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【结 构 式】 
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【分子编号】25266 【品名】benzyl [(2S,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2S,3S)-2,3-bis[(benzyloxy)methyl]oxirane 【CA登记号】 |
【 分 子 式 】C18H20O3 【 分 子 量 】284.355 【元素组成】C 76.03% H 7.09% O 16.88% |
合成路线1
该中间体在本合成路线中的序号：(XIII)The reaction of the chiral propyl iodide (VIII) with KCN in hot DMF gives the chiral butyronitrile (IX), which is reduced with DIBAL in dichloromethane to yield the butyraldehyde (X). The reaction of (X) with CBr4, PPH3 and BuLi in THF/dichloromethane affords the chiral alkyne (XI), which is treated with Me3Al, Cp2ZrCl2 and BuLi in dichloroethane to provide the vinyl aluminate (XII). The condensation of (XII) with the chiral epoxide (XIII) in benzene gives the unsaturated 2-octenol (XIV), which is protected with BnBr and NaH to yield the benzyl ether (XV). The desilylation of (XV) by means of TBAF in THF afford the primary alcohol (XVI), which is treated with diphenyl disulfide and Bu3P in DMF to provide the thioether (XVII). The oxidation of (XVII) with oxone in THF/methanol/water gives the corresponding sulfone (XVIII), which is condensed with the intermediate desired tetrahydropyran-carboxylic acid methyl ester (VII) by means of BuLi in THF to yield the adduct (XIX). The removal of the sulfone group of (XIX) is performed by means of Bu3SnH and AIBN in refluxing toluene affording the ketonic intermediate (XX).
| 【1】 Smith, A.B. III; Hale, K.J.; An enantioselective synthesis of the C(10) to C(23) backbone of the potent immunosuppressant FK506. Tetrahedron Lett 1989, 30, 9, 1037. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (VII) | 57282 | methyl (2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-carboxylate | C15H30O5Si | 详情 | 详情 | |
| (VIII) | 57283 | tert-butyl{[(2R)-3-iodo-2-methylpropyl]oxy}diphenylsilane; tert-butyl(diphenyl)silyl (2R)-3-iodo-2-methylpropyl ether | C20H27IOSi | 详情 | 详情 | |
| (IX) | 57284 | (3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methylbutanenitrile | C21H27NOSi | 详情 | 详情 | |
| (X) | 57285 | (3S)-4-{[tert-butyl(diphenyl)silyl]oxy}-3-methylbutanal | C21H28O2Si | 详情 | 详情 | |
| (XI) | 57286 | tert-butyl(diphenyl)silyl (2S)-2-methyl-4-pentynyl ether; tert-butyl{[(2S)-2-methyl-4-pentynyl]oxy}diphenylsilane | C22H28OSi | 详情 | 详情 | |
| (XII) | 57287 | lithium butyl((E,4S)-5-{[tert-butyl(diphenyl)silyl]oxy}-2,4-dimethyl-1-pentenyl)dimethylaluminate(1-) | C29H46AlLiOSi | 详情 | 详情 | |
| (XIII) | 25266 | benzyl [(2S,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2S,3S)-2,3-bis[(benzyloxy)methyl]oxirane | C18H20O3 | 详情 | 详情 | |
| (XIV) | 57288 | (2S,3S,4E,7S)-1-(benzyloxy)-3-[(benzyloxy)methyl]-8-{[tert-butyl(diphenyl)silyl]oxy}-5,7-dimethyl-4-octen-2-ol | C41H52O4Si | 详情 | 详情 | |
| (XV) | 57289 | ({(2S,4E,6S,7S)-7,8-bis(benzyloxy)-6-[(benzyloxy)methyl]-2,4-dimethyl-4-octenyl}oxy)(tert-butyl)diphenylsilane; benzyl (2S,3S,4E,7S)-2-(benzyloxy)-3-[(benzyloxy)methyl]-8-{[tert-butyl(diphenyl)silyl]oxy}-5,7-dimethyl-4-octenyl ether | C48H58O4Si | 详情 | 详情 | |
| (XVI) | 57290 | (2S,4E,6S,7S)-7,8-bis(benzyloxy)-6-[(benzyloxy)methyl]-2,4-dimethyl-4-octen-1-ol | C32H40O4 | 详情 | 详情 | |
