Diacetone Glucose Research Articles

Synthesis, Biological Evaluation, and Docking Studies of Open-Chain Carbohydrate Amides as Acetylcholinesterase Inhibitors.

Alzheimer's disease is a multifactorial syndrome, which is not yet fully understood, causing memory loss, dementia, and, ultimately, death. Acetylcholinesterase inhibitors are the mainstay drugs that are used in disease-symptomatic treatment. In this work, we report a new synthetic route yielding sugar amides as low to moderate acetylcholinesterase inhibitors. Commercially available diacetone glucose was converted into perbenzyl D-glucono-1,4- lactone, which reacted with aromatic or aliphatic amines to afford the corresponding new amides in a high isolated yield. Docking studies of the most promising hydroxybutylamide and benzylamide were performed to assign binding interactions with acetylcholinesterase and determine the key features for bioactivity. The inhibitors are accommodated in enzyme gorge, blocking the access to Ser203 mainly due to π-π stacking interactions of sugar benzyl groups with the aromatic gorge residues, Tyr337 and Tyr341 for both inhibitors and Trp439 only for the hydroxybutylamide. Bonding is also significant through sugar interaction with the residues Tyr124 and Ser125-OH in both inhibitors. Flexibility of these open-chain structures seems to be quite relevant for the observed binding to acetylcholinesterase.

Synthesis, characterization and polymerization of novel sugars based on methacrylate

The present study describes the synthesis and characterizations of polymerizable vinyl sugars. Glucose, mannose, galactose and fructose are abundant and sustainable natural compounds. As it is not possible to make many derivatives of sugars without using protective groups, first of all, diacetone derivatives [diacetone-d-glucose (1), diacetone-d-mannose (2), diacetone-d-galactose (3) and diacetone-d-fructose (4)] were synthesized according to the literature as starting compounds. The remaining free hydroxyl groups on C-3 (diacetone glucose), C-6 (diacetone galactose), C-1 (diacetone fructose) and C-1 (diacetone mannose), were reacted with epichlorohydrin (1-chloro-2,3-epoxypropane) to produce then “-O-(2′,3′-epoxypropane-1′-yl)” ether derivatives (5, 6, 7, and 8) which are epoxy sugars in the basic medium. Next, the epoxy rings of the ethers (5, 6, 7, and 8) were opened with methacrylic acid in DMF to produce new sugar based methacrylates (9, 10, 11, and 12). Finally, free radical polymerization of these sugar based methacrylate monomers was performed, producing related polymers (13, 14, 15 and 16). The polymerizations were carried out using AIBN as an initiator at 70 °C in DMF. All the products were characterized by FTIR, 1HNMR and 13CNMR techniques. Thermal properties of all polymers were investigated by TG, DTG and DSC. The data obtained has suggested that thermal stability of the synthesized polymers has changed with the structure of the sugar and increase in molecular weight.

Stereoselective Michael addition of O-nucleophiles to carbohydrate-based nitro-olefin

Abstract Michael addition reactions of O-nucleophiles to C(3) exocyclic nitromethylene derivative of diacetone glucose are reported. The reactions with primary alcohols proceed at ambient temperature in the presence of different bases with good yields and give products with excellent diastereoselectivity. The addition of the nucleophile occurs from the β-face of the carbohydrate as shown by single crystal X-ray analysis. The reactions with secondary alcohols give low yields of products while phenolic compounds do not react. Under certain conditions, isomerization of starting material is observed.

Synthesis of Novel Pyran β-Amino Acid and 5,6-Dihydro-2H-pyran β-aminoxy Acid from Carbohydrate Derivatives

Synthesis of two new amino acids, containing pyran rings, is reported from carbohydrate derivatives. The cis-3-amino-pyran-2-carboxylic acid (cis-APyC) was prepared from (R)-glyceraldehyde derivative, using nucleophilic substitution reaction for pyran ring formation. Similarly, the trans-3-aminoxy-5,6-dihydro-2H-pyran-2-carboxylic acid (trans-AmPyC) was prepared from diacetone glucose (DAG), using ring closing metathesis (RCM) reaction for the ring formation.

Modular Synthesis of Constrained Ethyl (cEt) Purine and Pyrimidine Nucleosides.

A modular and scalable approach to pyrimidine- and purine-containing constrained ethyl (cEt) nucleosides is demonstrated. Minimizing stereochemical adjustments and protecting group manipulations, diacetone glucose is converted to two representative cEt nucleosides via a functionalized, common intermediate. The retrosynthetic approach to this complex class of drug precursors offers clear benefits over existing routes based on step count and efficiency.

