Camphanic Acid Research Articles

Organocatalytic hydrogen bond donor/Lewis base (HBD/LB) synthesis and chiroptical properties of thiabridged [5]helicenes.

Thiabridged [5]helicenes are obtained from thioaryl-N-phthalimido benzo[a]phenothiazines using a hydrogen bond donor/Lewis base organocatalytic approach. Resolution of [5]helicenes using either (1S)-(-)-camphanic acid as a chiral auxiliary or CSP-HPLC is reported. Thiabridged [5]helicenes show an exceptional configurational stability with racemization energy barriers higher than 40 kcal mol-1. Electronic circular dichroism and TD-DFT calculations permit the assignment of the absolute configuration, demonstrating that the sign of optical rotation is not easily related to the M or P structure. Separated enantiomers show circularly polarized luminescence with high dissymmetry ratio.

Synthesis and properties of (+)-ketopinic and (-)-camphanic acids esters bearing a nitrogen-containing heterocycle

A three-stage method was proposed for the synthesis of (1 S )-(+)-camphor-10-sulfonic acid, (+)-ketopinic and (-)-camphanic acids esters containing a saturated nitrogen-containing heterocycle. It was found that (1 S )-(+)camphor-10-sulfonic acid esters undergo destruction with elimination of the sulfonic acid group in substitution reactions involving nitrogen-containing heterocycles. Esters of (+)-ketopinic and (-)-camphanic acids were formed during the proposed synthetic route, but undergo transesterification under column chromatography conditions. Quantum chemical calculations showed that the destruction of the ester bond in the case of (+)-ketopinic and (-)-camphanic acids requires less energy than the breaking of a similar bond in (-)-borneol esters. It was revealed that the internal bond strength index (IBSI) for the alkyl C-O bond in (-)-borneol esters is higher than in (+)-ketopinic and (-)-camphanic acid esters. Antiviral properties against the H1N1 influenza virus were studied for derivatives of (+)-ketopinic and (-)-camphanic acids.

Synthesis and Properties of (+)-Ketopinic and (–)-Camphanic Acids Esters Bearing a Nitrogen-Containing Heterocycle

A three-stage method was proposed for the synthesis of (1S)-(+)-camphor-10-sulfonic acid, (+)-ketopinic and (–)-camphanic acids esters containing a saturated nitrogen-containing heterocycle. It was found that (1S)-(+)-camphor-10-sulfonic acid esters undergo destruction with elimination of the sulfonic acid group in substitution reactions involving nitrogen-containing heterocycles. Esters of (+)-ketopinic and (–)-camphanic acids were formed during the proposed synthetic route, but undergo transesterification under column chromatography conditions. Quantum chemical calculations showed that the destruction of the ester bond in the case of (+)-ketopinic and (–)-camphanic acids requires less energy than the breaking of a similar bond in (–)-borneol esters. It was revealed that the internal bond strength index (IBSI) for the alkyl C–O bond in (–)-borneol esters is higher than in (+)-ketopinic and (–)-camphanic acid esters. Antiviral properties against the H1N1 influenza virus were studied for derivatives of (+)-ketopinic and (–)-camphanic acids.

Design, Synthesis, and Biological Evaluation of Novel Camphor-Based Hydrazide and Sulfonamide Derivatives as Laccase Inhibitors against Plant Pathogenic Fungi/Oomycetes.

To discover novel natural product-based fungicidal agrochemicals, 41 novel camphanic acid hydrazide and camphor sulfonamide derivatives were designed, synthesized, and tested for their antifungal profile against four plant pathogenic fungi and three oomycetes. As a result, some derivatives presented pronounced inhibitory activities toward Botryosphaeria dothidea, Fusarium graminearum, Phytophthora capsici, and Phytophthora nicotianae. Especially, compound 4b demonstrated the most potent anti-B. dothidea activity (EC50 = 1.28 mg/L), much stronger than positive control chlorthalonil. The in vivo assay showed that 4b displayed significant protective and curative effects on apple fruits infected by B. dothidea. The primary antifungal mechanism study revealed that 4b could obviously enhance the cell membrane permeability, destroy the mycelial surface morphology and the cell ultrastructure, and reduce the ergosterol and exopolysaccharide contents of B. dothidea. Further, 4b showed potent laccase inhibitory activity in vitro with an IC50 value of 11.3 μM, superior to positive control cysteine. The molecular docking study revealed that 4b could dock well into the active site of laccase by forming multiple interactions with the key residues in the pocket. The acute oral toxicity test in rats presented that 4b had slight toxicity with an LD50 value of 849.1 mg/kg bw (95% confidence limit: 403.9-1785.3 mg/kg bw). This research identified that the camphanic acid hydrazide derivatives could be promising leads for the development of novel laccase-targeting fungicides.

