29514-28-1

The invention relates to the technical field of organic synthesis, in particular to a method for preparing an eribulin dehydroxylation intermediate by a one-pot method, which comprises the following steps of in an organic solvent, taking a compound I as a raw material, carrying out oxidation-reduction reaction on the compound I, a reducing agent, a catalyst and alkali, and separating and purifying reaction liquid to obtain a compound as shown in a formula II, namely the eribulin dehydroxylation intermediate. According to the method disclosed by the invention, sulfonyl chloride, Pd/C, iodine elementary substance and pyridine which are not green and are high in price are not used, but cheap and green reagents are adopted for replacement, so that the greenness, the economical efficiency and the safety of the reaction are remarkably improved. The reaction efficiency is greatly improved and the reaction cost is reduced by shortening the reaction steps and the reaction time.

The present invention relates to novel intermediates of Eribulin and process for the preparation of the same. The process of the present invention is commercially viable and can be easily adopted for plant scale operations. The present invention relates to tetrahydrofuran compounds of formula I, X, XI, D and B.

A novel, practical and concise synthesis of 1,3,4,6-tetra-O-acetyl-l-gulose is described, using d-glucuronolactone as the starting material and other inexpensive and readily available agents (22% overall yield in 9 steps). With this method, the synthesis of l-gulose and the tumor-targeting disaccharide of BLMs can be more efficient and convenient.

Glucuronolactones were used as precursors for N9 and N 7 purine nucleosides containing glucuronic acid derivatives in their structures. Acetylated N-benzylglucofuran- and glucopyranuronamides were synthesized in a few steps from glucofuranurono-6,3-lactone. They were converted into the corresponding furanosyl and pyranosyl uronamide-based nucleosides by N-glycosylation with silylated 2-acetamido-6-chloropurine in the presence of trimethylsilyl triflate. The triacetylated bicyclic lactone was coupled itself with the nucleobase to give bicyclic N9,N7 nucleosides. Tri-O-acetylglucopyranurono-6,1-lactone was used for the first time as a glycosyl donor for N-glycosylation, and led to β-configured N9- and N7-linked purinylglucuronides under reaction conditions similar to those used with the 1-O-acetyl-substituted glycosyl donors. The cholinesterase inhibitory profiles of the synthetic nucleosides bearing glucuronic acid derivatives as glycons were evaluated, and they showed moderate selective acetylcholinesterase inhibitory activities (Ki = 14.78-50.53 μM). The best inhibition was shown by the furanosyl N 9-linked uronamide-based purine nucleoside. The synthesis of furanosyl and pyranosyl N9 and N7 purine nucleosides containing glucofuranurono-6,3-lactone, N-benzylglucuronamide, and glucuronic acid moieties is reported. Glucuronolactones were used as glycosyl donors or converted into suitable 1-O-acetyl derivatives for purine glycosylation. Some nucleosides showed moderate and selective inhibition of acetylcholinesterase. Copyright

Attempted synthesis of the imidazylate derivative of 1,2-O-isopropylidene- α-D-glucurono-6,3-lactone (2) via treatment with sulfuryl chloride in the presence of excess imidazole in DMF at either -40°C or -70°C resulted in the unexpected formation of 5-chloro-5-deoxy-1,2-O-isopropylidene-β-l- idurono-6,3-lactone (7). Chloride 7 presumably forms via the rapid S N2 displacement by a chloride ion of an initially formed chlorosulfate ester intermediate, which is evidently unusually reactive. The identity of the product was confirmed by a single-crystal X-ray structure determination. Taylor & Francis Group, LLC.

