Mosher's Acid Research Articles

Isolation and characterization of synthesis intermediates and side products in hexahydrocannabiphorol

AbstractAfter the Swiss ban of hexahydrocannabinol (HHC) in March 2023, other semisynthetic dibenzopyran cannabinoids emerged on the Swiss gray market. Hexahydrocannabiphorol (HHCP) was the most prominent of them due to its potent cannabimimetic effects, as anecdotal reports from recreational users suggest. In October 2023, a class wide ban of dibenzopyran cannabinoids was introduced in Switzerland to prevent new similar substances from entering the drug market. Various vendors in online shops claim that HHCP is made from CBD, even though they possess different alkyl chain lengths. An HHCP sample was analyzed by gas chromatography coupled to mass spectrometry (GC‐MS), showing that a mixture of molecules with the same or a similar molecular mass as HHCP was present. Six different substances could be isolated from this sample using column chromatography. Four phenols ((9R)‐HHCP, iso‐HHCP, cis‐HHCP, and abn‐HHCP) and two ketones (possible intermediates to (9R)‐HHCP and abn‐HHCP) were identified by various nuclear magnetic resonance spectroscopy (NMR) techniques. (9S)‐HHCP was obtained in an impure fraction. In addition, a fraction was obtained that showed characteristic molecular and fragment ions consistent with bisalkylated products from the synthesis of similar compounds. The presence of abnormal cannabinoids (abn‐HHCP) and bisalkylated cannabinoids is a confirmation that this sample was produced purely synthetically as initially suspected, as these compounds have not been reported in Cannabis. Chiral derivatization of the phenols with Mosher acid chlorides showed that only iso‐HHCP was present as a scalemic mixture, indicating a good stereocontrol of this synthetic procedure.

Enantioselective high-performance liquid chromatographycombined with spectroscopic methods and theoretical calculations: A valid strategy to determine the absolute configuration of eugenol derivatives.

The absolute configuration of three chiral eugenol derivatives was assigned by a multi-step methodology based on enantioselective HPLC combined with spectroscopic and theoretical calculations. Milligram amounts of enantiopure forms used for stereochemical characterization were isolated by HPLC on the immobilized amylose-based chiral stationary phase Chiralpak IG using normal phase elution conditions. The absolute configuration was indirectly determined for one of the three compounds by 1H NMR via methoxy-α-trifluoromethyl-α-phenylacetic acid derivatization (Mosher's acid). Comparison of the experimental and predicted electronic circular dichroism spectra confirmed the stereochemical assignment by Mosher's method and extended the absolute configuration assignment to two other chiral compounds.

Differentiation and identification of enantiomers by nuclear magnetic resonance spectroscopy with support of quantum mechanical computations.

We report nuclear magnetic resonance studies of two chiral building blocks of solifenacin, phenyltetrahydroisoquinoline and quinuclidinol, in which chiral solvating agents, Mosher's acid, and Pirkle's alcohol were used for spectral discrimination between enantiomers of solifenacin constituents. Based on the constraints following from measurements of the nuclear Overhauser effect, structures of phenyltetrahydroisoquinoline and Pirkle's alcohol solvates were found. Next, shifts of nuclear magnetic resonance signals of phenyltetrahydroisoquinoline due to the application of Pirkle's alcohol were computed using density functional theory methods. The computed carbon-13 shifts reproduce those determined experimentally, allowing us to attribute the absolute configuration to phenyltetrahydroisoquinoline enantiomers without the need for the use of empirical rules.

Chiral 2-phenyl-3-hydroxypropyl esters as PKC-alpha modulators: HPLC enantioseparation, NMR absolute configuration assignment, and molecular docking studies.

