Menthyl Esters Research Articles

The powerful potential of amino acid menthyl esters for anti-inflammatory and anti-obesity therapies.

Our newly developed menthyl esters of valine and isoleucine exhibit anti-inflammatory properties beyond those of the well-known menthol in macrophages stimulated by lipopolysaccharide (LPS) and in a mouse model of colitis induced by sodium dextran sulfate. Unlike menthol, which acts primarily through the cold-sensitive TRPM8 channel, these menthyl esters displayed unique mechanisms that operate independently of this receptor. They readily penetrated target cells and efficiently suppressed LPS-stimulated tumour necrosis factor-alpha (Tnf) expression mediated by liver X receptor (LXR), a key nuclear receptor that regulates intracellular cholesterol and lipid balance. The menthyl esters showed affinity for LXR and enhanced the transcriptional activity through their non-competitive and potentially synergistic agonistic effect. This effect can be attributed to the crucial involvement of SCD1, an enzyme regulated by LXR, which is central to lipid metabolism and plays a key role in the anti-inflammatory response. In addition, we discovered that the menthyl esters showed remarkable efficacy in suppressing adipogenesis in 3T3-L1 adipocytes at the mitotic clonal expansion stage in an LXR-independent manner as well as in mice subjected to diet-induced obesity. These multiple capabilities of our compounds establish them as formidable allies in the fight against inflammation and obesity, paving the way for a range of potential therapeutic applications.

Development of Menthyl Esters of Valine for Pest Control in Tomato and Lettuce Crops.

Menthyl ester of valine (MV) has been developed as a plant defense potentiator to induce pest resistance in crops. In this study, we attempted to establish MV hydrochloride (MV-HCl) in lettuce and tomato crops. When MV-HCl solutions were used to treat soil or leaves of potted tomato and lettuce plants, 1 µM MV-HCl solution applied to potted plant soil was most effective in increasing the transcript level of defense genes such as pathogenesis-related 1 (PR1). As a result, leaf damage caused by Spodoptera litura and oviposition by Tetranychus urticae were significantly reduced. In addition, MV-HCl-treated plants showed an increased ability to attract Phytoseiulus persimilis, a predatory mite of T. urticae, when they were attacked by T. urticae. Overall, our findings showed that MV-HCl is likely to be effective in promoting not only direct defense by activating defense genes, but also indirect defense mediated by herbivore-induced plant volatiles. Moreover, based on the results of the sustainability of PR1 expression in tomato plants treated with MV-HCl every 3 days, field trials were conducted and showed a 70% reduction in natural leaf damage. Our results suggest a practical approach to promoting organic tomato and lettuce production using this new plant defense potentiator.

Acremonamide, a Cyclic Pentadepsipeptide with Wound-Healing Properties Isolated from a Marine-Derived Fungus of the Genus Acremonium.

Acremonamide (1) was isolated from a marine-derived fungus belonging to the genus Acremonium. The chemical structure of 1 was established using MS, UV, and NMR spectroscopic data analyses. Acremonamide (1) was found to contain N-Me-Phe, N-Me-Ala, Val, Phe, and 2-hydroxyisovaleric acid. The absolute configurations of the four aforementioned amino acids were determined through acid hydrolysis followed by the advanced Marfey's method, whereas the absolute configuration of 2-hydroxyisovaleric acid was determined through GC-MS analysis after formation of the O-pentafluoropropionylated derivative of the (-)-menthyl ester of 2-hydroxyisovaleric acid. As an intrinsic biological activity, acremonamide (1) did not exert cytotoxicity to cancer and noncancer cells and increased the migration and invasion. Based on these activities, the wound healing properties of acremonamide (1) were confirmed in vitro and in vivo.

An amino acid ester of menthol elicits defense responses in plants.

