Achiral Acid Research Articles

Isolipoic acid-linked gold nanoparticles bearing the thomsen friedenreich tumor-associated carbohydrate antigen: Stability and in vitro studies.

We have previously prepared gold nanoparticles (AuNPs) bearing the Thomsen-Friedenreich antigen disaccharide (TFag), a pan-carcinoma, Tumor-Associated Carbohydrate Antigen (TACA), as tools for various assays and biological applications. Conjugation to AuNPs typically involves the use of thiols due to the affinity of sulfur for the gold surface of the nanoparticle. While a use of a single thiol-containing ligand bound to the gold surface is standard practice, several studies have shown that ligands bearing multiple thiols can enhance the strength of the conjugation in a nearly linear fashion. (R)-(+)-α-Lipoic acid (LA), a naturally occurring disulfide-containing organic acid that is used as a cofactor in many enzymatic reactions, has been used as a linker to conjugate various molecules to AuNPs through its branched di-thiol system to enhance nanoparticle stability. We sought to use a similar system to increase nanoparticle stability that was devoid of the chiral center in (R)-(+)-α-lipoic acid. Isolipoic acid, an isomer of LA, where the exocyclic pentanoic acid chain is shifted by one carbon on the dithiolane ring to produce an achiral acid, was thought to act similarly as LA without the risk of any contaminating (L)-(−) isomer. We synthesized AuNPs with ligands of both serine and threonine glycoamino acids bearing the TFag linked to isolipoic acid and examined their stability under various conditions. In addition, these particles were shown to bind to Galectin-3 and inhibit the interaction of Galectin-3 with a protein displaying copies of the TFag. These agents should prove useful in the design of potential antimetastatic therapeutics that would benefit from achiral linkers that are geometrically linear and achiral.

Enantiomer Separation of Nitriles and Epoxides by Crystallization with Chiral Organic Salts: Chirality Switching Modulated by Achiral Acids

Enantiomer Separation of Nitriles and Epoxides by Crystallization with Chiral Organic Salts: Chirality Switching Modulated by Achiral Acids

Role of Hydrogen Transfer and Ionic Bonding on RR, SS and RS Medetomidine Conglomerates/Acids Stability: A Theoretical Study

This study focuses on RR, SS and RS medetomidine (MM) and inclusion of several achiral acids to distinguish which acid can help conglomerate formation instead of crystallizating racemic mixtures by defining the low-lying energy of their structures. Favorable orientation of acids was determined in interaction with the MM enantiomers after optimization. The most noticeable interactions include hydrogen transfer from acids to nitrogen (N) atom of the MM enantiomers, which was confirmed through quantum theory of atom in molecule (QTAIM) and natural bond orbital (NBO) analysis. In addition, nature and source of change of these bonds were investigated by determination of significant donor-acceptor interactions. The results revealed for obtaining RR and SS conglomerates; oxalic acid solvent provides the optimum stability. Furthermore, application of propanoic acid solvent should be neglected since MM crystallization is nonspontaneous with this solvent. Therefore, oxalic acid is the acid of choice for preferential conglomerate formation.

Improved Synthesis and Impurity Identification of (R)-Lacosamide

An improved synthesis of Lacosamide 1 with high purity has been developed. Critical parameters of each step were identified as well as the impurities generated. Moreover, a creative method to improve chiral purity and stability of the key intermediate (R)-2-amino-N-benzyl-3-methoxypropionamide 10 by forming salt with an achiral acid (phosphoric acid) was discovered to ensure the chiral purity of (R)-Lacosamide. Phosphoric acid was further developed for the deprotection of the Boc group.

A Silica‐Supported Catalyst Containing 9‐Amino‐9‐deoxy‐9‐epi‐quinine and a Benzoic Acid Derivative for Stereoselective Batch and Flow Heterogeneous Reactions

A heterogeneous, silica‐based catalyst containing 9‐amino‐9‐deoxy‐epi‐quinine (or quinidine) and a derivative of benzoic acid was synthesized through radical thiol‐ene click reaction. The acid component allows the in situ activation of cinchona amino group, acting as a bifunctional catalyst. The heterogenized catalysts efficiently promoted the reaction of ketones with trans‐β‐nitrostyrene, with diastereo‐ and enantioselectivity comparable to those of the homogeneous counterparts (dr up to 90:10 and 90 % ee). In addition, the catalyst retained a constant activity for at least four cycles. Finally, the supported catalyst (9‐amino‐9‐deoxy‐epi‐quinine/achiral acid) was employed under continuous‐flow conditions. Two enantioselective Michael reactions were in sequence performed with the same homemade packed‐bed reactor. The addition of cyclohexanone to trans‐β‐nitrostyrene provided the evaluation of optimal residence time with high level of stereoselection (2 µL/min flow rate, 83 % ee). Furthermore, the flow reactor well performed in the preparation of warfarin (isolated yield 95 %, 78 % ee. in 16 h at room temperature). The dual (chiral amine/achiral acid) solid supported system, making an even easier work‐out, represents a valuable tool for green chemistry and is attractive for large scale applications.

