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【结 构 式】 
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【分子编号】10016 【品名】D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal 【CA登记号】50-69-1 |
【 分 子 式 】C5H10O5 【 分 子 量 】150.1314 【元素组成】C 40% H 6.71% O 53.28% |
合成路线1
该中间体在本合成路线中的序号：(I)A total synthesis of (+)-sinefungin has been reported: The reaction of D-ribose (I) with acetone and methanol by means of CuSO4 and a catalytic amount of H2SO4 gives methyl 2,3-O-isopropylidene-beta-D-ribofuranoside (II), which is oxidized to the aldehyde (III) with oxalyl chloride in DMSO/dichloromethane. The Wittig condensation of (III) with triethyl phosphonoacetate (IV) by means of NaH in THF affords the unsaturated ester (V), which is hydrogenated with H2 over Pd/C in ethyl acetate and saponified with LiOH in methanol/water to give the propionic acid (VI). The condensation of (VI) with the chiral oxazolidone (VII) by means of pivaloyl chloride and triethylamine in THF yields the oxalidone (VIII). The stereoselective alkylation of (VIII) with allyl bromide by means of lithium hexamethyldisylazide in THF affords the 2(S)-allyl derivative (IX), which is hydrolyzed with LiOH in THF/water to the corresponding free acid (X). The Curtius degradation of the acid (X) by means of diphenyl phosphorazidate and benzyl alcohol gives the corresponding benzyloxycarbonylamino derivative (XI), which is benzylated with benzyl bromide to the fully protected compound (XII). The ozonolysis of the allyl double bond of (XII) with O3 in methanol/dichloromethane yields the aldehyde (XIII).
| 【1】 Ghosh, A.K.; Liu, W.M.; Total synthesis of (+)-sinefungin. J Org Chem 1996, 61, 18, 6175. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 32112 | 3-iodo-1-propene;3-iodo-propen;allyl iodide | 556-56-9 | C3H5I | 详情 | 详情 | |
| (I) | 10016 | D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal | 50-69-1 | C5H10O5 | 详情 | 详情 |
| (II) | 10017 | [(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methanol | 4099-85-8 | C9H16O5 | 详情 | 详情 |
| (III) | 10018 | (3aR,4S,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxole-4-carbaldehyde | C9H14O5 | 详情 | 详情 | |
| (IV) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (V) | 10020 | Ethyl (E)-3-[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]-2-propenoate | C13H20O6 | 详情 | 详情 | |
| (VI) | 10021 | 3-[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]propionic acid | C11H18O6 | 详情 | 详情 | |
| (VII) | 10022 | [(3aS,8aR)-2-Oxo-8,8a-dihydro-2H-indeno[1,2-d][1,3]oxazol-3(3aH)-yl]lithium | C10H8LiNO2 | 详情 | 详情 | |
| (VIII) | 10023 | (3aS,8aR)-3-[3-[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]propanoyl]-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazol-2-one | C21H25NO7 | 详情 | 详情 | |
| (IX) | 10024 | (3aS,8aR)-3-((2S)-2-[[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-4-pentenoyl)-3,3a,8,8a-tetrahydro-2H-indeno[1,2-d][1,3]oxazol-2-one | C24H29NO7 | 详情 | 详情 | |
| (X) | 10025 | (2S)-2-[[(3aR,4R,6R,6aR)-6-Methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-4-pentenoic acid | C14H22O6 | 详情 | 详情 | |
| (XI) | 10026 | Benzyl N-((1S)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-butenyl)carbamate | 180776-29-8 | C21H29NO6 | 详情 | 详情 |
| (XII) | 10027 | Benzyl (1S)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-butenyl(benzyl)carbamate | C28H35NO6 | 详情 | 详情 | |
| (XIII) | 10028 | Benzyl (1R)-1-[[(3aR,4R,6R,6aR)-6-methoxy-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl]methyl]-3-oxopropyl(benzyl)carbamate | C27H33NO7 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(I)The reaction of D-ribose (I) with 2,2-dimethoxypropane (II) by means of HClO4 in methanol gives the isopropylidene derivative (III), which is oxidized with PCC in benzene to yield the tetrahydrofuranone (IV). The reaction of (IV) with the lithium salt of dimethyl methylphosphonate (V) affords the chiral cyclopentenone (VI), which is condensed with tert-butyl methyl ether (VII) by means of tBu-OK and sec-BuLi in THF to provide the cyclopentenol derivative (VIII). The reaction of (VIII) with Ac2O, TEA and DMAP in dichloromethane gives the corresponding acetate (IX), which is submitted to rearrangement catalyzed by PdCl2(acetonitrile)2 and benzoquinone in refluxing THF to yield the regioisomeric acetate (X). The hydrolysis of (X) by means of K2CO3 in methanol yields the corresponding alcohol (XI), which is condensed with 6-chloropurine (XII) by means of PPh3 and DIEA to afford the adduct (XIII). The reaction of (XIII) with ammonia in ethanol at 80 C in a steel bomb affords the protected adenine nucleoside (XIV), which is finally deprotected with aqueous TFA to provide the target cyclopentenyl nucleoside.