Valine menthyl ester (ment-Val) acts as a plant defense potentiator for several crop species including soybean. Terpenoids, including menthol, exhibit potent abilities as plant defense potentiators in agriculture and horticulture. In the current study, we developed new terpene derivatives that consisted of menthol and various amino acids and that were expected to act as powerful plant defense potentiators. We used 6 amino acids possessing low-reactive sidechains to synthesize an array of amino acid ester of menthol (ment-aa) compounds. Transcript levels of two defense genes (pathogenesis-related protein 1 [PR1] and trypsin inhibitor [TI]) were evaluated in leaves of soybean plants 24h after application of aquatic solution of menthol or menthol-aa, and revealed that the valine menthyl ester (ment-Val) alone elevated the transcript level of defense genes, and it did so only at the low dose of 1 µM, not at higher or lower doses tested. Moreover, it appeared that histone acetylation was involved in this effect. Application of ment-Val enabled soybean plants to sustain the increased transcript levels in their leaves for up to 3 days. Moreover, when ment-Val was additionally applied at day 4, at which time the transcript level had declined to the basal level, the transcript level was re-elevated, indicating the possibility that ment-Val could be repeatedly used to sustain pest control. Ment-Val was found to be chemically stable and effective for defense of several crop species. Collectively, these data show that terpenoid conjugates are useful for pest control instead of or in addition to pesticides.

Asymmetric synthesis of 2,4,5- substituted prolines through 1,3-dipolar addition reaction of N-arylidene menthyl esters of α-aminoacid with methyl acrylate

Proline and its derivatives constitute the important organic entities as organocatalyst, ACE inhibitors, bioactive molecules/intermediates to bioactive molecules as well as components of various natural products e . g . Kainic acid, (-)-domoic acid, etc . Due to its wide range of utility extensive studies have been made for the synthesis of 2, 3, 4 or 5 substituted prolines. One pot synthesis of 2,4,5-substituted prolines through 1,3-dipolar addition of various amino acids with homochiral acrylate has also been carried out successfully. Herein we wish to report the 1,3-dipolar addition of Schiff bases, where chiral auxiliary has been introduced in the Schiff bases and 1,3dipolar addition with methyl acrylate leading to the synthesis of 2(S),4(S),5(R)-substituted prolines has been achieved successfully.

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.

FeCl3·6H2O catalyzed diastereoselective synthesis of (L)-menthyl 4-oxo-2-arylpiperidine-3-carboxylates

An efficient diastereoselective synthesis of substituted piperidines is accomplished by using catalytic amount of FeCl3·6H2O via intramolecular aza-Michael addition of carbamate on alkylidene β-keto (L)-menthyl esters in a very short time.

Enantioseparation and optical rotation of flavor-relevant 4-alkyl-branched fatty acids

Short chain 4-alkyl-branched fatty acids are character impact compounds of the flavor of sheep and goat milk and meat. Due to their methyl or ethyl branches these volatile fatty acids are chiral, and both enantiomers are characterized by different aroma intensities. Recently, it was found that 4-methyloctanoic acid (4-Me-8:0), 4-ethyloctanoic acid (4-Et-8:0), and 4-methylnonanoic acid (4-Me-9:0) are enantiopure in goat and sheep samples, if present. Here we generated enantiopure or enantioenriched standards from racemates by means of (R)-selective esterification with lipase B and verified that 4-Me-8:0, 4-Et-8:0 and 4-Me-9:0 were (R)-enantiopure in these tissues. Determination of the optical rotation and [α]D value was carried out to show that (R)-4-Et-8:0 is dextrorotary and to verify the literature values of (R)-4-methyl-branched fatty acids. The elution order of free acids and the methyl and ethyl esters of 4-Me-8:0, 4-Et-8:0, 4-Me-9:0 and 4-methylhexanoic acid (4-Me-6:0) enantiomers was investigated on different chiral columns as well as the (−)-menthyl ester by indirect enantiomer separation on an ionic liquid phase. Different chiral recognition processes were suggested for free acid and esters of 4-Me-8:0 and 4-Me-9:0 on the one hand (decisive: 4-alkyl branch) compared to 4-Me-6:0 on the other hand (decisive: branch on antepenultimate carbon).

