L-核糖的化学合成研究
摘要
本文以α-D-葡萄糖为原料,经过丙酮保护、PDC(重铬酸吡啶盐)氧化-硼氢化钠还原、酸选择性水解、高碘酸钠氧化降解、甲氧胺醛基保护、DDQ(二氯二氰基苯醌)完全水解-硼氢化钠还原及三氯化钛脱肟等九步反应合成了L-核糖,重点对PDC氧化、高碘酸钠氧化降解、甲氧胺醛基保护反应进行了研究。
研究了葡萄糖的羟基保护反应,以丙酮-浓硫酸体系对α-D-葡萄糖进行异丙叉化,合成1,2:5,6-氧-二异丙叉基-α-D-呋喃葡萄糖(2),重结晶后收率为38%。研究了以氧化还原方法改变糖的羟基构型的方法,以2为原料,以PDC-醋酐-二氯甲烷体系氧化,再进行硼氢化钠还原,改变了C-3上羟基构型,得到1,2:5,6-氧-二异丙叉基-α-D-呋喃阿洛糖(3),两步收率为70%。研究了氧化剂PDC的制备方法。
研究了阿洛糖衍生物3的异丙叉基选择性水解反应,以硫酸-甲醇体系进行水解反应,合成1,2-氧-异丙叉基-α-D-呋喃阿洛糖(4),收率为92.2%。研究了选择性水解产物4的氧化降解反应,在高碘酸钠-碳酸氢钠-水体系进行氧化降解,合成1,2-氧-异丙叉基-α-D-核糖-戊二醛-1,4-呋喃糖(5),收率为86.9%。研究了氧化降解物5的醛基保护反应,分别以羟胺-甲醇、乙硫醇-盐酸、甲氧胺-甲醇体系进行醛基保护反应,确定了以甲氧胺为醛基保护试剂,合成1,2-氧-异丙叉基-α-D-核糖-戊二醛-1,4-呋喃糖-氧-甲基肟(6c),收率为73.6%。
研究了醛基保护物6c的全水解-还原反应,以6c为原料,以DDQ-乙腈体系进行全水解,再进行硼氢化钠还原,合成L-核糖-氧-甲基肟(7c),两步收率为79%。初步研究了甲基肟7c的脱保护反应,以三氯化钛-四氢呋喃体系进行脱保合成L-核糖(8),收率为23.9%。九步反应的总收率为2.9%,除了最后一步其它各步均未采用柱分离方法,并用1H-NMR对各步产物进行了表征。
Withα-D-glucose as starting material, L-ribose was synthesized by nine step reactions such as acetone protection, PDC (pyridinium dichromate) oxidation-NaBH4 reduction, acid selective hydrolysis, NaIO4 oxidative degradation, aldehyde group protection with methoxyl amine, DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) thorough hydrolysis- NaBH4 reduction and deoximation with titanium trichloride .
Particularly, PDC oxidation method, NaIO4 oxidative degradation method and aldehyde group protection with methoxyl amine method were studied intensively. The hydroxyl group protecting reactions ofα-D-gluofuranose was studied. The isopropylidenation reaction ofα-D-gluofuranose was carried to synthesis 1,2:5,6-O-diisopropylidene-α-D-gluofuranose (2) with acetone-conc. H2SO4 system, by crystallization, the yield was 38%. Hydroxyl group stereo structure conversion in sugar was studied. The C-3 position hydroxyl group stereo structure of 2 was converted by PDC-Ac2O-CH2Cl2 oxidation and NaBH4 reduction, Thus 1,2:5,6-O-diisopropylidene-α-D-allofuranose (3) was synthesized, two steps overall yield was 70%. The preparation method of PDC was studied.
Selective hydrolysis reaction ofα-D-allofuranose derivative 3 was studied. The selective hydrolysis reaction of 3 was carried to synthesize 1,2-O-isopropylidene-α-D-allofuranose (4) with dilute H2SO4–CH3OH, the yield was 92.2%. Oxidative degradation reaction of 4 was studied. The hydrolysis product 4 was carbon-decreasing oxidated with NaIO4-NaHCO3-H2O system. Thus 1,2-O-isopropylidene-α-D-ribo-pentodialdo-1,4-furanose (5) was synthesized , the yield was 86.9%. Aldehyde group protection reaction ofα-D-ribose derivative 5 was studied. The reaction was carried out with NH2OH-CH3OH system, CH3CH2SH-HCl system and NH2OCH3- CH3OH system. The methoxyl amine was determined as aldehyde group protection reagent. Thus 1,2-O-isopropylidene-α-D-ribo- pentodialdo-1,4-furanose-O-methyl-oxime (6c) was synthesized, the yield was 73.6%.
