Efficient syntheses of optically pure chiro- and allo-inositol derivatives, azidocyclitols and aminocyclitols from myo-inositol

Efficient routes for the syntheses of optically pure and hitherto unknown l-chiro- and d-allo-inositol derivatives, azido- and aminocyclitols of l-chiro-configuration, diazido- and diaminocyclitols of d-allo-configuration from economically viable myo-inositol are described. These routes provide access to synthetically flexible 1,2:4,5-di-O-isopropylidene-chiro-inositol and 1,6:3,4-di-O-isopropylidene-allo-inositol, which are otherwise difficult to synthesize directly from their parent inositols. A one pot methodology that allows rapid access to both chiro- and allo-inositol derivatives has also been developed. Investigations on the glycosidase inhibitory properties of these novel azido- and amino-inositols unraveled the potentials of these classes of compounds as novel class of glycosidase inhibitors. Both d and l forms of these cyclitols could be synthesized from myo-inositol in gram scales and hence by exploiting the difference in reactivities of cis- and trans-ketals, a variety of protected derivatives, which are useful for the synthesis of unnatural phosphoinositols and natural products, can be synthesized.     

Total synthesis of the proposed structure of `brahol' and the structural revision

Proposed structure of brahol, a natural product, has been disproved by total synthesis of the proposed molecule from myo-inositol. Readily available 1,2;4,5-di-O-isopropylidene-myo-inositol, 3 was converted to 2,5-di-O-acetyl-1,6;3,4-di-O-isopropylidene-allo-inositol by epimerization of the di-triflate of 3. The acetyl group at O-5-position was selectively deprotected by aminolysis or methanolysis enabling the total synthesis of 5-O-methyl-allo-inositol, the proposed structure of brahol in six steps from myo-inositol. A comparison of spectral data of synthetic 5-O-methyl-allo-inositol with that reported for natural brahol revealed that the proposed structure of brahol is incorrect. A detailed structural revision revealed that brahol is nothing but quebrachitol. This study contradicts the first and only report on the natural occurrence of allo-inositol derivative.     

Efficient routes to optically active azido-, amino-, di-azido- and di-amino-cyclitols with chiro- and allo-configuration from myo-inositol

Efficient routes to hitherto unknown 1d-2,5-di-azido-di-deoxy-allo-inositol, 1d-2,5-di-amino-di-deoxy-allo-inositol, 1l-1-azido-1-deoxy-chiro-inositol and 1l-1-amino-1-deoxy-chiro-inositol were developed by using cheaply available myo-inositol as the starting material. Preliminary investigations on the enzyme inhibitory properties were done. The methodology reported is amenable to gram scale synthesis and thus can find application in natural product synthesis.     

Sulfonate protecting groups. Synthesis of O- and C-methylated inositols: d- and l-ononitol, d- and l-laminitol, mytilitol and scyllo-inositol methyl ether

Syntheses of d- and l-ononitol, d- and l-laminitol, mytilitol and scyllo-inositol methyl ether starting from myo-inositol are described. One or two of the myo-inositol 1,3,5-orthoformate hydroxyl groups were protected as tosylates. These mono or ditosylates served as key intermediates for the preparation of O- and C-methyl inositols. Racemic 2,4-di-O-tosyl-myo-inositol 1,3,5-orthoformate was resolved as its diastereomeric camphanates. Use of sulfonate groups for the protection of inositol hydroxyl groups resulted in substantial improvement in the overall yield of O- and C-methyl inositols.     

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.     

Development of a microwave-assisted extraction method for the recovery of bioactive inositols from lettuce (Lactuca sativa) byproducts

A microwave-assisted extraction (MAE) method was developed for the extraction of bioactive inositols (D-chiro- and myo-inositols) from lettuce (Lactuca sativa) leaves as a strategy for the revalorization of these agrofood residues. Gas chromatography-mass spectrometry was selected for the simultaneous determination of inositols and sugars (glucose, fructose, and sucrose) in these samples. A Box–Behnken experimental design was used to maximize the extraction of inositols based on the results of single factor tests. Optimal conditions of the extraction process were as follows: liquid-to-solid ratio of 100:1 v/w, 40°C, 30 min extraction time, 20:80 ethanol:water (v/v), and one extraction cycle. When compared with conventional solid-liquid extraction (SLE), MAE was found to be more effective for the extraction of target bioactive carbohydrates (MAE 5.42 mg/g dry sample versus SLE 4.01 mg/g dry sample). Then, MAE methodology was applied to the extraction of inositols from L. sativa leaves of different varieties (var. longifolia, var. capitata and var. crispa). D-chiro- and myo-inositol contents varied between 0.57–7.15 and 0.83–3.48 mg/g dry sample, respectively. Interfering sugars were removed from the extracts using a biotechnological procedure based on the use of Saccharomyces cerevisiae for 24 h. The developed methodology was a good alternative to classical procedures to obtain extracts enriched in inositols from lettuce residues, which could be of interest for the agrofood industry.     

