合成路线:The isomerization of arecoline (I) with LDA gives 1-methyl-1,2,3,6-tetrahydropyridine-3-carboxylic acid methyl ester (II),which is reduced with LiAlH4 in THF yielding the carbinol (III).The protection of (III) with trichloroethyl chloroformate (Troc-Cl) and DIEA in toluene affords the demethylated compound (IV),which is treated with K2CO3 in methanol providing 3-(hydroxymethyl)-1,2,3,6-tetrahydropyridine-1-carboxylic acid 2,2,2-trichloroethyl ester (V).The silylation of (V) with TBDPSCl and imidazole in DMF gives the silyl ether (VI),which is epoxidized with MCPBA in dichloromethane yielding the epoxide (VII).Epoxide (VII) opening by means of HClO4 in refluxing water affords a diastereomeric mixture of racemates (VIII) and (IX) that could not be separated.The cleavage of the carbamate group of (VIII) and (IX) by means of HCl in water gives a new mixture that could be separated by flash chromatography to furnish the target compound as a racemate.Alternatively,intermediate (IV) is epoxidized with MCPBA in dichloromethane yielding the epoxide (X),which is treated as before.
参考文献标题:Synthesis of (?-isofagomine and its stereoisomers from arecoline
文献作者:Bols,M.; Hansen,S.U.
参考来源:J Chem Soc - Perkins Trans I 2000,(6),911
合成路线:The reaction of D-tartaric acid (I) with refluxing acetone and sulfuric acid gives the isopropylidene ketal (II),which is reduced with LiAlH4 to yield 2,3-O-isopropylidene-D-threitol (III).The monosilylation of (III) with Tbdms-Cl and NaH affords the monosilyl ether (IV),which is submitted to a Swern oxidation to provide the aldehyde (V).The reaction of (V) with CBr4,PPh3 and BuLi in dichloromethane gives the acetylene (VI),which is desilylated with TBAF in THF to yield the carbinol (VII).The carbinol (VII) is treated with CBr4 and PPh3 in dichloromethane to afford the bromide (VIII),which is condensed with N-benzyl-N-(trimethylsilyl)amine (IX) by means of K2CO3 in refluxing acetonitrile,providing the tertiary amine (X).The cyclization of (X) by means of ultraviolet light in isopropanol/dichloromethane gives the methylenepiperidine (XI),which is submitted to hydroboration with 9-BBN and NaOH in THF to yield the carbinol (XII) as a single diastereomer.The cleavage of the ketal group of (XII) by treatment with HCl in methanol affords the chiral 1-benzyl-5-(hydroxymethyl)piperidine-3,4-diol (XIII),which is finally debenzylated by means of H2 over Pd(OH)2 in ethanol to furnish the target isofagomine.
参考文献标题:A general strategy towards the synthesis of 1-N-iminosugar type glycosidase inhibitors: Demonstration by the synthesis of D- as well as L-glucose type iminosugars (isofagomines)
文献作者:Pandey,G.; Kapur,M.
参考来源:Tetrahedron Lett 2000,41(45),8821
合成路线:The selective reduction of methyl nicotinate (I) with simultaneous protection of the resulting NH group with phenyl chloroformate gives the 1,2-dihydropyridine derivative (II),which is treated with MCPBA (III) to afford the hydroxyester (IV).The reduction of (IV) with Tms-OTf and borane/THF complex affords the allylic alcohol (V),which is oxidized with CrO3 in acetone to provide the ketone (VI).The asymmetric reduction of (VI) with LiAlH4 catalyzed by (-)-N-methyl-ephedrine gives the chiral alcohol (VII),which is treated with refluxing 1N HCl to yield the carboxylic acid (VIII).The reduction of (VIII) with borane/THF complex and H2O2 affords the chiral carbinol (IX),which is finally deprotected by treatment with LiOH to provide the target isofagomine.
参考文献标题:Selective fowler reductions: Asymmetric total synthesis of isofagomine and other 1-azasugars from methyl nicotinate
文献作者:Zhao,G.; Deo,U.C.; Ganem,B.