Chiral probe for mass spectrometric identification and quantitation of levodropropizine and its enantiomer, dextrodropropizine.

Acyl chlorides react rapidly with hydroxyl and amino groups in the absence of catalysts and therefore hold great promise for chiral mass spectrometry. Herein, a tandem mass spectrometry method based on derivatization with (-)-camphanic acid chloride as a simple chiral probe was developed for the highly sensitive detection and quantitation of levodropropizine and its enantiomer, namely, dextrodropropizine. The diastereomeric derivatization products were quantified based on the relative abundances of their fragment ions produced upon collision-induced dissociation in positive-ion mode. The reactive site was elucidated using nuclear magnetic resonance spectroscopy and two-dimensional total correlation spectroscopy, and the reaction mechanism was proved by stoichiometry studies. The degree of isomer recognition was investigated at different collision energies and determined as Rchiral ≈1.5. Thus, this study gives the way to the mass spectrometric identification and quantitation of levodropropizine and its enantiomer, and the developed method represents a new and practical technique for rapid and sensitive determination and quality control of enantiomers of chiral drugs.

Resolution of a Configurationally Stable Hetero[4]helicene.

We have developed an efficient chemical resolution of racemic hydroxy substituted dithia-aza[4]helicenes (DTA[4]H) 1(OH) using enantiopure acids as resolving agents. The better diastereomeric separation was achieved on esters prepared with (1S)-(−)-camphanic acid. Subsequent simple manipulations produced highly optically pure (≥ 99% enantiomeric excess) (P) and (M)-1(OH) in good yields. The role of the position where the chiral auxiliary is inserted (cape- vs. bay-zone) and the structure of the enantiopure acid used on successful resolution are discussed.

Molecular dynamics simulation of typical molecular ferroelectrics based on polarized crystal charge model

Molecular ferroelectrics are a promising class of ferro-electrics, with environmental friendliness, flexibility and low cost. In this work, a set of characteristic molecular ferroelectrics are simulated by molecular dynamics (MD) with polarized crystal charge (PCC). From the simulated results, their ferroelectric switching mechanisms are elucidated, with their ferroelectric hysteresis loops. The PCC charge model, recently developed by our group, containing the quantum electric polarization effect, is suitable in nature for studying molecular ferroelectrics. The simulated systems include the typical molecular ionic ferroelectrics, di-isopropyl-ammonium halide (DIPAX, X=C (Cl), B (Br), and I), as well as a pair of newly validated organic molecular ferroelectrics, salicylideneaniline and (-)-camphanic acid. In total, there are five systems under investigation. Results demonstrate that the PCC MD method is efficient and reliable. It not only elucidates the ferroelectric switching mechanism of the studied molecular ferroelectrics, but also extends the application range of the PCC MD. In conclusion, PCC MD provides an efficient protocol for extensive computer simulations of molecular ferroelectrics, with reliable ferroelectric properties and associated mechanisms, and would promote further exploration of novel molecular ferroelectrics.

An organic plastic ferroelectric with high Curie point.

Plastic ferroelectrics, featuring large entropy changes in phase transitions, hold great potential application for solid-state refrigeration due to the electrocaloric effect. Although conventional ceramic ferroelectrics (e.g., BaTiO3 and KNbO3) have been widely investigated in the fields of electrocaloric material and catalysis, organic plastic ferroelectrics with a high Curie point (Tc) are rarely reported but are of great importance for the sake of environmental protection. Here, we reported an organic plastic ferroelectric, (−)-camphanic acid, which crystallizes in the P21 space group, chiral polar 2 (C2) point group, at room temperature. It undergoes plastic paraelectric-to-ferroelectric phase transition with the Aizu notation of 23F2 and high Tc of 414 K, showing large entropy gain (ΔSt = 48.2 J K−1 mol−1). More importantly, the rectangular polarization–electric field (P–E) hysteresis loop was recorded on the thin film samples with a large saturated polarization (Ps) of 5.2 μC cm−2. The plastic phase transition is responsible for its multiaxial ferroelectric feature. This work highlights the discovery of organic multiaxial ferroelectrics driven by the motive of combining chirality and plastic phase transition, which will extensively promote the practical application of such unique functional materials.