A panel of 1-deoxynojirimycin (DNJ) N-linked peptides were synthesized. Their IC50 values were measured in vitro against a-glucosidases I and II and were found to be in the micromolar range for both isozymes, and better than that of the iminosugar NB-DNJ (miglustat, 3) against a-glucosidase II. Cell-based studies revealed that although the free iminosugar 3 is most effective at disrupting N-linked glycan processing for shortterm incubations (one day), when the cell-based studies were extended to three days, the DNJ N-linked tetrapeptide KDEL, which is an endoplasmic reticulum (ER)-retaining sequence, performed far better than 3. In low inhibitor washout studies, NB-DNJ inhibition was decreased to zero after 24 h, but DNJ- KDEL retained 13% activity. This method offers a general approach for targeting drugs to the ER and prolonging their activity. Moreover, it is modular, so as new iminosugars of increased potency are discovered, they can be added to this template for targeting.

Multikilogram manufacturing process of the Halaven C14-C35 fragment is described. The synthesis features convergent assembly of subunits by iterative asymmetric Ni/Cr-mediated coupling executed in fixed equipment. Georg Thieme Verlag Stuttgart - New York.

The efficient scalable syntheses of 2-acetamido-1,2-dideoxy-D-galacto- nojirimycin (DGJNAc) and 2-acetamido-1,2-dideoxy-D-gluco-nojirimycin (DNJNAc) from D-glucuronolactone, as well as of their enantiomers from L-glucuronolactone, are reported. The evaluation of both enantiomers of DNJNAc and DGJNAc, along with their N-alkyl derivatives, as glycosidase inhibitors showed that DGJNAc and its N-alkyl derivatives were all inhibitors of α-GalNAcase but that none of the epimeric DNJNAc derivatives inhibited this enzyme. In contrast, both DGJNAc and DNJNAc, as well as their alkyl derivatives, were potent inhibitors of β-GlcNAcases and β-GalNAcases. Neither of the L-enantiomers showed any significant inhibition of any of the enzymes tested. Correlation of the in vitro inhibition with the cellular data, by using a free oligosaccharide analysis of the lysosomal enzyme inhibition, revealed the following structure-property relationship: hydrophobic side-chains preferentially promoted the intracellular access of iminosugars to those inhibitors with more-hydrophilic side-chain characteristics. Getting the NAc of it: Scalable syntheses of DGJNAc and DNJNAc from D-glucuronolactone are reported. DGJNAc and its N-alkyl derivatives were inhibitors of α-GalNAcase and both DGJNAc and DNJNAc were potent inhibitors of β-GlcNAcases and β-GalNAcases. Copyright

The first stereocontrolled synthesis of vittarilide-A and its C5-epimer was completed from d-glucuronolactone. Comparison with the spectroscopic properties reported for authentic material has given a clear indication as to the absolute stereochemistry of the natural vittarilide-A.

A library of paclitaxel (taxol) mimics was obtained by a straightforward strategy involving rational design and an efficient synthesis of a simplified taxane core substitute, together with a click-chemistry combinatorial search for phenylisoserine side-chain surrogates.

The monosaccharide moieties found in heparin (HP) and heparan sulfate (HS), glucosamine and two kinds of uronic acids, glucuronic and iduronic acids, were efficiently synthesized by use of glucosamine hydrochloride and glucurono-6,3-lactone as starting compounds. In the synthesis of the disaccharide building block, the key issues of preparation of uronic acids (glucuronic acid and iduronic acid moieties) were achieved in 12 steps and 15 steps, respectively, without cumbersome C-6 oxidation. The resulting monosaccharide moieties were utilized to the syntheses of HP/HS disaccharide building blocks possessing glucosamine-glucuronic acid (GlcN-GlcA) or iduronic acid (GlcN-IdoA) sequences. The disaccharide building blocks were also suitable for further modification such as glycosylation, selective deprotection, and sulfation.

