【结 构 式】 |
【分子编号】57274 【品名】methyl 2-[(2,4-dimethoxybenzyl)oxy]acetate 【CA登记号】 |
【 分 子 式 】C12H16O5 【 分 子 量 】240.25604 【元素组成】C 59.99% H 6.71% O 33.3% |
合成路线1
该中间体在本合成路线中的序号:(LIV)5) A second coupling reaction was the addition of the phosphonamide (XX) to the aldehyde (LI) by means of butyllithium in THF to give the dithianylolefin (LII), which was treated first with TFIB and methanol and then with acetic acid, yielding the free aldeyde (LIII). The condensation of (LIII) with methyl 2-(2,4-dimethoxybenzyloxy)acetate (LIV) by means of lithium diisopropylamide in THF, followed by a treatment with LiOH affords the hydroxy acid (LV), which is protected with TES trifluoromethylsulfonate and treated with 2,6-dimethylpyridine to give the free amino acid (LVI), the open-chain precursor of FK-506.
【1】 Smith, D.B.; Schreiber, S.L.; Ragan, J.A.; Uehling, D.E.; Nakatsuka, M.; Sammakia, T.; Total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK5. J Am Chem Soc 1990, 112, 14, 5583. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
33696 | 3-[([1-[(1-[[(3-hydroxypropyl)amino]methyl]cyclohexyl)disulfanyl]cyclohexyl]methyl)amino]-1-propanol | C20H40N2O2S2 | 详情 | 详情 | ||
(XX) | 11491 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide | C28H61N2O4PS2Si | 详情 | 详情 | |
(LI) | 11490 | 1-(tert-butyl) 2-[(1S,2S,3S,5S,6S)-6-formyl-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl] (2S)-1,2-piperidinedicarboxylate | C58H101NO9Si2 | 详情 | 详情 | |
(LII) | 11492 | 2-[(1S,2S,3S,5S,6S,7E,10S,12S,13R,14S,16R)-6-allyl-16-(1,3-dithian-2-yl)-12,14-dimethoxy-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10-trimethyl-3,13-bis[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C85H155NO11S2Si3 | 详情 | 详情 | |
(LIII) | 11493 | 2-[(1S,2S,3S,5S,6S,7E,10S,12S,14R,15S,16R)-6-allyl-15-[[tert-butyl(dimethyl)silyl]oxy]-12,14-dimethoxy-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-17-oxo-3-[(triisopropylsilyl)oxy]-7-heptadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C79H143NO12Si3 | 详情 | 详情 | |
(LIV) | 57274 | methyl 2-[(2,4-dimethoxybenzyl)oxy]acetate | C12H16O5 | 详情 | 详情 | |
(LV) | 11494 | 2-[(1S,2S,3S,6S,7E,10S,12S,13R,14S,16R)-6-allyl-13-[[tert-butyl(dimethyl)silyl]oxy]-18-[(2,4-dimethoxybenzyl)oxy]-17-hydroxy-12,14,19-trimethoxy-5-(4-methoxybenzyl)-1-((E)-2-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-1-methylethenyl)-2,8,10,16-tetramethyl-19-oxo-3-[(triisopropylsilyl)oxy]-7-nonadecenyl] 1-(tert-butyl) (2S)-1,2-piperidinedicarboxylate | C91H159NO17Si3 | 详情 | 详情 | |
(LVI) | 11495 | (4R,6S,7R,8S,10S,12E,14R,15S,17S,18S,19S,20E)-14-Allyl-7-[[tert-butyl(dimethyl)silyl]oxy]-2-[(2,4-dimethoxybenzyl)oxy]-6,8-dimethoxy-15-[(4-methoxybenzyl)oxy]-21-[(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl]-4,10,12,18,20-pentamethyl-19-[[(2S)piperidinylcarbonyl]oxy]-3-[(triethylsilyl)oxy]-17-[(triisopropylsilyl)oxy]-12,20-henicosadienoic acid | C91H163NO16Si4 | 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 condensation of carbaldehyde (XLVIII) with the chiral intermediate phosphonamide (XXXII), by means of BuLi, gives the adduct (XLIX), which is treated with phenyliodonium trifluoroacetate and AcOH to cleave the 1,3-dithiane ring and yield the carbaldehyde (L). The cyclocondensation of (L) with 2-(2,4-dimethoxybenzyloxy)acetic acid methyl ester (LI) by means of LDA, LiOH, TesOTf and 2-chloro-1-methylpyridinium iodide (CMPI) affords the macrolactone (LII), which is submitted to a sequence of deprotection (DDQ), oxidation (DMP), deprotection (TFA) and oxidation (DMP) to provide the tricarbonyl compound (LIII). A similar sequence (TFA, DMP, DDQ, and DMP) can also be used to obtain the tricarbonyl compound (LIII). Finally this compound is fully desilylated by means of HF in acetonitrile to provide the target FK-506.
