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【结 构 式】 
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【分子编号】52911 【品名】[(4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol 【CA登记号】 |
【 分 子 式 】C7H14O4 【 分 子 量 】162.18576 【元素组成】C 51.84% H 8.7% O 39.46% |
合成路线1
该中间体在本合成路线中的序号：(I)The monoprotection of acetonide dol (I) by means of Pmb-Cl and KOH in refluxing benzene gives the alcohol (II), which is submitted to a Swern oxidation, yielding the aldehyde (III). The Horner Wadswort Emmons condensation of (III) with phosphonate (IV) by means of NaH in THF affords the unsaturated ester (V), which is deprotected by means of HCl in hot ethanol to provide the diol (VI), which is reprotected by means of Tbdms-OTf and TEA in dichloromethane to gives the bis silyl ether (VII).The selective deprotection of (VII) by means of DDQ in aqueous acetonitrile yields the primary alcohol (VIII), which is submitted to a Swern oxidation to afford the corresponding aldehyde (IX). The cyclization of (IX) by means of PhCH2-S-Li in THF provides the chiral cyclopentanol (X), which is desilylated by means of HF in aqueous acetonitrile to give the trihydroxy compound (XI). The vicinal cis diols of (XI) are selectively protected with acetone and Ts-OH to yield the acetonide (XII), which is desulfurized by oxidation with NaIO4 and heating at 180 C in decalin to afford the cyclopentenol (XIII). The oxidation of (XIII) by means of PDC in dichloromethane provides the cyclopentenone (XIV), which is reduced at the ester and ketone groups by means of DIBAL in toluene to give the diol (XV). The selective silylation of the primary OH group of (XV) by means of Tbdms-Cl, TEA and DMAP in dichloromethane yields the primary silyl ether (XVI), which is condensed with adenine (XVII) by means of DIAD and PPH3 in THF to afford the protected adduct (XVIII). Finally this compound is deprotected by means of HCl in methanol to provide the target Neplanocin A.
| 【1】 Ono, M.; et al.; Total synthesis of (-)-neplanocin A by using lithium thiolate-initiated Michael-aldol tandem cyclization reaction. J Org Chem 2001, 66, 24, 8199. |
| 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) | 52911 | [(4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol | C7H14O4 | 详情 | 详情 | |
| (II) | 58117 | ((4R,5R)-5-{[(4-methoxybenzyl)oxy]methyl}-2,2-dimethyl-1,3-dioxolan-4-yl)methanol | C15H22O5 | 详情 | 详情 | |
| (III) | 58118 | (4S,5R)-5-{[(4-methoxybenzyl)oxy]methyl}-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | C15H20O5 | 详情 | 详情 | |
| (IV) | 10019 | Ethyl 2-(diethoxyphosphoryl)acetate; Triethyl phosphonoacetate | 867-13-0 | C8H17O5P | 详情 | 详情 |
| (V) | 58119 | ethyl (E)-3-((4R,5R)-5-{[(4-methoxybenzyl)oxy]methyl}-2,2-dimethyl-1,3-dioxolan-4-yl)-2-propenoate | C19H26O6 | 详情 | 详情 | |
| (VI) | 58120 | ethyl (E,4R,5R)-4,5-dihydroxy-6-[(4-methoxybenzyl)oxy]-2-hexenoate | C16H22O6 | 详情 | 详情 | |
| (VII) | 58121 | ethyl (E,4R,5R)-4,5-bis{[tert-butyl(dimethyl)silyl]oxy}-6-[(4-methoxybenzyl)oxy]-2-hexenoate | C28H50O6Si2 | 详情 | 详情 | |
| (VIII) | 58122 | ethyl (E,4R,5R)-4,5-bis{[tert-butyl(dimethyl)silyl]oxy}-6-hydroxy-2-hexenoate | C20H42O5Si2 | 详情 | 详情 | |
| (IX) | 58123 | ethyl (E,4R,5S)-4,5-bis{[tert-butyl(dimethyl)silyl]oxy}-6-oxo-2-hexenoate | C20H40O5Si2 | 详情 | 详情 | |
| (X) | 58124 | ethyl (1S,2R,3S,4R,5R)-2-(benzylsulfanyl)-3,4-bis{[tert-butyl(dimethyl)silyl]oxy}-5-hydroxycyclopentanecarboxylate | C27H48O5SSi2 | 详情 | 详情 | |
