A stereodivergent approach to 1-deoxynojirimycin, 1-deoxygalactonojirimycin and 1-deoxymannojirimycin derivatives

A stereodivergent synthesis of N-alkylated 1-deoxygalactonojirimycin and 1-deoxymannojirimycin derivatives has been achieved from a protected 1-deoxynojirimycin intermediate having two free OH groups tactically positioned at C-2 and C-4. The inversion of configuration of the secondary alcohols was performed by way of a Swern oxidation followed by a highly diastereoselective reduction using NaBH₄ or L-Selectride.     

Facile syntheses of 1-deoxynojirimycin (DNJ) and 1-deoxymannojirimycin (DMJ)

1-Deoxynojirimycin (DNJ) and 1-deoxymannojirimycin (DMJ) were synthesized through a concise and practicable pathway. A strategy of using carbohydrate derivatives bearing two leaving groups in the preparation of azasugars by di-N-alkylation of amines was developed. The strategy involved the selective partial protection of dibromo alditols.     

A combined chemical and enzymatic procedure for the synthesis of 1-deoxynojirimycin and 1-deoxymannojirimycin

1-Deoxynojirimycin and 1-deoxymannojirimycin have been prepared via fructose diphosphate aldolase catalyzed condensation followed by catalytic intramolecular reductive amination.     

N-正丁基-1-脱氧野尻霉素的合成

在植物和微生物体内广泛存在一系列类单糖化合物,其糖环氧被氮原子取代,异头碳羟基或保留或已脱去,统称为氮杂糖(azasugar).     

Synthesis of somatostatin mimetics based on the 1-deoxymannojirimycin scaffold

A novel synthesis of somatostatin mimetics based on the 1-deoxymannojirimycin (DMJ) scaffold has been developed. This involved development of a route suitable for the strategic grafting of pharmacophoric tryptophan and lysine side chains to the nitrogen atom of the piperidine ring and to the primary hydroxyl group of DMJ, respectively. The novel peptidomimetics were found to bind with higher affinity to sst4 receptors than to sst5 receptors.     

Modifications at the 6-O-position of 1-deoxynojirimycin: facile and efficient synthesis of 6-O-alkylated-N-octyl-1-deoxynojirimycin derivatives

A straightforward synthesis of N-alkylated 1-deoxynojirimycin derivatives modified at the 6-O-position has been described. The key intermediate in the synthesis of target compounds was 2,3,4-tri-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol, which was prepared from 2,3,4,6-tetra-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol. Optimal conditions have been established for the synthesis of the key intermediate by varying reaction parameters. Reductive amination and subsequent alkylation of the 6-O-position followed by hydrogenolysis were the main reaction steps, which gave target compounds 6-O-ethyl-N-octyl-1,5-dideoxy-1,5-imino-D-glucitol and 6-O-butyl-N-octyl-1,5-dideoxy-1,5-imino-D-glucitol. This synthetic route is flexible and can be useful for the synthesis of other lipophilic iminosugar derivatives.     

Total synthesis of 3,3-difluorinated 1-deoxynojirimycin analogues

Difluorination of 1-deoxynojirimycin at position C(3) creates a competitive inhibitor 15 of 10 times higher activity against an α-glucosidase than the parent compound. Its screening against a panel of human cell lines showed a low cytotoxicity therefore making this compound an interesting candidate for further clinical investigations.     

Asymmetric synthesis of (+)-1-deoxynojirimycin and (+)-castanospermine

Asymmetric total syntheses of (+)-1-deoxynojirimycin (1) and (+)-castanospermine (2) are described. Starting from diene 3, the required absolute stereochemistry is introduced by an asymmetric hydroxylation followed by epoxidation. An intramolecular cyclization of amine 17 gives access to the corresponding tetrasubstituted piperidine 18, which is a precursor to compounds 1 and 2. (+)-Deoxynojirimicyn (1) was obtained in 36% yield over 11 steps from diene 3, while (+)-castanospermine (2) was achieved in 13% after 19 steps from the same starting material.     

Palladium(II)-catalyzed cyclization of urethanes and total synthesis of 1-deoxymannojirimycin

The palladium(II)-catalyzed cyclization of the urethane 8, which was derived from D-mannitol, gave the cyclic compound 9 with excellent diastereoselectivity. During these transformations, the Pd(II) species are not reduced and thus the catalyst can recycle without its reoxidation. The cycloadduct 9 was converted to 1-deoxymannojirimycin.     

Selective protecting group manipulations on the 1-deoxynojirimycin scaffold

Iminosugars are inhibitors of glycoprocessing and are of interest as scaffolds for medicinal chemistry, as their successful application as peptide mimetics has shown. The synthesis of novel peptidomimetics based on 1-deoxynojirimycin (DNJ) requires practical strategies that allow introduction of amino acid side chains or pharmacophore groups at each of its hydroxyl groups or to the nitrogen atom. This paper describes one approach towards achieving selective protection and deprotection at the hydroxyl and amino groups of DNJ and a novel synthesis of DNJ from l-sorbose is included.     

New access to 1-deoxynojirimycin derivatives via azide-alkene cycloaddition

The synthesis of 1-deoxynojirimycin (DNJ) derivatives is described from D-glucono-delta-lactone. The DNJ derivatives were obtained via a sequence that included a stereoselective intramolecular Huisgen reaction, decomposition to an aziridine, and its subsequent reaction with a nucleophile. Minimization of allylic strain in the transition state accounts for the stereoselectivity of the cycloaddition reaction.     

