Water‐mediated intermolecular interactions in 1,2‐O‐cyclohexylidene‐myo‐inositol: a quantitative analysis

The syntheses of new myo‐inositol derivatives have received much attention due to their important biological activities. 1,2‐O‐Cyclohexylidene‐myo‐inositol is an important intermediate formed during the syntheses of certain myo‐inositol derivatives. We report herein the crystal structure of 1,2‐O‐cyclohexylidene‐myo‐inositol dihydrate, C₁₂H₂₀O₆·2H₂O, which is an intermediate formed during the syntheses of myo‐inositol phosphate derivatives, to demonstrate the participation of water molecules and hydroxy groups in the formation of several intermolecular O—H…O interactions, and to determine a low‐energy conformation. The title myo‐inositol derivative crystallizes with two water molecules in the asymmetric unit in the space group C 2/c , with Z = 8. The water molecules facilitate the formation of an extensive O—H…O hydrogen‐bonding network that assists in the formation of a dense crystal packing. Furthermore, geometrical optimization and frequency analysis was carried out using density functional theory (DFT) calculations with B3LYP hybrid functionals and 6‐31G(d), 6‐31G(d,p) and 6‐311G(d,p) basis sets. The theoretical and experimental structures were found to be very similar, with only slight deviations. The intermolecular interactions were quantitatively analysed using Hirshfeld surface analysis and 2D (two‐dimensional) fingerplot plots, and the total lattice energy was calculated.     

Synthesis of oligo(spiroketal)s by polycondensation of silyl ethers derived from naturally occurring myo‐inositol with 1,4‐cyclohexanedione

Oligo(spiroketal)s (OSKs) were synthesized from myo‐inositol, a naturally occurring cyclic compound bearing six hydroxyl groups. The successful synthesis of OSKs was achieved using silyl ethers 2 derived from 1,4‐di‐O‐alkylated myo‐inositol 1 as monomers, which underwent polycondensation with 1,4‐cyclohexanedione (CHD) at 0 °C in the presence of trimethylsilyl triflate as a catalyst. Because of the irreversible nature of the condensation reaction of silyl ethers with ketones, the resulting OSKs 7 had higher molecular weights than previously reported OSKs that were obtained by polycondensation of tetraols 1 with CHD, where backward hydrolysis of the ketal functions occurred. In addition, another series of OSKs, 8, were synthesized using silyl ethers 3 derived from 2,5‐di‐O‐alkylated myo‐inositol 6 , which are more symmetric monomers than silyl ethers 2 . Silyl ethers 3 underwent efficient polycondensation with CHD, whereas tetraol 6 did not, demonstrating that the derivation of such tetraols into the corresponding silyl ethers is a powerful strategy to access OSKs. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019 , 57, 2407–2414     

Chemical Constituents of the Aerial Part of Celastrus Hypoleucus

Fourteen compounds including eight triterpenoids, 12‐oleanaen‐3β‐ol (β‐amyrin) ( 1 ), 12‐oleanaen‐3β‐caffeate ( 2 ), 9(11),12‐oleanadien‐3β‐ol ( 3 ), 9(11),12‐oleanadien‐3‐one ( 4 ), 9(11),12‐oleanadien‐3 β‐caffeate ( 5 ), friedela‐3‐one (friedelin) ( 6 ), friedela‐3‐one‐29‐ol ( 7 ), and 12‐gammateraen‐3 β‐ol (tetrehymanol) ( 8 ); one steroid, β‐sitosterol ( 9 ); one long‐chain acid, octadecadienoic acid ( 10 ); two esters, ester of n‐octaolecyl‐4‐hydroxy‐cinnamate ( 11 ), and ester of n‐octadecyl‐caffeic acid ( 12 ); one diterpene, 8β,19‐dihydroxy‐3‐oxopimar‐15‐ene ( 13 ); one sesquiterpene, 1β,2β,9α‐trihydroxy‐β‐dihydroagarofuran ( 14 ) were isolated from the aerial part of Celastrus hypoleucus. These compounds were characterized and identified by physical and spectral methods. All compounds were isolated for the first time from this plant. Among them 12‐oleanaen‐3β‐caffeate ( 2 ) and 9(11),12‐oleanadien‐3β‐caffeate ( 5 ) are two new compounds, and ester of n‐octadecyl‐caffeic acid (12) possessed antilipoperoxidative effect by specifically scavenging the hydroxyl free radical (?OH) in vitro.     

