Chelation controlled regiospecific O-substitution of myo-inositol orthoesters: convenient access to orthogonally protected myo-inositol derivatives

A general method for the completely regioselective protection of the three secondary hydroxyl groups of orthoester derivatives of myo-inositol, utilizing the subtle differences in reactivity exhibited by its alkali metal alkoxides due to differences in their ability to form chelates, is described. This method provides convenient access to orthogonally protected myo-inositol derivatives. A comparison of the methylation of racemic 4-O-trityl-myo-inositol 1,3,5-orthoformate in the presence of sodium or lithium ions showed that stabilization of the C4-alkoxide by chelation with lithium overrides steric hindrance offered by the C6-axial substituent in deciding the regioselectivity during the nucleophilic O-substitution.     

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.     

Regioselective phosphorylation of vicinal 3,4-hydroxy myo-inositol derivative promoted practical synthesis of d-PtdIns(4,5)P2 and d-Ins(1,4,5)P3

The reactivity of 3 and 4-OH in 3,4-diol myo-inositol derivatives were observed through the phosphorylation, acylation and silylation. The results indicated that 3-OH is much more reactive than 4-OH, giving regiospecifically 3-mono-functionalized products. This investigation provided a concise methodology for the synthesis of natural d-form of PtdIns(4,5)P2 and d-Ins(1,4,5)P3 from l-1,2-O-cyclohexylidene-3,4-O-(tetraisopropyl disiloxane-1,3-diyl)-myo-inositol.     

NMR and X-Ray Diffraction Study of Some Inositol Derivatives 1

Abstract

We have determined the preferred conformers in solution by a detailed NMR analysis using COSY and HETCOR experiments of three inositol isomers: myo (1), scyllo (2) and epi (3) plus sixteen derivatives of myo-inositol: 1,2,3,4,5,6-hexa-O-acetyl-myo-inositol (4), 1,2,-O-isopropylidene-myo-inositol (5), 1,2:4,5-di-O-isopropylidene-myo-inositol (6), 3,4,5,6-tetra-O-acetyl-1,2-O-isopropylidene-myo-inositol (7), 3,4,5,6-tetra-O-acetyl-myo-inositol (8), 1,2-O-isopropylidene-3,6-di-O-tosyl-myo-inositol (9), 1,2-O-isopropylidene-3,4,6-tri-O-tosyl-myo-inositol (10), 1,2:4,5-di-O-isopropylidene-3-O-tosyl-myo-inositol (11), 3,6-di-O-benzyl, 1,2:4,5-di-O-isopropylidene-myo-inositol (12), 3,6-di-O-benzyl-1,2-O-isopropylidene-myo-inositol (13), 3,6-di-O-benzyl-myo-inositol (14), 1,2-O-cyclohexylidene-myo-inositol (15), 1,2:4,5-di-O-cyclohexylidene-myo-inositol (16), 1,2:5,6-di-O-cyclohexylidene-myo-inositol (17), 1,3,5-O-(orthoformate)-myo-inositol (18) and 2-benzyl-1,3,5-O-(orthoformate)-myo-inositol (19). The X-ray diffraction structure of compounds 2, 6-8, 18 and 19 are reported.

     

Inositol derived crown ethers: effect of auxiliary protecting groups and the relative orientation of crown ether oxygen atoms on their metal ion binding ability

The binding constants of crown ethers prepared from tetra-O-substituted myo- and scyllo-inositol derivatives and 2-O-substituted myo- and scyllo-inositol-1,3,5-orthoformates, with metal picrates show that the O-substituents and the relative orientation of the crown ether oxygen atoms contribute significantly to the binding of crown ethers with metal ions. In particular, the binding efficiency of myo-inositol derived crown ethers to silver and potassium ions could be enhanced by introducing benzyl ethers in the inositol ring. Hence binding efficacy and selectivity of metal ions to inositol derived crown ethers can be tuned by varying substituents on the myo-inositol ring and/or the relative orientation of crown ether oxygen atoms.     