Design and synthesis of novel oxetane β3-amino acids and α, β-peptides

The study describes synthesis of (S)- and (R)-oxetane-β3-amino acid (β3-Oaa) monomers from diacetone glucose (DAG). The oxetane ring is prepared by a nucleophilic cyclization reaction, wherein, the C-3 and C-4 stereocenters of DAG represent the C-2 and C-1 of oxetane ring, respectively. The hydroxy methyl group generated from C-1/C-2 was used for the ring formation, and C-5/C-6 of DAG were used for the introduction of amine and ester groups via aza-Michael addition reaction on the α, β-unsaturated ester. The stereochemistry at the newly created amine center was defined through modified Mosher method. The (S)-β3-Oaa monomer and l-Ala were used for the synthesis of regular 1:1 was converted into α, β-peptides. The conformational analysis of the peptides revealed the presence of 11/9-helical patterns from the NMR, CD and MD studies.

DMAP‐Catalysed Sulfinylation of Diacetone‐D‐Glucose: Improved Method for the Synthesis of Enantiopure tert‐Butyl Sulfoxides and tert‐Butanesulfinamides

AbstractAn improved method for the tert‐butanesulfinylation of diacetone glucose with tert‐butanesulfinyl chloride is reported. The method is based on a beneficial effect of catalytic DMAP, which enhances both the rate of the reaction and the enantioselectivity of the process to give (RS)‐diastereomer 2RS with a 94 % de and in quantitative yield. (RS)‐DAG sulfinate ester 2RS is an excellent intermediate for the synthesis of enantiopure tert‐butyl sulfoxides. Grignard agents and organolithium reagents can displace smoothly the diacetone glucose moiety to give synthetically relevant enantiopure sulfoxides, including highly functionalized derivatives, in high yields and with high enantioselectivities. (RS)‐DAG sulfinate ester 2RS is also an excellent N‐sulfinylating agent; simple addition of LiHMDS (lithium hexamethyldisilazide) in THF gives (SS)‐tert‐butanesulfinamide, and N‐tert‐butanesulfinylimines are then formed in a two‐step one‐pot manner. N‐Alkylated tert‐butanesulfinamides are formed by the condensation of 2RS with lithium amides.

Total Synthesis of 6-O-Benzoylzeylenol from Diacetone Glucose

A total synthesis of 6-<i>O</i>-benzoylzeylenol from diacetone glucose is described. The key steps were a crossed aldol–Cannizzaro reaction to create a quaternary carbon stereocenter, and cyclization through ring closure metathesis (RCM). Of the four stereogenic centers, two were derived from diacetone glucose, the quaternary stereocenter was created by means of the crossed aldol–Cannizzaro reaction, and the fourth stereogenic center was produced by a Sharpless asymmetric epoxidation. Finally, cyclization through RCM and deprotection by removal of a benzyl group with titanium(IV) chloride gave the target molecule.

Total Synthesis of Macrosphelide M from Diacetone Glucose

AbstractThe total synthesis of macrosphelide M is described. The key steps include the preparation of the acid and alcohol fragments from diacetone glucose and (S)‐malic acid, respectively, followed by Yamaguchi esterification and macrocyclization of the tris‐olefin by ring‐closing metathesis. Finally, one‐pot deprotection of the PMB and TBS groups with TiCl4 results in the target. The C‐3/C‐4 stereocenters of diacetone glucose are used for the introduction of four stereocenters, whereas the fifth stereocenter is realized from (S)‐malic acid.

Structural requirements for hybridization at the 5′-position are different in α-l-LNA as compared to β-d-LNA

The synthesis and biophysical evaluation of R and S-5'-Me-α-l-LNA nucleoside phosphoramidites and modified oligo-2'-deoxyribonucleotides is reported. Synthesis of the nucleoside phosphoramidites was accomplished in multi-gram quantities starting from diacetone glucose. The 5'-methyl group in the S configuration was introduced by reacting the sugar 5'-aldehyde with MeMgBr. Synthesis of the R-5'-Me isomer was accomplished from the S-5'-Me nucleoside by a late stage inversion using Mitsunobu conditions. Evaluation of the modified oligonucleotides in thermal denaturation experiments revealed that R-5'-Me-α-l-LNA showed similar RNA affinity as α-l-LNA while the S-5'-Me analog was less stabilizing. This result is in contrast to the β-d-series where the S-5'-Me isomer showed LNA-like affinity for RNA while the R-5'-Me group completely reversed the stabilization effect on duplex thermostability.

3- O-Acyl triggered tandem Lewis acid catalyzed intramolecular cyclization of diacetone glucose derivatives to 5- O-acyl-3,6-anhydro- d-glucose

BF 3 mediated one-pot conversion of 3- O-acyl- d-glucose-1,2:5,6-diacetonide derivatives to 5- O-acyl-3,6-anhydro- d-glucose is described through a tandem selective intramolecular cyclization sequence.