Protein kinase C (PKC) isoforms play a pivotal role in the regulation of numerous cellular functions, making them extensively studied and highly attractive drug targets. In our previous work, we identified in racemate 1-2, based on the 2-benzyl-3-hydroxypropyl ester scaffold, two new potent and promising PKCα and PKCδ ligands, targeting the C1 domain of these two kinases. Herein, we report the resolution of the racemates by enantioselective semi-preparative HPLC. The attribution of the absolute configuration (AC) of homochirals 1 was performed by NMR, via methoxy-α-trifluoromethyl-α-phenylacetic acid derivatization (MTPA or Mosher's acid). Moreover, the match between the experimental and predicted electronic circular dichroism (ECD) spectra confirmed the assigned AC. These results proved that Mosher's esters can be properly exploited for the determination of the AC also for chiral primary alcohols. Lastly, homochiral 1 and 2 were assessed for binding affinity and functional activity against PKCα. No significative differences in the Ki of the enantiopure compounds was observed, thus suggesting that chirality does not seem to play a significant role in targeting PKC C1 domain. These results are in accordance with the molecular docking studies performed using a new homology model for the human PKCαC1B domain.

Complexation in situ of 1-methylpiperidine, 1,2-dimethylpyrrolidin, and 1,2-dimethylpiperidine with rhodium(II) tetracarboxylates: Nuclear magnetic resonance spectroscopy, chiral recognition, and density functional theory studies.

Complexation in situ of 1-methylpiperidine, racemic 1,2-dimethylpyrrolidin, and racemic 1,2-dimethylpiperidine with rhodium(II) tetracarboxylates in chloroform was studied by 1 H and 13 C nuclear magnetic resonance (NMR) spectroscopy and density functional theory (DFT) methods. As substrates, three dirhodium(II) compounds were applied, tetraacetate, tetrakistrifluoroacetate, and a derivative of optically pure Mosher's acid. Due to conformational flexibility, free and complexed ligands can adopt potentially various conformations. The NMR titration experiments revealed the subsequent formation of 1:1 and 1:2 complexes, depending on the molar ratio of substrate to ligand. Conformations of free and complexed ligands were examined by the comparison of experimental and DFT gauge-independent atomic orbital (GIAO) calculated chemical shifts and by the analysis of the internal energy of the compounds. For some ligand and substrate combinations, a mixture of complexes differing in ligand conformations was formed. Complexes of Mosher's acid derivative of rhodium(II) with racemic 1,2-dimethylpyrrolidin and 1,2-dimethylpiperidine exhibited NMR chiral recognition phenomenon, manifested by splitting of signals in 13 C NMR and 1 H,13 C HSQC spectra.

Crystallographic and spectroscopic characterization of racemic Mosher's Acid.

The title compound, C10H9F3O3, represents the structure of racemic Mosher's Acid (systematic name: 3,3,3-tri-fluoro-2-meth-oxy-2-phenyl-propanoic acid), a carb-oxy-lic acid that when resolved can be employed as a chiral derivatizing agent. The compound contains a carb-oxy-lic acid group, a meth-oxy group and a tri-fluoro-methyl substituent on an asymmetric benzylic carbon atom. The two independent mol-ecules in the asymmetric unit form a non-centrosymmetric homochiral dimer via inter-molecularly hydrogen-bonded head-to-tail dimers with graph-set notation R 2 2(8) and donor-acceptor hydrogen-bonding distances of 2.6616 (13) and 2.6801 (13) Å.

Synthesis and applications of carbohydrate based chiral ionic liquids as chiral recognition agents and organocatalysts

Chiral ionic liquids (CILs) have shown a wide range of applications in variety of domains in chemistry. Because of this, synthesis and applications of CILs have always been areas of interest for research in the last 20 years. Present work describes, the synthesis of six carbohydrate based chiral ionic liquids (CCILs) by following simple procedures and their applications. Structures of the CCILs were confirmed through various analytical techniques like NMR spectroscopy (1H, 13C, 11B, 31P, 19F), EI-MS, and polarimetry. Designed CCILs were tested as chiral recognising agents using sodium salt of Mosher's acid as model substrate through 19F NMR spectroscopy. Further, CCILs were used as organocatalyst in the enantioselective reduction of aromatic prochiral ketones to achieve corresponding chiral secondary alcohols.

Axially Chiral Trifluoromethylbenzimidazolylbenzoic Acid: A Chiral Derivatizing Agent for α-Chiral Primary Amines and Secondary Alcohols To Determine the Absolute Configuration.