The solution conformation of glycosyl inositols related to inositolphosphoglycan (IPG) mediators

The preferred solution conformation of the pseudodisaccharides 7–15, containing the structural motifs that have been proposed for the putative inositolphosphoglycan (IPG) mediators of intracellular signalling processes, have been investigated using NMR spectroscopy and molecular mechanics calculations. The results indicate that the different structural motifs (α and β 1–6 or α and β 1–4 glucosaminyl-d-myo-inositol; α and β 1–6 glucosaminyl-d-chiro-inositol) adopt various three-dimensional shapes that may modulate their biological properties.     

Untersuchungen über die Biosynthese der Cyclite, 22. Mitt.: Cyclite inChlorella fusca

Zusammenfassung Das Vorkommen von Cycliten inChlorella fusca wurde mit Hilfe der Methode der Photoassimilation in einer Atmosphäre von¹⁴CO₂ untersucht. Außer dem bereits als Bestandteil dieser Algenart bekanntenmyo-Inosit konnten auch andere Cyclite, nämlichd-chiro-Inosit, Mytilit, Laminit undl-Leucanthemit nachgewiesen werden. Einbauversuche mit markierten Vorstufen ergaben, daßmyo-Inosit höchstwahrscheinlich auf dem schon in vielen Organismen nachgewiesenen Weg ausd-Glucose entsteht undd-chiro-Inosit das Produkt einer direkten Epimerisierung vonmyo-Inosit ist. Hingegen besteht keine biogenetische Beziehung zwischenmyo-Inosit und den beiden C-Methylinositen Mytilit und Laminit; die Methylgruppe vonl-Methionin wird nicht in diese beiden Verbindungen eingebaut.

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Studies on the biosynthesis of the cyclitols, XXII: Cyclites in chlorella fusca

The occurrence of cyclitols inChlorella fusca has been studied, using the method of photoassimilation in an atmosphere of¹⁴CO₂. Besidesmyo-inositol which is known to be a constituent of this algal species, other cyclitols were detected, namelyd-chiro-inositol, mytilitol, laminitol, andl-leucanthemitol. Incorporation experiments with labelled precursors make it most probable thatmyo-inositol is formed fromd-glucose through a pathway already established in many organisms, whereasd-chiro-inositol is the product of a direct epimerization ofmyo-inositol. No biogenetic relation exists betweenmyo-inositol and the two C-methylinositols; the methyl group ofl-methionine is not incorporated into these compounds.

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21. Mitt.:E. Molinari undO. Hoffmann-Ostenhof,Z. physiol. Chem.349, 1797 (1968).     

Catalytic One-Pot Osmylation of Cyclohexadienes: Stereochemical and conformational studies of the resulting polyols

Catalytic double osmylation is described for a series of cyclohexadienes in acetone/H₂O in the presence of the co-oxidant N-methylmorpholine N-oxide (NMO). The formation of polyols occurred stereospecifically with cyclohexadienes 3,7 , and 11a , leading thereby to tetrols 5a , and 9a and to allo-inositol ( 14a ), respectively. To the contrary, trans-cyclohexadiene-diol 15a gave a mixture of the stereoisomeric inositols 18a (epi), 19a (neo), and 20a (chiro). High-field NMR let to clearcut conformational analyses of the polyhydroxylated derivatives.     

Quest for inosito-inositols: synthesis of novel, annulated and conformationally locked inositols

A new family of annulated inositols (inosito-inositols) has been conceptualized. Naphthalene has been elaborated into novel cyclohexa-annulated neo- and chiro-inositols, with two additional hydroxyl functionalities, through a series of stereoselective oxyfunctionalization protocols. The trans-ring fusion present in these new annulated inositols ensures conformational locking.     