Synthesis and biophysical evaluation of 3′-Me-α-l-LNA – Substitution in the minor groove of α-l-LNA duplexes

The synthesis and biophysical evaluation of 3'-Me-α-L-LNA is reported. The synthesis of the nucleoside building block phosphoramidite was accomplished starting from diacetone glucose. The 3'-Me group was introduced in the desired configuration by hydride mediated opening of an exocyclic epoxide. Inversion of the 2'-hydroxyl group was achieved by means of an oxidation/reduction sequence followed by cyclization onto a 5'-leaving group to assemble the [2.2.1] ring system. Biophysical evaluation of 3'-Me-α-L-LNA modified oligonucleotides showed good duplex thermal stabilizing properties which were similar to α-L-LNA. Mismatch discrimination experiments revealed that 3'-Me-α-L-LNA possess slightly enhanced discrimination properties for the GU wobble base-pair as compared to related nucleic acid analogs.

First synthesis of 4a-carba-β- d-galactofuranose

The synthesis of 4a-carba-β- d-galactofuranose is described starting from diacetone glucose. The key ring-closure step was carried out by metathesis to form a cyclopentene. Catalytic hydrogenation of the C C double bond gave the galacto configured saturated carbahexofuranose with excellent diastereoselectivity.

Practical and Efficient Synthesis of a Chiral C5 Building Block, 2-O-Allyl-d-arabinose, from Diacetone-d-glucose

The first syntheses of a 2-O-allylpentose are described. Starting from D-arabinose (2), 2-O-allyl-D-arabinose (1) was obtained in 36-42% yield over five steps. A practical and efficient synthesis from cheap and abundant diacetone glucose yielded 56% of 1 over only three steps.

A Modular Strategy Toward the Synthesis of Heparin-like Oligosaccharides Using Monomeric Building Blocks in a Sequential Glycosylation Strategy

A novel flexible assembly strategy is described for the modular synthesis of heparin and heparan sulfates. The reported strategy uses monomeric building blocks to construct the oligosaccharide chain to attain a maximum degree of flexibility. In the assembly, 1-hydroxyl glucosazido- and 1-thio uronic acid donors are combined in a sequential glycosylation protocol using sulfonium triflate activator systems. The key 1-thio uronic acids were obtained in an efficient manner from diacetone glucose employing a chemo- and regioselective oxidation of partially protected glucose and idose thioglycosides.

A radical mediated first total synthesis from ‘diacetone glucose’ and determination of the absolute stereochemistry of xylobovide

The first total synthesis by an intramolecular radical cyclisation protocol on a carbohydrate derived 5-hexynyl system, and determination of the absolute stereochemistry of xylobovide are reported.

Practical synthesis of a potent hepatitis C virus RNA replication inhibitor.

A practical, efficient synthesis of 1, a hepatitis C virus RNA replication inhibitor, is described. Starting with the inexpensive diacetone glucose, the 12-step synthesis features a novel stereoselective rearrangement to prepare the key crystalline furanose diol intermediate. This is followed by a highly selective glycosidation to couple the C-2 branched furanose epoxide with deazapurine.

Synthesis of Iduronic Acid Building Blocks for the Modular Assembly of Glycosaminoglycans

The modular synthesis of glycosaminoglycans requires straightforward methods for the production of large quantities of protected uronic acid building blocks. In particular, the preparation of fully differentiated iduronic acids has proven particularly challenging. An efficient route to methyl 3-O-benzyl-1,2-O-isopropylidene-alpha-l-idopyranosiduronate 6 from diacetone glucose in nine steps and 36% overall yield is described. Idopyranosiduronate 6 is useful as a glycosyl acceptor and as an intermediate that may be further elaborated into iduronic acid trichloroacetimidate glycosyl donors for the assembly of glycosaminoglycan structures as illustrated here.

Synthesis and structure of titanium alkoxide complexes with bulky ligands derived from natural products: Asymmetric epoxidation of cinnamyl alcohol

A family of titanium(IV) alkoxide compounds [{Ti(OPr i ) 3(OR)} 2], [{Ti(OPr i ) 2(OR) 2} 2], and Ti(OR) 4 ( 1– 12) have been prepared using two different routes: by metathesis reaction of TiCl(OPr i ) 3 and TiCl 2(OPr i ) 2 with ROH in the presence of Et 3N and alternatively by alcohol exchange of Ti(OPr i ) 4 and the corresponding higher boiling alcohol (ROH=adamantanol, 1,2:3,4-di- O-isopropylidene-α- d-galactopyranose, 1,2:5,6-di- O-isopropylidene-α- d-glucofuranose, 1 R,2 S,5 R-(−)-menthol). These tetra alkoxide titanium(IV) compounds have been characterized by spectroscopic techniques. In addition, some of these chiral Lewis acid titanium compounds, derived from diacetone galactose and diacetone glucose, have been studied in the asymmetric epoxidation of cinnamyl alcohol in order to evaluate their catalytic activity and stereoselectivity.

Synthesis of C‐Linked Sugar Butenolides and Their Conversion into C‐Linked Isoxazolidine Saccharides.

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