Rigid diol bearing 6‐6‐6 fused ring system derived from naturally occurring myo‐inositol and its polyaddition with diisocyanates

Naturally occurring myo‐inositol was developed into a highly rigid diol by converting its 3,4‐ and 1,6‐vicinal diols in trans configuration into the corresponding butane‐2,3‐diacetals. The resulting diol bearing 6‐6‐6 fused ring system, in which conformational change is strictly suppressed, was combined with diisocyanates to perform polyadditions. The resulting polyurethanes were analyzed by differential scanning calorimetry, and it was found that their glass transition temperatures were much higher than those of the previously reported myo‐inositol‐derived polyurethanes, which were synthesized from a myo‐inositol‐derived diol bearing 5‐6‐5 fused ring system. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 3798–3803     

Comparison of racemic epi‐inosose and (−)‐epi‐inosose

The conversion of myo‐inositol to epi‐inositol can be achieved by the hydride reduction of an intermediate epi‐inosose derived from myo‐inositol. (−)‐epi‐Inosose, (I), crystallized in the monoclinic space group P2₁, with two independent molecules in the asymmetric unit [Hosomi et al. (2000). Acta Cryst. C 56 , e584–e585]. On the other hand, (2RS,3SR,5SR,6SR)‐epi‐inosose, C₆H₁₀O₆, (II), crystallized in the orthorhombic space group Pca2₁. Interestingly, the conformation of the molecules in the two structures is nearly the same, the only difference being the orientation of the C‐3 and C‐4 hydroxy H atoms. As a result, the molecular organization achieved mainly through strong O—H...O hydrogen bonding in the racemic and homochiral lattices is similar. The compound also follows Wallach's rule, in that the racemic crystals are denser than the optically active form.     

Two New Lignan Glycosides from Saussurea laniceps

Two new lignan glycosides, lanicepsides A and B ( 1 and 2 ), along with the eight known compounds 3 – 6 , epipinoresinol, syringin, ethyl caffeate, and 5,6,7‐trihydroxy‐4′‐methoxyflavone, including sesquiterpene lactones, lignans, and a flavone, were isolated from the ethanol extract of Saussurea laniceps. Their structures were determined by spectroscopic methods especially 1D‐ and 2D‐NMR techniques.     

Partially bio‐based tri‐ and hexaallyl monomers: Synthesis from naturally occurring myo‐inositol and polyaddition with dithiols

myo‐Inositol, a naturally occurring cyclic hexaol, was converted to 2,4,6‐tri‐O‐allyl‐myo‐inositol and 1,2,3,4,5,6‐hexa‐O‐allyl‐myo‐inositol. Polyaddition of the former product, a tri(allyl ether) bearing three hydroxyl groups, with dithiols yielded the corresponding networked polymers. Their glass transition temperatures (T_gs) were higher than those of networked polymers formed by the polyaddition of 1,3,5‐tri‐O‐methyl‐2,4,6‐tri‐O‐allyl‐myo‐inositol. This implied the reinforcement of the networks by hydrogen bonding between the hydroxyl groups. Polyaddition of the latter product, a hexa(allyl ether), with dithiols yielded the corresponding networked polymers with much higher T_gs than those of all of the aforementioned networked polymers. This implied that efficient use of the hexafunctional monomer leads to the formation of more densely crosslinked polymers. © 2017 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2017 , 55, 1524–1529     

The “Other” Inositols and Their Phosphates: Synthesis,Biology, and Medicine (with Recent Advances in myo‐Inositol Chemistry)

Cell signaling via inositol phosphates, in particular via the second messenger myo‐inositol 1,4,5‐trisphosphate, and phosphoinositides comprises a huge field of biology. Of the nine 1,2,3,4,5,6‐cyclohexanehexol isomers, myo‐inositol is pre‐eminent, with “other” inositols (cis‐, epi‐, allo‐, muco‐, neo‐, l ‐chiro‐, d ‐chiro‐, and scyllo‐) and derivatives rarer or thought not to exist in nature. However, neo‐ and d ‐chiro‐inositol hexakisphosphates were recently revealed in both terrestrial and aquatic ecosystems, thus highlighting the paucity of knowledge of the origins and potential biological functions of such stereoisomers, a prevalent group of environmental organic phosphates, and their parent inositols. Some “other” inositols are medically relevant, for example, scyllo‐inositol (neurodegenerative diseases) and d ‐chiro‐inositol (diabetes). It is timely to consider exploration of the roles and applications of the “other” isomers and their derivatives, likely by exploiting techniques now well developed for the myo series.     