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.     

A potassium–18-crown-6 salt of a cyclic myo-inositol phosphate

The six-membered phosphorinane ring in (1,4,7,10,13,16-hexaoxa­cyclo­octa­decane)­potassium 2-O-benzoyl-1,3,5-O-methyl­idyne-myo-in­osi­tol 4,6-cyclo­phosphate trihydrate, [K(C₁₂H₂₄O₆)](C₁₄H₁₂O₉P)·3H₂O, has a boat rather than a chair conformation. The K⁺ ion is eight-coordinate and is connected to one of the phosphate O atoms, one of the O atoms of the myo-inositol residue and the six O atoms of the crown ether.     

Thermal epimerization of inositol 1,3-benzylidene acetals in the molten state

1,3-O-Benzylidene-2,4,5,6-tetra-O-substituted-myo-inositol derivatives obtained by the DIBAL-H reduction of the corresponding myo-inositol 1,3,5-orthobenzoate derivatives undergo epimerization at the acetal carbon on heating, in the molten state, just above their melting point. The same epimerization reaction does not proceed either in the crystalline state or in solution. DFT calculations suggest that the epimeric acetal obtained by this thermal process is relatively more stable than the starting acetal. Either of these acetals could not be obtained by the reaction of the corresponding inositol derived diol with benzaldehyde. These observations constitute a novel reaction solely in the molten state, which are rarely encountered in the literature. X-ray crystal structures of the epimeric acetals as well as their radical deoxygenation reaction are also reported.     

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 kinetic resolution of (±)-1,2-O-isopropylidene-3,6-di-O-benzyl-myo-inositol with the lipase B of Candida antarctica

(±)-1,2-O-Isopropylidene-3,6-di-O-benzyl-myo-inositol is a relevant starting material in the synthesis of inositol phosphates and their analogs. In this study, we disclose our efforts toward an efficient methodology for the kinetic resolution of this compound by lipase B of Candida antarctica (Novozym 435). This reaction selectively affords L-(?)-1,2-O-isopropylidene-5-O-acetyl-3,6-di-O-benzyl-myo-inositol. From a conversion of 34% with EtOAc as an acylating agent, the use of vinyl acetate increased the yield to over 49%, while maintaining a very high ee (>99%). The combination of the latter reagent with TBME as a solvent accelerates the reaction.     

Iodonium Ion-Mediated Mannosylations of Myo-Inositol : Synthesis of a Mycobacteria Phospholipid Fragment

Abstract

Iodonium ion-mediated glycosylation of 1-O-allyl-3,4,5-tri-O-benzyl-6-O-para-methoxybenzyl-D/L-myo-inositol by ethyl 2-O-benzoyl-3,4,6-tri-O-benzyl-l-thio-α-D-mannopyranoside gave, after removal of the para-methoxybenzyl group and column chromatography, an α/β-mixture of the individual diastereoisomeric disaccharides. Subsequent stereospecific glycosylation of the α(1-2) linked mannopyranosyl-D-myo-inositol enantiomorph by the same ethyl 1-thiomannopyranoside donor afforded, after debenzoylarion, benzylation and subsequent deallylation the partially benzylated 2,6-dimannopyranosyl-D-myo-inositol derivative, the HO-1 position of which was phosphorylated, via the H-phosphonate method, with 1,2-dipalmitoyl-sn-glycerol. Oxidation of the intermediate phosphonate diester, and subsequent hydrogenolysis of the O-benzyl groups, furnished the target compound 1-O-(1,2-dipalmitoyl-sn-glycero-3-phosphoryl)-2,6-di-O-α-D-mannopyranosyl-D-myo-inositol.     

Practical synthesis of a differentially protected myo-inositol

An enantiospecific synthesis of 3,4,5-tri-O-benzyl-6-O-triisopropylsilyl-D-myo-inositol from D-xylose is reported. The synthesis features a diastereofacially selective SmI₂-promoted pinacol cyclization.     