Ruthenium complexes that incorporate a chiro-inositol derived diphosphinite ligand as catalysts for asymmetric hydrogenation reactions

The diol, 1d-1,2,5,6-tetra-O-methyl-chiro-inositol (D-9), can be conveniently prepared from 1d-chiro-inositol using a series of standard protection/deprotection steps. Treatment of D-9 with Ph₂PCl gives the chiral diphosphinite, 1d-3,4-bis(O-diphenylphosphino)-1,2,5,6-tetra-O-methyl-chiro-inositol (D-10). The structure of D-10 has been determined by X-ray crystallography. Using 1l-chiro-inositol as starting material and following the same synthetic sequence used to produce D-10, the other enantiomer of this diphosphinite, 1l-3,4-bis(O-diphenylphosphino)-1,2,5,6-tetra-O-methyl-chiro-inositol (L-10) can also be obtained. Ruthenium complexes of these diphosphinite ligands can be conveniently prepared through ligand substitution reactions with appropriate substrate complexes. Thus, treatment of [RuCl₂(COD)]_n with D-10 in the presence of triethylamine produces the bis(diphosphinite) complex, RuHCl{κ²(P,P)-1d-3,4-bis(O-diphenylphosphino)-1,2,5,6-tetra-O-methyl-chiro-inositol}₂ (11). In addition, reaction between RuCl₂(PPh₃)₃, D-10 and (1R,2R)-(+)-1,2-diphenylethylenediamine gives the mono(diphosphinite) complex, RuCl₂{κ²(P,P)-1d-3,4-bis(O-diphenylphosphino)-1,2,5,6-tetra-O-methyl-chiro-inositol}{κ²(N,N)-(1R,2R)-(+)-1,2-diphenylethylenediamine} (12). The closely related complex RuCl₂{κ²(P,P)-1d-3,4-bis(O-diphenylphosphino)-1,2,5,6-tetra-O-methyl-chiro-inositol}{κ²(N,N)-(1S,2S)-(−)-1,2-diphenylethylenediamine} (13) can be obtained in a similar manner using (1S,2S)-(−)-1,2-diphenylethylenediamine in place of the corresponding (+)-isomer. These new chiral, diphosphinite complexes catalyse the hydrogenation of the ketones acetophenone and 3-quinuclidinone to give the corresponding alcohols with low to moderate enantiomeric excesses. The complexes are not catalytically active for the hydrogenation of the olefin dimethylitaconate or the α-ketoester methyl benzoylformate.     

Syntheses of D-Myo-Inositol-1,2,6-Trisphosphate and -2,6-bisphosphate

Abstract

A D-myo-inositol derivative (3), obtained from methyl α-D-glucopyranoside by Ferrier rearrangement, was efficiently transformed to D-myo-inositol 1,2,6-trisphosphate (1, α-trinositol) and D-myo-inositol 2,6-bisphosphate (2).     

Novel Substrates for Kinases Involved in the Biosynthesis of Inositol Pyrophosphates and Their Enhancement of ATPase Activity of a Kinase

IP6K and PPIP5K are two kinases involved in the synthesis of inositol pyrophosphates. Synthetic analogs or mimics are necessary to understand the substrate specificity of these enzymes and to find molecules that can alter inositol pyrophosphate synthesis. In this context, we synthesized four scyllo-inositol polyphosphates—scyllo-IP₅, scyllo-IP₆, scyllo-IP₇ and Bz-scyllo-IP₅—from myo-inositol and studied their activity as substrates for mouse IP6K1 and the catalytic domain of VIP1, the budding yeast variant of PPIP5K. We incubated these scyllo-inositol polyphosphates with these kinases and ATP as the phosphate donor. We tracked enzyme activity by measuring the amount of radiolabeled scyllo-inositol pyrophosphate product formed and the amount of ATP consumed. All scyllo-inositol polyphosphates are substrates for both the kinases but they are weaker than the corresponding myo-inositol phosphate. Our study reveals the importance of axial-hydroxyl/phosphate for IP6K1 substrate recognition. We found that all these derivatives enhance the ATPase activity of VIP1. We found very weak ligand-induced ATPase activity for IP6K1. Benzoyl-scyllo-IP₅ was the most potent ligand to induce IP6K1 ATPase activity despite being a weak substrate. This compound could have potential as a competitive inhibitor.     

Biobased myo-inositol as nucleator and stabilizer for poly(lactic acid)

myo-Inositol made from a biomass feedstock was used as an additive for poly (l-lactic acid) (PLLA) which was also made from biomass feedstock. The crystallization and stabilization of PLLA by the addition of myo-inositol were evaluated by the melt injection molding process. While the isothermal crystallization of PLLA at 100 °C had finished over 14 min after melting, that of PLLA with 5 wt% myo-inositol finished within 2 min. The crystal growth of PLLA started when the myo-Inositol crystal was added, and the crystallization was promoted. Furthermore, the molecular weight of PLLA with myo-inositol did not decrease during the melt-mixed at 200 °C, different from that of PLLA without the myo-inositol. myo-Inositol prevented the degradation of PLLA during the thermal melting process. The biomass carbon ratio measured by the accelerator mass spectroscopy method showed that the PLLA with 5 wt% myo-inositol was a fully biobased material. It was demonstrated that myo-inositol was a multi-functional biobased additive for the modification of PLLA without decreasing its mechanical properties.     