New Steryl Esters of Fatty Acids from the Mangrove Fungus Aspergillus awamori

The polyhydroxylated ergostane‐type sterol 9 , its derivatives 10 – 15 , and the fatty acid esters 1 – 8 were isolated from a fungus strain which was collected from mangrove areas at Wenchang, Hainan Province, P. R. China, exhibited potent cytotoxic activity, and was identified as Aspergillus awamori. The structures of 1 – 15 were elucidated by spectroscopic and chemical methods. Among them, the six steryl esters 1 – 6 of fatty acids were new compounds, i.e., (3β,5α,6α,22E)‐ergosta‐7,22‐diene‐3,5,6‐triol 6‐palmitate ( 1 ), (3β,5α,6α,22E)‐ergosta‐7,22‐diene‐3,5,6‐triol 6‐stearate ( 2 ), (3β,5α,6α,22E)‐ergosta‐7,22‐diene‐3,5,6‐triol 6‐oleate ( 3 ), (3β,5α,6α,22E)‐ergosta‐7,22‐diene‐3,5,6‐triol 6‐linoleate ( 4 ), (3β,5α,6β,22E)‐ergosta‐7,22‐diene‐3,5,6‐triol 6‐palmitate ( 5 ), and (3β,5α,6β,22E)‐ergosta‐7,22‐diene‐3,5,6‐triol 6‐stearate ( 6 ). The related known fatty acids stearic acid (=octadecanoic acid) and palmitic acid (=octadecanoic acid) were also obtained. A speculative biogenetic relationship of the metabolites is proposed. The known polyhydroxylated sterols and derivatives showed cytotoxic activities, in agreement with earlier reports. The cytotoxic activities against B16 and SMMC‐7721 cell lines of the new steryl esters 1 – 6 by the MTT method were weak.     

Metabolic Profiling of Human Colorectal Cancer Using High Resolution 1H Nuclear Magnetic Resonance Spectroscopy

Colorectal cancer (CRC) is the third commonest malignancy cancer worldwide. Clear understandings of global metabolic profiling of the normal mucosa and cancer tissues are vitally important to aid optimizing the clinical management strategy and understanding CRC biology. We studied metabolic characteristics of 20 CRC and 20 distant normal mucosa tissues extracts from 20 patients using high resolution ¹H NMR spectroscopy in conjunction with multivariate analyses, such as principal component analysis (PCA). Compared with distant normal mucosa tissues, lactate, taurine, ornithine and polyamine were present at significantly higher levels in CRC tissue extracts whereas myo‐inositol was present at significantly lower level. Two metabolites ratios such as myo‐inositol/taurine and myo‐inositol/(ornithine+polyamine) appear to be the most valuable biomarkers for the differentiation CRC from normal mucosa tissues. Our data suggested that HR ¹H NMR spectroscopy combined with multivariate analyses is a potentially useful technology for detecting malignant changes in the normal mucosa tissues, the technique may be further exploited for future CRC biomarker research or identification of targets for therapeutic manipulations.     

Three New Monoterpene Alkaloids and a New Caffeic Acid Ester from Incarvillea mairei var. multifoliolata

Three new monoterpene alkaloids, mairine A ( 1 ), mairine B ( 2 ), and mairine C ( 3 ), and a new caffeic acid ester, 2‐(1‐hydroxy‐4,4‐dimethoxycyclohexyl)ethyl caffeate ( 4 ), were isolated from the EtOH extract of the whole plants of Incarvillea mairei var. multifoliolata. The structures of these compounds were established on the basis of 1D‐ and 2D‐NMR and HR‐ESI‐MS analysis.     

Synthesis of high‐performance polyurethanes with rigid 5‐6‐5‐fused ring system in the main chain from naturally occurring myo‐inositol

A bisketal of myo‐inositol was used as a diol‐type monomer for synthesis of polyurethanes. The monomer was obtained by treatment of myo‐inositol with 1,1‐dimethoxycyclohexane in the presence of p‐toluenesulfonic acid as a catalyst. The ketalization resulted in the formation of a 5‐6‐5‐fused ring system, which endowed the diol‐type monomer with high rigidity. The diol readily reacted with diisocyanate to give the corresponding polyurethane, which exhibited excellent heat resistance due to the rigid 5‐6‐5 system in the main chain. © 2013 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2013 , 51, 3956–3963     

Enhancing Intermolecular Benzoyl‐Transfer Reactivity in Crystals by Growing a “Reactive” Metastable Polymorph by Using a Chiral Additive

