Benzylidene Acetal Group Research Articles

Acceleration and Deceleration Factors on the Hydrolysis Reaction of 4,6-O-Benzylidene Acetal Group.

The benzylidene acetal group is one of the most important protecting groups not only in carbohydrate chemistry but also in general organic chemistry. In the case of 4,6-O-benzylidene glycosides, we previously found that the stereochemistry at 4-position altered the reaction rate constant for hydrolysis of benzylidene acetal group. However, a detail of the acceleration or deceleration factor was still unclear. In this work, the hydrolysis reaction of benzylidene acetal group was analyzed using the Arrhenius and Eyring plot to obtain individual parameters for glucosides (Glc), mannosides (Man), and galactosides (Gal). The Arrhenius and Eyring plot indicated that the pre-exponential factor (A) and ΔS⧧ were critical for the smallest reaction rate constant of Gal among nonacetylated substrates. On the other hand, both Ea/ΔH⧧ and A/ΔS⧧ were influential for the smallest reaction rate constant of Gal among diacetylated substrates. All parameters obtained suggested that the rate constant for hydrolysis reaction was regulated by protonation and hydration steps along with solvation. The obtained parameters support wide use of benzylidene acetal group as orthogonal protection of cis- and trans-fused bicyclic systems through the fast hydrolysis of the trans-fused benzylidene acetal group.

ChemInform Abstract: The Total Synthesis of (.+‐.)‐Naupliolide: A Tetracyclic Sesquiterpene Lactone.

AbstractThe first total synthesis of racemic naupliolide is accomplished from a known cyclic acetal in a total of 18 steps and includes a Simmons‐Smith cyclopropanation of an allylic alcohol, diastereoselective cleavage of a benzylidene acetal group, radical cyclization of an aldehyde with a cyclopropane ring, and construction of an eight‐membered ring by ring‐closing metathesis.

The Total Synthesis of (±)-Naupliolide: A Tetracyclic Sesquiterpene Lactone.

The first total synthesis of (±)-naupliolide has been achieved. The synthetic method includes a Simmons-Smith cyclopropanation of an allyl alcohol, diastereoselective cleavage of a benzylidene acetal group, radical cyclization of an aldehyde with a cyclopropane ring, and construction of an eight-membered ring by ring-closing metathesis.

The Total Synthesis of (±)‐Naupliolide: A Tetracyclic Sesquiterpene Lactone

AbstractThe first total synthesis of (±)‐naupliolide has been achieved. The synthetic method includes a Simmons–Smith cyclopropanation of an allyl alcohol, diastereoselective cleavage of a benzylidene acetal group, radical cyclization of an aldehyde with a cyclopropane ring, and construction of an eight‐membered ring by ring‐closing metathesis.

Graft Copolymer Nanoparticles with pH and Reduction Dual-Induced Disassemblable Property for Enhanced Intracellular Curcumin Release

Nanoparticle (NP)-assisted drug delivery systems with disassemblable behaviors in response to intracellular microenvironment are urgently demanded in systemic cancer chemotherapy for enhanced intracellular drug release. Curcumin (CUR), an effective and safe anticancer agent, was limited by its water insolubility and poor bioavailability. Herein, pH and reduction dual-induced disassemblable NPs for high loading efficiency and improved intracellular release of CUR were developed based on an acid degradable cyclic benzylidene acetal groups (CBAs)-functionalized poly(2,4,6-trimethoxybenzylidene-1,1,1-tris(hydroxymethyl)ethane methacrylate)-g-SS-poly(ethylene glycol) (PTTMA-g-SS-PEG) graft copolymer, which was readily prepared via RAFT copolymerization and coupling reaction. The NPs self-assembled from PTTMA-g-SS-PEG copolymers were stable at physiological pH, and quickly disassembled in mildly acidic and reductive environments because of the hydrolysis of CBAs in hydrophobic PTTMA core and the cleavage of disulfide-linked detachable PEG shell. PTTMA-g-SS-PEG NPs exhibited excellent CUR loading capacity with drug loading content up to 19.2% and entrapment efficiency of 96.0%. Within 20 h in vitro, less than 15.0% of CUR was released from the CUR-loaded NPs in normal physiological conditions, whereas 94.3% was released in the presence of reductive agent and mildly acidic conditions analogous to the microenvironment in endosome/lysosome and cytoplasm. Confocal fluorescence microscopies revealed that the CUR-loaded PTTMA-g-SS-PEG NPs exhibited more efficiently intracellular CUR release for EC-109 cells than that of CUR-loaded reduction-unresponsive PTTMA-g-PEG NPs and free CUR. In vitro cytotoxicity studies displayed blank PTTMA-g-SS-PEG NPs showed low toxicity at concentrations up to 1.0 mg/mL, whereas CUR-loaded PTTMA-g-SS-PEG NPs demonstrated more efficient growth inhibition toward EC-109 and HepG-2 cells than reduction-unresponsive controls and free CUR. Therefore, the above results indicated that pH and reduction dual-induced disassemblable PTTMA-g-SS-PEG NPs may have emerged as superior nanocarriers for active loading and promoted intracellular drug delivery in systemic cancer chemotherapy.