2‐(1S)‐Camphanoyloxy‐2′‐phosphanylbiphenyl Ligands – Synthesis, Structure, and Preliminary Tests in Transition‐Metal Catalysis

Diastereoisomer separation of the (1S)‐camphanic acid 2‐isopropylphenylphosphanyl‐phenyl ester 1 exemplifies the potential of (1S)‐camphanoyl chloride for enantiomer separation of hydroxyl‐functional asymmetric phosphanes. Esterification of lithium 2′‐phosphanylbiphenyl‐2‐olates, generated from the respective 2‐OH or 2‐OSiMe3 precursors 2aOH and 2b–fSi, furnished the 2‐(1S)‐camphanoyloxy‐biphenylphosphanes 3a–c as 1:1 mixtures of diastereomers with low barriers for interconversion by rotation around the C–C axis (ΔG# = 70–73 kJ mol–1 for 3a and 3c by 31P VT NMR spectroscopy). The P‐asymmetric compounds 3d–f form 1:1 mixtures of stereoisomers. There is a tendency to cocrystallization of two preferred diastereoisomers, as shown by the crystal structure analyses of 3dD and 3fD, and in solution, there is a tendency toward partial isomerization to the sterically less‐favored atropisomers. The [RhCl(cod)(3dD)] complex 4dD, however, seems stable in solution. Excess 2dLi reacted with (1S)‐camphanoyl chloride preferentially to form the (SP,Rax,1S) isomer, which was separated by crystallization as enantiopure 3dE, characterized by single‐crystal XRD. Preliminary screening tests of this ligand in Rh‐catalyzed asymmetric hydrogenations of N‐(1‐phenylvinyl)acetamide allowed high conversion and up to 59 % ee. Hydrosilylation of acetophenone proceeded with 78 % conversion and 48 % ee; Suzuki–Miyaura couplings of 1‐bromo‐2‐naphthol with PhB(OH)2, in the presence of 3b/[Pd(OAc)2], gave yields up to 98 %.

Camphanic acid chloride: a powerful derivatization reagent for stereoisomeric separation and its DMPK applications.

Camphanic acid chloride has proven to be an efficient chiral derivatization reagent for determination of stereoisomers. The utility of chemical derivatization of various stereoisomers containing hydroxy functional groups with camphanic acid chloride in the presence or absence of a base is highlighted. This procedure is shown to be relatively simple, fast and a cost-effective method of separating racemic drugs and stereoisomeric metabolites in biological matrices. Camphanic derivatives contain two additional chirogenic centers, which are found to enhance stereoisomeric separation on both traditional and chiral stationary phases. Four methodologies described herein for separation of multiple stereoisomers in biological samples confirm camphanic acid chloride to be a powerful chiral reagent for stereoisomeric resolution for drug metabolism and PK applications.

Three coordination polymers constructed from bis(imidazol-l-yl-methyl)benzene: syntheses, structures, and third-order nonlinear optical properties

Three coordination polymers, {[Ni(H2O)2(bib)2]-(H2BTA)·2H2O} n (1), {[Co2(bib)2(BTA)]·H2O} n (2), and {[Co2(bib)2(CA)2]·H2O} n (3), (H4BTA = biphenyl-3,3′,4,4′-tetracarboxylic acid; bib = 1, 2-bis(imidazol-l-yl-methyl)benzene; H2CA = camphanic acid), have been synthesized under hydrothermal conditions. In complex 1, bib serves a bridging ligand to link two Ni(II) atoms into an infinite joint-like chain. In 2, binuclear units are connected by BTA and bib ligands to form 2-D sheets. In 3, each Ni(II) atom is coordinated with two bib ligands to give a 22-membered ring, which is further linked by CA ligands to form a ladder-like chain. The third-order nonlinear optical (NLO) properties of the complexes were determined by Z-scan technique in DMSO solution. All three complexes exhibit strong third-order NLO absorption with absorptive coefficients β(MKS) 1.44 × 10−10 m W−1 for 1, 1.68 × 10−10 m W−1 for 2, and −6.31 × 10−10 m W−1 for 3, respectively, of which compound 3 shows saturable absorption. The third-order NLO susceptibilities |χ (3)| were calculated as 0.32 × 10−10 for 1, 0.37 × 10−10 for 2, and 1.39 × 10−10 esu for 3, while the hyperpolarizabilities γ′ are 9.95 × 10−29 for 1, 5.85 × 10−29 for 2 and 4.64 × 10−28 esu for 3, respectively.