| (XVII) | 57291 | 1-({[(2S,3S,4E,7S)-2-(benzyloxy)-3-[(benzyloxy)methyl]-5,7-dimethyl-8-(phenylsulfanyl)-4-octenyl]oxy}methyl)benzene; benzyl (2S,3S,4E,7S)-2-(benzyloxy)-3-[(benzyloxy)methyl]-5,7-dimethyl-8-(phenylsulfanyl)-4-octenyl ether | C38H44O3S | 详情 | 详情 | |
| (XVIII) | 57292 | (2S,4E,6S,7S)-7,8-bis(benzyloxy)-6-[(benzyloxy)methyl]-2,4-dimethyl-4-octenyl phenyl sulfone; {(2S,4E,6S,7S)-7,8-bis(benzyloxy)-6-[(benzyloxy)methyl]-2,4-dimethyl-4-octenyl}(dioxo)phenyl-lambda~6~-sulfane | C38H44O5S | 详情 | 详情 | |
| (XIX) | 57293 | (3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-((2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl)-3,5-dimethyl-2-(phenylsulfonyl)-5-nonen-1-one | C52H70O9SSi | 详情 | 详情 | |
| (XX) | 57294 | (3S,5E,7S,8S)-8,9-bis(benzyloxy)-7-[(benzyloxy)methyl]-1-((2S,3S,5R,6S)-3-{[tert-butyl(dimethyl)silyl]oxy}-6-methoxy-5-methyltetrahydro-2H-pyran-2-yl)-3,5-dimethyl-5-nonen-1-one | C46H66O7Si | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XXXV)Preparation of the allyl alcohol precursor (XXX) was further reported by an alternative method described in the two following schemes: The symmetrical epoxide (XXXV) was cleaved by 1,3-propanediol (II) in the presence of potassium tert-butoxide to give the diol (XXXVI). After protection of the primary alcohol of (XXXVI) as the pivalate ester (XXXVII), the benzyl ether groups of (XXXVII) were removed by hydrogenation in the presence of palladium hydroxide to provide (XXXVIII). Protection of the vicinal diol moiety of (XXXVII) as the corresponding acetonide (XXXIX) was achieved by treatment with 2,2-dimethoxypropane and p-TsOH. Subsequent Swern oxidation of the primary alcohol function of (XXXIX) gave aldehyde (XL). Addition of vinylmagnesium bromide to aldehyde (XL) afforded the allylic alcohol (XLI) as a diastereomeric mixture. Esterification of (XLI) with pivaloyl chloride provided dipivalate ester (XLII). Epoxide (XLIII) was then prepared by acidic acetonide (XLII) hydrolysis, followed by cyclization of the resultant vicinal diol under Mitsunobu conditions to afford epoxide (XLIII). Addition of the O-protected lithium acetylide (XLIV) to epoxide (XLIII) furnished the acetylene adduct (XLV)
| 【1】 Hatakeyama, S.; Ikeda, T.; Maeyama, J.; Esumi, T.; Iwabuchi, Y.; Irie, H.; Convergent synthesis of 1alpha, 25-dihydroxy-2beta-(3-hydroxypropoxy)vitamin D3 (ED-71). Bioorg Med Chem Lett 1997, 7, 22, 2871. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (II) | 14685 | 1,3-propanediol; Trimethylene Glycol | 504-63-2 | C3H8O2 | 详情 | 详情 |
| (XXXV) | 25266 | benzyl [(2S,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2S,3S)-2,3-bis[(benzyloxy)methyl]oxirane | C18H20O3 | 详情 | 详情 | |
| (XXXVI) | 46308 | (2R,3S)-1,4-bis(benzyloxy)-3-(3-hydroxypropoxy)-2-butanol | C21H28O5 | 详情 | 详情 | |
| (XXXVII) | 46309 | 3-([(1S,2R)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-hydroxypropyl]oxy)propyl pivalate | C26H36O6 | 详情 | 详情 | |
| (XXXVIII) | 59880 | 3-{[(1S,2R)-2,3-dihydroxy-1-(hydroxymethyl)propyl]oxy}propyl pivalate | C12H24O6 | 详情 | 详情 | |
| (XXXIX) | 46310 | 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxyethyl]oxy)propyl pivalate | C15H28O6 | 详情 | 详情 | |