A convenient large-scale synthesis of 1-deoxynojirimyin (DNJ) from d-glucuronolactone involves introduction of azide at C-5 with retention of configuration to give 5-azido-5-deoxy-1,2-O-isopropylidene-α-d-glucofuranose as a key intermediate in an overall yield of up to 72%; the same intermediate can be transformed into DMDP [(2R,3R,4R,5R)-2,5-bis(hydroxymethyl)pyrrolidine-3,4-diol] and (3R)-3-hydroxy-l-bulgecinine [(2S,3R,4R,5R)-3,4-dihydroxy-5-hydroxymethyl-l-proline]. l-Glucuronolactone, a readily available l-sugar chiron, may similarly be used to access the enantiomers l-DNJ, l-DMDP, and (3S)-3-hydroxy-d-bulgecinine. A comparison of glycosidase inhibition by DMDP (an inhibitor of β-glucosidases and β-galactosidases) and l-DMDP (a potent and specific α-glucosidase inhibitor) with the corresponding enantiomeric hydroxybulgecinines is reported; DMDP and (3R)-3-hydroxy-l-bulgecinine show weak inhibition of glycogen phosphorylase.

An efficient and short total synthesis of tetrahydroxy-1c and trihydroxy-azepane 1d is reported in 72% and 57% overall yields, respectively, from d-(+)-glucurono-γ-lactone. Thus, d-glucuronolactone 2 on acetonide protection, DIBAL-H reduction and one-pot intermolecular reductive amination followed by -NCbz protection afforded 6-(N-benzyl-N-benzyloxycarbonyl) amino-6-deoxy-1,2-O-isopropylidene-α-d-gluco-1,4-furanose 5a. 1,2-Acetonide hydrolysis in 5a and Pd-mediated intramolecular reductive aminocyclization afforded tetrahydroxyazepane 1c. An analogous pathway with 5-deoxy-1,2-O-isopropylidene-α-d-glucurono-6,3-lactone 3b gave trihydroxy-azepane 1d. Glycosidase inhibitory activity of 1c/1d was studied and 1d was found to be potent inhibitor of α-mannosidase and β-galactosidase.

1,2-O-Isopropylidene-α-l-glucurono-3,6-lactone may be synthesized on a 100-200 g scale from cheaply available d-glucoheptonolactone in an overall yield of 94% in four steps via l-glucuronolactone. Subsequent elaboration to l-glucose, diacetone-l-glucose (1,2:5,6-di-O-isopropylidene-α-l-glucofuranose), and monoacetone-l-glucose (1,2-O-isopropylidene-α-l-glucofuranose) allows easy access to a range of l-sugar chirons.

An efficient and divergent strategy for the total synthesis of the first 3,6-dihydroaminosugars, furanodictines A (2-acetamido-3,6-anhydro-2-deoxy-5-O-isovaleryl-d-glucofuranose) and B (2-acetamido-3,6-anhydro-2-deoxy-5-O-isovaleryl-d-mannofuranose), has been developed. The synthetic process is featured by readily accessible and stereodefined manipulation of highly functionalized bicyclic tetrahydrofuran derivatives incorporating the glucuronolactone (common starting material)-derived skeleton.

An efficient and stereodefined strategy is described for the asymmetric synthesis of a new styryllactone from the stem bark of Goniothalamus cardiopetalus, cardiobutanolide. The synthetic process is based on requisite manipulation of the functionalized bicyclic lactol-lactone intermediate incorporating the glucuronolactone-derived skeleton in a complete stereoselective manner.

The present invention provides macrocyclic compounds, synthesis of the same and intermediates thereto. Such compounds, and compositions thereof, are useful for treating or preventing proliferative disorders Formula (F-4).

A convenient and practical strategy for the construction of a natural amino sugar analogue, furanodictine B, isolated from the multicellular fruit body has been developed in an optically active form. The synthetic process is based on readily accessible and stereodefmed manipulation of the highly functionalized bicyclic derivative incorporating the glucuronolactone-derived skeleton.