Preparation of (3R, 3′R)-astaxanthin monoester and (3R, 3′R)-astaxanthin from Antarctic krill (Euphausia superba Dana)

A special method is described for the preparation of (3R, 3′R)-astaxanthin monoester (AM) and (3R, 3′R)-astaxanthin from Antarctic krill (Euphausia superba Dana). Purified AM was obtained on a large scale from crude extract extracted from Antarctic krill in 38.14 % yield by silica gel column chromatography. After the AM was saponified with methanolic KOH (0.10 mol L−1) and separated by high-performance thin-layer chromatography, pure astaxanthin was obtained. There was only one optical (3R, 3′R)-isomer of the esterification of astaxanthin with (-)-camphanic acid chloride detected by high-performance liquid chromatography compared with astaxanthin standard. It was further proved that the AM consists of only one optical (3R, 3′R)-isomer. Twelve types of fatty acids in the AM from Antarctic krill were found by gas chromatography–mass spectrometer. Eicosapentaenoic and docosahexaenoic acids are the major fatty acids. It is the first time to prepare (3R, 3′R)-AM and (3R, 3′R)-astaxanthin from Antarctic krill. The purified (3R, 3′R)-AM and (3R, 3′R)-astaxanthin can be used as a standard for further related study.

Practical Synthesis of PGI2 Agonist: Resolution–Inversion–Recycle Approach of Its Chiral Intermediate

Practical synthesis of ((2R)-5-benzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methanol ((R)-7b), a key chiral intermediate for the synthesis of the novel PGI2 agonist, (R)-[6-[(diphenylcarbamoyloxy)methyl]-6-hydroxy-5,6,7,8-tetrahydronaphthalen-1-yloxy]acetic acid (1), was achieved via optical resolution by diastereoselective crystallization of ester derivative 18 of racemic (5-benzyloxy-2-hydroxy-1,2,3,4-tetrahydronaphth-2-yl)methanol (7b) with (1S,4R)-(−)-camphanic acid ((−)-CpOH) followed by saponification. Starting from commercially available 5-hydroxy-1-tetralone (2), this process features recycling of the undesired enantiomer (S)-7b via inversion of the C2 hydroxyl group by acid-catalyzed hydrolysis of its epoxide derivative (S)-11. Performing this resolution–inversion–recycle approach provided a 44% overall yield of (R)-7b (>99% ee) from racemic 7b. The enantiopure (R)-7b synthesized by this approach was then used to prepare 1. This robust, reproducible, and scalable synthesis of 1 was successfu...

ChemInform Abstract: Preparation of Enantiomerically Pure Pyrazolines by an Enantioconvergent Process.

Derivatization of insecticidally active rac-pyrazoline 2 with (1S)-(−)-camphanic acid chloride led to the separable diastereomers 3a and 3b. Regioselective cleavage to the enantiomerically pure pyrazolines 2a and 2b was achieved under mild conditions. Diastereomer 3b was transformed into diastereomer 3a by crystallization under equilibrating conditions making the overall process enantioconvergent.

ChemInform Abstract: Enantiodifferentiation of Odour Perception of α-Ambrinols.

Abstract Racemic α-ambrinol has been resolved by fractional crystallization of the diastereomeric mixture of its 1S(−) camphanic acid esters and subsequent reduction of the chemically pure diastereoisomers with lithium aluminium hydride.

