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【结 构 式】 
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【分子编号】57369 【品名】(2S)-1-{(4R,6S,7R,8S,10S,12E,14R,15R,17S,18S,19S,20E)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-19-hydroxy-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-3-oxo-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid 【CA登记号】 |
【 分 子 式 】C82H151NO14Si4 【 分 子 量 】1487.44128 【元素组成】C 66.21% H 10.23% N 0.94% O 15.06% Si 7.55% |
合成路线1
该中间体在本合成路线中的序号：(LI)The silylation of the remaining OH group of (XLV) with Tes-OTf and lutidine in dichloromethane gives the fully silylated intermediate (XLVI), which is treated with a mild acid in order to cleave the 1,3-dithiane ring and yield the carbaldehyde (XLVII). The condensation of (XLVII) with the chiral piperidine carboxylic acid (XLVIII) by means of LDA in THF affords the adduct (XLIX). The oxidation of the OH group of (XLIX) provides the beta dioxo compound (L), which is treated with Ac-OH in THF/water to selectively cleave the triethylsilyl protecting group and yield the secondary alcohol (LI).
| 【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (XLV) | 57363 | (1E,3S,4S,5S,7R,8R,9E,12S,14S,15R,16S,18R)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16,19,19-tetramethoxy-1-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,4,10,12,18-pentamethyl-5-[(triisopropylsilyl)oxy]-1,9-nonadecadien-3-ol | C68H138O10Si4 | 详情 | 详情 | |
| (XLVI) | 57364 | (1S,2R,3S,5S,7E,9R,10R,12S,13S,14S,15E)-9-allyl-2,10-bis{[tert-butyl(dimethyl)silyl]oxy}-1-[(2R)-3,3-dimethoxy-2-methylpropyl]-3-methoxy-16-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-5,7,13,15-tetramethyl-14-[(triethylsilyl)oxy]-12-[(triisopropylsilyl)oxy]-7,15-hexadecadienyl methyl ether | C74H152O10Si5 | 详情 | 详情 | |
| (XLVII) | 57365 | (2R,4S,5R,6S,8S,10E,12R,13R,15S,16S,17S,18E)-12-allyl-5,13-bis{[tert-butyl(dimethyl)silyl]oxy}-4,6-dimethoxy-19-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-2,8,10,16,18-pentamethyl-17-[(triethylsilyl)oxy]-15-[(triisopropylsilyl)oxy]-10,18-nonadecadienal | C72H146O9Si5 | 详情 | 详情 | |
| (XLVIII) | 57366 | (2S)-1-{2-[(4-methoxybenzyl)oxy]acetyl}-2-piperidinecarboxylic acid | C16H21NO5 | 详情 | 详情 | |
| (XLIX) | 57367 | (2S)-1-{(4R,6S,7R,8S,10S,12E,14R,15R,17S,18S,19S,20E)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-3-hydroxy-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-19-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid | C88H167NO14Si5 | 详情 | 详情 | |
| (L) | 57368 | (2S)-1-{(4R,6S,7R,8S,10S,12E,14R,15R,17S,18S,19S,20E)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-3-oxo-19-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid | C88H165NO14Si5 | 详情 | 详情 | |
| (LI) | 57369 | (2S)-1-{(4R,6S,7R,8S,10S,12E,14R,15R,17S,18S,19S,20E)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-19-hydroxy-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-3-oxo-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid | C82H151NO14Si4 | 详情 | 详情 |
合成路线2
该中间体在本合成路线中的序号：(LI)The macrocyclization of (LI) by means of EDC and DMAP in dichloromethane gives the macrolactone (LII), which is treated with DDQ and oxidized with DMP in dichloromethane to yield the tricarbonyl compound (LIII). The cyclization and desilylation of (LIII) by means of HF in acetonitrile affords the tricyclic macrolactone (LIV), which is treated with Tes-Cl and oxidized with DMP to provide the silylated precursor (LV). Finally, this compound is desilylated with HF in acetonitrile to give the target FK-506.
| 【1】 Chen, K.; Formal total synthesis of (-)-FK506. Diss Abstr Int B - Sci Eng 1993, 53, 9, 4663. |
| 中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
|---|---|---|---|---|---|---|
| (LI) | 57369 | (2S)-1-{(4R,6S,7R,8S,10S,12E,14R,15R,17S,18S,19S,20E)-14-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-19-hydroxy-6,8-dimethoxy-2-[(4-methoxybenzyl)oxy]-21-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-4,10,12,18,20-pentamethyl-3-oxo-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoyl}-2-piperidinecarboxylic acid | C82H151NO14Si4 | 详情 | 详情 | |
| (LII) | 57370 | (3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,26aS)-8-allyl-7,15-bis{[tert-butyl(dimethyl)silyl]oxy}-14,16-dimethoxy-20-[(4-methoxybenzyl)oxy]-3-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,24,25,26,26a-hexadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,19,21(4H,20H,23H)-trione | C82H149NO13Si4 | 详情 | 详情 | |
| (LIII) | 11564 | (3S,4S,5S,7R,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-7,15-bis[[tert-butyl(dimethyl)silyl]oxy]-14,16-dimethoxy-3-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-4,10,12,18-tetramethyl-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,24,25,26,26a-hexadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,19,20,21(4H,23H)-tetrone | C74H139NO12Si4 | 详情 | 详情 | |
| (LIV) | 11565 | (1R,9S,12S,13S,14S,16R,17R,21S,23S,24R,25S,27R)-17-Allyl-1,16-dihydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10-trione | C44H71NO12 | 详情 | 详情 | |
| (LV) | 11567 | (1R,9S,12S,13S,14S,17R,21S,23S,24R,25S,27R)-17-Allyl-1-hydroxy-23,25-dimethoxy-12-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triethylsilyl)oxy]cyclohexyl]-1-methylethenyl)-13,19,21,27-tetramethyl-14-[(triethylsilyl)oxy]-11,28-dioxa-4-azatricyclo[22.3.1.0(4,9)]octacos-18-ene-2,3,10,16-tetrone | C56H97NO12Si2 | 详情 | 详情 |