| (XI) | 58125 | ethyl (1S,2R,3S,4R,5R)-2-(benzylsulfanyl)-3,4,5-trihydroxycyclopentanecarboxylate | C15H20O5S | 详情 | 详情 | |
| (XII) | 58126 | ethyl (3aR,4S,5R,6S,6aS)-5-(benzylsulfanyl)-6-hydroxy-2,2-dimethyltetrahydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxylate | C18H24O5S | 详情 | 详情 | |
| (XIII) | 58127 | ethyl (3aR,6R,6aS)-6-hydroxy-2,2-dimethyl-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxylate | C11H16O5 | 详情 | 详情 | |
| (XIV) | 58128 | ethyl (3aR,6aR)-2,2-dimethyl-6-oxo-6,6a-dihydro-3aH-cyclopenta[d][1,3]dioxole-4-carboxylate | C11H14O5 | 详情 | 详情 | |
| (XV) | 58129 | (3aS,4S,6aR)-6-(hydroxymethyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol | C9H14O4 | 详情 | 详情 | |
| (XVI) | 58130 | (3aS,4S,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-ol | C15H28O4Si | 详情 | 详情 | |
| (XVII) | 10343 | 9H-Purin-6-amine; 9H-Purin-6-ylamine; Adenine | 73-24-5 | C5H5N5 | 详情 | 详情 |
| (XVIII) | 58131 | 9-[(3aS,4R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-ylamine; 9-[(3aS,4R,6aR)-6-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-4,6a-dihydro-3aH-cyclopenta[d][1,3]dioxol-4-yl]-9H-purin-6-amine | C20H31N5O3Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(III)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.
| 【1】 Feit, P.W.; 1,4-Bismethanesulfonates of the stereoisomeric butanetetraols and related compounds. J Med Chem 1964, 7, 14. |
| 【2】 Iida, H.; et al.; Total synthesis of (+)-nojirimycin and (+)-1-deoxynojirimycin. J Org Chem 1987, 52, 15, 3337. |
| 【3】 Pandey, G.; Kapur, M.; 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). Tetrahedron Lett 2000, 41, 45, 8821. |
| 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) | 16696 | Diethyl L-(+)-Tartrate; diethyl (2S,3S)-2,3-dihydroxybutanedioate | 87-91-2 | C8H14O6 | 详情 | 详情 |
| (II) | 52910 | diethyl (4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5-dicarboxylate | C11H18O6 | 详情 | 详情 | |
| (III) | 52911 | [(4R,5R)-5-(hydroxymethyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol | C7H14O4 | 详情 | 详情 | |
| (IV) | 52912 | [(4R,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolan-4-yl]methanol | C13H28O4Si | 详情 | 详情 | |
| (V) | 52913 | (4S,5R)-5-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2,2-dimethyl-1,3-dioxolane-4-carbaldehyde | C13H26O4Si | 详情 | 详情 | |
| (VI) | 52914 | tert-butyl{[(4R,5R)-5-ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl]methoxy}dimethylsilane; tert-butyl(dimethyl)silyl [(4R,5R)-5-ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl ether | C14H26O3Si | 详情 | 详情 | |
| (VII) | 52915 | [(4R,5R)-5-ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl]methanol | C8H12O3 | 详情 | 详情 | |
| (VIII) | 52916 | (4S,5R)-4-(bromomethyl)-5-ethynyl-2,2-dimethyl-1,3-dioxolane | C8H11BrO2 | 详情 | 详情 | |
| (IX) | 52917 | N-benzyl-N-[(trimethylsilyl)methyl]amine; phenyl-N-[(trimethylsilyl)methyl]methanamine | C11H19NSi | 详情 | 详情 | |
| (X) | 52918 | N-benzyl-N-{[(4R,5R)-5-ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl]methyl}-N-[(trimethylsilyl)methyl]amine; N-benzyl[(4R,5R)-5-ethynyl-2,2-dimethyl-1,3-dioxolan-4-yl]-N-[(trimethylsilyl)methyl]methanamine | C19H29NO2Si | 详情 | 详情 | |
| (XI) | 52919 | (3aR,7aR)-5-benzyl-2,2-dimethyl-7-methylenehexahydro[1,3]dioxolo[4,5-c]pyridine | C16H21NO2 | 详情 | 详情 | |
| (XII) | 52920 | [(3aR,7R,7aR)-5-benzyl-2,2-dimethylhexahydro[1,3]dioxolo[4,5-c]pyridin-7-yl]methanol | C16H23NO3 | 详情 | 详情 | |
| (XIII) | 52921 | (3R,4R,5R)-1-benzyl-5-(hydroxymethyl)-3,4-piperidinediol | C13H19NO3 | 详情 | 详情 |