Thorough hydrolysis- reduction reaction of 6c was studied. The diversion was converted by DDQ-CH3CN thorough hydrolysis and NaBH4 reduction. Thus L-ribose-O-methyl-oxime (7c) was synthesized, two steps overall yield was 79%. Deoximation reaction of the oxime 7c was studied premilinarily. The reaction of 7c was carried out to synthesize L-ribose (8) with TiCl3-THF system, the yield was 23.9%. Nine steps overall yield was 2.9%. Except the final step, no column chromatography separating method was applied in each step in all nine steps, Each step product was characterized with 1H-NMR.
研究了葡萄糖的羟基保护反应,以丙酮-浓硫酸体系对α-D-葡萄糖进行异丙叉化,合成1,2:5,6-氧-二异丙叉基-α-D-呋喃葡萄糖(2),重结晶后收率为38%。研究了以氧化还原方法改变糖的羟基构型的方法,以2为原料,以PDC-醋酐-二氯甲烷体系氧化,再进行硼氢化钠还原,改变了C-3上羟基构型,得到1,2:5,6-氧-二异丙叉基-α-D-呋喃阿洛糖(3),两步收率为70%。研究了氧化剂PDC的制备方法。
研究了阿洛糖衍生物3的异丙叉基选择性水解反应,以硫酸-甲醇体系进行水解反应,合成1,2-氧-异丙叉基-α-D-呋喃阿洛糖(4),收率为92.2%。研究了选择性水解产物4的氧化降解反应,在高碘酸钠-碳酸氢钠-水体系进行氧化降解,合成1,2-氧-异丙叉基-α-D-核糖-戊二醛-1,4-呋喃糖(5),收率为86.9%。研究了氧化降解物5的醛基保护反应,分别以羟胺-甲醇、乙硫醇-盐酸、甲氧胺-甲醇体系进行醛基保护反应,确定了以甲氧胺为醛基保护试剂,合成1,2-氧-异丙叉基-α-D-核糖-戊二醛-1,4-呋喃糖-氧-甲基肟(6c),收率为73.6%。
研究了醛基保护物6c的全水解-还原反应,以6c为原料,以DDQ-乙腈体系进行全水解,再进行硼氢化钠还原,合成L-核糖-氧-甲基肟(7c),两步收率为79%。初步研究了甲基肟7c的脱保护反应,以三氯化钛-四氢呋喃体系进行脱保合成L-核糖(8),收率为23.9%。九步反应的总收率为2.9%,除了最后一步其它各步均未采用柱分离方法,并用1H-NMR对各步产物进行了表征。
Withα-D-glucose as starting material, L-ribose was synthesized by nine step reactions such as acetone protection, PDC (pyridinium dichromate) oxidation-NaBH4 reduction, acid selective hydrolysis, NaIO4 oxidative degradation, aldehyde group protection with methoxyl amine, DDQ (2,3-dichloro-5,6-dicyano-1,4-benzoquinone) thorough hydrolysis- NaBH4 reduction and deoximation with titanium trichloride .
Particularly, PDC oxidation method, NaIO4 oxidative degradation method and aldehyde group protection with methoxyl amine method were studied intensively. The hydroxyl group protecting reactions ofα-D-gluofuranose was studied. The isopropylidenation reaction ofα-D-gluofuranose was carried to synthesis 1,2:5,6-O-diisopropylidene-α-D-gluofuranose (2) with acetone-conc. H2SO4 system, by crystallization, the yield was 38%. Hydroxyl group stereo structure conversion in sugar was studied. The C-3 position hydroxyl group stereo structure of 2 was converted by PDC-Ac2O-CH2Cl2 oxidation and NaBH4 reduction, Thus 1,2:5,6-O-diisopropylidene-α-D-allofuranose (3) was synthesized, two steps overall yield was 70%. The preparation method of PDC was studied.
