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【结 构 式】 
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【分子编号】35339 【品名】(2S,6S,9S)-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4,4,7,13,14,14-hexamethyl-3,5-dioxatetracyclo[8.3.1.0(1,9).0(2,6)]tetradeca-7,12-dien-9-ol 【CA登记号】 |
【 分 子 式 】C25H42O4Si 【 分 子 量 】434.69158 【元素组成】C 69.08% H 9.74% O 14.72% Si 6.46% |
合成路线1
该中间体在本合成路线中的序号：(XI)The condensation of verbenone (I) with 1-bromo-3-methyl-2-butene (II) by means of t-BuOK in DME, followed by ozonolysis of the aliphatic double bond gives acetaldehyde (III), which is isomerized with UV light in methanol to the chrysanthenone derivative (IV). The condensation of (IV) with ethyl propynoate (V) by means of LDA in THF, followed by silylation with TMSCl affords the silylated 4-hydroxy-2-pentynoate (VI), which is cyclized by means of Me2CuLi in ethyl ether giving the methanonaphthalene derivative (VII). The oxidation of the secondary OH group of (VII) with Dess Martin periodinane (DMP) yields the ketoester (VIII), which is hydroxylated with Davis' oxaziridine to the ketonic dihydroxyester (IX). The reduction of the ester group of (IX) with LiAlH4 in ethyl ether affords the tetrahydroxy compound (X), which is protected by silylation with TBDMS-Cl and imidazole and ketalization with PPTS and 2-methoxypropene providing the silylated acetonide (XI). The rearrangement of (XI) by means of MCPBA, followed by silylation with Tips-OTf gives (XII) with the A-B-bicycle of Taxol. The hydroxylation of (XII) with t-BuOK and oxygen, followed by reduction of its ketonic group with NaBH4 yields the trihydroxy compound (XIII), which is stereoselectively reduced with H2 and Crabtree catalyst, silylated with TMSCl and treated with triphosgene to afford the cyclic carbonate (XIV). The oxidation of (XIV) with pyridinium chlorochromate (PCC) in dichloromethane gives the carbaldehyde (XV), which is condensed with methoxymethyl(triphenyl)phosphorane to yield the acetaldehyde derivative (XVI). The selective silylation of (XVI) with Tes-Cl, followed by oxidation of the remaining secondary OH group with Dess Martin periodinane (DMP) and methylenation acetaldehyde CH2 group with Me2N-CH2-I affords the substituted propenoic aldehyde (XVII).
| 【1】 Wender, P.A.; et al.; The pinene path to taxanes. 5. Stereocontrolled synthesis of a versatile taxane precursor. J Am Chem Soc 1997, 119, 11, 2755. |
| 【2】 Wender, P.A.; et al.; The pinene path to taxanes. 6. Concise stereocontrolled synthesis of Taxol. J Am Chem Soc 1997, 119, 11, 2757. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| 17354 | isopropenyl methyl ether; 2-methoxy-1-propene | 116-11-0 | C4H8O | 详情 | 详情 | |
| 40589 | methyl (triphenylphosphoranylidene)methyl ether; (methoxymethylene)(triphenyl)phosphorane | C20H19OP | 详情 | 详情 | ||
| 40590 | iodo-N,N-dimethylmethanamine; N-(iodomethyl)-N,N-dimethylamine | C3H8IN | 详情 | 详情 | ||
| (I) | 35330 | 4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-one | 1196-01-6 | C10H14O | 详情 | 详情 |
| (II) | 12989 | 4-Bromo-2-methyl-2-butene; 1-Bromo-3-methyl-2-butene | 870-63-3 | C5H9Br | 详情 | 详情 |
| (III) | 35331 | 2-(2,6,6-trimethyl-4-oxobicyclo[3.1.1]hept-2-en-3-yl)acetaldehyde | C12H16O2 | 详情 | 详情 | |
| (IV) | 35332 | 2-(2,6,6-trimethyl-7-oxobicyclo[3.1.1]hept-2-en-1-yl)acetaldehyde | C12H16O2 | 详情 | 详情 | |
| (V) | 35333 | ethyl propiolate | 623-47-2 | C5H6O2 | 详情 | 详情 |