参考来源:Org Lett 2001,3(2),201
合成路线:The demethylation of 1-methyl-1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (I) by reaction with 1-chloroethyl chloroformate,followed by reaction with Boc2O gives 1-(tert-butoxycarbonyl) -1,2,5,6-tetrahydropyridine-3-carboxylic acid methyl ester (II).The isomerization of (II) by means of LDA in THF yields 1-(tert-butoxycarbonyl) -1,2,3,6-tetrahydropyridine-3-carboxylic acid methyl ester (III),which is reduced with LiBHEt3 in THF to afford the hydroxymethyl derivative (IV).The reaction of (IV) with MCPBA in dichloromethane provides the epoxide (V),which is treated with refluxing aq.KOH,resulting in a racemic mixture of the enantiomers (VI) and (VII) as the major products.Finally,the target isofagomine is separated by chiral chromatography.
参考文献标题:Iminosugars: Potential inhibitors of liver glycogen phosphorylase
文献作者:Jakobsen,P.; Lundbeck,J.M.; Kristiansen,M.; Breinholt,J.; Demuth,H.-U.; Pawlas,J.; Candela,M.P.; Andersen,B.; Westergaard,N.; Lundgren,K.; Asano,N.
参考来源:Bioorg Med Chem 2001,9(3),733
合成路线:The reaction of D-tartaric acid (I) with refluxing acetone and sulfuric acid gives the isopropylidene ketal (II),which is reduced with LiAlH4 to yield 2,3-O-isopropylidene-D-threitol (III).The monosilylation of (III) with Tbdms-Cl and NaH affords the monosilyl ether (IV),which is submitted to a Swern oxidation to provide the aldehyde (V).The reaction of (V) with CBr4,PPh3 and BuLi in dichloromethane gives the acetylene (VI),which is desilylated with TBAF in THF to yield the carbinol (VII).The carbinol (VII) is treated with CBr4 and PPh3 in dichloromethane to afford the bromide (VIII),which is condensed with N-benzyl-N-(trimethylsilyl)amine (IX) by means of K2CO3 in refluxing acetonitrile,providing the tertiary amine (X).The cyclization of (X) by means of ultraviolet light in isopropanol/dichloromethane gives the methylenepiperidine (XI),which is submitted to hydroboration with 9-BBN and NaOH in THF to yield the carbinol (XII) as a single diastereomer.The cleavage of the ketal group of (XII) by treatment with HCl in methanol affords the chiral 1-benzyl-5-(hydroxymethyl)piperidine-3,4-diol (XIII),which is finally debenzylated by means of H2 over Pd(OH)2 in ethanol to furnish the target isofagomine.
参考文献标题:Total synthesis of (+)-nojirimycin and (+)-1-deoxynojirimycin
文献作者:Iida,H.; et al.
参考来源:J Org Chem 1987,52(15),3337
合成路线:The reaction of D-tartaric acid (I) with refluxing acetone and sulfuric acid gives the isopropylidene ketal (II),which is reduced with LiAlH4 to yield 2,3-O-isopropylidene-D-threitol (III).The monosilylation of (III) with Tbdms-Cl and NaH affords the monosilyl ether (IV),which is submitted to a Swern oxidation to provide the aldehyde (V).The reaction of (V) with CBr4,PPh3 and BuLi in dichloromethane gives the acetylene (VI),which is desilylated with TBAF in THF to yield the carbinol (VII).The carbinol (VII) is treated with CBr4 and PPh3 in dichloromethane to afford the bromide (VIII),which is condensed with N-benzyl-N-(trimethylsilyl)amine (IX) by means of K2CO3 in refluxing acetonitrile,providing the tertiary amine (X).The cyclization of (X) by means of ultraviolet light in isopropanol/dichloromethane gives the methylenepiperidine (XI),which is submitted to hydroboration with 9-BBN and NaOH in THF to yield the carbinol (XII) as a single diastereomer.The cleavage of the ketal group of (XII) by treatment with HCl in methanol affords the chiral 1-benzyl-5-(hydroxymethyl)piperidine-3,4-diol (XIII),which is finally debenzylated by means of H2 over Pd(OH)2 in ethanol to furnish the target isofagomine.
参考文献标题:1,4-Bismethanesulfonates of the stereoisomeric butanetetraols and related compounds
文献作者:Feit,P.W.
参考来源:J Med Chem 1964,714
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