Selective hydrolysis reaction ofα-D-allofuranose derivative 3 was studied. The selective hydrolysis reaction of 3 was carried to synthesize 1,2-O-isopropylidene-α-D-allofuranose (4) with dilute H2SO4–CH3OH, the yield was 92.2%. Oxidative degradation reaction of 4 was studied. The hydrolysis product 4 was carbon-decreasing oxidated with NaIO4-NaHCO3-H2O system. Thus 1,2-O-isopropylidene-α-D-ribo-pentodialdo-1,4-furanose (5) was synthesized , the yield was 86.9%. Aldehyde group protection reaction ofα-D-ribose derivative 5 was studied. The reaction was carried out with NH2OH-CH3OH system, CH3CH2SH-HCl system and NH2OCH3- CH3OH system. The methoxyl amine was determined as aldehyde group protection reagent. Thus 1,2-O-isopropylidene-α-D-ribo- pentodialdo-1,4-furanose-O-methyl-oxime (6c) was synthesized, the yield was 73.6%.
Thorough hydrolysis- reduction reaction of 6c was studied. The diversion was converted by DDQ-CH3CN thorough hydrolysis and NaBH4 reduction. Thus L-ribose-O-methyl-oxime (7c) was synthesized, two steps overall yield was 79%. Deoximation reaction of the oxime 7c was studied premilinarily. The reaction of 7c was carried out to synthesize L-ribose (8) with TiCl3-THF system, the yield was 23.9%. Nine steps overall yield was 2.9%. Except the final step, no column chromatography separating method was applied in each step in all nine steps, Each step product was characterized with 1H-NMR.
引文
[1] 张卫红,D-阿洛糖及衍生物的合成及应用研究:[博士学位论文],天津;天津大学,2004
[2] 张力田,碳水化合物化学,北京:轻工业出版社,1988. 22-123
[3] 郭振楚,糖类化学,北京:化学工业出版社,2005. 59-65
[4] Merino P, Heterocyclic nucleosides. Chemical synthesis and biological properties, Curr Med Chem -Anti-infective Agents, 2002, (1): 389-411
[5] Wengel J, Lau J, Pedersen B E, Nielsen M C, Synthesis of 3'-azido- 3'-deoxythymidine and its stereoisomers, J Org Chem, 1991, 56: 3591-3594
[6] Mugnaini C, Botta M, Coletta M, et al, Research on L-nucleosides. Synthesis and biological evaluation of a series of L- and D-2',3'-dideoxy-3'-[tris(methylthio)methyl] -pentofuranosyl, Nucleosides Bioorganic & Medicinal Chemistry, 2003, (3): 357–366
[7] Marchand A, Lioux T, Mathé C, et al, Stereospecific synthesis of unnatural L-enantiomers of 2-chloroadenine pentofuranonucleoside derivatives, J Chem Soc Perkin Trans, 1999: 2249–2254
[8] Augustyns K, Rozenski J, Aerschot V A, et al, Synthesis of 2,4-Dideoxy- β-D-erthro-hexopyranosyl nucleosides, J Org Chem, 1993, 58: 2977-2982
[9] 张卫红, 冯亚青, 战佩英, L-核糖的合成研究进展, 有机化学, 2002, 22(3): 153-158
[10] Acton E M, Ryan E J, Goodman L J, Synthesis of L-ribofuranose and L-adenosine, J Am Chem Soc, 1964, 86: 5352-5354
[11] Ma T W, Pai S B, Zhu Y L, et al, Structure-activity relations of 1-(2- deoxy-2-fluoro- β -L-arabino-furanosyl) pyrimidine nucleosides as anti- hepatitis B virus agents, J Med Chem, 1996, 39: 2835-2843
[12] Jung M E, Xu Y, Efficient synthesis of L-ribose and 2-deoxy-L-ribose from D-ribose and L-arabinose, Tetrahedron Letters, 1997: 4199-4202
[13] Matteson D S, Sadhu K M, Peterson M L, 99% Chirally selective synthesis via pinanediol boronic esters: insect pheromones, diols, and amino alcohol, J Am Chem Soc, 1986, 108: 810-819