Total Synthesis of (–)-Herbaric Acid through Organocatalyzed Asymmetric Halolactonization of Acrylate-Type Benzoic Acids

The total synthesis of (–)-herbaric acid has been achieved through the stereoselective synthesis of 3-substituted isobenzofuranones with a new organocatalytic route. When combined with a catalytic amount of benzoic acid, quinidine thiocarbamate based bifunctional catalysts have demonstrated their efficiency for the diastereoselective halolactonization reaction of acrylate-type benzoic acids bearing a chiral alkoxycarbonyl group on the carbon–carbon double bond. High diastereomeric excesses were obtained thanks to a positive match effect between the (+)-menthyl ester group and the chiral organocatalyst.

Straightforward and Highly Stereoselective Synthesis of 3,3,4‐Trifluoropyrrolidines Involving 1,3‐Dipolar Cycloaddition with 2,3,3‐Trifluoroacrylate

The reactions of benzyl 2,3,3‐trifluoroacrylate with azomethine ylides, generated by the treatment of imino esters with lithium diisopropylamide, took place smoothly to give the corresponding 1,3‐dipolar cycloadducts, fluorine‐containing pyrrolidines, in good yields and with high diastereoselectivities (>95:<5). When the fluorinated acrylate bore a chiral auxiliary as a substituent, for instance (l)‐(–)‐menthyl ester, the 1,3‐dipolar cycloaddition reaction was found to give the corresponding fluorinated pyrrolidine derivatives in not only a diastereoselective but also an enantioselective manner.

Influence of chirality on the cyclohexene-fused C60 fullerene derivatives as an accepter partner in a photovoltaic cell

Organic photovoltaic devices (OPVs) using chiral cyclohexene-fused [C60]-fullerene derivatives that have (l)-menthyl ester moiety have been prepared and their properties evaluated as acceptor molecules with P3HT polymer: racemic cyclohexene-fused [C60] fullenene, (RS)-(1R,2S,5R)-2a showed higher PCE (2.81%) than that of standard [C60]-PCBM (2.64%) under the same analysis conditions. On the contrary, devices using chiral (R)-(1R,2S,5R)-2a and (S)-(1R,2S,5R)-2a, showed PCE as 1.08% and 1.10%, respectively. The main origin of the differences in PCE was found to be their poor JSC values. The results indicate that the aggregation state might influence the interaction state with P3HT and impact the results of the OPV properties, JSC values in particular.

Relationship between chromatographic resolution and amide structure of chiral 2-hydroxy acids as O-(-)-menthoxycarbonylated diastereomeric derivatives for enantiomeric separation on achiral gas chromatography.

The relationship between chromatographic resolution and amide structure of chiral 2-hydroxy acids as O-(-)-menthoxycarbonylated diastereomeric derivatives on achiral gas chromatography was investigated to elucidate the best diastereomeric conformation for enantiomeric separation of chiral 2-hydroxy acids. Thirteen chiral 2-hydroxy acids were converted into nine different diastereomeric O-(-)-menthoxycarbonylated amide derivatives using the primary, secondary and cyclic amines to achieve complete enantiomeric separation through an achiral column. Each enantiomeric pair of 2-hydroxy acids as O-(-)-menthoxycarbonylated tert-butylamide derivatives was resolved on both the DB-5 and DB-17 columns with resolution factors ranging from 1.7 to 4.8 and 1.7 to 3.4, respectively. The results revealed that the structure of the amide moiety is shown to significantly affect chromatographic resolution. In addition, O-(-)-menthoxycarbonylated tert-butylamide derivatives were shown to be the best diastereomeric conformations for enantiomeric separation of 2-hydroxy acids. When comparing with our previous O-trifluoroacetylated(-)-menthyl ester derivatization method, the present results suggested that size differences between groups attached to the chiral center and conformational rigidity can have stronger effects on resolution than the distance between chiral centers. The elution of R- and S-stereoisomers was affected by the class of amine; i.e., primary, secondary, or cyclic, regardless of the substituents on the amine group, the structure of the 2-hydroxy acid, and the polarity of the column.