The synthesis of 5-amino-5-deoxy-1,2-O-isopropylidene-α-D-glucofuranose (8) was carried out via 5-azido-5-deoxy-1,2:3,4-O-diisopropylidene-α-D-glucofuranose (6), its reduction with Raney-Nickel and deprotection. 5-N-(β-Ketoen)amino-5-deoxy-1,2-O-isopropylidene-α-D-glucofuranoses (8a-f) were synthesized from 5-amino-5-deoxy-1,2-O-isopropylidene-α-D-glucofuranose and β-ketoenolethers leading to ligands with symmetrically substituted double bonds (8a, 8b) and e/z isomeric mixtures with unsymmetrical substitution (8c-f). Reactin of the ligands with Cu(II) ions leads to binuclear complexes of the general formula Cu1L2. In contrast to copper(II) complexes which are not derived from amino carbohydrates the metal centers in the compounds saturate their coordination sphere by complexation of additional solvent molecules interaction with neighboring complex molecules, or free hydroxyl groups of the own ligand. Residues of the ketoen moiety, R1 and R2, also influence the electronic properties of the metal centers. The combination of factors leads to different catalytic properties of the complexes in catecholoxidase-like reactions.

Antisense oligonucleotides are efficient tools for the inhibition of gene expression in a sequence specific way. Natural oligonucleotides are decomposed rapidly in biological systems, which strongly restrict their application. In contrast, artificial oligonucleotides are designed to be more stable against degradation than the target mRNA, which results in a catalytic effect of the drug. Modification of the phosphate linkage has been the first successful strategy for antisense drug developments and Fomivirsene the first antisense drug in therapy. The launch of Fomivirsene has resulted in a revolutionary spin off to antisense research leading to a second generation of antisense oligonucleotides, which are stable against oligonucleotide cleaving enzymes. Among these, oligonucleotides bearing an alkoxy substituent in position 2′ were the most successful ones. The third generation of antisense oligonucleotides contains structure elements, which enhance the antisense action. Zwitterionic oligonucleotides show remarkable results, first, because the stability against ribozymes is largely increased, and secondly, because the electrostatic repulsion between the anionic sense and the zwitterionic antisense cords is minimized. Promising new target molecules in antisense reseach are oligonucleotide chimaeres, which enhance the antisense action (chimaeres with intercalators, chelators or polyamines) or enable an application as sequence specific detectors (chimaeres with biotin, fluorescein or radioligands).

An efficient and practical strategy has been developed for the construction of the antipode of 3,4-dihydroxy-2,5-disubstituted tetrahydrofuran, goniothalesdiol, isolated from the bark of the Malaysian tree. The synthetic process is based on the convenient manipulation via Lewis acid-induced deoxygenation of the highly functionalized lactone derived from D-glucuronolactone.

The regio- and diastereoselectivities of metal-mediated allenylation of carbonyl compounds were investigated in aqueous media. Different metal mediators showed varied regioselectivities on product formation during propargylation-allenylation reactions of carbonyl compounds with simple propargyl bromide. Under the standard reaction conditions, the use of indium provided the highest regioselectivity, with a preference of formation of the homopropargyl alcohol. The use of tin and bismuth as the metal mediator provided slightly lower selectivities with the same preference. The use of zinc and cadmium as the mediators further lowered the product selectivity. The reactions of an alipathic aldehyde with simple propargyl bromide showed a lower selectivity than the reaction of an aromatic aldehyde in most cases, except for the use of tin or zinc (where comparable selectivities were observed). On the other hand, the reaction of terminal-substituted propargyl bromides with aldehydes mediated by indium showed a high regioselectivity in forming allenylation products. The indium-mediated allenylation of carbonyl compounds bearing an α-hydroxyl group also proceeded with a high diastereoselectivity, forming syn-diols predominantly in aqueous ethanol. The high diastereoselectivity in allenylation of α-hydroxyl-substituted aldehydes was attributed to the chelation effect exhibited by the α-hydroxyl substituent. Through the use of this highly diastereoselective allenylation, (+)-goniofufurone was synthesized from D'-glucurono-6,3-lactone.

Synthesis of new and potentially universal L-idopyranuronic glycosyl-donor and/or -acceptor 13 was performed starting from D-glucofuranurono-6,3-lactone 1.After simple C-5-epimerization, C-1-thioacetalization and regioselective p-methoxybenzylidenation to the hydroxylactone 6, the lactone ring was opened.The resulting diolamide stereoselectively protected, providing compound 7.Regioselective reductive cleavage of the 1,3-dioxane ring and subsequent deprotection afforded the target molecule 13.