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.

Protonated Bis-1,2,3-triazole as an Anion-Binding Chiral Brønsted Acid for Catalytic Asymmetric Friedel–Crafts Reaction of Indoles with Imines

Abstract The complex of chiral C2-symmetric bis-1,2,3-triazole and an achiral Brønsted acid is introduced as a new class of chiral acid catalysts. The catalytic activity and stereocontrolling ability of this chiral Brønsted acid can be tuned simply by changing the achiral acid. The synthetic relevance of this salient feature is demonstrated in the asymmetric Friedel–Crafts reaction of indoles with N-sulfonyl imines.

Enantioseparation of Sulfoxides and Nitriles by Inclusion Crystallization with Chiral Organic Salts Based on l‐Phenylalanine

Enantioselective inclusion of aromatic sulfoxides and nitriles was achieved in a host framework created by organic salts comprising achiral benzoic acids and a chiral primary amine (1a) derived from l‐phenylalanine. Tuning of the combined achiral acid component successfully changed the chiral recognition ability of the organic salts. The guest molecules were hydrogen‐bonded to form three‐component inclusion crystals, and the enantiomers of nitriles and sulfoxides were separated with high selectivity up to 92 and 98 % ee. As far as we know, this is the first example of the enantioseparation of non‐functionalized aromatic nitriles.

PH-dependent Co(II) assemblies from achiral 2-benzothiazolylthioacetic acid: crystal structures, symmetry breaking, and magnetic properties

Based on an achiral 2-benzothiazolylthioacetic acid (HL) ligand, three Co(II) coordination compounds, {[Co(L)2(H2O)3]·H2O}n (1), [Co(L)2(H2O)2]n (2), and [Co(L)2(H2O)4]·2H2O (3), were obtained under different pH environments. Compound 1 possessing an interesting chiral 1-D helical double chain was synthesized with pH of 5.0~6.5, and the chiral symmetry breaking has been probed by single-crystal X-ray diffraction and circular dichroism spectroscopy. Switching pH to 4.0~5.0 and 3.0~4.0 resulted in achiral 2 and 3, respectively. Compound 2 has a 1-D chain structure and 3 is mononuclear.

Conjugate-Base-Stabilized Brønsted Acids: Catalytic Enantioselective Pictet–Spengler Reactions with Unmodified Tryptamine

A conjugate-base-stabilized Brønsted acid facilitates catalytic enantioselective Pictet-Spengler reactions with unmodified tryptamine. The chiral carboxylic acid catalyst is readily assembled in just two steps and enables the formation of β-carbolines with up to 92% ee. Achiral acid additives or in situ Boc-protection facilitate catalyst turnover.

A Mechanistic Rationale for the 9-Amino(9-deoxy)epi Cinchona Alkaloids Catalyzed Asymmetric Reactions via Iminium Ion Activation of Enones

The 9-amino(9-deoxy)epi cinchona alkaloids have expanded the synthetic potential of asymmetric aminocatalysis, enabling the highly stereoselective functionalization of a variety of sterically hindered carbonyl compounds. However, there is a lack of basic understanding of the mechanisms of cinchona-based primary aminocatalysis. Herein, we describe how a combination of experimental and theoretical mechanistic studies has revealed the origin of the stereoselectivity of the Friedel-Crafts alkylation of indoles with α,β-unsaturated ketones catalyzed by 9-amino(9-deoxy)epi quinine. An essential role for the achiral acid cocatalyst is uncovered: upon condensation of the cinchona catalyst with the enone, the resulting covalent imine intermediate and the acid interact to build-up a well-structured ion-pair supramolecular catalytic assembly, which is stabilized by multiple attractive noncovalent interactions. All the components of the assembly cooperatively participate in the stereocontrolling event, with the anion of the achiral acid being the structural element responsible for the π-facial discrimination of the iminium ion intermediate.

Chiral anthracene fluorescence system using achiral 1-naphthylmethylamine

A chiral anthracene fluorescence system was developed from achiral 2-anthracenecarboxylic acid and 1-naphthylmethylamine. Although chiral functional organic materials are usually prepared using chiral molecules, in this system, a chiral supramolecular organic fluorophore, which exhibited fluorescence in the solid state, was prepared from achiral molecular components.

Enantioselectivity Switch Induced by an Achiral Acid

Enantioselectivity Switch Induced by an Achiral Acid

Dependence of solid-state optical properties on binding groups in biphenyl acid/amine supramolecular organic complexes

Chiral carboxylic acid/amine and sulfonic acid/amine supramolecular organic complexes composed of biphenyl units were successfully prepared using achiral biphenylcarboxylic acid (or biphenylsulfonic acid) derivatives and chiral 1-phenylethylamine as component molecules. The solid-state circular dichroism (CD) and fluorescent properties of the supramolecular complexes change significantly with the type and number of binding groups.