Racemic 2,4‐di‐O‐benzoyl‐myo‐inositol‐1,3,5‐orthoacetate, which normally crystallizes in a monoclinic form (form I, space group P2₁/n) could be persuaded to crystallize out as a metastable polymorph (form II, space group C2/c) by using a small amount of either D ‐ or L ‐ 2,4‐di‐O‐benzoyl‐myo‐inositol‐1,3,5‐orthoformate as an additive in the crystallization medium. The structurally similar enantiomeric additive was chosen by the scrutiny of previous experimental results on the crystallization of racemic 2,4‐di‐O‐benzoyl‐myo‐inositol‐1,3,5‐orthoacetate. Form II crystals can be thermally transformed to form I crystals at about 145 °C. The relative organization of the molecules in these dimorphs vary slightly in terms of the helical assembly of molecules, that is, electrophile (El)???nucleophile (Nu) and C? H???π interactions, but these minor variations have a profound effect on the facility and specificity of benzoyl‐group‐transfer reactivity in the two crystal forms. While form II crystals undergo a clean intermolecular benzoyl‐group‐transfer reaction, form I crystals are less reactive and undergo non‐specific benzoyl‐group transfer leading to a mixture of products. The role played by the additive in fine‐tuning small changes that are required in the molecular packing opens up the possibility of creating new polymorphs that show varied physical and chemical properties. Crystals of D ‐2,6‐di‐O‐benzoyl‐myo‐inositol‐1,3,5‐orthoformate (additive) did not show facile benzoyl‐group‐transfer reactivity (in contrast to the corresponding racemic compound) due to the lack of proper juxtaposition and assembly of molecules.     

LC-MS/MS method for the quantification of myo- and chiro-inositol as the urinary biomarkers of insulin resistance in human urine

A simple LC‐MS/MS method has been developed and validated for the quantification of endogenous myo‐ and chiro‐inositol in human urine. myo‐ and chiro‐Inositol were completely resolved from other carbohydrates and there were no interference peaks in human urine. The correlation coefficient (n = 3) was greater than 0.9991 over the range 0.05–25.0 µg/mL with the weighted (1/C²) least square method. Precision (%RSD) and accuracy (%RE) were 0–10.0% and 0–6.0% for the intra‐day assay (n = 5) and 0–14.3% and 0–10.0% for the inter‐day assay (n = 5). myo‐ and chiro‐Inositol have been shown to be stable in human urine stored at room temperature and for three freeze–thaw cycles. Copyright © 2011 John Wiley & Sons, Ltd.     

Synthesis of hydroxyl‐bearing polyurethanes from naturally occurring myo‐inositol

A route from naturally occurring myo‐inositol to hydroxyl‐bearing polyurethanes has been developed. The diol prepared from the bis‐acetalization of myo‐inositol with 1,1‐dimethoxycyclohexane was reacted with a rigid diisocyanate, 1,3‐bis(isocyanatomethyl)cyclohexane to afford the corresponding polyurethane, of which glass transition temperature (T_g) was quite high as 192 °C. The polyurethane contains side chains inherited from the acetal moieties of the diol monomer and was treated with trifluoroacetic acid to hydrolyze the acetal moieties and afford the target polyurethane functionalized with hydroxyl groups. The presence of many hydroxyl groups in the side chains, which can form hydrogen bonds with each other, resulted in a high T_g, 186 °C. In addition, the hydroxyl groups were reacted with isocyanates to achieve further side‐chain modifications. © 2019 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2019, 57, 1358–1364     

A highly rigid diamine monomer derived from naturally occurring myo‐inositol and its use for polyamide synthesis

A rigid diamine was synthesized from myo‐inositol, a naturally occurring cyclic hexaol, and used as a monomer to synthesize polyamides. myo‐Inositol was treated with 1,1‐dimethoxycyclohexane to yield a bisketal bearing two hydroxyl groups, and from this bisketal, the target diamine was synthesized in three steps: (1) derivation of the diol into the corresponding bistriflate, (2) nucleophilic substitution of the bistriflate with sodium azide yielding a diazide, and (3) reduction of the diazide to the target diamine. The target diamine readily underwent polycondensation with dicarboxylic acid chloride in solution. The resulting polyamides, whose main chain inherited the rigid 5‐6‐5 system from the diamine monomers, have high glass transition temperatures. © 2016 Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2016 , 54, 3436–3443     

Dipolar S=O...C=O and C—H...O interactions in the molecular organization of 4,6‐di‐O‐acetyl‐2‐O‐tosyl‐myo‐inositol 1,3,5‐orthoesters

In the absence of conventional hydrogen bonding, the molecules of 4,6‐di‐O‐acetyl‐2‐O‐tosyl‐myo‐inositol 1,3,5‐orthoformate, C₁₈H₂₀O₁₀S, (I), and 4,6‐di‐O‐acetyl‐2‐O‐tosyl‐myo‐inositol 1,3,5‐orthobenzoate, C₂₄H₂₄O₁₀S, (II), are associated via C—H...O interactions. Molecules of (II) are additionally linked via dipolar S=O...C=O contacts. It is interesting to note that the sulfonyl O atom involved in the dipolar S=O...C=O contacts does not take part in any other interaction, indicating the competitive nature of this contact relative to the weak hydrogen‐bonding interactions.     

