59920-31-9

Usage

InChI:InChI=1/C6H13NO4/c8-1-3-5(10)6(11)4(2-9)7-3/h3-11H,1-2H2/t3-,4-,5-,6-/m1/s1

Upstream product

• 98260-71-0 N-benzyloxycarbonyl-3-O-benzyyl-2,5-dideoxy-2,5-imino-D-mannitol 
• 848347-55-7 3-O-(2-bromomethyl)benzyl-1,2:4,5-di-O-isopropylidene-β-D-fructopyranose 
• 1684-29-3 D-5-ketofructose 
• 94801-01-1 5-azido-5-deoxy-1,2-O-isopropylidene-β-D-fructopyranose 
• 22529-61-9 (1R)-1-((3aR,6S,6aR)-6-(benzyloxy)-2,2-dimethyltetrahydrofuro(2,3-d)(1,3)dioxol-5-yl)ethane-1,2-diol 
• 914650-04-7 (2R,3R,4R,5R)-N-benzyloxycarbonyl-2-benzyloxymethyl-3,4-dihydroxy-5-hydroxymethylpyrrolidine 
• 1225455-71-9 C₂₀H₂₅NO₄ 
• 157363-86-5 N-benzyl-3,4-di-O-benzyl-1,5-dideoxy-1,5-imino-D-glucitol 
• 534573-30-3 (2S,3R,4R,5R)-3,4-Diacetoxy-5-acetoxymethyl-pyrrolidine-1,2-dicarboxylic acid 1-methyl ester 
• 534573-28-9 (2R,3R,4R,5R)-3,4-Dihydroxy-2-hydroxymethyl-5-(4-methoxy-phenyl)-pyrrolidine-1-carboxylic acid methyl ester 
• 223595-45-7 (5S)-N-(methoxycarbonyl)-5-(trityloxymethyl)-2-pyrroline 
• 223595-49-1 (2S,5S)-N-(methoxycarbonyl)-5-(hydroxymethyl)-2-(p-methoxyphenyl)-3-pyrroline 
• 16838-89-4 2,3,5-tri-O-benzyl-L-xylofuranose 
• 368452-21-5 5-azideo-3,4-di-O-benzoyl-5-deoxy-1,2-O-isopropylidene-β-L-sorbopyranose 

Downstream Products

• 697288-36-1 (5R,6R,7R,7aR)-6,7-Dihydroxy-5-hydroxymethyl-tetrahydro-pyrrolo[1,2-c]oxazole-3-thione 
• 697288-34-9 (5R,6R,7R,7aR)-6,7-Dihydroxy-5-hydroxymethyl-tetrahydro-pyrrolo[1,2-c]oxazol-3-one 
• 697288-31-6 (2R,3R,4R,5R)-N-(β-D-glucopyranosyl)thiocarbamoyl-3,4-dihydroxy-2,5-di(hydroxymethyl)-pyrrolidine 
• 697288-30-5 (2R,3R,4R,5R)-3,4-dihydroxy-2,5-di(hydroxymethyl)-N-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl)thiocarbamoylpyrrolidine 
• 697288-29-2 (2R,3R,4R,5R)-3,4-Dihydroxy-2,5-bis-hydroxymethyl-pyrrolidine-1-carbothioic acid phenylamide 

Relevant academic research and scientific papers

Iminosugars from Baphia nitida Lodd.

Chromatographic separation of the 50% aqueous EtOH extract of the leaves of the African medicinal tree Baphia nitida resulted in isolation of 10 iminosugars. The plant contained 2R,5R-dihydroxymethyl-3R,4R-dihydroxypyrrolidine (DMDP) as a major alkaloid. The structure of a new alkaloid was also elucidated by spectroscopic methods as the 1-O-β-d-fructofuranoside of DMDP, and this plant produced 3-O-β-d-glucopyranosyl-DMDP as well. DMDP is a potent inhibitor of β-glucosidase and β-galactosidase, whereas the other two derivatives lowered inhibition toward both of these enzymes and improved inhibitory activities toward rice α-glucosidase and rat intestinal maltase.

METHODS OF TREATING POMPE DISEASE

Disclosed herein are novel uses of ADMDP stereoisomers or their derivatives for the manufacture of a medicament for treating Pompe disease. Accordingly, the present disclosure provides a method of treating Pompe disease in a subject. The method includes the step of, administering to the subject a therapeutically effective amount of a compound of formula (I), or a salt, an ester or a solvate thereof, wherein R1 and R2 are independently H or alkyl optionally substituted by -NH2 or -OH, so as to ameliorate, alleviate mitigate and/or prevent symptoms associated with the Pompe disease. According to certain embodiments of the present disclosure, the compound of formula (I) may serve a stabilizer of α-glucosidase via preventing its denaturalization of deactivation.

1,3-Oxazine as a chiral building block used in the total synthesis of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine

Concise and stereocontrolled syntheses of (+)-1-deoxynojirimycin and (2R,5R)-dihydroxymethyl-(3R,4R)-dihydroxypyrrolidine [(+)-DMDP] were achieved via a diastereomerically enriched oxazine intermediate. The key strategies include the use of 1,3-oxazine as a chiral building block and diastereoselective nucleophilic addition to an aldehyde. Starting from readily available (R)-methyl 2-benzamido-3-((tert-butyldimethylsilyl)oxy)propanoate, (+)-1-deoxynojirimycin was synthesized in 11 steps and 26.2% overall yield while (+)-DMDP was synthesized in 11 steps and 27.1% overall yield, respectively.