Racemic 2-(2-trifluoromethyl)-1H-benzo[d]imidazol-1-yl)benzoic acid (TBBA) was synthesized in three steps from 1-fluoro-2-nitrobenzene. Target (P)- and (M)-TBBA atropisomers were stable with a racemization barrier above 30 kcal/mol. As a chiral derivatizing agent, TBBA showed much higher differences in chemical shifts (ΔδPM) than the conventional Mosher's acid.

Complexation of selenomethionine and its derivatives with some dimeric rhodium(II) tetracarboxylates: 1H and 13C nuclear magnetic resonance spectroscopy

Complexation of three dimeric rhodium(II) tetracarboxylates: tetraacetylate, tetrakistrifluoroacetylate and optically pure rhodium(II) Mosher's acid derivative, with selenomethionine, the methyl ester of selenomethionine and its N-phthaloyl and N-formyl derivatives, have been investigated by 1H and 13C nuclear magnetic resonance (NMR) spectroscopy. Studies were performed using the NMR titration procedure, in D2O or CDCl3 solution depending on the solubility of substrates and ligands. In the presence of rhodium substrate, ligands formed subsequently 1:1 and 1:2 complexes, consisting of one dirhodium moiety and one or two ligand molecules, respectively. The parameter complexation shift Δδ, defined as a difference between the chemical shift of a nucleus in a complex and corresponding chemical shift in the free ligand, varied from −0.3 to +0.6 ppm (1H) and from −3.3 to +5.4 ppm (13C). Complexation shift pattern indicated the complexation via the selenium atom. For chiral substrate and racemic ligands, diastereomeric dispersions Δν(1H) reached the value up to 140 Hz.

Thiamine Diphosphate Dependent KdcA‐Catalysed Formyl Elongation of Aldehydes

AbstractThe formose reaction, one of the oldest name reactions in organic chemistry, uses formaldehyde as a C1 unit resulting in different monosaccharides and sugar‐like compounds. Nucleophilic formyl elongation is an attractive option to obtain 1,2‐functionalised building blocks for organic synthesis and pharmaceuticals; however, it has rarely been applied in asymmetric catalysis. The thiamine diphosphate dependent enzyme 2‐keto acid decarboxylase (KdcA) from Lactococcus lactis is able to transfer formyl units to aliphatic and aromatic aldehydes, both in an electrophilic and in a nucleophilic way. We have established the formation of unstable chiral 2‐hydroxy aldehydes by subsequent modifications (chemical derivatisation with 2,4‐dinitrophenylhydrazine, (R)‐Mosher's acid chloride) or by enzymatic trapping (oxidation and reductive amination).

Synthesis and characterization of chiral ionic liquids based on quinine, l-proline and l-valine for enantiomeric recognition

The separation of enantiomers remains a major challenge for the pharmaceutical industry. In this work, eight chiral ionic liquids (CILs) directly derived from the ‘chiral pool’ were synthesized and characterized in order to develop enantioselective systems, for the chiral resolution. According to their chiral cations, three different groups of CILs were prepared, namely based on quinine, l-proline and l-valine, and their enantiomeric recognition ability evaluated. For that purpose the diastereomeric interactions between a racemic mixture of Mosher's acid sodium salt and each CIL were studied using 19F NMR spectroscopy. The remarkable chemical shift dispersion induced by some CILs demonstrates their potential application in chiral resolution. Additionally the optical rotation, thermophysical properties and ecotoxicity against the marine bacteria Aliivibrio fischeri of these chiral ionic liquids were addressed.

Two new glutarimide antibiotics from Streptomyces sp. HS-NF-780.

Two new glutarimide antibiotics, 9-methylstreptimidone 2-α-D-glucopyranoside (1), and hydroxyiso-9-methylstreptimidone (2), along with a known compound, 9-methylstreptimidone (3), have been isolated from the broth of Streptomyces sp. HS-NF-780. Their structures were determined on the basis of spectroscopic analysis, including 1D and 2D NMR techniques as well as ESI-MS and comparison with data from the literature. By modified Mosher's method and acid hydrolysis, the absolute configurations of compounds 1 and 2 were established. Compounds 1 and 2 exhibited moderate cytotoxic activity.