Three New Phenyl Ether Derivatives from Aspergillus carneus HQ889708

Three new phenyl ether derivatives, 3‐hydroxy‐5‐(3‐hydroxy‐5‐methylphenoxy)benzoic acid ( 1 ), 3,4‐dihydroxy‐5‐(3‐hydroxy‐5‐methylphenoxy)benzoic acid ( 2 ), 3‐[3‐hydroxy‐5‐(hydroxymethyl)phenoxy]‐5‐methylphenol ( 3 ), and three known compounds 4 – 6 were obtained from the fermentation broth of Aspergillus carneus HQ889708, which was isolated from sea water from South China Sea. The structures of compounds 1 – 3 were established on the basis of spectroscopic methods including ESI‐MS and NMR. Compounds 4 – 6 were reported before as synthesized products, herein, they are reported from nature for the first time.     

Simultaneous determination of inositol and inositol phosphates in complex biological matrices: quantitative ion‐exchange chromatography/tandem mass spectrometry

myo‐Inositol (Ins) and myo‐inositol phosphates (InsPs) are widely distributed in plants and animals. The evaluation of the distribution of Ins and InsPs in cells and plant sources can impact the understanding of their role in nutrition, cellular processes and diseases, and how they may be modulated by diet. We developed an anion‐exchange chromatography/tandem mass spectrometry (HPLC/ESI‐MS/MS) method for the separation and simultaneous quantitation of Ins and different naturally occurring phosphorylated inositol compounds. Chromatographic separation was achieved in 30 min on a commercial anion‐exchange column (0.5 × 150 mm) using a gradient of 200 mM ammonium carbonate buffer (pH 9.0) and 5% methanol in H₂O. Analytes were identified by selective reaction monitoring using a triple quadrupole mass spectrometer in negative ion electrospray ionization mode. Adenosine 5′‐monophosphate was used as a general internal standard for quantitation. Detection is linear in the range of 0.25–400 pmol for Ins, InsP₁, InsP₄, and InsP₅, 40–400 pmol for InsP₂ and InsP₃, and 60–400 pmol for InsP₆, with a minimum r² > 0.994. The limit of detection is 0.25 pmol with a signal‐to‐noise ratio of 10:1 for all analytes. The intra‐day and inter‐day variations were within 17% at three concentration levels. Recovery values for the seven analytes spiked into extraction solution or different matrices were between 63 and 121%. Using this approach, Ins and InsPs were measured in three different plant samples and in cultured cells, illustrating significant differences in the distribution of inositol compounds in food samples compared to cells and between cell types. Copyright © 2009 John Wiley & Sons, Ltd.     

A New Taraxastane‐Type Triterpene from Vitex trifolia var. simplicifolia

3‐Oxotaraxer‐14‐en‐30‐al ( 1 ), a new taraxastane‐type triterpene, together with 14 known compounds, taraxerone ( 2 ), 3‐epiursolic acid ( 3 ), 2α,3β‐dihydroxyurs‐12‐en‐28‐oic acid ( 4 ), lupeol ( 5 ), betulinic acid ( 6 ), casticin ( 7 ), artemetin ( 8 ), luteolin ( 9 ), 4‐hydroxybenzoic acid ( 10 ), docosanoic acid ( 11 ), tetracosanoic acid ( 12 ), cerotic acid ( 13 ), β‐sitosterol ( 14 ), and β‐daucosterol ( 15 ), was isolated from the leaves and twigs of Vitex trifolia var. simplicifolia . Compounds 2 – 6 were found for the first time in this plant. Their structures were established by spectroscopic analysis, including 2D‐NMR techniques. Cytotoxic activities of compounds 3 , and 5 – 10 were tested on the three cancer cell lines, PANC‐1, K562, and BxPC‐3. Results revealed that 7 exhibited cytotoxicity against PANC‐1, K562, and BxPC‐3, with IC₅₀ values of 4.67, 0.72, and 4.01 μg/ml, respectively, whereas 8 was inactive against these cancer cell lines. The structure? activity relationship of compound 7 and 8 indicated that the 3′‐OH group in polymethoxyflavonoids is essential for antitumor activity.