Substituted benzyl ethers are easily cleaved by their treatment with an excess of dimethyldioxirane; the corresponding alcohols are obtained in high yields.

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The potential of D-glucuronolactone for the synthesis of polyhydroxylated amino acids is illustrated by the enantiospecific syntheses of 2S,3R,4R,5S-trihydroxypipecolic acid, 2R,3R,4R,5S-trihydroxypipecolic acid and 2R,3R,4R-dihydroxyproline.

The potential of D-glucuronolactone as a starting material for the synthesis of polyfunctional amino acids is illustrated by its conversion to 2S,3R,4R,5S-trihydroxypipecolic acid, 2R,3R,4R,5S-trihydroxypipecolic acid, 2S,4S,5S-dihydroxypipecolic acid, and bulgecinine.

Several routes for synthesis of 3,5,6-tri-O-acetyl-1,2-O-isopropylidene-β-L-idofuranose have been evaluated.Previously described routes, which involved selective sulphonylation, were not reproducible on a 100-g scale.To overcome this difficulty, a new variation was developed, involving complete tosylation of 1,2-O-isopropylidene-α-D-glucofuranurono-6,3-lactone followed by reduction and acetylation.The idofuranose derivative was converted into the desired 1,2,3,4,6-penta-O-acetyl-α-L-idopyranose via 1,6-anhydro-β-L-idopyranose.Fusion of 1,2,3,4,6-penta-O-acetyl-α-L-idopyranose with 4-nitrophenol, 1- or 2-naphtol, or 4-methylcoumarin-7-ol, using freshly fused zinc chloride as catalyst, gave an anomeric mixture of glycosides, with the α anomer being preponderant.The major 4-methylcoumarin-7-yl glycoside was deacylated and converted, by catalytic oxidation, into 4-methylcoumarin-7-yl α-L-idopyranosiduronic acid, fluorogenic substrate for α-L-iduronidase.

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A shorter synthesis of 5-thio-D-glucose is described in 8 steps from commercially available D-glucofurano-3,6-lactone.

The sites of oxidation, by catalytic transfer of H, of derivatives of 1,2-O-isopropylidene-α-D-glucofuranose suggest a regiospecific reaction.Compounds having vicinal hydroxyl groups at C-5 and C-6, or at C-3 and C-5, are oxidized at OH-5, whereas compounds having two hydroxyl groups at C-3 and C-6 or three hydroxyl groups give first aldehydes and then lactones.

The products (1) from the periodate oxidation of 1,2-O-isopropylidene-alpha-D-glucofuranose were converted by ethynylmagnesium bromide into a separable, 14:11 mixture of 6,7-dideoxy-1,2-O-isopropylidene-beta-L-ido-hept-6-ynofuranose (2) and its alpha-D-gluco analog 3. These crystalline products were further characterized as their respective 3,5-diacetates (5 and 7) and 3,5-dibenzoates (4 and 6). Ozonolysis of 2 and 3 led to 1,2-O-isopropylidene-beta-L-idofuranurono-6,3-lactone (8) and its alpha-D-gluco analog 9, respectively; similar ozonolysis of the dibenzoates 4 and 6, followed by treatment with diazomethane, gave methyl 3,5-di-O-benzoyl-1,2-O-isopropylidene-alpha-L-idofuranuronate (10) and its alpha-D-gluco analog 11, respectively. Diborane reduction of the ozonolysis products from 4 gave 1,2-O-isopropylidene-beta-tl-idofuranose (13) as its 3,5-dibenzoate (12), and a similar sequence was performed with 6. The propargylic alcohols 2 and 3 were reduced by lithium aluminum hydride, in high yield, to the allylic alcohol analogs 15 and 16, further characterized as their 3,5-dibenzoates 17 and 18; compounds 15 and 16 were also obtainable by vinylation of compounds 1. The two series of derivatives in this work, epimeric at C-5, were examined comparatively by polarimetry and p.m.r. spectroscopy.