastereomeric complexes with malate also agree with binding data. Circular dichroism was also used in this case at different pH values, showing a very good correlation between the helical content of the receptor and the stereoselectivity of the molecular recognition process.

A highly enantioselective receptor for N-protected glutamate and anomalous solvent-dependent binding properties.

The development of enantioselective receptors continues to be a challenging endeavor for supramolecular chemists, and enantioselective recognition of biologically relevant molecules in competitive solvents is particularly demanding.[1] Although numerous receptors have been developed for dicarboxylic acids and dicarboxylates,[2] only a few enantioselective receptors for chiral dicarboxylic acids (in the neutral diprotonated form) have been described,[3] and very few examples of enantioselective receptors for chiral dicarboxylates have been reported.[4] We recently described an acyclic monothiourea receptor 1a, which bound a range of N-protected amino acid carboxylate salts with modest enantioselectivity.[5] Building on this work, we have now prepared macrocyclic receptor 2, which features two thiourea moieties flanked by carboxypyridines and separated by a chiral diamine. The receptor was designed to produce a chiral pocket for dicarboxylates by forming up to eight hydrogen-bonding interactions with the carboxylate oxygen atoms and intramolecular hydrogen bonding with the pyridine unit to help preorganize[6] the receptor (Scheme 1). Binding measurements, by NMR titration and isothermal

グルコースの分子骨格を足場に用いる不斉合成法の開発

Reaction of racemic biaryldicarboxylic dichloride with methyl 4, 6-O-benzylidene-α-D-glucopyranoside gave methyl 4, 6-O-benzylidene-2, 3-O- [(R) -biaryldicarbonyl] -α-D-glucopyranoside with perfect diastereoselection. This reaction provided a new method of optical resolution of axially- and planar chiral dicarboxylates. Using the methodology, several types of novel ferrocenyl sugars which showed anti-malaria parasite (P. falciparum) activity have been prepared. Ten types of chiral azacrown ethers were synthesized from α-D-glucose and their catalytic property for the asymmetric Michael addition has been investigated; enantioselectivity switching which is dependent on the azacrown ether catalysts has been achieved.

The first supramolecular assemblies comprised of dimetal units and chiral dicarboxylates

The first molecules containing metal–metal bonded Mo 2 4+ units linked by chiral dicarboxylates have been prepared and characterized by X-ray crystallography and 1H NMR spectroscopy; the compounds [Mo 2(DAniF) 3] 2(dicarboxylate), 1 for l-tartrate and 2 for d-aspartate (DAniF= N, N ′-di- p-anisylformamidinate) represent a first step toward the synthesis of more complex polygonal structures assembled from M 2 units and chiral linkers.

Optically Active Hexaazamacrocycles: Protonation Behavior and Chiral-Anion Recognition

The protonation features of two optically active 22-membered hexaazamacrocycles possessing one (L1) or two (L2) (R,R)-cyclohexane-1,2-diamine moieties have been studied by means of potentiometric 1H- and 13C-NMR techniques. This study allows the determination of the basicity constants and the stepwise protonation sites. The presence of the cyclohexane decreases the protonation ability, and this effect can be explained in terms of conformational and electrostatic factors. Binding of different chiral dicarboxylates has been studied by potentiometry. Macrocycle L2 presents higher anion-complexation equilibrium constants than L1. The stability of the diastereoisomeric complexes depends on the pH, and the structures of the macrocycles and anions. Receptor L1⋅6 H+ shows moderate D-selectivity towards tartrate anion, whereas L2⋅6 H+ exhibits a good preference for N-Ac-D-aspartate. Both protonated L1 and L2 form strong complexes with N-Ac-glutamate, and the stoichiometry of the complex depends on the degree of protonation and the absolute configuration of the anion. For this last anion, both azamacrocycles exhibit a clear D-preference.

Optically active dioxatetraazamacrocycles: chemoenzymatic syntheses and applications in chiral anion recognition

Two new C2 and D2 symmetrical dioxatetraaza 18-membered macrocycles [(R,R)-1 and (S,S,S,S)-2] are efficiently synthesized in enantiomerically pure forms by a chemoenzymatic method starting from (+/-)-trans-cyclohexane-1,2-diamine. The protonation constants and the binding constants with different chiral dicarboxylates are determined in aqueous solution by means of pH-metric titrations. The triprotonated form of (S,S,S,S)-2 shows moderate enantioselectivity with malate and tartrate anions (deltadeltaG=0.62 and 0.66 kcal mol(-1), respectively), being the strongest binding observed in both cases with the L enantiomer. Good enantiomeric discrimination is obtained with tetraprotonated (R,R)-1 and N-acetyl aspartate, the complex with the D-enantiomer being 0.92 kcalmol(-1) more stable than its diastereomeric counterpart. Despite the lack of enantioselectivity of tri- and tetraprotonated (R,R)-1 for the tartrate anion, a very good diastereopreference for meso-tartrate is found. All these experimental results allow us to propose a model for the host-guest structure based on coulombic interactions and hydrogen bonds.

ChemInform Abstract: Enantioselective Complexation of Chiral Dicarboxylic Acids in Clefts of Functionalized 9,9′‐Spirobifluorenes.

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