N-[3-(4-乙氧基苄基)-4-氯苯基]-1-脱氧野尻霉素的合成及其降血糖作用

以具有降血糖活性的达格列净、卡格列净和脱氧野尻霉素为参照,设计合成了新化合物N-[3-(4-乙氧基苄基)-4-氯苯基]-1-脱氧野尻霉素(A)。以2-氯-5-硝基苯甲酸为原料,先将羧酸转化为酰氯、再经Friedel-Crafts酰基化、羰基还原及硝基还原,合成了中间体2-氯-5-氨基-4'-乙氧基二苯基甲烷;另一方面,以单丙酮葡萄糖为原料,经选择性氧化和水解反应得到5-氧化-D-葡萄糖。该化合物和2-氯-5-氨基-4'-乙氧基二苯基甲烷发生双还原胺化反应得到化合物A的粗品。将粗品A与乙酸酐反应,经柱色谱分离得到高纯度的四乙酰基-N-[3-(4-乙氧基苄基)-4-氯苯基]-1-脱氧野尻霉素(B),再将其水解制得纯的化合物A。将化合物A口服给药SD大鼠后,发现该化合物可以降低SD大鼠血糖,增加尿量和葡萄糖从尿液中的排出。     

HPLC-ELSD在1-脱氧野尻霉素,葡萄糖和葡萄糖胺的杂质分析中的应用

建立了一种高效液相分析方法可用于1-脱氧野尻霉素,葡萄糖和葡萄糖胺的杂质分析.该方法以乙腈/水酸性系统为流动相体系,色谱柱采用WatersAtlantis HILIC Silica(5 μm,150×4.6 mm),以蒸发光散射检测器(ELSD)进行检测,采用主成分自身对照法用于杂质含量的计算.方法验证结果表明,1-脱氧野尻霉素,葡萄糖和葡萄糖胺在0.008～0.04 mg/mL范围内峰面积对质量浓度呈现良好的线性,线性回归系数分别为0.9993,0.9998,0.9996.1-脱氧野尻霉素,葡萄糖和葡萄糖胺的最低检测浓度分别为0.0045,0.0040,0.0039 mg/mL.3种化合物在0.02,0.04,0.08 mg/mL 3种质量浓度点的重现性良好,RSD%均小于10%.     

Efficient preparation of enantiomerically pure cyclic aminoalditols,total synthesis of 1-deoxynojirimycin and 1-deoxymannojirimycyn

Expeditious new syntheses of the title compounds, which are potent glycosidase inhibitors, have been developed based on a high-yield, ring-forming aminomecuration.     

Asymmetric synthesis of 1-deoxynojirimycin and its congeners from a common chiral building block

A new, promising chiral building block 9 for the synthesis of 1-deoxy-4,5-trans-oriented azasugars such as 1-deoxynojirimycin (1) was prepared in only four steps from the Garner aldehyde 10 using catalytic ring-closing metathesis (RCM) for the construction of the piperidine ring. In practical test, the first synthesis of all four isomers (1 and 6-8) of trans-4,5-orientated 1-deoxyiminosugars using 9 as a common chiral building block was demonstrated.     

Total syntheses of (+)-castanospermine and (+)-deoxynojirimycin

The absolute configuration of castanospermine has been determined by total synthesis to be as shown in 1.     

Syntheses of the enantiomers of 1-deoxynojirimycin and 1-deoxyaltronojirimycin via chemo- and diastereoselective olefinic oxidation of unsaturated amines

Oxidation of enantiomerically pure (R)-N(1)-1'-(1'-naphthyl)ethyl-2,7-dihydro-1H-azepine with m-CPBA in the presence of HBF(4) and BnOH gave (3S,4R,5S,6S,1'R)-N(1)-1'-(1'-naphthyl)ethyl-3-hydroxy-4-benzyloxy-5,6-epoxyazepane as the major product and as a single diastereoisomer after chromatography. Elaboration of this highly functionalized intermediate via ring contraction to (2S,3R,4S,5S,1'R)-N(1)-benzyl-2-chloromethyl-3-benzyloxy-4,5-epoxypiperidine followed by regioselective epoxide ring opening, functional group manipulation, and deprotection gave (+)-1-deoxyaltronojirimycin. Alternatively, resolution of (RS,RS)-N(1)-benzyl-3-hydroxy-4-benzyloxy-2,3,4,7-tetrahydro-1H-azepine or (3RS,4SR,5RS,6RS)-N(1)-benzyl-3-hydroxy-4-benzyloxy-5,6-epoxyazepane by preparative chiral HPLC and subsequent elaboration allows access to the enantiomers of 1-deoxynojirimycin and 1-deoxyaltronojirimycin, respectively.     

Development of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives as selective inhibitors of glucosylceramide metabolism in man

In this article, we present a straightforward synthesis of adamantan-1-yl-methoxy-functionalized 1-deoxynojirimycin derivatives. The used synthetic routes are flexible and can be used to create a wide variety of lipophilic mono- and difunctionalized 1-deoxynojirimycin derivatives. The compounds reported here are lipophilic iminosugar based on lead compound 4, a potent inhibitor of the three enzymes involved in the metabolism of the glycosphingolipid glucosylceramide. Iminosugar-based inhibitors of glucosylceramide synthase, one of these three enzymes, have attracted increasing interest over the past decade due to the crucial role of this enzyme in glycosphingolipid biosynthesis. Combined with the fact that an increasing number of pathological processes are being linked to excessive glycosphingolipid levels, glucosylceramide synthase becomes a very attractive therapeutic and research target. Our results presented here demonstrate that relocating the lipophilic moiety from the nitrogen atom to other positions on the 1-deoxynojirimycin ring system does not lead to a more potent or selective inhibitor of glucosylceramide synthase. The beta-aza-C-glycoside analogue (17) retained the best inhibitory potency for glucosylceramide synthase and is a more potent inhibitor than the therapeutic agent N-butyl-1-deoxynojirimycin (3), marketed as treatment for Gaucher disease under the commercial name Zavesca.