Ring Cleavage Reactions of Methyl α-D-Allopyranoside Derivatives with Phenylboron Dichloride and Triethylsilane

In the course of our studies on the regioselective carbon-oxygen bond cleavage of the benzylidene acetal group of hexopyranosides with a reducing agent, we found that a combination of a Lewis acid and a reducing agent triggered a ring-opening reaction of the pyranose ring of methyl α-D-allopyranosides. The formation of an acyclic boronate ester by the attachment of a hydride ion at C-1 indicated that the unexpected endocyclic cleavage of the bond between the anomeric carbon atom and the pyranose ring oxygen atom proceeded via an oxacarbenium ion intermediate produced by the chelation between O5/O6 of the pyranoside and the Lewis acid, followed by nucleophile substitution with a hydride ion at C1.

Poly(isoglycerol methacrylate)-b-poly(d or l-lactide) Copolymers: A Novel Hydrophilic Methacrylate as Building Block for Supramolecular Aggregates

On the basis of a new acetal-protected glycerol monomethacrylate monomer (cis-1,3-benzylidene glycerol methacrylate/BGMA) a series of potentially biocompatible and partially biodegradable homo- and block copolymers were synthesized. ATRP polymerization of BGMA yielded well-defined polyacrylates with pendant benzylidene acetal groups and high glass transition temperatures (115−130 °C). This hydrophobic poly(cis-1,3-benzylidene glycerol methacrylate) could be readily transformed into the hydrophilic and water-soluble poly(1,3-dihydroxypropyl methacrylate), referred to as poly(isoglycerol methacrylate) (PIGMA). It exclusively contains primary hydroxyl groups and therefore differs significantly from the commonly known poly(glycerol methacrylate) (PGMA). Block copolymer systems based on poly(lactide) and BGMA were realized via two orthogonal living polymerization techniques starting from a bifunctional initiator, employing first atom transfer radical polymerization (ATRP) of BGMA and in the second step organo-...

マイクロフロー反応を鍵とする生理活性天然物の実用的合成戦略

Microfluidic conditions were applied to the acid-mediated reactions, namely, glycosylations, reductive opening of the benzylidene acetal groups, and dehydration, which are the keys to the practical synthesis of N-glycans and immunostimulating natural product, pristane. A distinctly different reactivity from that in the conventional batch stirring was found; the vigorous micromixing of the reactants with the concentrated acids is critical, especially for the “fast” reactions to be successful. Such a common feature might owe to the integration of all favorable aspects of microfluidic conditions, i.e., efficient mixing, precise temperature control, and the easy handling of the reactive intermediate by controlling the residence time. Distinctly different reactivity under microfluidic conditions also led to the success of the large-scale aldol condensation in aqueous biphasic system, as an example of the base-mediated reactions. The microfluidic reactions cited in this review, provoke the need to reinvestigate the traditional or imaginary reactions which have so far been performed and evaluated only in batch apparatus, and therefore, they could be recognized as a new strategy in synthesizing the natural products of the prominent biological activity in a “practical” and an “industrial” manner.

Acid-mediated reactions under microfluidic conditions: a new strategy for practical synthesis of biofunctional natural products.

Microfluidic conditions were applied to acid-mediated reactions, namely, glycosylation, reductive opening of the benzylidene acetal groups, and dehydration, which are the keys to the practical synthesis of N-glycans and the immunostimulating natural product, pristane. A distinctly different reactivity from that in conventional batch stirring was found; the vigorous micromixing of the reactants with the concentrated acids is critical especially for the “fast” reactions to be successful. Such a common feature might be due to the integration of all favorable aspects of microfluidic conditions, i.e., efficient mixing, precise temperature control, and the easy handling of the reactive intermediate by controlling the residence time. The microfluidic reactions cited in this review indicate the need to reinvestigate the traditional or imaginary reactions which have so far been performed and evaluated only in batch apparatus, and therefore they could be recognized as a new strategy in synthesizing natural products of prominent biological activity in a “practical” and a “industrial” manner.