Thermal behavior of two synthesized flavor precursors of pyrazine esters

To develop thermal stable flavor of pyrazines, the two new flavor precursors of 3,6-dimethyl-2,5-pyrazinedicarboxylic acid leaf alcohol ester (DPALE) and 3,6-dimethyl-2,5-pyrazinedicarboxylic acid menthyl ester (DPAME) were synthesized by KMnO4 oxidation, acylating chlorination, and esterification reaction. TG, DSC and Py-GC/MS were conducted to investigate the thermal decomposition process and the pyrolysis products of DPALE and DPAME. TG–DTG curves showed that T p of DPALE and DPAME with the largest mass loss rate were 304.9 and 319.9 °C, respectively. The T peak of DPALE and DPAME measured by DSC were 307.1 and 327.7 °C, respectively. The pyrolysis products were qualitatively and semiquantitatively analyzed by Py-GC/MS technology at 300, 600, and 900 °C. The results indicated that 600 °C was better than the other two temperatures to release specific aromas of leaf alcohol, 2-methylpyrazine, 2,5-dimethylpyrazine, menthol, and 3-p-menthene. Finally, the thermal behavior and the thermal decomposition mechanism of the flavor precursors of DPALE and DPAME were discussed. The study on the thermal behavior and pyrolysis products of these two flavor precursors of pyrazine esters would have them applied in food stuffs and tobacco to provide specific flavor of leaf alcohol, menthol, and alkylpyrazines.

Cloning and Characterization of an Enantioselective l-Menthyl Benzoate Hydrolase from Acinetobacter sp. ECU2040.

A new esterase gene abmbh, encoding a benzoate hydrolase which can enantioselectively hydrolyze l-menthyl benzoate to l-menthol, was recently identified from the genomic library of a soil isolate Acinetobacter sp. ECU2040. The abmbh gene contains a 1080-bp open reading frame encoding a protein of 360 amino acids with a calculated molecular mass of 40.7kDa. The corresponding enzyme AbMBH was functionally expressed in Escherichia coli BL21 (DE3), purified, and characterized. The AbMBH displayed the maximum activity towards p-nitrophenyl butyrate at 50°C, and an optimum pH of 8.5. A K M of 2.6mM and a k cat of 0.26s(-1) were observed towards dl-menthyl benzoate. The AbMBH exhibited a moderate enantioselectivity (E = 27.5) towards dl-menthyl benzoate. It can also catalyze the enantioselective hydrolysis of a variety of racemic menthyl esters, including dl-menthyl acetate, dl-menthyl chloroacetate, and dl-menthyl butyrate.

Copper and zinc complexes of kojic acid and related ligands

M(II) (M = Cu, Zn) complexes of kojic acid (1, 2) have been synthesised, but characterisation was hampered by their lack of solubility. Related metal derivatives (5, 6) of benzyl-protected comenic acid (4), an oxidised variant of kojic acid, have been prepared, and the structures of 5·H2O·3DMSO (5a) and 6·2H2O (6a) were determined. The menthyl ester of O-benzyl comenic acid (7) has been prepared, but complete de-protection proved difficult. 3-Hydroxy-6-menthoxyacetyloxymethyl-4-pyrone (9) was prepared along with its M(II) derivatives (10, 11), though both were of low solubility; 10 forms soluble 1:1 adducts with pyridine (12) and 2,2′-bipyridine (13). Menthyl-3-oxo-butanoate (14) has been prepared along with its copper complex (15), whose structure has been determined. Included in the report are the structures of 4·DMSO (4a), 4·MeOH (4b), 4·THF (4c) and 9.

Structural revision and absolute configuration of lateritin

‘Lateritin’ (1), a morpholine-2,5-dione (depsipeptide), was reinvestigated for its structure and absolute configuration. On the basis of thorough 1D and 2D NMR and mass spectrometrical analyses, the structure of 1 was revised to be identical with beauvericin (8) and confirmed that beauvericin (8) is the trimeric lactone of ‘lateritin’ (1). The absolute configuration was determined by acidic hydrolysis, followed by application of Marfey’s method, menthyl ester derivatization, and GC–MS analysis. In addition, the specific optical rotation values of the hydrolysis products were compared with those of available standards.

Stereospecific ring-opening metathesis polymerization of norbornadienes employing tungsten oxo alkylidene initiators.