| 【1】 Ali, S.M.; et al.; Efficient enantioselective syntheses of carbocyclic nucleoside and prostaglandin synthons. Tetrahedron Lett 1990, 31, 11, 1509. |
| 【2】 Song, G.Y.; et al.; Enantiomeric synthesis of D-and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus. J Med Chem 2001, 44, 23, 3985. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10016 | D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal | 50-69-1 | C5H10O5 | 详情 | 详情 |
| (II) | 10722 | 1-Methoxy-1-methylethyl methyl ether; 2,2-Dimethoxypropane | 77-76-9 | C5H12O2 | 详情 | 详情 |
| (III) | 49594 | Methyl 2,3-O-Isopropylidene-beta-D-Ribofuranoside | C9H16O5 | 详情 | 详情 | |
| (IV) | 49585 | (3aS,6aR)-6-methoxy-2,2-dimethyldihydrofuro[3,4-d][1,3]dioxol-4(3aH)-one | C8H12O5 | 详情 | 详情 | |
| (V) | 29720 | [(dimethoxyphosphoryl)methyl]lithium | C3H8LiO3P | 详情 | 详情 | |
| (VI) | 49586 | (3aS,6aS)-2,2-dimethyl-3a,6a-dihydro-4H-cyclopenta[d][1,3]dioxol-4-one | C8H10O3 | 详情 | 详情 | |
| (VII) | 49587 | 2-methoxy-2-methylpropane; tert-butyl methyl ether | C5H12O | 详情 | 详情 | |
| (VIII) | 49588 | tert-Butylmethyl ether; Methyl tert-butyl ether | 1634-04-4 | C13H22O4 | 详情 | 详情 |
| (IX) | 49589 | (3aS,4S,6aS)-4-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl acetate | C15H24O5 | 详情 | 详情 | |
| (X) | 49590 | (3aR,4S,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl acetate | C15H24O5 | 详情 | 详情 | |
| (XI) | 49591 | (3aS,4S,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol | C13H22O4 | 详情 | 详情 | |
| (XII) | 17692 | 6-Chloropurine; 6-chloro-9H-purine | 87-42-3 | C5H3ClN4 | 详情 | 详情 |
| (XIII) | 49592 | 9-[(3aS,4R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-6-chloro-9H-purine; [(3aR,6R,6aS)-6-(6-chloro-9H-purin-9-yl)-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]methyl tert-butyl ether | C18H23ClN4O3 | 详情 | 详情 | |
| (XIV) | 49593 | 9-[(3aS,4R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-amine; 9-[(3aS,4R,6aR)-6-(tert-butoxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-ylamine | C18H25N5O3 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)The synthesis of [1'-14C]-labeled stavudine has been published: The reaction of labeled D-ribofuranose (I) first with methanol and acetyl chloride and then with benzoyl chloride gives 2,3,5-tri-O-benzoyl-1-O-methyl-D-ribofuranoside (II), which is acetylated with acetic anhydride and acetic acid to 1-O-acetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranoside (III). The condensation of (III) with thymine (IV) by means of hexamethyldisylazane (HMDS), trimethylsilyl chloride (TMS-Cl) and trifluoromethanesulfonic acid, followed by a basic hydrolysis with NaOMe affords 1-(beta-D-ribofuranosyl)thymine (V), which is treated with methanesulfonyl chloride in pyridine giving the trimesylate (VI). The reaction of (VI) with sodium benzoate in hot DMF yields the benzoylated internal ether (VII), which is treated with acetyl bromide in acetic acid/HBr affording 1-[2-bromo-2-deoxy-5-O-benzoyl-3-O-(methanesulfonyl)-beta-D-ribofuranos yl]thymine (VIII). The reaction of (VIII) with Zn in the same solvent as before gives 5'-O-benzoylstavudine (IX), which is finally debenzoylated with NaOCH3 in methanol.