Renaissance of Traditional Organic Reactions under Microfluidic Conditions: A New Paradigm for Natural Products Synthesis

Continuous flow synthesis for bioactive natural products is described. Efficient procedures using the microfluidic system were developed for the large-scale synthesis of important synthetic units of asparagine-linked oligosaccharide in glycoprotein. Advantageous aspects of microfluidic conditions, i.e., efficient mixing, fast heat transfer, and residence time control led to cation-mediated reactions, such as α-sialylation, β-mannosylation, and reductive opening of the benzylidene acetal groups in high yields. Microfluidic dehydration was developed for the industrial-scale synthesis of the immunostimulating natural terpenoid, pristane. The base-mediated aldol condensation in an aqueous biphasic system enabled the multigram synthesis of β-hydroxyketones in high yields.

Regioselective ring openings in the 3,5-dioxa-8-azabicyclo[5.2.0]nonane ring system

In order to distinguish primary and secondary hydroxyl groups in the presence of a β-lactam moiety benzylidene acetal protection and reductive cleavage were used. When the reductive ring opening was carried out using diisobutylaluminium hydride, the benzylidene acetal group remained intact, while the β-lactam was reduced to the corresponding β-amino alcohol. The acetal cleavage with sodium cyanoborohydride was successful, resulting mainly in a β-lactam compound bearing the benzyloxy group on the secondary carbon atom.

Synthesis of sialyl lewis X ganglioside analogues containing modified l-fucose residues

Sialyl Le x ganglioside analogues containing 2- epi-, 2,3-di- epi-, 4- epi-, and 2- O-methyl- l-fucose in place of the l-fucose residue have been synthesized. Glycosylation of 2-(trimethylsilyl)ethyl O-(2-acetamido-4,6- O-benzylidene-2-deoxy-β- d-glucopyranosyl)-(1 → 3)-2,4,6-tri- O-benzyl-β- d-galactopyranoside with the methyl 1-thioglycoside derivatives of the respective fucose analogues, using dimethyl(methylthio)sulfonium triflate (DMTST) as a promoter, gave the corresponding protected 2-(trimethylsilyl)ethyl deoxy-α- l-hexopyranosyl-(1 → 3)- O-(2-acetamido-2-deoxy-β- d-glucopyranosyl)-(1 → 3)-β- d-galactopyranosides. These were transformed by reductive ring-opening of their benzylidene acetal groups into the glycosyl acceptors. Dimethyl(methylthio)sulfonium triflate-promoted glycosylation of these compounds with methyl O-(methyl 5-acetamido-4,7,8,9-tetra- O-acetyl-3,5-dideoxy- d-glycero-α- d-galacto-2-nonulopyranosylonate)-(2 → 3)-2,4,6-tri- O-benzoyl-1-thio-β- d-galactopyranoside afforded the desired pentasaccharides, which were converted via reductive removal of their benzyl groups, O-acetylation, selective removal of the 2-(trimethylsilyl)ethyl group, and reaction with trichloroacetonitrile, into the corresponding α-trichloroacetimidates. Glycosylation of (2 S,3 R,4 E)-2-azido-3- O-benzoyl-4-octadecene-1,3-diol these in the presence of boron trifluoride etherate afforded the expected β-glycosides, which were transformed in good yields, via selective reduction of the azido group, coupling with octadecanoic acid, O-deacylation, and deesterification, into the target gangliosides. The 2-(trimethylsilyl)ethyl glycosides of sialyl Le x oligosaccharides containing modified fucose were also prepared from the intermediates of the ganglioside synthesis.

A Convenient Route to Functionalized Branched-Chain Sugars Via a Tosyl-Epoxide Derivative

Abstract Starting from methyl 4,6-O-benzylidene-2-deoxy-α-D-ribo-hexopyranoside-3-ulose 1 and proceeding through its corresponding tosyl-epoxide derivative 2, various branched-chain sugars (3-8) were prepared by nucleophilic and reductive ring openings. The presence of the sulfonylated oxirane group was found to be compatible with chemical transformations of the benzylidene acetal group (9-11), allowing facile access to the 6-deoxyhexoses (12-13).

3-O-benzoyl-4,6;4',6'-di-O-benzylidene-2,2'-dideoxy,alpha,alpha-ribo- trehalose.