Ternary complexes consisting of chiral rhodium(II) tetracarboxylates, derivatives of amino acid and triphenylphosphine: The 31P NMR study

Thirteen ternary complexes of optically pure chiral rhodium(II) tetracarboxylates with chiral ligands and triphenylphosphine, formed in situ in CDCl3 solution, were examined by nuclear magnetic resonance spectroscopy. As chiral substrates, two dimeric rhodium tetracarboxylates, derivatives of Mosher's acid and N-phthaloyl tert-leucine, were used. Two chiral amines, N,N-dimethyl-butan-2-amine and N,N-dimethyl-1-phenylethanamine, and some derivatives of methionine, selenomethionine, S-methylcysteine, leucine and proline, were applied as chiral ligands, both optically pure and racemic. An achiral component of ternary complexes, triphenylphosphine, acted as a 31P NMR probe.Ternary complexes containing optically pure ligands revealed 31P NMR signals (233 K, CDCl3) within the range from ca. −24 to −36 ppm, appearing as doublets due to 1J(103Rh,31P) coupling constants of ca. 90 Hz. For some combinations of racemic ligand and dirhodium tetracarboxylate, the signals appeared as quartets due to the presence of two diastereomeric ternary complexes. In these cases, diastereomeric dispersion varied from 14 to 88 Hz. Such signal splitting was not observed for the corresponding complexes of optically pure ligands. The presence of bulky substituents in rhodium tetracarboxylate increases diastereomeric dispersion. These results suggested that ternary complexes in question, in combination with 31P NMR technique, can serve, in some cases, as a means of the optical purity analysis of chiral ligands.

1H NMR spectroscopy in the presence of Mosher acid to rapidly determine the enantiomeric composition of amino acid benzyl esters, chirons susceptible to easy racemization.

Amino acid benzyl esters are very useful chiral synthons, whose enantiomeric purity needs to be carefully verified because of their susceptibility to easy racemization. Alternative to chiral HPLC, 1H NMR in the presence of a chiral solvating agent (CSA) can allow a more rapid and acceptably accurate determination of the enantiomeric composition, if explicit spectral non-equivalence of one or more protons of the analyte enantiomers is found. Here, we have studied the enantiodiscrimination of 13 amino acid benzyl esters by 1H NMR in the presence of (R)-Mosher acid and in different solvents proving that, for 5 of them (Ala, Pro, Glu, Met, Ser), efficient enantiodifferentiation can be achieved and ≤ 98% enatiomeric excesses accurately determined. Generally, as expectable, the best enantiodifferentiated proton was that on the amino acid stereogenic α-carbon, but also the spectral non-equivalence of methyl protons and of protons on the β-carbon and on the benzylic carbon could be exploited to distinguish the two enantiomers and to quantify the minor one. Structural feature favoring the amino acid ester enantiodiscrimination by the CSA seems to be low sterical hindrance at the amino acid β-carbon.

Synthesis, characterization and applications of some novel DMAP-based chiral ionic liquids

A convenient and efficient procedure for the synthesis of some novel chiral ionic liquids (CILs) from 4-dimethylaminopyridinium cation has been reported. The synthesis of the CILs includes the treatment of optically active (−)-menthyl ester with 4-dimethylaminopyridine and after that the anion exchange reactions in water. The synthesized ionic salts have been characterized using polarimetry, NMR spectroscopy and EI-MS techniques. The synthesized CIL was used in chiral recognition of Mosher's acid by 1H NMR and also to induce the enantioselectivity in the sodium borohydride reduction of some prochiral ketones.

Supramolecular interaction of non-racemic benzimidazolium based ion pairs with chiral substrates.

A series of novel benzimidazolium-based non-racemic ionic liquids (ILs) was synthesized from low-cost chiral terpenoid alcohols and fully characterized by the use of a wide variety of techniques, such as DSC, ESI-MS, ATR FT-IR, polarimetry as well as 1H and 13C NMR spectroscopy. The ILs were investigated as chiral shift agents for the chiral recognition of racemic mixtures of Mosher's acid potassium salt by 19F NMR spectroscopy, leading to high splitting values of the CF3 signal. Supramolecular interactions between salt and H-C2 of chiral benzimidazolium cation are responsible for the chiral recognition, as was demonstrated by experimental evidences. Indeed, the enantiomeric excess value of enantioenriched substrates depends mainly on the strength of the contact ion pairs.