| 【1】 Discordia, R.P.; Synthesis of 1'-[C-14]-Stavudine(R) (d4T). J Label Compd Radiopharm 1996, 38, 7, 613. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (I) | 10016 | D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal | 50-69-1 | C5H10O5 | 详情 | 详情 |
| (I) | 45109 | (3R,4S,5R)-5-(hydroxymethyl)tetrahydro-2,3,4-furantriol | C5H10O5 | 详情 | 详情 | |
| (II) | 12247 | [(2R,3R,4R)-3,4-bis(benzoyloxy)-5-methoxytetrahydro-2-furanyl]methyl benzoate | C27H24O8 | 详情 | 详情 | |
| (II) | 45110 | [(2R,3R,4R)-3,4-bis(benzoyloxy)-5-methoxytetrahydro-2-furanyl]methyl benzoate | C27H24O8 | 详情 | 详情 | |
| (III) | 17523 | [(2S,3S,4S,5R)-5-(acetoxy)-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate | 6974-32-9 | C28H24O9 | 详情 | 详情 |
| (III) | 45111 | [(2R,3R,4R,5S)-5-(acetoxy)-3,4-bis(benzoyloxy)tetrahydro-2-furanyl]methyl benzoate | C28H24O9 | 详情 | 详情 | |
| (IV) | 12204 | 5-Methyl-2,4(1H,3H)-pyrimidinedione; Thymine | 65-71-4 | C5H6N2O2 | 详情 | 详情 |
| (V) | 12206 | 1-[(2R,3R,4S,5R)-3,4-Dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione; 5-Methyluridine | 1463-10-1 | C10H14N2O6 | 详情 | 详情 |
| (V) | 45112 | 1-[(2R,3R,4S,5R)-3,4-dihydroxy-5-(hydroxymethyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C10H14N2O6 | 详情 | 详情 | |
| (VI) | 12251 | 1-[(2R,3R,4R,5R)-3,4-Bis[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-5-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C19H32N2O6S3 | 详情 | 详情 | |
| (VI) | 45113 | 1-[(2R,3R,4R,5R)-3,4-bis[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-5-([[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]methyl)tetrahydro-2-furanyl]-5-methyl-2,4(1H,3H)-pyrimidinedione | C19H32N2O6S3 | 详情 | 详情 | |
| (VII) | 12252 | ((2R,3R,3aS,9aR)-7-methyl-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-oxo-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-2-yl)methyl benzoate | C20H22N2O6S | 详情 | 详情 | |
| (VII) | 45114 | ((2R,3R,3aS,9aR)-7-methyl-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-6-oxo-2,3,3a,9a-tetrahydro-6H-furo[2',3':4,5][1,3]oxazolo[3,2-a]pyrimidin-2-yl)methyl benzoate | C20H22N2O6S | 详情 | 详情 | |
| (VIII) | 12253 | [(2R,3R,4R,5R)-4-bromo-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C20H23BrN2O6S | 详情 | 详情 | |
| (VIII) | 45115 | [(2R,3R,4R,5R)-4-bromo-3-[[methyl(dimethylene)-lambda(6)-sulfanyl]oxy]-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]tetrahydro-2-furanyl]methyl benzoate | C20H23BrN2O6S | 详情 | 详情 | |
| (IX) | 12254 | [(2S,5R)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl]methyl benzoate | C17H16N2O5 | 详情 | 详情 | |
| (IX) | 45116 | [(2S,5R)-5-[5-methyl-2,4-dioxo-3,4-dihydro-1(2H)-pyrimidinyl]-2,5-dihydro-2-furanyl]methyl benzoate | C17H16N2O5 | 详情 | 详情 |
合成路线4
该中间体在本合成路线中的序号：(XX)Methylation of D-ribose (XX) with MeOH using HCl yields methyl Dribofuranoside (XXI), which is then benzoylated with BzCl in CHCl3/pyr to give the protected intermediate (XXII). Bromination of methyl ether (XXII) with HBr in AcOH furnishes bromide (X). Acetylation of methyl ether (XXII) with Ac2O and AcOH produces acetate (XIV) .
| 【1】 Recondo, E.F., Rinderknecht, H. Eine neue, einfache Synthese des 1-OAcetyl-2,3,5-tri-O-benzoyl-beta-D-ribofuranosides. Helv Chim Acta 1959, 42(4): 1171. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (X) | 33832 | [(2R,3S,4R)-3,4-bis(benzoyloxy)-5-bromotetrahydro-2-furanyl]methyl benzoate | C26H21BrO7 | 详情 | 详情 | |
| (XIV) | 26984 | (2R,3R,4R,5S)-5-(acetoxy)-4-(benzoyloxy)-2-[(benzoyloxy)methyl]tetrahydro-3-furanyl benzoate | C28H24O9 | 详情 | 详情 | |
| (XX) | 10016 | D-Ribose; (3R,4S,5R)-5-(Hydroxymethyl)tetrahydro-2,3,4-furantriol; (2R,3R,4R)-2,3,4,5-Tetrahydroxypentanal | 50-69-1 | C5H10O5 | 详情 | 详情 |
| (XXI) | 41258 | (2R,3S,4R)-2-(hydroxymethyl)-5-methoxytetrahydro-3,4-furandiol | C6H12O5 | 详情 | 详情 | |
| (XXII) | 12247 | [(2R,3R,4R)-3,4-bis(benzoyloxy)-5-methoxytetrahydro-2-furanyl]methyl benzoate | C27H24O8 | 详情 | 详情 |