Synthesis oftertiaryamidomethyl derivatives of 2-isobornyl-4-methylphenol

Derivatives containing tertiary amidomethyl groups were prepared by reaction of a secondary aminomethyl derivative of 2-isobornyl-4-methylphenol with succinic and phthalic anhydrides and (1S)-camphanic acid chloride.

Total Asymmetric Synthesis of Glycomimetics and Polypropionates of Biological Interest

Using readily available chiral auxiliaries such as (+)- and (?)-camphanic acid, (R,R)- and (S,S)-tartaric acid derivatives (e.g. RADO(R)-COCl, SADO(R)-COCl) efficient diastereoselective syntheses of rare sugars and glycomimetics have been developed. They engage the 'naked sugar' (enantiomerically pure 7-oxanorbornene) methodologies in which the chiral auxiliaries are recovered at an early stage of the multistep syntheses. A new reaction cascade starting with the hetero-Diels-Alder addition of sulfur dioxide to 1-(1-phenylethoxy)-1,3-dienes derived from inexpensive (+)- and (?)-1-phenylethanol allows the one-pot, four-component synthesis of polyfunctional sulfones, sulfonamides and sulfonic esters containing up to three stereogenic centers. The method ensures a high molecular and stereochemical diversity. The reaction cascade can also produce polyketide and polypropionate fragments in one-pot operations. The latter contain up to three contiguous stereogenic centers and do not have to be modified (deprotection, activation) before using them as nucleophilic partners in diastereoselective cross-aldol reactions, thus permitting the quick access to complicated polypropionate antibiotics such as Baconipyrones, Ryfamicyn S and Apoptolidines.

Novel strategy for the synthesis of chiral pseudo- ortho-substituted hydroxy[2.2]paracyclophane-based ligands from the resolved 4-bromo-12-hydroxy[2.2]paracyclophane as a parent compound

A simple and efficient resolution of racemic 4-bromo-12-hydroxy[2.2]paracyclophane into its enantiomers via diastereomeric esters with (1 S)-(−)-camphanic acid was carried out. New synthetic routes to enantiomerically pure 4,12-dihydroxy- and 4-hydroxy[2.2]paracyclophanes starting from the enantiomers of an intermediate 4-bromo-12-hydroxy[2.2]paracyclophane are proposed.

A new enantiopure unsaturated dicarboxylate as a 4-connected unit in a flexible homochiral PtS-type framework

Metal cation mediated chiral ligand transformation of (S)-camphanic acid leads to a new enantiopure unsaturated dicarboxylate that links tetrahedral Zn(2+) sites into 3-D homochiral 4-connected PtS-type framework structures, Zn(tced) (1, H(2)tced=1,2,2-trimethyl-3-cyclopentene-1,3-dicarboxylic acid) and Zn(4)(tced)(4)(4,4'-bipy) (2, 4,4'-bipy=4,4'-bipyridine).

Ruthenium-Catalyzed Asymmetric Electrophilic Fluorination of 1,3-Dicarbonyl Compounds

Upon activation with (Et3O)PF6 (2 equiv), the ruthenium(II) complex [RuCl2(PNNP)] (1; PNNP is (1S,2S)-N,N‘-bis(o-(diphenylphosphino)benzylidene)cyclohexane-1,2-diamine) catalyzes the electrophilic fluorination of 1,3-dicarbonyl compounds by N-fluorobenzenesulfonimide (NFSI). Oxygen donors, in particular Et2O as cosolvent, increase the activity of the catalyst and, in some cases, the enantioselectivity. The absolute configuration of 2-tert-butoxycarbonyl-2-fluorocyclopentanone (5a), which is obtained with up to 93% ee in catalysis, was determined to be R by derivatization to (1S)-(−)-camphanic acid (1R,2R)-2-tert-butoxycarbonyl-2-fluoro-cyclopentyl ester (7) and X-ray analysis. A model for enantioselection is proposed on the basis of the known structures of the dicationic complex [Ru(4a)(PNNP)]2+ (2a; 4a is 2-tert-butoxycarbonylcyclopentanone), which is formed under catalysis conditions, and of its monocationic enolato analogue (3a). The stoichiometric reactions of 2a and 3a with NFSI in pure CH2Cl2 and in the presence of substrate, product, or Et2O show that proton-transfer processes promoted by oxygen donors are pivotal in catalysis.