A remarkable chiral recognition of racemic Mosher's acid salt by naturally derived chiral ionic liquids using 19F NMR spectroscopy

A new class of d-xylose derived imidazolium-based chiral ionic liquids were designed and synthesized via simple tuning approaches.

Chiral Recognition Studies of α-(Nonafluoro-tert-butoxy)carboxylic Acids by NMR Spectroscopy.

Three chiral α-(nonafluoro-tert-butoxy)carboxylic acids (R)-1, (RS)-2, (R)-3 were synthesized to examine their application as chiral solvating agents with amines. As a model compound, first (S)- and/or (RS)-α-phenylethylamine was used, and their diastereomeric salts were investigated by (1)H and (19)F NMR and ECD spectroscopy. The NMR spectroscopic studies were carried out at room temperature using the slightly polar CDCl3 and apolar C6D6 as solvents in 5 mM and 54 mM concentrations. The difference of the chemical shifts (Δδ) in the diastereomeric complexes is comparable with other, well-known chiral derivatizing and solvating agents (e.g., Mosher's acid, Pirkle's alcohol). Diastereomeric salts of racemic acids (RS)-1 and (RS)-2 with biologically active amines (1R,2S)-ephedrine and (S)-dapoxetine were also investigated by (19)F NMR spectroscopy.

Application of the modified 2-methoxy-2-(1-naphthyl)propionic (MαNP) acid method to steroidal alcohols and the most efficient HPLC separation found in diastereomeric MαNP esters

A resolution method using enantiopure 2-methoxy-2-(1-naphthyl)propionic (MαNP) acid 1 has been successfully applied to various racemic alcohols for preparing enantiopure (100% ee) alcohols and also for determining their absolute configurations by 1H NMR diamagnetic anisotropy and/or by X-ray crystallography. A modification of this method was applied to steroidal alcohols, where racemic MαNP acid (±)-1 was used instead of chiral acid 1. Although the absolute configurations of steroidal compounds are established, the studies reported herein are important to check whether the MαNP acid method is applicable to steroidal alcohols or not. In fact, in the case of steroidal 3α-alcohols, the observed 1H NMR diamagnetic anisotropy Δδ values were large enough to determine their absolute configurations, while it was reported that the Mosher acid method was not applicable to 5-cholesten-3α-ol 5, because the small Δδ values were irregularly distributed. The MαNP acid has thus a wider applicability than the Mosher acid. Furthermore, we have found that 5-cholestene-3β,4β-diol 8 was very useful for enantioresolving racemic MαNP acid (±)-1; diol 8 was esterified with acid (±)-1 giving diastereomeric mono-esters 15a/15b, which were efficiently separated by HPLC on silica gel: α=2.57, Rs=6.74. This separation factor, α, is the largest ever found in diastereomeric MαNP esters. From the separated esters 15a and 15b, enantiopure MαNP acids (R)-(−)-1 and (S)-(+)-1 could be easily recovered. Our results are thus useful for the efficient preparation of enantiopure MαNP acids.

Synthesis and applications of secondary amine derivatives of (+)-dehydroabietylamine in chiral molecular recognition.

(+)-Dehydroabietylamine (1a), the novel derivatives (2a-6a) and their NTf2 salts (1b-6b) were tested as chiral NMR solvating agents for the resolution of enantiomers of the model compound Mosher's acid (7) and its n-Bu4N salt (8). Best enantiomeric discrimination of 7 was obtained using bisdehydroabietylamino-N(1),N(2)-ethane-1,2-diamine (6a), and of 8 using N-(dehydroabietyl)-2-(dehydroabietylamino)ethanaminium bis((trifluoromethyl)-sulfonyl)-amide (6b). For the maximal resolution of enantiomers of 8, 1.0 eq. of 6b were needed. However, 0.5 eq. of 6a sufficed for the maximal resolution of enantiomers of 7. Enantiomeric excess studies were successfully conducted using 6a and 6b. The capability of 6a and 6b to recognize the enantiomers of various α-substituted carboxylic acids and their n-Bu4N salts were examined. Best resolutions were observed for aliphatic and aromatic carboxylic acids bearing an electronegative α-substituent. Now the ee studies on such non-aromatic carboxylic acids are also feasible.