[14] Matteson D S, Peterson M L, Synthesis of L-(+)-ribose via (S)-pinanediol (.alpha.S)-.alpha.-bromoboronic esters, J Org Chem, 1987, 52: 5116-5121
[15] Yamaguchi M, Mukaiyama T, The stereoselective of D- and L-ribose, Chem Lett, 1981: 1005-1008
[16] Abe Y, Takizava T, Kunieda T, Epimerzation of aldoses catalyzed by dioxobis(2,4-pentanedionato-O,O ′ )-molybdenum ( Ⅵ ). An improved procedure for C-2 epimer preparation, Chem Pharm Bull, 1980, 28: 1324-1326
[17] 荣国斌,有机合成中的保护基,上海:华东理工大学出版社, 2004. 329-359
[18] Burton S J, Overend G W, Williams R N, Branched-chain sugars. Part III. The introduction of branching into methyl 3,4-O-isoprogylidene-β-L-arabinoside and the synthesis of L-hamamelsoe, J Chem Soc, 1965: 3433-3445
[19] Collins M P, Overend G W, A synthesis of 6-deoxy-L-talose, J Chem Soc, 1965: 1912-1918
[20] Garegg J P, Samuetesson B, Oxidation of primary and secondary alcohols in partially protected sugars with chromium trioxide-pyridine complex in the presence of acetic anhydride, Carbohydrate Research, 1978, 67: 267-270
[21] Corey J E, Suggs W J, Pyridinium chlorochromate an ifficient for oxidation of primary and secondary alcohols to carbonyl compounds, Tetrahedron Letters, 1975: 2647-2650
[22] Corey J E, Schmidt G, Useful procedures for the oxidation of alcohols involving pyridinium dichromate in aprotic media, Tetrahedron Letters, 1979: 399-402
[23] Hollenberg H D, Klein S K, Fox J J, Pyridinium chlorochromate for the oxidation of carbohydrates, Carbohydrate Research, 1978, 67: 491-494
[24] Herscovici J, Antonadis, Molecurlar sieve-assisted oxidations: new methods for carbohydrate derivative oxidations, J Chem Soc Chem Commun, 1980: 561-562
[25] Czernecki S, Georgoulis C, Stevens L C, et al, Pyridinium dichromate oxidation. Modification enhancing its synthetic utility, Tetrahedron Letters, 1985: 1699-1702
[26] Andersson F, Samuelsson B, Pyridinium dichromate-acetic anhydride: a new and highly efficient reagent for the oxidation of alcohols, Carbohydrate Research, 1984, 129: C1-C4
[27] Stefan P, An efficient synthesis of enantiomeric ribonucleic acids from D-gluose, Helvetica Chimica Acta, 1997, 80: 2286-2314
[28] 张卫红, 冯亚青, 刘云华, 等, 1,2-氧-异丙叉基-α-D-呋喃葡萄糖的合成, 化学工业与工程, 2005, 22(2): 92-95
[29] Paulsen H, Günther C, Untersuchungen zur darstellung von 5-amino-5- desoxyhexuronsauren, Chem Ber, 1977, 110: 2150-5157
[30] Fernández G M J, Mellet O C, Marín M A, et al, A mild and efficient procdure to remove acetal and dithioacetal protecting groups in carbohydrate derivatives using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, Carbohydrate Research,1995, 274: 263-268
[31] Kiss J, D'Souza R, Taschner P, Pr?parative hertellung von 5-desoxy- L-arabinose, xylit und D-ribose aus diacetonglucose, Helv Chim Acta, 1975, 58: 311-317
[32] Christian M, Synthesis of racemic ribose from D-glucose, Synlett, 1999, (S1): 948-950
[33] Shankar B B, Kirkup P M, Mccombic W S, et al, A novel application of benzotriazole methodology: reactions of polyhydroxylated bis-(benzotriazolyl) piperidines with mono- and bidentate nucleophiles, Tetrahedron Letters, 1993: 7171-7174
[34] Zhong Y L, Shing M K T, Efficient and facile glycol cleavage oxidation using improved silica gel-supported sodium metaperiodate, J Org Chem, 1997, 62: 2622-2624