Cooperative Thiourea–Brønsted Acid Organocatalysis: Enantioselective Cyanosilylation of Aldehydes with TMSCN

We report a new thiourea-Brønsted acid cooperative catalytic system for the enantioselective cyanosilylation of aldehydes with yields up to 90% and enantioselectivities up to 88%. The addition of an achiral acid was found to be crucial for high asymmetric induction. Mechanistic investigations using a combination of NMR, ESI-MS, and density functional theory computations (including solvent corrections) at the M06/6-31G(d,p) level of theory suggest that the key catalytic species results from the cooperative interaction of bifunctional thioureas and an achiral acid that form well-defined chiral hydrogen-bonding environments.

Achiral and α-Amino Acid Derived Dicationic Imidazoliophanes

Achiral and chiral imidazoliophanes were prepared by N-alkylation of chiral imidazole derivatives featuring an α-amino acid motif and subsequent double quartemization of the imidazole N3-position of the corresponding precyclophanes. Eight new optically pure imidazoliophanes were synthesized in good yields, whereas the molecular structure of one achiral analogue was confirmed by X-ray analysis.

ChemInform Abstract: Investigations into the Enantioselective Protonation of Enolates Derived from 2-Methyl-1-tetralone Using a Chiral Diamine Ligand.

Abstract The synthesis of enantiomerically enriched (+)-( R )-2-methyl-1-tetralone 1 (up to 47% e.e.) was achieved by enantioselective protonation of an achiral lithium enolate 3 using a chiral diamine additive in the presence of acetic acid. We discuss the factors (like salt effects and chelation) that are responsible for this observed enantioselectivity and comment on the role of the achiral acid.

Synthesis of meso-tetraarylporphyrins possessing amino and carboxy groups and their peptides

meso-Tris(3,5-di-tert-butylphenyl)porphyrin (P- H ) is bonded with L-phenylalanine (H-Phe-OH) directly at the unsubstituted meso-position of the former and the p-position of phenyl group of the latter to afford chiral porphyrin-amino acid conjugate H-Phe(p-P)-OH. The N-(9-fluorenyl)-methyloxycarbonyl compound, Fmoc-Phe(p-P)-OH, was synthesized without any loss of enantiomeric purity (based on chiral HPLC analysis) from commercially available L-tyrosine and was useful for preparation of the peptides in both liquid and solid phases. Other meso-tetraarylporphyrins possessing multi-amino acid moieties are reported, as well as achiral porphyrin-amino acids readily prepared and their dipeptidyl porphyrin dyads.

Asymmetric Cooperative Catalysis of Strong Brønsted Acid–Promoted Reactions Using Chiral Ureas

Cationic organic intermediates participate in a wide variety of useful synthetic transformations, but their high reactivity can render selectivity in competing pathways difficult to control. Here, we describe a strategy for inducing enantioselectivity in reactions of protio-iminium ions, wherein a chiral catalyst interacts with the highly reactive intermediate through a network of noncovalent interactions. This interaction leads to an attenuation of the reactivity of the iminium ion and allows high enantioselectivity in cycloadditions with electron-rich alkenes (the Povarov reaction). A detailed experimental and computational analysis of this catalyst system has revealed the precise nature of the catalyst-substrate interactions and the likely basis for enantioinduction.

Crystal structures of crown ethers containing an alkyl diarylphosphinate or a diarylphosphinic acid unit

This paper describes the structures of pseudo-18-crown-6 compounds (2, R,R-4 and 5) in the crystals together with theoretical calculations of the electronic circular dichroism (ECD) spectra. The achiral macrocyclic phosphinic acid 5 forms hydrogen-bonded dimers in the crystal. The O1–O2 distance (2.489 Ǻ) indicates strong H-bondings. The conformations of the macrorings of the achiral phosphinate 2 and the monomers of the achiral phosphinic acid 5 are chiral. A comparison of the torsion angles of the achiral methyl phosphinate 2 and the monomeric units of achiral 5 indicates a similar geometry. The torsion angles of the chiral methyl phosphinate (R,R)-4 differ more significantly from those in achiral methyl phosphinate 2. A negative 1Bb exciton couplet was observed in the ECD spectrum of monomeric (R,R)-6 in MeOH and H2O as in the spectra of (R,R)-4 in all solvents. To support the idea that (R,R)-4 has basically the same conformation in the crystal and in solution, the ECD spectrum of (R,R)-4 was calculated using the geometry of the molecule in the crystal. The calculated ECD spectrum shows a reasonable agreement with the ECD spectra obtained in solution. This shows that the steric structure observed in the crystal is predominant in solution as well.