Synthesis of partially bio-based triepoxides from naturally occurring myo-inositol and their polyadditions

Partially bio-based triepoxides, 1,3,5-tri-O-methyl-2,4,6-tri-O-(oxiran-2-yl-methyl)-myo-inositol ( 4 ) and 2,4,6-tri-O-(oxiran-2-yl-methyl)-myo-inositol 1,3,5-orthoacetate ( 5 ), were synthesized from naturally occurring myo-inositol. These two triepoxides differ from each other in terms of rigidity of the core structure; while the former triepoxide has a more flexible cyclohexane core, the latter has a highly rigid adamantane-like orthoester core. Triepoxide 5 readily reacted with nucleophilic monomers such as diamines, dithiol, and trithiol to yield networked polymers. The glass transition temperatures (T_gs) of these polymers were higher than those of comparable networked polymers obtained by the polyaddition of triepoxide 4 with the same nucleophilic monomers, implying that the rigidity of the orthoester moiety contributed to the efficient restriction of the polymer chain in the synthesized networked polymers.     

Inositol synthesis: concise preparation of l-chiro-inositol and muco-inositol from a common intermediate

Fully stereoselective large-scale syntheses have been attained for l-chiro-inositol (2) and muco-inositol (3) by means of controlled peripheral oxygenation of cyclohexadiene diol 1.     

Die γ-Bestrahlung von Phytinsäure in wäßriger Lösung

Cleavage products observed to arise as a result of irradiation at a dose of 30 Mrad weremyo-inositol tetraphosphate,myo-inositol pentaphosphate andmyo-inositol isopentaphosphate.     

Stereoselective enzymatic synthesis of monoglucosyl-myo-inositols with in vivo anti-inflammatory activity

The monoglucosyl-inositols α-d-glucopyranosyl-(1→4)-4d-myo-inositol 3 and α-d-glucopyranosyl-(1→1)-1d-myo-inositol 4 were synthesized by a combined enzymatic transglucosylation and hydrolysis strategy, using cyclodextrin glucosyl transferase (CGTase) from Thermoanaerobacter sp., followed by hydrolysis with Aspergillus niger glucoamylase. The glucosides were separated by preparative HPLC and fully characterized by extensive 1D and 2D NMR studies. The structure of the regioisomer 4 was confirmed by X-ray crystallography of its perbenzoylated derivative 4a. Both isomers demonstrated in vivo anti-inflammatory activity at comparative levels to corticosterone on mouse ear oedema induced by 12-O-tetradecanoylphorbol-13-acetate (TPA) and in rat hind paw oedema induced by carrageenan.     

Regioselective O-acylation of myo-inositol 1,3,5-orthoesters: dependence of regioselectivity on the stoichiometry of the base

A metal mediated unusual 1-3 acyl migration from C4-O to C2-OH of myo-inositol 1,3,5-orthoformate was observed during the alkylation of racemic 4-O-benzoyl-myo-inositol 1,3,5-orthoformate. This has been exploited for the selective esterification of either the C4(6)-OH or the C2-OH of myo-inositol by varying the amount of the base used. While the use of 1 equiv of the base (sodium hydride or potassium tert-butoxide) for the acylation of myo-inositol orthoesters gives the corresponding C4-ester exclusively, the use of two or more equivalents of base for the same reaction gives the C2-ester exclusively. The relatively higher stability of the alkoxide of racemic 2-O-acyl-myo-inositol 1,3,5-orthoester as compared to the alkoxide of 4-O-acyl-myo-inositol 1,3,5-orthoester is suggested to be responsible for the observed isomerization.     

Regio- and stereospecific synthesis of dl-4,5-dibromo-4,5-dideoxy-3,6-O-methyl-chiro-inositol

The regio- and stereospecific synthesis of dl-4,5-dibromo-4,5-dideoxy-3,6-O-methyl-chiro-inositol is reported. Bromination of p-benzoquinone followed by reduction of the carbonyl groups with NaBH₄ gave the corresponding trans-dibromodiol compound, which was reacted with sodium methoxide to produce dimethoxy conduritol-B. Regiospecific bromination of the alkene moiety furnished the desired chiro-inositol derivative.