Diastereoselective concise syntheses of the polyhydroxylated alkaloids DMDP and DAB

A diastereoselective concise synthesis of the iminosugars DMDP and DAB is presented starting from l-xylose and affording the two alkaloids in good yields of 35% and 22% over seven and eight steps, respectively. The Petasis borono-Mannich reaction of 3,5-di-O-benzyl-l-xylofuranose with benzylamine and (E)-styrylboronic acid served as the nitrogen-introducing key step furnishing the new C-N bond in an entirely diastereoselective manner. A chemo- and regioselective O-mesylation followed by an intramolecular SN2- cyclisation allowed the formation of the pyrrolidine ring. Ozonolysis of the styryl double bond and subsequent reduction to form the C-5 hydroxymethyl substituent followed by hydrogenolysis of the benzyl protecting groups concluded the DMDP synthesis. Furthermore, an unexpected fragmentation process during the ozonolysis reaction also gave access to the C-5 decarbinolated DMDP derivative DAB.

C-branched iminosugars: α-glucosidase inhibition by enantiomers of isoDMDP, isoDGDP, and isoDAB- l -isoDMDP compared to miglitol and miglustat

The Ho crossed aldol condensation provides access to a series of carbon branched iminosugars as exemplified by the synthesis of enantiomeric pairs of isoDMDP, isoDGDP, and isoDAB, allowing comparison of their biological activities with three linear isomeric natural products DMDP, DGDP, and DAB and their enantiomers. l-IsoDMDP [(2S,3S,4R)-2,4-bis(hydroxymethyl)pyrrolidine-3,4-diol], prepared in 11 steps in an overall yield of 45% from d-lyxonolactone, is a potent specific competitive inhibitor of gut disaccharidases [Ki 0.081 μM for rat intestinal maltase] and is more effective in the suppression of hyperglycaemia in a maltose loading test than miglitol, a drug presently used in the treatment of late onset diabetes. The partial rescue of the defective F508del-CFTR function in CF-KM4 cells by l-isoDMDP is compared with miglustat and isoLAB in an approach to the treatment of cystic fibrosis.

Stereoselective synthesis of (2S,3S,4R,5S)-3,4-dihydroxy-2,5- dihydroxymethyl pyrrolidine from l-sorbose

One of the most frequently synthesized iminosugar derivatives is DMDP. Starting from l-sorbose, a practical method for the synthesis of derivatives of this five-membered iminocyclitol has been developed, involving straightforward steps and a convenient selective reduction of a ketoxime intermediate.

Enantioselective construction of a polyhydroxylated pyrrolidine skeleton from 3-vinylaziridine-2-carboxylates: Synthesis of (+)-DMDP and a potential common intermediate for (+)-hyacinthacine A1 and (+)-1-epi-australine

We report an enantioselective synthesis of the polyhydroxylated pyrrolidine alkaloid (+)-DMDP. The key steps in the synthesis were guanidinium ylide mediated asymmetric aziridination, stereospecific ring opening of trans-3-vinylaziridine-2- carboxylate with an oxygen nucleophile, iodine-mediated 5-endo-trig amino cyclization, and Prevost displacement. In addition, a potential common intermediate for the polyhydroxylated pyrrolizidine alkaloids (+)-hyacinthacine A1 and (+)-1-epi-australine was synthesized from a diastereoisomeric cis-aziridine coformed in the asymmetric aziridination using the same strategy. A rationale for the diastereoselectivity observed for the iodine-mediated amino cyclization reactions is proposed on the basis of the heats of formation of the products.

Looking glass inhibitors: scalable syntheses of DNJ, DMDP, and (3R)-3-hydroxy-l-bulgecinine from d-glucuronolactone and of l-DNJ, l-DMDP, and (3S)-3-hydroxy-d-bulgecinine from l-glucuronolactone. DMDP inhibits β-glucosidases and β-galactosidases whereas l-DMDP is a potent and specific inhibitor of α-glucosidases

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.

A convenient approach toward the synthesis of enantiopure isomers of DMDP and ADMDP

A practical method for the synthesis of five-membered iminocyclitols, pyrrolidine alkaloids bearing multiple hydroxyl substituents, has been developed. All of the eight key intermediates, enantiopure tri-O-benzyl cyclic nitrones, are prepared from four cheap, readily available d-aldopentoses. The nucleophilic addition of cyclic nitrones with vinyl magnesium chloride and TMSCN shows high 2,3-trans stereoselectivity. To construct the 2,3-cis configurations, inversion of the C-2 nitrile group is achieved via an elimination-reduction sequence. Using this approach, five isomers of DMDP and six isomers of ADMDP are prepared efficiently. In the biological evaluation, iminocyclitol 27 is a new and potent inhibitor against β-hexosaminidase with an IC50 value of 0.2 μM.

A concise synthesis of 2,5-dideoxy-2,5-imino-d-mannitol (DMDP) and HomoDMDP from l-xylose

A short and practical procedure for the preparation of C-2 substituted polyhydroxypyrrolidines is described. The C-2 substituent is introduced by a stereoselective addition of a Grignard reagent to a 2,3,5-protected aldofuranose and the cyclization to the pyrrolidine ring system is performed through a bis-mesylation/double nucleophilic displacement sequence. The efficiency of the methodology was demonstrated by its application to the synthesis of HomoDMDP and DMDP.