[35] Zinner H, Notiz über mercaptale der d-ribose, Chem Ber, 1950, 83: 275-277
[36] Wolfrom M L, Newlin R M, Stahly E E, Aldehydo-D-xylose tetra-acetate and the mercaptals of xylose and maltose, J Am Chem Soc, 1931, 53: 4379-4383
[37] Asbun W, Binkley B S, Synthesis of 5-substituted pyrimidines, J Org Chem, 1966, 31: 2215-2219
[38] Kumar P, Schmidt R R, An efficient stereoselective synthesis of sphingosine, Synthesis, 1997: 33-35
[39] Corsaro A, Chiacchio U, Pistarà V, Regeneration of carbonyl compounds from the corresponding oximes, Synthesis, 2001: 1903-1931
[40] Weitz J D, Bednarski D M, Synthesis of acyclic sugar aldehydes by ozonolysis of oximes, J Org Chem, 1989, 54: 4957-4959
[2] 张力田,碳水化合物化学,北京:轻工业出版社,1988. 22-123
[3] 郭振楚,糖类化学,北京:化学工业出版社,2005. 59-65
[4] Merino P, Heterocyclic nucleosides. Chemical synthesis and biological properties, Curr Med Chem -Anti-infective Agents, 2002, (1): 389-411
[5] Wengel J, Lau J, Pedersen B E, Nielsen M C, Synthesis of 3'-azido- 3'-deoxythymidine and its stereoisomers, J Org Chem, 1991, 56: 3591-3594
[6] Mugnaini C, Botta M, Coletta M, et al, Research on L-nucleosides. Synthesis and biological evaluation of a series of L- and D-2',3'-dideoxy-3'-[tris(methylthio)methyl] -pentofuranosyl, Nucleosides Bioorganic & Medicinal Chemistry, 2003, (3): 357–366
[7] Marchand A, Lioux T, Mathé C, et al, Stereospecific synthesis of unnatural L-enantiomers of 2-chloroadenine pentofuranonucleoside derivatives, J Chem Soc Perkin Trans, 1999: 2249–2254
[8] Augustyns K, Rozenski J, Aerschot V A, et al, Synthesis of 2,4-Dideoxy- β-D-erthro-hexopyranosyl nucleosides, J Org Chem, 1993, 58: 2977-2982
[9] 张卫红, 冯亚青, 战佩英, L-核糖的合成研究进展, 有机化学, 2002, 22(3): 153-158
[10] Acton E M, Ryan E J, Goodman L J, Synthesis of L-ribofuranose and L-adenosine, J Am Chem Soc, 1964, 86: 5352-5354
[11] Ma T W, Pai S B, Zhu Y L, et al, Structure-activity relations of 1-(2- deoxy-2-fluoro- β -L-arabino-furanosyl) pyrimidine nucleosides as anti- hepatitis B virus agents, J Med Chem, 1996, 39: 2835-2843
[12] Jung M E, Xu Y, Efficient synthesis of L-ribose and 2-deoxy-L-ribose from D-ribose and L-arabinose, Tetrahedron Letters, 1997: 4199-4202
[13] Matteson D S, Sadhu K M, Peterson M L, 99% Chirally selective synthesis via pinanediol boronic esters: insect pheromones, diols, and amino alcohol, J Am Chem Soc, 1986, 108: 810-819
[14] Matteson D S, Peterson M L, Synthesis of L-(+)-ribose via (S)-pinanediol (.alpha.S)-.alpha.-bromoboronic esters, J Org Chem, 1987, 52: 5116-5121
[15] Yamaguchi M, Mukaiyama T, The stereoselective of D- and L-ribose, Chem Lett, 1981: 1005-1008
[16] Abe Y, Takizava T, Kunieda T, Epimerzation of aldoses catalyzed by dioxobis(2,4-pentanedionato-O,O ′ )-molybdenum ( Ⅵ ). An improved procedure for C-2 epimer preparation, Chem Pharm Bull, 1980, 28: 1324-1326
[17] 荣国斌,有机合成中的保护基,上海:华东理工大学出版社, 2004. 329-359
[18] Burton S J, Overend G W, Williams R N, Branched-chain sugars. Part III. The introduction of branching into methyl 3,4-O-isoprogylidene-β-L-arabinoside and the synthesis of L-hamamelsoe, J Chem Soc, 1965: 3433-3445
[19] Collins M P, Overend G W, A synthesis of 6-deoxy-L-talose, J Chem Soc, 1965: 1912-1918