【1】 Ragan, J.A.; The total synthesis of FK506 and an FKBP probe reagent, (C8,C9-13C2)-FK506. Diss Abstr Int B - Sci Eng 1991, 51, 8, 3849. |
中间体序号 | 中间体编号 | 品名 | CAS号 | 分子式 | 供应商 | 用于合成 |
---|---|---|---|---|---|---|
(XXXII) | 11491 | (3R,5S,6R,7S,9R)-6-[[tert-Butyl(dimethyl)silyl]oxy]-9-(1,3-dithian-2-yl)-5,7-dimethoxy-1,3-dimethyldecyl-N,N,N',N'-tetramethylphosphonic diamide | C28H61N2O4PS2Si | 详情 | 详情 | |
(XLVIII) | 57271 | 1-(tert-butyl) 2-{(1S,2S,3S,5S,6S)-6-formyl-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2-methyl-3-[(triisopropylsilyl)oxy]-8-nonenyl} (2S)-1,2-piperidinedicarboxylate | C58H101NO10Si2 | 详情 | 详情 | |
(XLIX) | 57272 | 2-{(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-13-{[tert-butyl(dimethyl)silyl]oxy}-16-(1,3-dithian-2-yl)-12,14-dimethoxy-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2,8,10-trimet | C82H149NO12S2Si3 | 详情 | 详情 | |
(L) | 57273 | 2-{(1S,2S,3S,5S,6R,7E,10S,12S,13R,14S,16R)-6-allyl-13-{[tert-butyl(dimethyl)silyl]oxy}-12,14-dimethoxy-5-[(4-methoxybenzyl)oxy]-1-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-2,8,10,16-tetramethyl-17-oxo-3-[(tr | C79H143NO13Si3 | 详情 | 详情 | |
(LI) | 57274 | methyl 2-[(2,4-dimethoxybenzyl)oxy]acetate | C12H16O5 | 详情 | 详情 | |
(LII) | 57275 | (3S,4S,5S,7S,8R,12S,14S,15R,16S,18R,26aS)-8-allyl-15-{[tert-butyl(dimethyl)silyl]oxy}-20-[(2,4-dimethoxybenzyl)oxy]-14,16-dimethoxy-7-[(4-methoxybenzyl)oxy]-3-((E)-2-{(1R,3R,4R)-3-methoxy-4-[(triisopropylsilyl)oxy]cyclohexyl}-1-methylethenyl)-4,10,12,18-tetramethyl-19-[(triethylsilyl)oxy]-5-[(triisopropylsilyl)oxy]-5,6,7,8,11,12,13,14,15,16,17,18,19,20,24,25,26,26a-octadecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,21(4H,23H)-dione | C91H161NO15Si4 | 详情 | 详情 | |
(LIII) | 11499 | (3S,4S,5S,8R,12S,14S,15R,16S,18R,26aS)-8-Allyl-15-[[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]-5,6,11,12,13,14,15,16,17,18,24,25,26,26a-tetradecahydro-3H-pyrido[2,1-c][1,4]oxazacyclotricosine-1,7,19,20,21(4H,8H,23H)-pentone | C68H123NO12Si3 | 详情 | 详情 |