| (VI) | 35334 | ethyl 5-(2,6,6-trimethyl-7-oxobicyclo[3.1.1]hept-2-en-1-yl)-4-[(trimethylsilyl)oxy]-2-pentynoate | C20H30O4Si | 详情 | 详情 | |
| (VII) | 35335 | ethyl (6R)-3,6-dihydroxy-4,10,11,11-tetramethyltricyclo[5.3.1.0(1,6)]undeca-4,9-diene-5-carboxylate | C18H26O4 | 详情 | 详情 | |
| (VIII) | 35336 | ethyl (6R)-6-hydroxy-4,10,11,11-tetramethyl-3-oxotricyclo[5.3.1.0(1,6)]undeca-4,9-diene-5-carboxylate | C18H24O4 | 详情 | 详情 | |
| (IX) | 35337 | ethyl (2S,6R)-2,6-dihydroxy-4,10,11,11-tetramethyl-3-oxotricyclo[5.3.1.0(1,6)]undeca-4,9-diene-5-carboxylate | C18H24O5 | 详情 | 详情 | |
| (X) | 35338 | (2S,3S,6S)-5-(hydroxymethyl)-4,10,11,11-tetramethyltricyclo[5.3.1.0(1,6)]undeca-4,9-diene-2,3,6-triol | C16H24O4 | 详情 | 详情 | |
| (XI) | 35339 | (2S,6S,9S)-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4,4,7,13,14,14-hexamethyl-3,5-dioxatetracyclo[8.3.1.0(1,9).0(2,6)]tetradeca-7,12-dien-9-ol | C25H42O4Si | 详情 | 详情 | |
| (XII) | 35340 | (2S,6S,12S)-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4,4,7,13,14,14-hexamethyl-12-[(triisopropylsilyl)oxy]-3,5-dioxatricyclo[8.3.1.0(2,6)]tetradeca-1(13),7-dien-9-one | C34H62O5Si2 | 详情 | 详情 | |
| (XIII) | 35341 | (2S,6S,9S,10S,12S)-8-(hydroxymethyl)-4,4,7,13,14,14-hexamethyl-12-[(triisopropylsilyl)oxy]-3,5-dioxatricyclo[8.3.1.0(2,6)]tetradeca-1(13),7-diene-9,10-diol | C28H50O6Si | 详情 | 详情 | |
| (XIV) | 35342 | (1S,5S,6S,7S,8S,12S,15S)-7,10,10,14,17,17-hexamethyl-15-[(triisopropylsilyl)oxy]-6-[[(trimethylsilyl)oxy]methyl]-2,4,9,11-tetraoxatetracyclo[11.3.1.0(1,5).0(8,12)]heptadec-13-en-3-one | C32H58O7Si2 | 详情 | 详情 | |
| (XV) | 35343 | (1S,5S,6R,7S,8S,12S,15S)-7,10,10,14,17,17-hexamethyl-3-oxo-15-[(triisopropylsilyl)oxy]-2,4,9,11-tetraoxatetracyclo[11.3.1.0(1,5).0(8,12)]heptadec-13-ene-6-carbaldehyde | C29H48O7Si | 详情 | 详情 | |
| (XVI) | 35344 | 2-[(1S,5S,6R,7S,8S,9S,12S)-8,9-dihydroxy-7,11,14,14-tetramethyl-3-oxo-12-[(triisopropylsilyl)oxy]-2,4-dioxatricyclo[8.3.1.0(1,5)]tetradec-10-en-6-yl]acetaldehyde | C27H46O7Si | 详情 | 详情 | |
| (XVII) | 35345 | 2-[(1S,5S,6S,7S,8S,12S)-7,11,14,14-tetramethyl-3,9-dioxo-8-[(triethylsilyl)oxy]-12-[(triisopropylsilyl)oxy]-2,4-dioxatricyclo[8.3.1.0(1,5)]tetradec-10-en-6-yl]acrylaldehyde | C34H58O7Si2 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(XIV)N-Alkylation of benzyl N-allylcarbamate (I) with 5-bromo-1-pentene (II) by means of NaH in DMF provides olefin metathesis substrate (III), which is then converted into azepine (IV) by means of catalytic bis(tricyclohexylphosphine)benzylideneruthenium (IV) dichloride (Grubbs catalyst) in refluxing CH2Cl2. Epoxidation of (IV) with m-CPBA in CH2Cl2 affords oxirane (V), which is then treated with NaN3 and NH4Cl in H2O/MeOH to provide a mixture of regioisomers from which (VI) is chromatographically isolated. Reduction of azide (VI) with 1,3-propanedithiol and Et3N in MeOH furnishes amino alcohol derivative (VII), which is then acylated with Boc-Leu-OH by means of EDC and HOBt to provide protected derivative (IX). Removal of the Z protecting group by hydrogenolysis over Pd/C in MeOH gives amine (X), which is then condensed with 2-pyridylsulfonyl chloride (XI) by means of Et3N in CH2Cl2 to yield compound (XII). Boc removal from (XII) by treatment with HCl in MeOH/AcOEt affords amine (XIII), which is then acylated with benzofuran-2-carboxylic acid (XIV) by means of EDC and HOBt to give derivative (XV). Finally, the desired product is obtained by oxidation of (XV) with pyridine sulfur trioxide complex and Et3N in DMSO followed by diastereomer separation by HPLC.