Syntheses of O-(2-Acetamido-2-Deoxy-α-D-Galactopyranosyl)-Myo-Inositols

ABSTRACT

The structure of an O-(2-acetamido-2-deoxy-α-D-galactopyranosyl)-myo-inositol isolated from human pregnancy urine has previously been identified as that of 1-O-(2-acetamido-2-deoxy-α-D-galactopyranosyl)-myo-inositol. In order to ascertain the absolute configuration in the inositol part of the compound, the 1D- and 1L- isomers were synthesised. Since none of these two stereoisomers corresponded to the natural product, the corresponding 2-O-, the mixture of the two 1DL-4-O-, and 5-O- isomers were also synthesised. None of these gave ¹H NMR spectra corresponding to the natural product, the structure of which therefore remains unresolved.     

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.     

A convenient synthesis of the core trisaccharide of the N-glycans

A convenient synthesis of the core trisaccharide of the N-glycans was described. Orthogonal one-pot glycosylation of three monosaccharide building blocks was performed to furnish β-glucosyl chitobiose, which was then transformed to β-mannosyl chitobiose by intramolecular epimerization of the C-2 position of the β-glucoside. The key glucosyl donor 7c with differentiated 2,3-OH was prepared following the 4,6-O-benzylidene-protected 1,2-orthoester strategy.     

An unusual twist conformation of 2-O-methyl-1,3,4,5-tetrakis-O-tert-butyldiphenylsilyl-myo-inositol

The ring conformation of 2-O-methyl-1,3,4,5-tetrakis-O-tert-butyldiphenylsilyl-myo-inositol was in a twist form both in solid state and in solution. This is the first observation of a stable twist conformer induced by the introduction of bulky silyl protecting groups.     

Improved Preparation of Cyclohexylidene Derivatives of MYO-Imositol

Condensation of myo-inositol with 1,1-dimethoxy-cyclohexane in the presence of Nafion-H affords directly 1,2-O-cyclohexylidene-myo-inositol in 45 - 50% yield, along with 1,2:3,4-, 1,2:4,5- and 1, 2 : 5,6-di-O-cyclohexylidene-myo-inositols in lesser amounts.     

A formal synthesis of valiolamine from myo-inositol

An efficient formal synthesis of racemic valiolamine starting from readily available myo-inositol is reported. In all the synthetic steps only one regioisomer is formed, which circumvents laborious purification of products. Regioselective benzylation of myo-inositol orthoformate, super-hydride mediated deoxygenation of a cyclitol derivative and stereoselective addition of dichloromethyllithium to an inosose are the key reactions in the synthesis.     

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.     

Composition analysis of positional isomers of phosphatidylinositol by high-performance liquid chromatography

An HPLC-based method has been developed for composition analysis of six positional isomers of phosphatidylinositol (PI), of which the phosphatidyl group was connected to different positions of the myo-inositol moiety. The method employed a combination of two types of HPLC analyses. One was direct separation of the six PI isomers into four peaks of 1(3)-PI, 2-PI, 4(6)-PI and 5-PI on a normal-phase silica gel column. The second method was for the separations of 1-PI from 3-PI and 4-PI from 6-PI, which were not separable on the normal-phase column. This method involved conversion of PI isomers into pentakis-(R)-1-phenylethylcarbamate (PEC) derivatives, which were separated on a reversed-phase column. Using the established method, positional specificity of several engineered phospholipases D in enzymatic synthesis of PI from myo-inositol and phosphatidylcholine was investigated. This was performed by analyzing the isomeric composition of PIs synthesized by the mutant enzymes. Among five mutant enzymes tested, two showed strong specificity to 1-OH, one showed moderate preference to 1-OH, one preferred 3-OH, and one showed broad specificity towards 1-, 3-, 4- and 6-OH.