We report here the polymerization of several 7-isopropylidene-2,3-disubstituted norbornadienes, 7-oxa-2,3-dicarboalkoxynorbornadienes, and 11-oxa-benzonorbornadienes with a single tungsten oxo alkylidene catalyst, W(O)(CH-t-Bu)(OHMT)(Me2Pyr) (OHMT = 2,6-dimesitylphenoxide; Me2Pyr = 2,5-dimethylpyrrolide) to give cis, stereoregular polymers. The tacticities of the menthyl ester derivatives of two polymers were determined for two types. For poly(7-isopropylidene-2,3-dicarbomenthoxynorbornadiene) the structure was shown to be cis,isotactic, while for poly(7-oxa-2,3-dicarbomenthoxynorbornadiene) the structure was shown to be cis,syndiotactic. A bis-trifluoromethyl-7-isopropylidene norbornadiene was not polymerized stereoregularly with W(O)(CHCMe2Ph)(Me2Pyr)(OHMT) alone, but a cis, stereoregular polymer was formed in the presence of 1 equiv of B(C6F5)3.

Tribenzotriquinacene receptors for C60 fullerene rotors: towards C3 symmetrical chiral stators for unidirectionally operating nanoratchets.

The synthesis of a stereochemically pure concave tribenzotriquinacene receptor (7) for C60 fullerene, possessing C3 point group symmetry, by threefold condensation of C2 -symmetric 1,2-diketone synthons (5) and a hexaaminotribenzotriquinacene core (6) is described. The chiral diketone was synthesized in a five-step reaction sequence starting from C2h -symmetric 2,6-di-tert-butylanthracene. The highly diastereo-discriminating Diels-Alder reaction of 2,6-di-tert-butylanthracene with fumaric acid di(-)menthyl ester, catalyzed by aluminium chloride, is the relevant stereochemistry introducing step. The structure of the fullerene receptor was verified by (1)H and (13)C NMR spectroscopy, mass spectrometry and single crystal X-ray diffraction. VCD and ECD spectra were recorded, which were corroborated by ab initio DFT calculations, establishing the chiral nature of 7 with about 99.7 % ee, based on the ee (99.9 %) of the chiral synthon (1). The absolute configuration of 7 could thus be established as all-S [(2S,7S,16S,21S,30S,35S)-(7)]. Spectroscopic titration experiments reveal that the host forms 1:1 complexes with either pure fullerene (C60) or fullerene derivatives, such as rotor 1'-(4-nitrophenyl)-3'-(4-N,N-dimethylaminophenyl)-pyrazolino[4',5':1,2][60]fullerene (R). The complex stability constants of the complexes dissolved in CHCl3/CS2 (1:1 vol. %) are K([C60 ⊂7]) = 319(±156) M(-1) and K([R⊂7]) = 110(±50) M(-1). With molecular dynamics simulations using a first-principles parameterized force field the asymmetry of the rotational potential for [R⊂7] was shown, demonstrating the potential suitability of receptor 7 to act as a stator in a unidirectionally operating nanoratchet.

Diastereoselective synthesis of a highly functionalized cyclohexene embedded with a quaternary stereogenic centre by self Diels–Alder dimerization of a [3]dendralene attached to a (−)-menthol auxiliary

A novel route to a chiral functionalized [3]dendralene attached to a (−)-menthol auxiliary has been developed, which involves a dimethylsulfonium methylide mediated olefination of a substituted ethenylidene phosphonoacetate (−)-menthyl ester, followed by a Horner–Wordsworth–Emmons reaction with 4-bromobenzaldehyde. The chiral [3]dendralene was reactive enough to undergo intermolecular Diels–Alder cyclodimerization to give the highly substituted cyclohexene with very high regio- and diastereoselectivity.

First Total Synthesis of (−)‐Ligustiphenol

AbstractThe first asymmetric total synthesis of (−)‐ligustiphenol is reported. The key step was conducted by exploiting a steric hindrance effect to control the formation of the adduct in a nucleophilic α‐Li‐phenolate addition reaction to the intermediate α‐oxo (−)‐menthyl ester. The synthesis is concise and feasible for the construction of analogous compounds and investigation of their biological activity.