The low-temperature X-ray structure of an asymmetrically substituted derivative of alpha,alpha-trehalose, 3-O-benzoyl-4,6;4',6'-di-O-benzylidene-2,2'-dideoxy-alpha,alpha-ribo-tre halose (3-O-benzoyl-4,6-O-benzylidene-2-deoxy-alpha-D-ribo-hexopyranosyl 4,6-O-benzylidene-2-deoxy-alpha-D-ribo-hexopyranoside, C33H34O10), is reported. The hexopyranosyl rings and the 1,3-dioxane rings have normal 4C1 chair conformations, so that each half of the molecule has a double-chair conformation, resembling a trans-decalin ring system. Each benzylidene acetal group takes the form of the thermodynamically more stable (R)-diastereomer with its phenyl group attached to the 1,3-dioxane ring in an equatorial orientation. The conformations about the glycosidic linkages are stabilized by the anomeric effect and by an intramolecular hydrogen bond between the lone hydroxy group and the glycosidic O atom.

Synthesis of deoxy- l-fucose-containing sialyl Lewis X ganglioside analogues

Sialyl Le x ganglioside anlogs containing 2-, 3-, and 4-deoxyfucose in the place of l-fucose have been synthesized. Glycosylation of 2-(trimethylsilyl)ethyl O-(2-acetamido-4,6- O-benzylidene-2-deoxy-β- d-glucopyranosyl)(1 → 3)-2,4,6-trio O-benzyl-β- d-galactopyranoside with the methyl 1-thioglycoside derivatives of the respective deoxyfucoses, using dimethyl(methylthio)sulfonium triflate (DMTST) as a promoter, gave the corresponding three protected 2-(trimethylsilyl)ethyl dideoxy-α- l-hexopyranosyl-(1 → 3)- O-2(-acetamido-2-deoxy-β- d-glucopyranosyl) (1 → 3)-β- d-galactopyranosides. These were transformed by reductive ring-opening of their benzylidene acetal groups into the glycosyl acceptors 6, 8, and 10. Dimethyl(methylthio)sulfonium triflate promoted glycosylation of 6, 8, and 10 with methyl O-(methyl 5-acetamido-4,7,8,9-tetra- O-acetyl-3,5-dideoxy- d- galacto-2-nonulopyranosylonate)- (2 → 3)-2,4,6-tri- O-benzoyl-1-thio-β- d-galactopyranoside afforded the desired pentasaccharides, which were converted via reductive removal of their benzyl groups, O-acetylation, selective removal of the 2-(trimethylsilyl)ethyl group, and reaction with trichloroacetonitrile, into the corresponding α-trichloroacetimidates 14, 18, and 22. Glycosylation of (2 S,3 R,4 E)-2-azido-3- O-benzoyl-4-octadecene-1,3-diol with 14, 18, and 22 in the presence of boron trifluoride etherate afforded the expected β-glycosides, which were transformed in good yields, via selective reduction of the azido group, coupling with octadecanoic acid, O-deacylation, and deesterification, into the target compounds.

Synthetic Mucin Fragments: Methyl-3-O-(2-Acetamido-2-Deoxy-4-O- and 6-O-β-D-Galactopyranosyl-β-D-Glucopyranosyl)-β-D-Galactopyranoside and Methyl 3-O-(2-Acetamido-2-Deoxy-4-O- and 3-O-Methyl-β-D-Glucopyranosyl-3-D-Galactopyranoside

Abstract Glycosylation of methyl 3-O-(2-acetamido-3, 6-di-O-benzyl-2-deoxy-β-D-glucopyranosyl)-2,4,6-tri-O-benzyl-β-D-galactopyranoside (2) with 2,3,4,6-tetra-O-acetyl-α-D-galactopyranosyl bromide (1), catalyzed by mercuric cyanide, afforded a trisaccharide derivative, which was not separated, but directly O-deacetylated to give methyl 3-O-(2-acetamido-3,6-di-O-benzyl-2-deoxy-4-O-β-D-galactopyranosyl-β-D-giucopyranosyl)-2,4,6-tri-O-benzyl-β-D-galactopyranoside (8). Hydrogenolysls of the benzyl groups of 8 then furnished the title trisaccharide (9). A similar pflyccsylation of methyl 3-O-(2-acetamido-3-O-acetyl-2-deoxy-β-D-glucopyranosyl)-2,4,6-tri-O-benzyl- β-D-galactopyranoside (obtained by acetylation of 4, followed by hydrolysis of the benzylidene acetal group) with bromide 1 gave a tribenzyl trisaccharide, which, on catalytic hydrogenolysls, furnished the isomeric trisaccharide (12). Methylation of 4 and 2 with methyl iodide-silver oxide in 1:1 dichloro-methane-N, N-dimethylformamide gave the 3-O- and 4-O-monomethyl ethers (13) and (15), respectively. Hydrogenolysis of the benzyl groups of 13 and 15 then provided the title monomethylated disaechartdes (15) and (16), respectively. The structures of trisacchacides 9 and 12, and disaccharides 14 and 16 were all established by 13C MMR spectroscopy.