| 【1】 Marquis, R.W.; et al.; Azepanone-based inhibitors of human and rat cathepsin K. J Med Chem 2001, 44, 9, 1380. |
| 【2】 Cummings, M.D.; Veber, D.F.; Yamashita, D.; Ru, Y.; Marquis, R.W. Jr.; Thompson, S.K. (SmithKline Beecham Corp.); Protease inhibitors. EP 1158986; WO 0038687 . |
| 【3】 Veber, D.F.; Marquis, R.W. Jr.; Thompson, S.K.; Ru, Y.; Cummings, M.D.; Yamashita, D. (GlaxoSmithKline Inc.); Protease inhibitors. WO 0195911 . |
| 【4】 Veber, D.F.; Marquis, R.W. Jr.; Thompson, S.K.; Yamashita, D.S.; Ru, Y.; Cummings, M.D. (GlaxoSmithKline Inc.); Methods of treatment. WO 0178734 . |
| 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) | 49723 | benzyl allylcarbamate | C11H13NO2 | 详情 | 详情 | |
| (II) | 49724 | 1-Bromo-4-Pentene; 5-Bromo-1-pentene; 4-Penten-1-yl Bromide | 1119-51-3 | C5H9Br | 详情 | 详情 |
| (III) | 49725 | benzyl allyl(4-pentenyl)carbamate | C16H21NO2 | 详情 | 详情 | |
| (IV) | 49726 | benzyl 2,3,4,7-tetrahydro-1H-azepine-1-carboxylate | C14H17NO2 | 详情 | 详情 | |
| (V) | 49727 | benzyl 8-oxa-3-azabicyclo[5.1.0]octane-3-carboxylate | C14H17NO3 | 详情 | 详情 | |
| (VI) | 49728 | benzyl 4-azido-3-hydroxy-1-azepanecarboxylate | C14H18N4O3 | 详情 | 详情 | |
| (VII) | 49729 | benzyl 4-amino-3-hydroxy-1-azepanecarboxylate | C14H20N2O3 | 详情 | 详情 | |
| (VIII) | 23663 | (2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoic acid；N-Boc-L-leucine | C11H21NO4 | 详情 | 详情 | |
| (IX) | 49730 | benzyl 4-([(2S)-2-[(tert-butoxycarbonyl)amino]-4-methylpentanoyl]amino)-3-hydroxy-1-azepanecarboxylate | C25H39N3O6 | 详情 | 详情 | |
| (X) | 49731 | tert-butyl (1S)-1-[[(3-hydroxy-4-azepanyl)amino]carbonyl]-3-methylbutylcarbamate | C17H33N3O4 | 详情 | 详情 | |
| (XI) | 49732 | 2-pyridinesulfonyl chloride | C5H4ClNO2S | 详情 | 详情 | |
| (XII) | 49733 | tert-butyl (1S)-1-([[3-hydroxy-1-(2-pyridinylsulfonyl)-4-azepanyl]amino]carbonyl)-3-methylbutylcarbamate | C22H36N4O6S | 详情 | 详情 | |
| (XIII) | 49734 | (2S)-2-amino-N-[3-hydroxy-1-(2-pyridinylsulfonyl)-4-azepanyl]-4-methylpentanamide | C17H28N4O4S | 详情 | 详情 | |
| (XIV) | 35339 | (2S,6S,9S)-8-([[tert-butyl(dimethyl)silyl]oxy]methyl)-4,4,7,13,14,14-hexamethyl-3,5-dioxatetracyclo[8.3.1.0(1,9).0(2,6)]tetradeca-7,12-dien-9-ol | C25H42O4Si | 详情 | 详情 | |
| (XV) | 49735 | N-[(1S)-1-([[3-hydroxy-1-(2-pyridinylsulfonyl)-4-azepanyl]amino]carbonyl)-3-methylbutyl]-1-benzofuran-2-carboxamide | C26H32N4O6S | 详情 | 详情 |