| (XL) | 46311 | 3-([(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-oxoethyl]oxy)propyl pivalate | C15H26O6 | 详情 | 详情 | |
| (XLI) | 46312 | 3-([(1S)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-hydroxy-3-butenyl]oxy)propyl pivalate | C17H30O6 | 详情 | 详情 | |
| (XLII) | 59883 | 3-({(1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]-2-[(2,2-dimethylpropanoyl)oxy]-3-butenyl}oxy)propyl pivalate | C22H38O7 | 详情 | 详情 | |
| (XLIII) | 46314 | 3-([(1R)-2-[(2,2-dimethylpropanoyl)oxy]-1-[(2R)oxiranyl]-3-butenyl]oxy)propyl pivalate | C19H32O6 | 详情 | 详情 | |
| (XLIV) | 59881 | {3-[(4-methoxybenzyl)oxy]-1-propynyl}lithium | C11H11LiO2 | 详情 | 详情 | |
| (XLV) | 59882 | 3-({(1R,2R)-1-{1-[(2,2-dimethylpropanoyl)oxy]-2-propenyl}-2-hydroxy-6-[(4-methoxybenzyl)oxy]-4-hexynyl}oxy)propyl pivalate | C30H44O8 | 详情 | 详情 |
合成路线3
该中间体在本合成路线中的序号：(I)Opening of the (S,S)-epoxide (I) with the silylmethyl Grignard reagent (II) in the presence of CuI, followed by oxidative cleavage of the silyl alcohol (III) with H2O2 gave diol (IV). Then, selective protection of the primary hydroxyl group of (IV) with tert-butyldimethylsilyl chloride, followed by condensation with methanesulfonyl chloride, afforded mesylate (V). Subsequent alkylation of the sodium salt of ethyl mercaptoacetate (VI) gave thioether (VII). Desilylation of (VII) with tetrabutylammonium fluoride, followed by mesylation provided sulfonate (VIII). Subsequent intramolecular ring closure of (VIII) using NaH in DMF produced the tetrahydrothiophene (IX) as a 2:3 mixture of stereoisomers. Hydrolysis of the ethyl ester of (IX) with LiOH gave carboxylic acid (X), which was submitted to a modified Hunsdiecker reaction with Pb(OAc)4 to furnish the 1-O-acetate (XI) as a 1:1 anomeric mixture.
| 【1】 Upcroft, P.; Campbell, R.W.; Benakli, K.; Upcroft, J.A.; Vanelle, P.; Efficacy of new 5-nitroimidazoles against metronidazole-susceptible and -resistant Giardia, Trichomonas, and Entamoeba spp. Antimicrob Agents Chemother 1999, 43, 1, 73. |
| 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) | 25266 | benzyl [(2S,3S)-3-[(benzyloxy)methyl]oxiranyl]methyl ether; (2S,3S)-2,3-bis[(benzyloxy)methyl]oxirane | C18H20O3 | 详情 | 详情 | |
| (III) | 25267 | (2R,3R)-1,4-bis(benzyloxy)-3-[[isopropoxy(dimethyl)silyl]methyl]-2-butanol | C24H36O4Si | 详情 | 详情 | |
| (IV) | 25268 | (2R,3R)-4-(benzyloxy)-2-[(benzyloxy)methyl]-1,3-butanediol | C19H24O4 | 详情 | 详情 | |
| (V) | 25269 | (1R,2S)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)propyl methanesulfonate | C26H40O6SSi | 详情 | 详情 | |
| (VI) | 23995 | ethyl 2-sulfanylacetate | 2713-34-0 | C4H8O2S | 详情 | 详情 |
| (VII) | 25270 | ethyl 2-[[(1S,2S)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-([[tert-butyl(dimethyl)silyl]oxy]methyl)propyl]sulfanyl]acetate | C29H44O5SSi | 详情 | 详情 | |
| (VIII) | 25271 | ethyl 2-[((1S,2S)-3-(benzyloxy)-1-[(benzyloxy)methyl]-2-[[(methylsulfonyl)oxy]methyl]propyl)sulfanyl]acetate | C24H32O7S2 | 详情 | 详情 | |
| (IX) | 25272 | ethyl (4R,5S)-4,5-bis[(benzyloxy)methyl]tetrahydro-2-thiophenecarboxylate | C23H28O4S | 详情 | 详情 | |
| (X) | 25273 | (4R,5S)-4,5-bis[(benzyloxy)methyl]tetrahydro-2-thiophenecarboxylic acid | C21H24O4S | 详情 | 详情 | |
| (XI) | 25274 | (4R,5S)-4,5-bis[(benzyloxy)methyl]tetrahydro-2-thiophenyl acetate | C22H26O4S | 详情 | 详情 |