[20] Garegg J P, Samuetesson B, Oxidation of primary and secondary alcohols in partially protected sugars with chromium trioxide-pyridine complex in the presence of acetic anhydride, Carbohydrate Research, 1978, 67: 267-270
[21] Corey J E, Suggs W J, Pyridinium chlorochromate an ifficient for oxidation of primary and secondary alcohols to carbonyl compounds, Tetrahedron Letters, 1975: 2647-2650
[22] Corey J E, Schmidt G, Useful procedures for the oxidation of alcohols involving pyridinium dichromate in aprotic media, Tetrahedron Letters, 1979: 399-402
[23] Hollenberg H D, Klein S K, Fox J J, Pyridinium chlorochromate for the oxidation of carbohydrates, Carbohydrate Research, 1978, 67: 491-494
[24] Herscovici J, Antonadis, Molecurlar sieve-assisted oxidations: new methods for carbohydrate derivative oxidations, J Chem Soc Chem Commun, 1980: 561-562
[25] Czernecki S, Georgoulis C, Stevens L C, et al, Pyridinium dichromate oxidation. Modification enhancing its synthetic utility, Tetrahedron Letters, 1985: 1699-1702
[26] Andersson F, Samuelsson B, Pyridinium dichromate-acetic anhydride: a new and highly efficient reagent for the oxidation of alcohols, Carbohydrate Research, 1984, 129: C1-C4
[27] Stefan P, An efficient synthesis of enantiomeric ribonucleic acids from D-gluose, Helvetica Chimica Acta, 1997, 80: 2286-2314
[28] 张卫红, 冯亚青, 刘云华, 等, 1,2-氧-异丙叉基-α-D-呋喃葡萄糖的合成, 化学工业与工程, 2005, 22(2): 92-95
[29] Paulsen H, Günther C, Untersuchungen zur darstellung von 5-amino-5- desoxyhexuronsauren, Chem Ber, 1977, 110: 2150-5157
[30] Fernández G M J, Mellet O C, Marín M A, et al, A mild and efficient procdure to remove acetal and dithioacetal protecting groups in carbohydrate derivatives using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, Carbohydrate Research,1995, 274: 263-268
[31] Kiss J, D'Souza R, Taschner P, Pr?parative hertellung von 5-desoxy- L-arabinose, xylit und D-ribose aus diacetonglucose, Helv Chim Acta, 1975, 58: 311-317
[32] Christian M, Synthesis of racemic ribose from D-glucose, Synlett, 1999, (S1): 948-950
[33] Shankar B B, Kirkup P M, Mccombic W S, et al, A novel application of benzotriazole methodology: reactions of polyhydroxylated bis-(benzotriazolyl) piperidines with mono- and bidentate nucleophiles, Tetrahedron Letters, 1993: 7171-7174
[34] Zhong Y L, Shing M K T, Efficient and facile glycol cleavage oxidation using improved silica gel-supported sodium metaperiodate, J Org Chem, 1997, 62: 2622-2624
[35] Zinner H, Notiz über mercaptale der d-ribose, Chem Ber, 1950, 83: 275-277
[36] Wolfrom M L, Newlin R M, Stahly E E, Aldehydo-D-xylose tetra-acetate and the mercaptals of xylose and maltose, J Am Chem Soc, 1931, 53: 4379-4383
[37] Asbun W, Binkley B S, Synthesis of 5-substituted pyrimidines, J Org Chem, 1966, 31: 2215-2219
[38] Kumar P, Schmidt R R, An efficient stereoselective synthesis of sphingosine, Synthesis, 1997: 33-35
[39] Corsaro A, Chiacchio U, Pistarà V, Regeneration of carbonyl compounds from the corresponding oximes, Synthesis, 2001: 1903-1931
[40] Weitz J D, Bednarski D M, Synthesis of acyclic sugar aldehydes by ozonolysis of oximes, J Org Chem, 1989, 54: 4957-4959